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Newly approved tirzepatide’s retail price announced
Tirzepatide (Mounjaro) – the new twincretin approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes – was priced by Lilly, the company that will market the drug, at a list price of $974.33 for four weekly doses regardless of dose size, a cost that adds up to about $12,666 per year, according to a statement made on May 20 by a Lilly spokesperson.
This price puts tirzepatide, which combines the activity of two of the primary human incretins in one molecule, roughly in the same ballpark as what might be its main competitor, semaglutide (Ozempic) for type 2 diabetes, which retails at many U.S. pharmacies for about $925 for four weekly doses, or about $12,025 per year, although Ozempic’s posted retail price is about $100 higher for four doses.
According to the Lilly spokesperson, discount programs could reduce the monthly out-of-pocket cost for patients to as little as $25.
Tirzepatide, which received approval from the FDA on May 13, is a dual glucagonlike peptide–1 (GLP-1) receptor agonist and glucose-dependent insulinotropic polypeptide agonist. Several GLP-1 receptor agonists are already approved in the United States, including semaglutide, which is indicated as Wegovy for weight loss in patients with obesity regardless of diabetes status.
A version of this article first appeared on Medscape.com.
Tirzepatide (Mounjaro) – the new twincretin approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes – was priced by Lilly, the company that will market the drug, at a list price of $974.33 for four weekly doses regardless of dose size, a cost that adds up to about $12,666 per year, according to a statement made on May 20 by a Lilly spokesperson.
This price puts tirzepatide, which combines the activity of two of the primary human incretins in one molecule, roughly in the same ballpark as what might be its main competitor, semaglutide (Ozempic) for type 2 diabetes, which retails at many U.S. pharmacies for about $925 for four weekly doses, or about $12,025 per year, although Ozempic’s posted retail price is about $100 higher for four doses.
According to the Lilly spokesperson, discount programs could reduce the monthly out-of-pocket cost for patients to as little as $25.
Tirzepatide, which received approval from the FDA on May 13, is a dual glucagonlike peptide–1 (GLP-1) receptor agonist and glucose-dependent insulinotropic polypeptide agonist. Several GLP-1 receptor agonists are already approved in the United States, including semaglutide, which is indicated as Wegovy for weight loss in patients with obesity regardless of diabetes status.
A version of this article first appeared on Medscape.com.
Tirzepatide (Mounjaro) – the new twincretin approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes – was priced by Lilly, the company that will market the drug, at a list price of $974.33 for four weekly doses regardless of dose size, a cost that adds up to about $12,666 per year, according to a statement made on May 20 by a Lilly spokesperson.
This price puts tirzepatide, which combines the activity of two of the primary human incretins in one molecule, roughly in the same ballpark as what might be its main competitor, semaglutide (Ozempic) for type 2 diabetes, which retails at many U.S. pharmacies for about $925 for four weekly doses, or about $12,025 per year, although Ozempic’s posted retail price is about $100 higher for four doses.
According to the Lilly spokesperson, discount programs could reduce the monthly out-of-pocket cost for patients to as little as $25.
Tirzepatide, which received approval from the FDA on May 13, is a dual glucagonlike peptide–1 (GLP-1) receptor agonist and glucose-dependent insulinotropic polypeptide agonist. Several GLP-1 receptor agonists are already approved in the United States, including semaglutide, which is indicated as Wegovy for weight loss in patients with obesity regardless of diabetes status.
A version of this article first appeared on Medscape.com.
Jury is in? Survival benefit with lap surgery for rectal cancer
, according to findings from a large meta-analysis.
The estimated 5-year OS rate for patients who underwent laparoscopic surgery was 76.2%, vs. 72.7% for those who had open surgery.
“The survival benefit of laparoscopic surgery is encouraging and supports the routine use of laparoscopic surgery for adult patients with rectal cancer in the era of minimally invasive surgery,” wrote the authors, led by Leping Li, MD, of the department of gastrointestinal surgery, Shandong (China) Provincial Hospital.
The article was published online in JAMA Network Open.
Surgery is an essential component in treating rectal cancer, but the benefits of laparoscopic vs. open surgery are not clear. Over the past 15 years, randomized clinical trials (RCTs) have shown comparable long-term outcomes for laparoscopic and open surgery. However, in most meta-analyses that assessed the evidence more broadly, researchers used an “inappropriate” method for the pooled analysis. Dr. Li and colleagues wanted to perform their own meta-analysis to more definitively understand whether the evidence on long-term outcomes supports or opposes the use of laparoscopic surgery for rectal cancer.
In the current study, the authors conducted an individual participant data meta-analysis using time-to-event data and focused on the long-term survival outcomes after laparoscopic or open surgery for adult patients with rectal cancer.
Ten articles involving 12 RCTs and 3,709 participants were included. In these, 2,097 patients were randomly assigned to undergo laparoscopic surgery, and 1,612 were randomly assigned to undergo open surgery. The studies covered a global population, with participants from Europe, North America, and East Asia.
In a one-stage analysis, the authors found that disease-free survival was slightly better among patients who underwent laparoscopic surgery, but the results were statistically similar (hazard ratio [HR], 0.92; P = .26).
However, when it came to OS, those who had undergone laparoscopic surgery fared significantly better (HR, 0.85; P = .02).
These results held up in the two-stage analysis for both disease-free survival (HR, 0.92; P = .25) and OS (HR, 0.85; P = .02). A sensitivity analyses conducted with large RCTs yielded similar pooled effect sizes for disease-free survival (HR, 0.91; P = .20) and OS (HR, 0.84; P = .03).
The authors highlighted several reasons why laparoscopic surgery may be associated with better survival. First, the faster recovery from the minimally invasive procedure could allow patients to begin adjuvant therapy earlier. In addition, the reduced stress responses and higher levels of immune function among patients undergoing minimally invasive surgery may contribute to a long-term survival advantage.
“These findings address concerns regarding the effectiveness of laparoscopic surgery,” the authors wrote. However, “further studies are necessary to explore the specific mechanisms underlying the positive effect of laparoscopic surgery on OS.”
No outside funding source was noted. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to findings from a large meta-analysis.
The estimated 5-year OS rate for patients who underwent laparoscopic surgery was 76.2%, vs. 72.7% for those who had open surgery.
“The survival benefit of laparoscopic surgery is encouraging and supports the routine use of laparoscopic surgery for adult patients with rectal cancer in the era of minimally invasive surgery,” wrote the authors, led by Leping Li, MD, of the department of gastrointestinal surgery, Shandong (China) Provincial Hospital.
The article was published online in JAMA Network Open.
Surgery is an essential component in treating rectal cancer, but the benefits of laparoscopic vs. open surgery are not clear. Over the past 15 years, randomized clinical trials (RCTs) have shown comparable long-term outcomes for laparoscopic and open surgery. However, in most meta-analyses that assessed the evidence more broadly, researchers used an “inappropriate” method for the pooled analysis. Dr. Li and colleagues wanted to perform their own meta-analysis to more definitively understand whether the evidence on long-term outcomes supports or opposes the use of laparoscopic surgery for rectal cancer.
In the current study, the authors conducted an individual participant data meta-analysis using time-to-event data and focused on the long-term survival outcomes after laparoscopic or open surgery for adult patients with rectal cancer.
Ten articles involving 12 RCTs and 3,709 participants were included. In these, 2,097 patients were randomly assigned to undergo laparoscopic surgery, and 1,612 were randomly assigned to undergo open surgery. The studies covered a global population, with participants from Europe, North America, and East Asia.
In a one-stage analysis, the authors found that disease-free survival was slightly better among patients who underwent laparoscopic surgery, but the results were statistically similar (hazard ratio [HR], 0.92; P = .26).
However, when it came to OS, those who had undergone laparoscopic surgery fared significantly better (HR, 0.85; P = .02).
These results held up in the two-stage analysis for both disease-free survival (HR, 0.92; P = .25) and OS (HR, 0.85; P = .02). A sensitivity analyses conducted with large RCTs yielded similar pooled effect sizes for disease-free survival (HR, 0.91; P = .20) and OS (HR, 0.84; P = .03).
The authors highlighted several reasons why laparoscopic surgery may be associated with better survival. First, the faster recovery from the minimally invasive procedure could allow patients to begin adjuvant therapy earlier. In addition, the reduced stress responses and higher levels of immune function among patients undergoing minimally invasive surgery may contribute to a long-term survival advantage.
“These findings address concerns regarding the effectiveness of laparoscopic surgery,” the authors wrote. However, “further studies are necessary to explore the specific mechanisms underlying the positive effect of laparoscopic surgery on OS.”
No outside funding source was noted. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to findings from a large meta-analysis.
The estimated 5-year OS rate for patients who underwent laparoscopic surgery was 76.2%, vs. 72.7% for those who had open surgery.
“The survival benefit of laparoscopic surgery is encouraging and supports the routine use of laparoscopic surgery for adult patients with rectal cancer in the era of minimally invasive surgery,” wrote the authors, led by Leping Li, MD, of the department of gastrointestinal surgery, Shandong (China) Provincial Hospital.
The article was published online in JAMA Network Open.
Surgery is an essential component in treating rectal cancer, but the benefits of laparoscopic vs. open surgery are not clear. Over the past 15 years, randomized clinical trials (RCTs) have shown comparable long-term outcomes for laparoscopic and open surgery. However, in most meta-analyses that assessed the evidence more broadly, researchers used an “inappropriate” method for the pooled analysis. Dr. Li and colleagues wanted to perform their own meta-analysis to more definitively understand whether the evidence on long-term outcomes supports or opposes the use of laparoscopic surgery for rectal cancer.
In the current study, the authors conducted an individual participant data meta-analysis using time-to-event data and focused on the long-term survival outcomes after laparoscopic or open surgery for adult patients with rectal cancer.
Ten articles involving 12 RCTs and 3,709 participants were included. In these, 2,097 patients were randomly assigned to undergo laparoscopic surgery, and 1,612 were randomly assigned to undergo open surgery. The studies covered a global population, with participants from Europe, North America, and East Asia.
In a one-stage analysis, the authors found that disease-free survival was slightly better among patients who underwent laparoscopic surgery, but the results were statistically similar (hazard ratio [HR], 0.92; P = .26).
However, when it came to OS, those who had undergone laparoscopic surgery fared significantly better (HR, 0.85; P = .02).
These results held up in the two-stage analysis for both disease-free survival (HR, 0.92; P = .25) and OS (HR, 0.85; P = .02). A sensitivity analyses conducted with large RCTs yielded similar pooled effect sizes for disease-free survival (HR, 0.91; P = .20) and OS (HR, 0.84; P = .03).
The authors highlighted several reasons why laparoscopic surgery may be associated with better survival. First, the faster recovery from the minimally invasive procedure could allow patients to begin adjuvant therapy earlier. In addition, the reduced stress responses and higher levels of immune function among patients undergoing minimally invasive surgery may contribute to a long-term survival advantage.
“These findings address concerns regarding the effectiveness of laparoscopic surgery,” the authors wrote. However, “further studies are necessary to explore the specific mechanisms underlying the positive effect of laparoscopic surgery on OS.”
No outside funding source was noted. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Male breast cancer risk linked with infertility
, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.
A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.
“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”
The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).
Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
Raised risk with history of male infertility
Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).
In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.
Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.
Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).
Potential underlying factors
“The causes of breast cancer in men are largely unknown, partly because it is rare and partly because previous studies have been small,” Dr. Jones said. “The evidence presented in our study suggests that the association of infertility and breast cancer should be confirmed with further research, and future investigations are needed into the potential underlying factors, such as hormone imbalances.”
Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, told this news organization: “Overall, there isn’t strong evidence that infertility is a risk factor for male breast cancer. This study helps to shed light onto a cancer type that is sadly still not very well understood, but much more research is needed to say that infertility is a risk factor for male breast cancer.”
She added that although male breast cancer is a rare condition, it’s still important for men to be aware of what looks and feels normal for them, and to be encouraged to seek medical advice if something is not quite right.
A spokesperson for Breast Cancer UK told this news organization: “[We] believe it’s important to understand what leads to breast cancer in men as well as women and that high quality, long-term studies such as this will help with this understanding.
The findings are consistent with an earlier study that found that U.S. men who have never fathered children are at higher risk of breast cancer. This new long-term U.K. study provides strong evidence, which supports this finding.
“As the authors note, the biological reasons are unclear, but may be associated with altered hormone levels. The ratio of circulating levels of estrogen and androgens (e.g. testosterone) is crucial in healthy functioning of breast tissue. Disruption to this, for example as a result of damage to testes, may affect both fertility and breast cancer risk.
“It is also possible that external factors, such as exposure to certain endocrine (hormone) disrupting chemicals (EDCs), which affect sex hormones, may also affect both fertility and breast cancer risk.
“More studies into breast cancer in men are needed to help us understand better all the risk factors associated with this disease including both hormonal factors and chemical exposures.”
Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now, said: “Research has discovered different treatments directed at some features of breast cancer in women; however, breast cancer is not as well understood for men. This is why Breast Cancer Now funds the Male Breast Cancer Study, which looks at what might cause the disease in men. Discovering a link between infertility and male breast cancer is a step towards us understanding male breast cancer and how we could find more ways to diagnose and treat men – and possibly women – with this devastating disease.”
A version of this article first appeared on Medscape UK.
, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.
A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.
“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”
The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).
Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
Raised risk with history of male infertility
Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).
In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.
Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.
Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).
Potential underlying factors
“The causes of breast cancer in men are largely unknown, partly because it is rare and partly because previous studies have been small,” Dr. Jones said. “The evidence presented in our study suggests that the association of infertility and breast cancer should be confirmed with further research, and future investigations are needed into the potential underlying factors, such as hormone imbalances.”
Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, told this news organization: “Overall, there isn’t strong evidence that infertility is a risk factor for male breast cancer. This study helps to shed light onto a cancer type that is sadly still not very well understood, but much more research is needed to say that infertility is a risk factor for male breast cancer.”
She added that although male breast cancer is a rare condition, it’s still important for men to be aware of what looks and feels normal for them, and to be encouraged to seek medical advice if something is not quite right.
A spokesperson for Breast Cancer UK told this news organization: “[We] believe it’s important to understand what leads to breast cancer in men as well as women and that high quality, long-term studies such as this will help with this understanding.
The findings are consistent with an earlier study that found that U.S. men who have never fathered children are at higher risk of breast cancer. This new long-term U.K. study provides strong evidence, which supports this finding.
“As the authors note, the biological reasons are unclear, but may be associated with altered hormone levels. The ratio of circulating levels of estrogen and androgens (e.g. testosterone) is crucial in healthy functioning of breast tissue. Disruption to this, for example as a result of damage to testes, may affect both fertility and breast cancer risk.
“It is also possible that external factors, such as exposure to certain endocrine (hormone) disrupting chemicals (EDCs), which affect sex hormones, may also affect both fertility and breast cancer risk.
“More studies into breast cancer in men are needed to help us understand better all the risk factors associated with this disease including both hormonal factors and chemical exposures.”
Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now, said: “Research has discovered different treatments directed at some features of breast cancer in women; however, breast cancer is not as well understood for men. This is why Breast Cancer Now funds the Male Breast Cancer Study, which looks at what might cause the disease in men. Discovering a link between infertility and male breast cancer is a step towards us understanding male breast cancer and how we could find more ways to diagnose and treat men – and possibly women – with this devastating disease.”
A version of this article first appeared on Medscape UK.
, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.
A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.
“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”
The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).
Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
Raised risk with history of male infertility
Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).
In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.
Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.
Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).
Potential underlying factors
“The causes of breast cancer in men are largely unknown, partly because it is rare and partly because previous studies have been small,” Dr. Jones said. “The evidence presented in our study suggests that the association of infertility and breast cancer should be confirmed with further research, and future investigations are needed into the potential underlying factors, such as hormone imbalances.”
Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, told this news organization: “Overall, there isn’t strong evidence that infertility is a risk factor for male breast cancer. This study helps to shed light onto a cancer type that is sadly still not very well understood, but much more research is needed to say that infertility is a risk factor for male breast cancer.”
She added that although male breast cancer is a rare condition, it’s still important for men to be aware of what looks and feels normal for them, and to be encouraged to seek medical advice if something is not quite right.
A spokesperson for Breast Cancer UK told this news organization: “[We] believe it’s important to understand what leads to breast cancer in men as well as women and that high quality, long-term studies such as this will help with this understanding.
The findings are consistent with an earlier study that found that U.S. men who have never fathered children are at higher risk of breast cancer. This new long-term U.K. study provides strong evidence, which supports this finding.
“As the authors note, the biological reasons are unclear, but may be associated with altered hormone levels. The ratio of circulating levels of estrogen and androgens (e.g. testosterone) is crucial in healthy functioning of breast tissue. Disruption to this, for example as a result of damage to testes, may affect both fertility and breast cancer risk.
“It is also possible that external factors, such as exposure to certain endocrine (hormone) disrupting chemicals (EDCs), which affect sex hormones, may also affect both fertility and breast cancer risk.
“More studies into breast cancer in men are needed to help us understand better all the risk factors associated with this disease including both hormonal factors and chemical exposures.”
Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now, said: “Research has discovered different treatments directed at some features of breast cancer in women; however, breast cancer is not as well understood for men. This is why Breast Cancer Now funds the Male Breast Cancer Study, which looks at what might cause the disease in men. Discovering a link between infertility and male breast cancer is a step towards us understanding male breast cancer and how we could find more ways to diagnose and treat men – and possibly women – with this devastating disease.”
A version of this article first appeared on Medscape UK.
FROM BREAST CANCER RESEARCH
Cancer patients unaware of their increased thrombosis risk
It is up to their physician to discuss this with them.
This link is explained by the authors of an article in Cancer Treatment and Research Communications that reports results of a survey carried out by the European Cancer Patient Coalition (ECPC). “The aim of this pan-European patient survey was to assess patient awareness and knowledge about cancer-associated thrombosis (CAT), including risk factors, signs and symptoms, and interventions, to better prevent and treat CAT,” write the authors. “The idea was to create a sort of starting point for subsequent communication and information strategies and for comparing the results of any action taken in this area,” they add.
A roundtable discussion that included oncology healthcare professionals, policymakers, and patient advocates was convened to discuss and review the evidence regarding their ongoing concerns of excessive CAT-associated morbidity and mortality, as well as patients’ desire for greater CAT awareness.
“These discussions demonstrated that very little change had occurred over the years and that greater knowledge about CAT was still needed across the spectrum of healthcare practitioners and patients, particularly regarding primary and secondary prevention of thrombosis,” the authors write.
It was from this starting point that the idea for the pan-European survey was born. The ECPC, widely viewed as the “unified voice of cancer patients across Europe,” led the survey. This survey spanned six countries (France, Germany, Greece, Italy, United Kingdom, and Spain) and involved 1,365 patients and caregivers. The ECPC survey result was originally released at World Thrombosis Day in late 2018.
In an interview, Anna Falanga, MD, the main author of the article and professor of hematology at the University of Milan-Bicocca, Italy, reviewed the results and explained how to improve knowledge of CAT among patients with cancer.
“Data support that up to 20% of patients with cancer will experience venous thromboembolism (VTE), which is approximately 4–5 times higher than the general population,” said Dr. Falanga, who is also chief of the department of immunohematology and transfusion medicine and the Thrombosis and Hemostasis Center at the Hospital Papa Giovanni XXIII, in Bergamo, Italy.
“We have known about the link between thrombosis and cancer since the 19th century, but it has taken until midway through the last century for our level of understanding and awareness of the problem to reach its current level. Initially, this was limited to fundamental research, with large advances in our understanding of the mechanisms of the link between the two; it has only been more recently that we have had clinical studies that have piqued the interest of healthcare professionals, who were previously uninterested in the topic,” she said.
Poor understanding
One piece of data stands out from the European survey: Nearly three quarters of respondents (72%) said that before taking part in the survey, they were not aware that people with cancer have a higher-than-normal risk of developing thrombosis. “We asked participants to rate their overall understanding of CAT on a scale of 1 (low) to 10 (high), with the average (mean) score obtained being 4.1. Only 21% of patients gave a rating of 7 or above (high understanding). The average rating was very similar in the different countries surveyed,” write the authors. They note that the survey also assessed how much participants had learned about the topic from their physicians.
Approximately 35% of patients were made aware of CAT either immediately before or at the time of their cancer diagnosis. Of particular concern, one quarter (26%) of respondents (the largest proportion) noted that they first became aware of CAT when they suffered a blood clot. The average rating was very similar in the different countries surveyed. “Let us not forget that cancer and cancer treatments themselves cause a number of side effects, some of which can be very serious, so in some ways, a clot might be seen as a minor problem. Yet, in reality, it isn’t. It is a significant cause of death and disease in cancer patients,” said Dr. Falanga.
When discussing prevention, most respondents (87%) said they were aware that taking a walk could reduce their risk. Slightly fewer were aware that stopping smoking could reduce their risk (75%), and even fewer were aware that keeping hydrated (63%) and stretching their legs (55%) could reduce their risk.
Symptoms of CAT appeared to be relatively well known; 73% of survey participants indicated that they were aware that swelling in the foot, ankle, or leg could be a sign of DVT, and 71% indicated that shortness of breath could be a sign of pulmonary embolism (PE). “Other symptoms, however, were less well known, with just over half (57%) of participants being aware that pain, cramping, and tenderness could be a sign of DVT. About one third (33%) knew that irregular heartbeat could be a sign of PE. These results varied between countries,” according to the authors.
The survey highlighted that just over a third of respondents said that they were currently using anticoagulants, although almost all (96%) knew that anticoagulants could be used to effectively treat thrombosis. Only 41% of those using anticoagulants said they had been told about any possible side effects.
The Italian situation
The report containing the full results of the European survey goes even further, since, in addition to its overall results, it also gives information about individual countries.
The data from Italy, which are based on 246 persons, show that only 27% of patients and caregivers were aware of the increased risk of thrombosis after a cancer diagnosis. This figure is in line with the overall results of the survey, although the average score of the 10-point scale was lower for the Italy cohort (3.3/10 vs 4.1/10).
The results are more variable in terms of knowledge of risk factors. Most respondents (89%) said that they were aware of the risks related to inactivity. Just over half (52%), however, said that they were aware of the risks related to radiotherapy. Nevertheless, 75% of participants knew about the risks relating to cancer surgery and chemotherapy. “To all intents and purposes, all types of cancer drug can significantly affect the risk of developing a clot. And this is also the case for more modern types of treatment, such as immunotherapy,” said Dr. Falanga.
Most respondents reported that they got information about cancer-associated thrombosis verbally, usually from their hospital doctor (11%). Some respondents (6%) said that they found out about it from their own research, usually online. Almost 1 in 4 patients (24%) in Italy said that they first became aware of CAT when they suffered a blood clot. Answers to questions about knowledge of symptoms show that 58% of Italian patients and caregivers know that swelling of the lower limbs can be a symptom of DVT, and the same percentage knows that shortness of breath might indicate PE.
In terms of preventive action, the picture in Italy is somewhat variable: 74% of participants were aware of the importance of walking, but far fewer knew about the need to stop smoking (57%) and stretch the legs (35%). Of the 41% of Italians who were also taking an anticoagulant drug, 53% said that they knew about the possible side effects of such medication.
Which way forward?
“The high rate of CAT suggests that, despite the clinical evidence and clear guideline recommendations for patients with cancer, CAT prevention and recognition remain low among healthcare professionals,” the authors write.
The results of the ECPC survey further confirm those of previous studies, highlighting patients’ lack of knowledge about CAT and the need for more in-depth discussions between physician and patient.
So, what can be done? As highlighted by previous studies, “patients’ experiences are an education in themselves, particularly for the oncology care team,” the authors write. “Once the patient has a thrombosis, the opportunity for thrombosis prevention, which should be the most crucial focus of the care clinics (surgical, oncology, and palliative care), is gone,” they add.
“Oncology professionals, as well as other members of the patient’s care team (eg, internists, surgeons, nurses), need to perform better, at every stage of the patient’s cancer pathway, to ensure patients are aware of CAT and their individual risk to develop a blood clot,” said Dr. Falanga. She explained that in this group, it is the general practitioner who is the first contact. “These professionals are on the front line of the battle; they are among the first healthcare workers given the chance to suspect a clot and should, therefore, be fully aware of the increased risk in oncology patients,” she reiterated.
Experts agree on the fact that a multidisciplinary approach is of utmost importance in this context: the different roles in the team must be clear. “It is also fundamental to establish who does what in terms of educating and informing the patient,” said Dr. Falanga.
The researchers also put forward an example of a successful initiative: the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTE-PACC) program. The initiative was developed by experts from the University of Vermont and was described in a recent article in JCO Oncology Practice.
Numerous resources are available online to help physicians talk to their patients and explain the risks linked to CAT along the continuum of cancer care. Among them is a resource titled, “Cancer Associated Thrombosis (CAT): Be Clot Conscious,” which can be found on the ECPC’s website.
“We have a collective responsibility using the ECPC patient survey as a baseline to inform patients with cancer on how to identify signs and symptoms of CAT to enable faster diagnosis and treatment,” the authors conclude.
This article was translated from Univadis Italy.
It is up to their physician to discuss this with them.
This link is explained by the authors of an article in Cancer Treatment and Research Communications that reports results of a survey carried out by the European Cancer Patient Coalition (ECPC). “The aim of this pan-European patient survey was to assess patient awareness and knowledge about cancer-associated thrombosis (CAT), including risk factors, signs and symptoms, and interventions, to better prevent and treat CAT,” write the authors. “The idea was to create a sort of starting point for subsequent communication and information strategies and for comparing the results of any action taken in this area,” they add.
A roundtable discussion that included oncology healthcare professionals, policymakers, and patient advocates was convened to discuss and review the evidence regarding their ongoing concerns of excessive CAT-associated morbidity and mortality, as well as patients’ desire for greater CAT awareness.
“These discussions demonstrated that very little change had occurred over the years and that greater knowledge about CAT was still needed across the spectrum of healthcare practitioners and patients, particularly regarding primary and secondary prevention of thrombosis,” the authors write.
It was from this starting point that the idea for the pan-European survey was born. The ECPC, widely viewed as the “unified voice of cancer patients across Europe,” led the survey. This survey spanned six countries (France, Germany, Greece, Italy, United Kingdom, and Spain) and involved 1,365 patients and caregivers. The ECPC survey result was originally released at World Thrombosis Day in late 2018.
In an interview, Anna Falanga, MD, the main author of the article and professor of hematology at the University of Milan-Bicocca, Italy, reviewed the results and explained how to improve knowledge of CAT among patients with cancer.
“Data support that up to 20% of patients with cancer will experience venous thromboembolism (VTE), which is approximately 4–5 times higher than the general population,” said Dr. Falanga, who is also chief of the department of immunohematology and transfusion medicine and the Thrombosis and Hemostasis Center at the Hospital Papa Giovanni XXIII, in Bergamo, Italy.
“We have known about the link between thrombosis and cancer since the 19th century, but it has taken until midway through the last century for our level of understanding and awareness of the problem to reach its current level. Initially, this was limited to fundamental research, with large advances in our understanding of the mechanisms of the link between the two; it has only been more recently that we have had clinical studies that have piqued the interest of healthcare professionals, who were previously uninterested in the topic,” she said.
Poor understanding
One piece of data stands out from the European survey: Nearly three quarters of respondents (72%) said that before taking part in the survey, they were not aware that people with cancer have a higher-than-normal risk of developing thrombosis. “We asked participants to rate their overall understanding of CAT on a scale of 1 (low) to 10 (high), with the average (mean) score obtained being 4.1. Only 21% of patients gave a rating of 7 or above (high understanding). The average rating was very similar in the different countries surveyed,” write the authors. They note that the survey also assessed how much participants had learned about the topic from their physicians.
Approximately 35% of patients were made aware of CAT either immediately before or at the time of their cancer diagnosis. Of particular concern, one quarter (26%) of respondents (the largest proportion) noted that they first became aware of CAT when they suffered a blood clot. The average rating was very similar in the different countries surveyed. “Let us not forget that cancer and cancer treatments themselves cause a number of side effects, some of which can be very serious, so in some ways, a clot might be seen as a minor problem. Yet, in reality, it isn’t. It is a significant cause of death and disease in cancer patients,” said Dr. Falanga.
When discussing prevention, most respondents (87%) said they were aware that taking a walk could reduce their risk. Slightly fewer were aware that stopping smoking could reduce their risk (75%), and even fewer were aware that keeping hydrated (63%) and stretching their legs (55%) could reduce their risk.
Symptoms of CAT appeared to be relatively well known; 73% of survey participants indicated that they were aware that swelling in the foot, ankle, or leg could be a sign of DVT, and 71% indicated that shortness of breath could be a sign of pulmonary embolism (PE). “Other symptoms, however, were less well known, with just over half (57%) of participants being aware that pain, cramping, and tenderness could be a sign of DVT. About one third (33%) knew that irregular heartbeat could be a sign of PE. These results varied between countries,” according to the authors.
The survey highlighted that just over a third of respondents said that they were currently using anticoagulants, although almost all (96%) knew that anticoagulants could be used to effectively treat thrombosis. Only 41% of those using anticoagulants said they had been told about any possible side effects.
The Italian situation
The report containing the full results of the European survey goes even further, since, in addition to its overall results, it also gives information about individual countries.
The data from Italy, which are based on 246 persons, show that only 27% of patients and caregivers were aware of the increased risk of thrombosis after a cancer diagnosis. This figure is in line with the overall results of the survey, although the average score of the 10-point scale was lower for the Italy cohort (3.3/10 vs 4.1/10).
The results are more variable in terms of knowledge of risk factors. Most respondents (89%) said that they were aware of the risks related to inactivity. Just over half (52%), however, said that they were aware of the risks related to radiotherapy. Nevertheless, 75% of participants knew about the risks relating to cancer surgery and chemotherapy. “To all intents and purposes, all types of cancer drug can significantly affect the risk of developing a clot. And this is also the case for more modern types of treatment, such as immunotherapy,” said Dr. Falanga.
Most respondents reported that they got information about cancer-associated thrombosis verbally, usually from their hospital doctor (11%). Some respondents (6%) said that they found out about it from their own research, usually online. Almost 1 in 4 patients (24%) in Italy said that they first became aware of CAT when they suffered a blood clot. Answers to questions about knowledge of symptoms show that 58% of Italian patients and caregivers know that swelling of the lower limbs can be a symptom of DVT, and the same percentage knows that shortness of breath might indicate PE.
In terms of preventive action, the picture in Italy is somewhat variable: 74% of participants were aware of the importance of walking, but far fewer knew about the need to stop smoking (57%) and stretch the legs (35%). Of the 41% of Italians who were also taking an anticoagulant drug, 53% said that they knew about the possible side effects of such medication.
Which way forward?
“The high rate of CAT suggests that, despite the clinical evidence and clear guideline recommendations for patients with cancer, CAT prevention and recognition remain low among healthcare professionals,” the authors write.
The results of the ECPC survey further confirm those of previous studies, highlighting patients’ lack of knowledge about CAT and the need for more in-depth discussions between physician and patient.
So, what can be done? As highlighted by previous studies, “patients’ experiences are an education in themselves, particularly for the oncology care team,” the authors write. “Once the patient has a thrombosis, the opportunity for thrombosis prevention, which should be the most crucial focus of the care clinics (surgical, oncology, and palliative care), is gone,” they add.
“Oncology professionals, as well as other members of the patient’s care team (eg, internists, surgeons, nurses), need to perform better, at every stage of the patient’s cancer pathway, to ensure patients are aware of CAT and their individual risk to develop a blood clot,” said Dr. Falanga. She explained that in this group, it is the general practitioner who is the first contact. “These professionals are on the front line of the battle; they are among the first healthcare workers given the chance to suspect a clot and should, therefore, be fully aware of the increased risk in oncology patients,” she reiterated.
Experts agree on the fact that a multidisciplinary approach is of utmost importance in this context: the different roles in the team must be clear. “It is also fundamental to establish who does what in terms of educating and informing the patient,” said Dr. Falanga.
The researchers also put forward an example of a successful initiative: the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTE-PACC) program. The initiative was developed by experts from the University of Vermont and was described in a recent article in JCO Oncology Practice.
Numerous resources are available online to help physicians talk to their patients and explain the risks linked to CAT along the continuum of cancer care. Among them is a resource titled, “Cancer Associated Thrombosis (CAT): Be Clot Conscious,” which can be found on the ECPC’s website.
“We have a collective responsibility using the ECPC patient survey as a baseline to inform patients with cancer on how to identify signs and symptoms of CAT to enable faster diagnosis and treatment,” the authors conclude.
This article was translated from Univadis Italy.
It is up to their physician to discuss this with them.
This link is explained by the authors of an article in Cancer Treatment and Research Communications that reports results of a survey carried out by the European Cancer Patient Coalition (ECPC). “The aim of this pan-European patient survey was to assess patient awareness and knowledge about cancer-associated thrombosis (CAT), including risk factors, signs and symptoms, and interventions, to better prevent and treat CAT,” write the authors. “The idea was to create a sort of starting point for subsequent communication and information strategies and for comparing the results of any action taken in this area,” they add.
A roundtable discussion that included oncology healthcare professionals, policymakers, and patient advocates was convened to discuss and review the evidence regarding their ongoing concerns of excessive CAT-associated morbidity and mortality, as well as patients’ desire for greater CAT awareness.
“These discussions demonstrated that very little change had occurred over the years and that greater knowledge about CAT was still needed across the spectrum of healthcare practitioners and patients, particularly regarding primary and secondary prevention of thrombosis,” the authors write.
It was from this starting point that the idea for the pan-European survey was born. The ECPC, widely viewed as the “unified voice of cancer patients across Europe,” led the survey. This survey spanned six countries (France, Germany, Greece, Italy, United Kingdom, and Spain) and involved 1,365 patients and caregivers. The ECPC survey result was originally released at World Thrombosis Day in late 2018.
In an interview, Anna Falanga, MD, the main author of the article and professor of hematology at the University of Milan-Bicocca, Italy, reviewed the results and explained how to improve knowledge of CAT among patients with cancer.
“Data support that up to 20% of patients with cancer will experience venous thromboembolism (VTE), which is approximately 4–5 times higher than the general population,” said Dr. Falanga, who is also chief of the department of immunohematology and transfusion medicine and the Thrombosis and Hemostasis Center at the Hospital Papa Giovanni XXIII, in Bergamo, Italy.
“We have known about the link between thrombosis and cancer since the 19th century, but it has taken until midway through the last century for our level of understanding and awareness of the problem to reach its current level. Initially, this was limited to fundamental research, with large advances in our understanding of the mechanisms of the link between the two; it has only been more recently that we have had clinical studies that have piqued the interest of healthcare professionals, who were previously uninterested in the topic,” she said.
Poor understanding
One piece of data stands out from the European survey: Nearly three quarters of respondents (72%) said that before taking part in the survey, they were not aware that people with cancer have a higher-than-normal risk of developing thrombosis. “We asked participants to rate their overall understanding of CAT on a scale of 1 (low) to 10 (high), with the average (mean) score obtained being 4.1. Only 21% of patients gave a rating of 7 or above (high understanding). The average rating was very similar in the different countries surveyed,” write the authors. They note that the survey also assessed how much participants had learned about the topic from their physicians.
Approximately 35% of patients were made aware of CAT either immediately before or at the time of their cancer diagnosis. Of particular concern, one quarter (26%) of respondents (the largest proportion) noted that they first became aware of CAT when they suffered a blood clot. The average rating was very similar in the different countries surveyed. “Let us not forget that cancer and cancer treatments themselves cause a number of side effects, some of which can be very serious, so in some ways, a clot might be seen as a minor problem. Yet, in reality, it isn’t. It is a significant cause of death and disease in cancer patients,” said Dr. Falanga.
When discussing prevention, most respondents (87%) said they were aware that taking a walk could reduce their risk. Slightly fewer were aware that stopping smoking could reduce their risk (75%), and even fewer were aware that keeping hydrated (63%) and stretching their legs (55%) could reduce their risk.
Symptoms of CAT appeared to be relatively well known; 73% of survey participants indicated that they were aware that swelling in the foot, ankle, or leg could be a sign of DVT, and 71% indicated that shortness of breath could be a sign of pulmonary embolism (PE). “Other symptoms, however, were less well known, with just over half (57%) of participants being aware that pain, cramping, and tenderness could be a sign of DVT. About one third (33%) knew that irregular heartbeat could be a sign of PE. These results varied between countries,” according to the authors.
The survey highlighted that just over a third of respondents said that they were currently using anticoagulants, although almost all (96%) knew that anticoagulants could be used to effectively treat thrombosis. Only 41% of those using anticoagulants said they had been told about any possible side effects.
The Italian situation
The report containing the full results of the European survey goes even further, since, in addition to its overall results, it also gives information about individual countries.
The data from Italy, which are based on 246 persons, show that only 27% of patients and caregivers were aware of the increased risk of thrombosis after a cancer diagnosis. This figure is in line with the overall results of the survey, although the average score of the 10-point scale was lower for the Italy cohort (3.3/10 vs 4.1/10).
The results are more variable in terms of knowledge of risk factors. Most respondents (89%) said that they were aware of the risks related to inactivity. Just over half (52%), however, said that they were aware of the risks related to radiotherapy. Nevertheless, 75% of participants knew about the risks relating to cancer surgery and chemotherapy. “To all intents and purposes, all types of cancer drug can significantly affect the risk of developing a clot. And this is also the case for more modern types of treatment, such as immunotherapy,” said Dr. Falanga.
Most respondents reported that they got information about cancer-associated thrombosis verbally, usually from their hospital doctor (11%). Some respondents (6%) said that they found out about it from their own research, usually online. Almost 1 in 4 patients (24%) in Italy said that they first became aware of CAT when they suffered a blood clot. Answers to questions about knowledge of symptoms show that 58% of Italian patients and caregivers know that swelling of the lower limbs can be a symptom of DVT, and the same percentage knows that shortness of breath might indicate PE.
In terms of preventive action, the picture in Italy is somewhat variable: 74% of participants were aware of the importance of walking, but far fewer knew about the need to stop smoking (57%) and stretch the legs (35%). Of the 41% of Italians who were also taking an anticoagulant drug, 53% said that they knew about the possible side effects of such medication.
Which way forward?
“The high rate of CAT suggests that, despite the clinical evidence and clear guideline recommendations for patients with cancer, CAT prevention and recognition remain low among healthcare professionals,” the authors write.
The results of the ECPC survey further confirm those of previous studies, highlighting patients’ lack of knowledge about CAT and the need for more in-depth discussions between physician and patient.
So, what can be done? As highlighted by previous studies, “patients’ experiences are an education in themselves, particularly for the oncology care team,” the authors write. “Once the patient has a thrombosis, the opportunity for thrombosis prevention, which should be the most crucial focus of the care clinics (surgical, oncology, and palliative care), is gone,” they add.
“Oncology professionals, as well as other members of the patient’s care team (eg, internists, surgeons, nurses), need to perform better, at every stage of the patient’s cancer pathway, to ensure patients are aware of CAT and their individual risk to develop a blood clot,” said Dr. Falanga. She explained that in this group, it is the general practitioner who is the first contact. “These professionals are on the front line of the battle; they are among the first healthcare workers given the chance to suspect a clot and should, therefore, be fully aware of the increased risk in oncology patients,” she reiterated.
Experts agree on the fact that a multidisciplinary approach is of utmost importance in this context: the different roles in the team must be clear. “It is also fundamental to establish who does what in terms of educating and informing the patient,” said Dr. Falanga.
The researchers also put forward an example of a successful initiative: the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTE-PACC) program. The initiative was developed by experts from the University of Vermont and was described in a recent article in JCO Oncology Practice.
Numerous resources are available online to help physicians talk to their patients and explain the risks linked to CAT along the continuum of cancer care. Among them is a resource titled, “Cancer Associated Thrombosis (CAT): Be Clot Conscious,” which can be found on the ECPC’s website.
“We have a collective responsibility using the ECPC patient survey as a baseline to inform patients with cancer on how to identify signs and symptoms of CAT to enable faster diagnosis and treatment,” the authors conclude.
This article was translated from Univadis Italy.
FROM CANCER TREATMENT AND RESEARCH COMMUNICATIONS
Clozapine and cancer risk in schizophrenia patients: New data
Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.
The study was published online in The Lancet Psychiatry.
An unresolved issue
Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.
Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.
Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.
“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen.
Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.
To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.
“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.
The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.
Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
Patient education, vigilant monitoring
The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.
Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.
Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.
Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).
Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.
Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.
The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.
These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
A ‘vital’ medication
Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.
“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.
In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.
The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.
“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.
“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.
The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.
The study was published online in The Lancet Psychiatry.
An unresolved issue
Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.
Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.
Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.
“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen.
Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.
To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.
“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.
The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.
Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
Patient education, vigilant monitoring
The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.
Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.
Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.
Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).
Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.
Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.
The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.
These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
A ‘vital’ medication
Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.
“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.
In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.
The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.
“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.
“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.
The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.
The study was published online in The Lancet Psychiatry.
An unresolved issue
Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.
Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.
Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.
“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen.
Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.
To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.
“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.
The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.
Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
Patient education, vigilant monitoring
The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.
Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.
Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.
Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).
Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.
Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.
The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.
These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
A ‘vital’ medication
Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.
“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.
In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.
The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.
“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.
“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.
The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LANCET PSYCHIATRY
Ordering and Interpreting Precision Oncology Studies for Adults With Advanced Solid Tumors: A Primer
The ability to find and target specific biomarkers in the DNA of advanced cancers is rapidly changing options and outcomes for patients with locally advanced and metastatic solid tumors. This strategy is the basis for precision oncology, defined here as using predictive biomarkers from tumor and/or germline sequencing to guide therapies. This article focuses specifically on the use of DNA sequencing to find those biomarkers and provides guidance about which test is optimal in a specific situation, as well as interpretation of the results. We emphasize the identification of biomarkers that provide adult patients with advanced solid tumors access to therapies that would not be an option had sequencing not been performed and that have the potential for significant clinical benefit. The best approach is to have an expert team with experience in precision oncology to assist in the interpretation of results.
Which test?
Deciding what test of the array of assays available to use and which tissue to test can be overwhelming, and uncertainty may prevent oncology practitioners from ordering germline or somatic sequencing. For the purposes of this article, we will focus on DNA sequencing for inherited/germline alterations (including mutations, copy number changes, or fusions), which may inform treatment, or alterations that arise in the process of carcinogenesis and tumor evolution (somatic alterations in tumor DNA). This focus is not meant to exclude any specific test but to focus on DNA-based tests in patients with locally advanced or metastatic malignancy.
Germline Testing
Germline testing is the sequencing of inherited DNA in noncancerous cells to find alterations that may play a role in the development of cancers and are actionable in some cases. Germline alterations can inform therapeutic decisions, predict future cancer risk, and provide information that can help family members to better manage their risks of malignancy. Detailed discussions of the importance of germline testing to inform cancer surveillance, risk-reducing interventions, and the testing of relatives to determine who carries inherited alterations (cascade testing) is extremely important with several advantages and is covered in a number of excellent reviews elsewhere.1-3 Testing of germline DNA in patients with a metastatic malignancy can provide treatment options otherwise not available for patients, particularly for BRCA1/2 and Lynch syndrome–related cancers. Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration.4,5
Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations. Germline testing is also less susceptible to the rare situations in which artifacts occur in formalin-fixed tissues and obscure relevant alterations.
The cost of germline testing varies, but most commercial vendor assays for germline testing are significantly less expensive than the cost of somatic testing. The disadvantages include the inability of germline testing to find any alterations that arise solely in tumor tissue and the smaller gene panels included in germline testing as compared to somatic testing panels. Other considerations relate to the inherited nature of pathogenic germline variants and its implications for family members that may affect the patient’s psychosocial health and potentially change the family dynamics.
Deciding who is appropriate for germline testing and when to perform the testing should be individualized to the patient’s wishes and disease status. Treatment planning may be less complicated if testing has been performed and germline status is known. In some cases urgent germline testing is indicated to inform pending procedures and/or surgical decisions for risk reduction, including more extensive tissue resection, such as the removal of additional organs or contralateral tissue. A minor point regarding germline testing is that the DNA of patients with hematologic malignancies may be difficult to sequence because of sample contamination by the circulating malignancy. For this reason, most laboratories will not accept peripheral blood or saliva samples for germline testing in patients with active hematologic malignancies; they often require DNA from another source such as fibroblasts from a skin biopsy or cells from a muscle biopsy. Germline testing is recommended for all patients with metastatic prostate cancer, as well as any patient with any stage of pancreatic cancer or ovarian cancer and patients with breast cancer diagnosed at age ≤ 45 years. More detailed criteria for who is appropriate for germline testing outside of these groups can be found in the appropriate National Comprehensive Cancer Network (NCCN) guidelines.6-8 In patients with some malignancies such as prostate and pancreatic cancer, approximately half of patients who have a BRCA-related cancer developed that malignancy because of a germline BRCA alteration.9-11 Testing germline DNA is therefore an easy way to quickly find almost half of all targetable alterations with a treatment approved by the US Food and Drug Administration (FDA) and at low cost, with the added benefit of providing critical information for families who may be unaware that members carry a relevant pathogenic germline alteration. In those families, cascade testing can provide surveillance and intervention strategies that can be lifesaving.
A related and particularly relevant question is when should a result found on a somatic testing panel prompt follow-up germline testing? Some institutions have algorithms in place to automate referral for germline testing based on specific genetic criteria.12 Excellent reviews are available that outline the following considerations in more detail.13 Typically, somatic testing results that would trigger follow-up germline testing would be truncating or deleterious or likely deleterious mutations per germline datasets in high-risk genes associated with highly penetrant autosomal dominant conditions (BRCA1, BRCA2, PALB2, MLH1, MSH2, and MSH6), selected moderate-risk genes (BRIP1, RAD51C, and RAD51D), and specific variants with a high probability of being germline because they are common germline founder mutations. Although the actionability and significance of specific genes remains a matter of some discussion, generally finding a somatic pathogenic sequencing result included in the 59-gene list of the American College of Medical Genetics and Genomics (ACMG) guidelines would be an indication for germline testing. Another indication for germline testing would be finding genes with germline mutations for which the NCCN has specific management guidelines, or the presence of alterations consistent with known founder mutations.14 When a patient’s tumor has microsatellite instability or is hypermutated (defined as > 10 mutations per megabase), a search for germline alterations is warranted given that about 15% of these patients with these tumors carry a Lynch syndrome gene.15 Genes that are commonly found as somatic alterations alone (eg, TP53 or APC) are generally not an indication for germline testing unless family history is compelling.
Although some clinicians use the variant allele fraction in the somatic sequencing report to decide whether to conduct germline testing, this approach is suboptimal, as allele fraction may be confounded by assay conditions and a high allele fraction may be found in pure tumors with loss of heterozygosity (LOH) of the other allele. There is also evidence that for a variety of reasons, somatic sequencing panels do not always detect germline alterations in somatic tissues.16 Reasons for this may include discordance between the genes being tested in the germline vs the somatic panel, technical differences such as interference of formalin-fixed paraffin-embedded (FFPE) artifact with detecting the germline variant, lack of expertise in germline variant interpretation among laboratories doing tumor-only sequencing, and, in rare cases, large deletions in tumor tissue masking a germline point mutation.
Variant Interpretation of Germline Testing
A general understanding of the terminology used for germline variant interpretation allows for the ordering health care practitioner (HCP) to provide the best quality care and an appreciation for the limitations of current molecular testing. Not all variants are associated with disease; the clinical significance of a genetic variant falls on a spectrum. The criteria for determining pathogenicity differ between molecular laboratories, but most are influenced by the standards and guidelines set forth by the ACMG.14 The clinical molecular laboratory determines variant classification, and a detailed discussion is beyond the scope of this primer. In brief, variant classification is based on evidence of varying strength in different categories including population data, computational and predictive data, functional data, segregation data, de novo data, allelic data, and information from various databases. The ACMG has proposed a 5-tiered classification system, by which most molecular laboratories adhere to in their genetic test reports (Table 1).14
Pathogenic and likely pathogenic variants are clinically actionable, whereas variants of uncertain significance (VUS) require additional data and/or functional studies before making clinical decisions. Depending on the clinical context and existing supporting evidence, it may be prudent to continue monitoring for worsening or new signs of disease in patients with one or more VUS while additional efforts are underway to understand the variant’s significance.
In some cases, variants are reclassified, which may alter the management and treatment of patients. Reclassification can occur with VUS, and in rare instances, can also occur with variants previously classified as pathogenic/likely pathogenic or benign/likely benign. In such a case, the reporting laboratory will typically make concerted efforts to alert the ordering HCP. However, variant reclassifications are not always communicated to the care team. Thus, it is important to periodically contact the molecular laboratory of interest to obtain updated test interpretations.
Somatic Testing
Testing of somatic (tumor) tissue is critical and is the approach most commonly taken in medical oncology (Table 2).
The advantages of primary tumor are that it is usually in hand as a diagnostic biopsy, acquisition is standard of care, and several targetable alterations are truncal, defined as driver mutations present at the time of tumor development. Also, the potential that the tumor arose in the background of a predisposing germline alteration can be suggested by sequencing primary tumor as discussed above. Moreover, sequencing the primary tumor can be done at any time unless the biopsy sample is considered too old or degraded (per specific platform requirements). The information gained can be used to anticipate additional treatment options that are relevant when patients experience disease progression. Disadvantages include the problem that primary specimens may be old or have limited tumor content, both of which increase the likelihood that sequencing will not be technically successful.
Alterations that are targetable and arise as a result of either treatment pressure or clonal evolution are considered evolutionary. If evolutionary alterations are the main focus for sequencing, then metastasis biopsy or ctDNA are better choices. The advantages of a metastasis biopsy are that tissue is contemporary, tumor content may be higher than in primary tumor, and both truncal and evolutionary alterations can be detected.
For specific tumors, continued analysis of evolving genomic alterations can play a critical role in management. In non–small cell lung cancer (NSCLC), somatic testing is conducted again at progression on repeat biopsies to evaluate for emerging resistance mutations. In epidermal growth factor receptor (EGFR)–mutated lung cancer, the resistance mutation, exon 20 p.T790M (point mutation), can present in patients after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKI). Even in patients who are treated with the third-generation EGFR TKI osimertinib that can treat T790M-mutated lung cancer, multiple possible evolutionary mutations can occur at progression, including other EGFR mutations, MET/HER2 amplification, and BRAF V600E, to name a few.20 Resistance mechanisms develop due to treatment selection pressure and the molecular heterogeneity seen in lung cancer.
Disadvantages for metastatic biopsy include the inability to safely access a metastatic site, the time considerations for preauthorization and arrangement of biopsy, and a lower-than-average likelihood of successful sequencing from sites such as bone.21,22 In addition, there is some concern that a single metastatic site may not capture all relevant alterations for multiple reasons, including tumor heterogeneity.
Significant advances in the past decade have dramatically improved the ability to use ctDNA to guide therapy. Advantages include ease of acquisition as acquiring a sample requires only a blood draw, and the potential that the pool of ctDNA is a better reflection of the relevant biology as it potentially reflects all metastatic tissues. Disadvantages are that sequencing attempts may not be productive if the sample is acquired at a time when the tumor is either quiescent or tumor burden is so low that only limited amounts of DNA are being shed. Performing ctDNA analysis when a tumor is not progressing is less likely to be productive for a number of tumor types.23,24 Sequencing ctDNA is also more susceptible than sequencing tumor biopsies to detection of alterations that are not from the tumor of interest but from clonal hematopoiesis of indeterminate potential (CHIP) or other clonal hematopoietic disorders (see Confounders section below).
Selecting the Tissue
Deciding on the tissue to analyze is a critical part of the decision process (Table 3). If the primary tumor tissue is old the likelihood of productive sequencing is lower, although age alone is not the only consideration and the methods of fixation may be just as relevant.
For prostate cancer in particular, the ability to successfully sequence primary tumor tissue decreases as the amount of tumor decreases in low-volume biopsies such as prostate needle biopsies. Generally, if tumor content is < 10% of the biopsy specimen, then sequencing is less likely to be productive.25 Also, if the alteration of interest is not known to be truncal, then a relevant target might be missed by sequencing tissue that does not reflect current biology. Metastasis biopsy may be the most appropriate tissue, particularly if this specimen has already been acquired. As above, a metastasis biopsy may have a higher tumor content, and it should reflect relevant biology if it is recent. However, bone biopsies have a relatively low yield for successful sequencing, so a soft tissue lesion (eg, liver or lymph node metastasis) is generally preferred.
The inability to safely access tissue is often a consideration. Proximity to vital structures such as large blood vessels or the potential for significant morbidity in the event of a complication (liver or lung biopsies, particularly in patients on anticoagulation medications) may make the risk/benefit ratio too high. The inability to conduct somatic testing has been reported to often be due to inadequate tissue sampling.26 ctDNA is an attractive alternative but should typically be drawn when a tumor is progressing with a reasonable tumor burden that is more likely to be shedding DNA. Performing ctDNA analysis in patients without obvious radiographic metastasis or in patients whose tumor is under good control is unlikely to produce interpretable results.
Interpreting the Results
The intent of sequencing tumor tissue is to identify alterations that are biologically important and may provide a point of therapeutic leverage. However, deciding which alterations are relevant is not always straightforward. For example, any normal individual genome contains around 10,000 missense variants, hundreds of insertion/deletion variants, and dozens of protein-truncating variants. Distinguishing these alterations, which are part of the individual, from those that are tumor-specific and have functional significance can be difficult in the absence of paired sequencing of both normal and tissue samples.
Specific Alterations
Although most commercial vendors provide important information in sequencing reports to assist oncology HCPs in deciding which alterations are relevant, the reports are not always clear. In many cases the report will specifically indicate whether the alteration has been reported previously as pathogenic or benign. However, some platforms will report alterations that are not known to be drivers of tumor biology. It is critical to be aware that if variants are not reported as pathogenic, they should not be assumed to be pathogenic simply because they are included in the report. Alterations more likely to be drivers of relevant biology are those that change gene and protein structure and include frameshift (fs*), nonsense (denoted by sequence ending in “X” or “*”), or specific fusions or insertions/deletions (indel) that occur in important domains of the gene.
For some genes, only specific alterations are targetable and not all alterations have the same effect on protein function. Although overexpression of certain genes and proteins are actionable (eg, HER2), amplification of a gene does not necessarily indicate that it is targetable. In NSCLC, specific alterations convey sensitivity to targeted therapies. For example, in EGFR-mutated NSCLC, the sensitizing mutations to EGFR TKIs are exon19 deletions and exon 21 L858R point mutations (the most common mutations), as well as less common mutations found in exon 18-21. Exon 20 mutations, however, are not responsive to EGFR TKIs with a few exceptions.27 Patients who have tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI. In a variety of solid tumors, gene fusions of the NTRK 1/2/3, act as oncogenic drivers. The chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and upstream amino-terminal partners lead to overexpression of the chimeric proteins tropomyosin receptor kinase (TRK) A/B/C, resulting in constitutively active, ligand-independent downstream signaling. In patients with NTRK 1/2/3 gene fusions, larotrectinib and entrectinib, small molecule inhibitors to TRK, have shown antitumor activity.28,29 No alterations beyond these fusions are known to be targetable.
Allele Fraction
Knowing the fraction (or proportion) of the alteration of interest in the sequenced tissue relative to the estimated tumor content can assist in decision making. Not all platforms will provide this information, which is referred to as mutation allele fraction (MAF) or variant allele fraction (VAF), but sometimes will provide it on request. Platforms will usually provide an estimate of the percent tumor in the tissue being sampled if it is from a biopsy. If the MAF is around 50% in the sequenced tissue (including ctDNA), then there is a reasonable chance that it is a germline variant. However, there are nuances as germline alterations in some genes, such as BRCA1/2, can be accompanied by loss of the other allele of the gene (LOH). In that case, if most of the circulating DNA is from tumor, then the MAF can be > 50%.
If there are 2 alterations of the same gene with MAF percentages that are each half of the total percent tumor, there is a high likelihood of biallelic alteration. These sorts of paired alterations or one mutation with apparent LOH or copy loss would again indicate a high likelihood that the alteration is in fact pathogenic and a relevant driver. Not all pathogenic alterations have to be biallelic to be driver mutations but in BRCA1/2, or mismatch repair deficiency genes, the presence of biallelic alterations increases the likelihood of their being pathogenic.
Tumors that are hypermutated—containing sometimes hundreds of mutations per megabyte of DNA—can be particularly complicated to interpret, because the likelihood increases that many of the alterations are a function of the hypermutation and not a driver mutation. This is particularly important when there are concurrent mutations in mismatch repair genes and genes, such as BRCA1/2. If the tumor is
Confounders
In some situations, interpretation can be particularly challenging. For example, several alterations for which there are FDA on-label indications (such as ATM or BRCA2) can be detected in ctDNA that may not be due to the tumor but to CHIP. CHIP represents hematopoietic clones that are dysplastic as a result of exposure to DNA-damaging agents (eg, platinum chemotherapy) or as a result of aging and arise when mutations in hematopoietic stem cells provide a competitive advantage.31 The most common CHIP clones that can be detected are DNMT3A, ASXL1, or TET2; because these alterations are not targetable, their importance lies primarily in whether patients have evidence of hematologic abnormality, which might represent an evolving hematopoietic disorder. Because CHIP alterations can overlap with somatic alterations for which FDA-approved drugs exist, such as ATM or CHEK2 (olaparib for prostate cancer) and BRCA2 (poly-ADP-ribose polymerase inhibitors in a range of indications) there is concern that CHIP might result in patient harm from inappropriate treatment of CHIP rather than the tumor, with no likelihood that the treatment would affect the tumor, causing treatment delays.32 General considerations for deciding whether an alteration represents CHIP include excluding alteration in which the VAF is < 1% and when the VAF in the alteration of interest is < 20% of the estimated tumor fraction in the sample. Exceptions to this are found in patients with true myelodysplasia or chronic lymphocytic leukemia, in whom the VAF can be well over 50% because of circulating tumor burden. The only way to be certain that an alteration detected on ctDNA reflects tumor rather than CHIP is to utilize an assay with matched tumor-normal sequencing.
Resources for Assistance
For oncology HCPs, perhaps the best resource to help in selecting and interpreting the appropriate testing is through a dedicated molecular oncology tumor board and subject matter experts who contribute to those tumor boards. In the US Department of Veterans Affairs, the national precision oncology program and its affiliated clinical services, such as the option to order a national consultation and molecular tumor board education, are easily accessible to all HCPs (www.cancer.va.gov). Many commercial vendors provide support to assist with questions of interpretation and to inform clinical decision-making. Other resources that can assist with deciding whether an alteration is pathogenic include extensive curated databases such as ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the Human Genetic Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) for germline alterations or COSMIC (cancer.sanger.ac.uk/cosmic) for somatic alterations. OncoKB (www.oncokb.org) is a resource for assistance in defining levels of evidence for the use of agents to target specific alterations and to assist in assigning pathogenicity to specific alterations. Additional educational resources for training in genomics and genetics are also included in the Appendix.
The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for men and women dealing with malignancy and our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.
Acknowledgments
Dedicated to Neil Spector.
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23. Schweizer MT, Gulati R, Beightol M, et al. Clinical determinants for successful circulating tumor DNA analysis in prostate cancer. Prostate. 2019;79(7):701-708. doi:10.1002/pros.23778
24. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra224. doi:10.1126/scitranslmed.3007094
25. Pritchard CC, Salipante SJ, Koehler K, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. J Mol Diagn. 2014;16(1):56-67. doi:10.1016/j.jmoldx.2013.08.004
26. Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer. 2017;18(6):651-659. doi:10.1016/j.cllc.2017.04.004
27. Malapelle U, Pilotto S, Passiglia F, et al. Dealing with NSCLC EGFR mutation testing and treatment: a comprehensive review with an Italian real-world perspective. Crit Rev Oncol Hematol. 2021;160:103300. doi:10.1016/j.critrevonc.2021.103300
28. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448
29. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. doi:10.1016/S1470-2045(19)30691-6
30. Jonsson P, Bandlamudi C, Cheng ML, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019;571(7766):576-579. doi:10.1038/s41586-019-1382-1
31. Steensma DP. Clinical consequences of clonal hematopoiesis of indeterminate potential. Hematology Am Soc Hematol Educ Program. 2018;2018(1):264-269. doi:10.1182/asheducation-2018.1.264
32. Jensen K, Konnick EQ, Schweizer MT, et al. Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. JAMA Oncol. 2021;7(1):107-110. doi:10.1001/jamaoncol.2020.5161
The ability to find and target specific biomarkers in the DNA of advanced cancers is rapidly changing options and outcomes for patients with locally advanced and metastatic solid tumors. This strategy is the basis for precision oncology, defined here as using predictive biomarkers from tumor and/or germline sequencing to guide therapies. This article focuses specifically on the use of DNA sequencing to find those biomarkers and provides guidance about which test is optimal in a specific situation, as well as interpretation of the results. We emphasize the identification of biomarkers that provide adult patients with advanced solid tumors access to therapies that would not be an option had sequencing not been performed and that have the potential for significant clinical benefit. The best approach is to have an expert team with experience in precision oncology to assist in the interpretation of results.
Which test?
Deciding what test of the array of assays available to use and which tissue to test can be overwhelming, and uncertainty may prevent oncology practitioners from ordering germline or somatic sequencing. For the purposes of this article, we will focus on DNA sequencing for inherited/germline alterations (including mutations, copy number changes, or fusions), which may inform treatment, or alterations that arise in the process of carcinogenesis and tumor evolution (somatic alterations in tumor DNA). This focus is not meant to exclude any specific test but to focus on DNA-based tests in patients with locally advanced or metastatic malignancy.
Germline Testing
Germline testing is the sequencing of inherited DNA in noncancerous cells to find alterations that may play a role in the development of cancers and are actionable in some cases. Germline alterations can inform therapeutic decisions, predict future cancer risk, and provide information that can help family members to better manage their risks of malignancy. Detailed discussions of the importance of germline testing to inform cancer surveillance, risk-reducing interventions, and the testing of relatives to determine who carries inherited alterations (cascade testing) is extremely important with several advantages and is covered in a number of excellent reviews elsewhere.1-3 Testing of germline DNA in patients with a metastatic malignancy can provide treatment options otherwise not available for patients, particularly for BRCA1/2 and Lynch syndrome–related cancers. Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration.4,5
Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations. Germline testing is also less susceptible to the rare situations in which artifacts occur in formalin-fixed tissues and obscure relevant alterations.
The cost of germline testing varies, but most commercial vendor assays for germline testing are significantly less expensive than the cost of somatic testing. The disadvantages include the inability of germline testing to find any alterations that arise solely in tumor tissue and the smaller gene panels included in germline testing as compared to somatic testing panels. Other considerations relate to the inherited nature of pathogenic germline variants and its implications for family members that may affect the patient’s psychosocial health and potentially change the family dynamics.
Deciding who is appropriate for germline testing and when to perform the testing should be individualized to the patient’s wishes and disease status. Treatment planning may be less complicated if testing has been performed and germline status is known. In some cases urgent germline testing is indicated to inform pending procedures and/or surgical decisions for risk reduction, including more extensive tissue resection, such as the removal of additional organs or contralateral tissue. A minor point regarding germline testing is that the DNA of patients with hematologic malignancies may be difficult to sequence because of sample contamination by the circulating malignancy. For this reason, most laboratories will not accept peripheral blood or saliva samples for germline testing in patients with active hematologic malignancies; they often require DNA from another source such as fibroblasts from a skin biopsy or cells from a muscle biopsy. Germline testing is recommended for all patients with metastatic prostate cancer, as well as any patient with any stage of pancreatic cancer or ovarian cancer and patients with breast cancer diagnosed at age ≤ 45 years. More detailed criteria for who is appropriate for germline testing outside of these groups can be found in the appropriate National Comprehensive Cancer Network (NCCN) guidelines.6-8 In patients with some malignancies such as prostate and pancreatic cancer, approximately half of patients who have a BRCA-related cancer developed that malignancy because of a germline BRCA alteration.9-11 Testing germline DNA is therefore an easy way to quickly find almost half of all targetable alterations with a treatment approved by the US Food and Drug Administration (FDA) and at low cost, with the added benefit of providing critical information for families who may be unaware that members carry a relevant pathogenic germline alteration. In those families, cascade testing can provide surveillance and intervention strategies that can be lifesaving.
A related and particularly relevant question is when should a result found on a somatic testing panel prompt follow-up germline testing? Some institutions have algorithms in place to automate referral for germline testing based on specific genetic criteria.12 Excellent reviews are available that outline the following considerations in more detail.13 Typically, somatic testing results that would trigger follow-up germline testing would be truncating or deleterious or likely deleterious mutations per germline datasets in high-risk genes associated with highly penetrant autosomal dominant conditions (BRCA1, BRCA2, PALB2, MLH1, MSH2, and MSH6), selected moderate-risk genes (BRIP1, RAD51C, and RAD51D), and specific variants with a high probability of being germline because they are common germline founder mutations. Although the actionability and significance of specific genes remains a matter of some discussion, generally finding a somatic pathogenic sequencing result included in the 59-gene list of the American College of Medical Genetics and Genomics (ACMG) guidelines would be an indication for germline testing. Another indication for germline testing would be finding genes with germline mutations for which the NCCN has specific management guidelines, or the presence of alterations consistent with known founder mutations.14 When a patient’s tumor has microsatellite instability or is hypermutated (defined as > 10 mutations per megabase), a search for germline alterations is warranted given that about 15% of these patients with these tumors carry a Lynch syndrome gene.15 Genes that are commonly found as somatic alterations alone (eg, TP53 or APC) are generally not an indication for germline testing unless family history is compelling.
Although some clinicians use the variant allele fraction in the somatic sequencing report to decide whether to conduct germline testing, this approach is suboptimal, as allele fraction may be confounded by assay conditions and a high allele fraction may be found in pure tumors with loss of heterozygosity (LOH) of the other allele. There is also evidence that for a variety of reasons, somatic sequencing panels do not always detect germline alterations in somatic tissues.16 Reasons for this may include discordance between the genes being tested in the germline vs the somatic panel, technical differences such as interference of formalin-fixed paraffin-embedded (FFPE) artifact with detecting the germline variant, lack of expertise in germline variant interpretation among laboratories doing tumor-only sequencing, and, in rare cases, large deletions in tumor tissue masking a germline point mutation.
Variant Interpretation of Germline Testing
A general understanding of the terminology used for germline variant interpretation allows for the ordering health care practitioner (HCP) to provide the best quality care and an appreciation for the limitations of current molecular testing. Not all variants are associated with disease; the clinical significance of a genetic variant falls on a spectrum. The criteria for determining pathogenicity differ between molecular laboratories, but most are influenced by the standards and guidelines set forth by the ACMG.14 The clinical molecular laboratory determines variant classification, and a detailed discussion is beyond the scope of this primer. In brief, variant classification is based on evidence of varying strength in different categories including population data, computational and predictive data, functional data, segregation data, de novo data, allelic data, and information from various databases. The ACMG has proposed a 5-tiered classification system, by which most molecular laboratories adhere to in their genetic test reports (Table 1).14
Pathogenic and likely pathogenic variants are clinically actionable, whereas variants of uncertain significance (VUS) require additional data and/or functional studies before making clinical decisions. Depending on the clinical context and existing supporting evidence, it may be prudent to continue monitoring for worsening or new signs of disease in patients with one or more VUS while additional efforts are underway to understand the variant’s significance.
In some cases, variants are reclassified, which may alter the management and treatment of patients. Reclassification can occur with VUS, and in rare instances, can also occur with variants previously classified as pathogenic/likely pathogenic or benign/likely benign. In such a case, the reporting laboratory will typically make concerted efforts to alert the ordering HCP. However, variant reclassifications are not always communicated to the care team. Thus, it is important to periodically contact the molecular laboratory of interest to obtain updated test interpretations.
Somatic Testing
Testing of somatic (tumor) tissue is critical and is the approach most commonly taken in medical oncology (Table 2).
The advantages of primary tumor are that it is usually in hand as a diagnostic biopsy, acquisition is standard of care, and several targetable alterations are truncal, defined as driver mutations present at the time of tumor development. Also, the potential that the tumor arose in the background of a predisposing germline alteration can be suggested by sequencing primary tumor as discussed above. Moreover, sequencing the primary tumor can be done at any time unless the biopsy sample is considered too old or degraded (per specific platform requirements). The information gained can be used to anticipate additional treatment options that are relevant when patients experience disease progression. Disadvantages include the problem that primary specimens may be old or have limited tumor content, both of which increase the likelihood that sequencing will not be technically successful.
Alterations that are targetable and arise as a result of either treatment pressure or clonal evolution are considered evolutionary. If evolutionary alterations are the main focus for sequencing, then metastasis biopsy or ctDNA are better choices. The advantages of a metastasis biopsy are that tissue is contemporary, tumor content may be higher than in primary tumor, and both truncal and evolutionary alterations can be detected.
For specific tumors, continued analysis of evolving genomic alterations can play a critical role in management. In non–small cell lung cancer (NSCLC), somatic testing is conducted again at progression on repeat biopsies to evaluate for emerging resistance mutations. In epidermal growth factor receptor (EGFR)–mutated lung cancer, the resistance mutation, exon 20 p.T790M (point mutation), can present in patients after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKI). Even in patients who are treated with the third-generation EGFR TKI osimertinib that can treat T790M-mutated lung cancer, multiple possible evolutionary mutations can occur at progression, including other EGFR mutations, MET/HER2 amplification, and BRAF V600E, to name a few.20 Resistance mechanisms develop due to treatment selection pressure and the molecular heterogeneity seen in lung cancer.
Disadvantages for metastatic biopsy include the inability to safely access a metastatic site, the time considerations for preauthorization and arrangement of biopsy, and a lower-than-average likelihood of successful sequencing from sites such as bone.21,22 In addition, there is some concern that a single metastatic site may not capture all relevant alterations for multiple reasons, including tumor heterogeneity.
Significant advances in the past decade have dramatically improved the ability to use ctDNA to guide therapy. Advantages include ease of acquisition as acquiring a sample requires only a blood draw, and the potential that the pool of ctDNA is a better reflection of the relevant biology as it potentially reflects all metastatic tissues. Disadvantages are that sequencing attempts may not be productive if the sample is acquired at a time when the tumor is either quiescent or tumor burden is so low that only limited amounts of DNA are being shed. Performing ctDNA analysis when a tumor is not progressing is less likely to be productive for a number of tumor types.23,24 Sequencing ctDNA is also more susceptible than sequencing tumor biopsies to detection of alterations that are not from the tumor of interest but from clonal hematopoiesis of indeterminate potential (CHIP) or other clonal hematopoietic disorders (see Confounders section below).
Selecting the Tissue
Deciding on the tissue to analyze is a critical part of the decision process (Table 3). If the primary tumor tissue is old the likelihood of productive sequencing is lower, although age alone is not the only consideration and the methods of fixation may be just as relevant.
For prostate cancer in particular, the ability to successfully sequence primary tumor tissue decreases as the amount of tumor decreases in low-volume biopsies such as prostate needle biopsies. Generally, if tumor content is < 10% of the biopsy specimen, then sequencing is less likely to be productive.25 Also, if the alteration of interest is not known to be truncal, then a relevant target might be missed by sequencing tissue that does not reflect current biology. Metastasis biopsy may be the most appropriate tissue, particularly if this specimen has already been acquired. As above, a metastasis biopsy may have a higher tumor content, and it should reflect relevant biology if it is recent. However, bone biopsies have a relatively low yield for successful sequencing, so a soft tissue lesion (eg, liver or lymph node metastasis) is generally preferred.
The inability to safely access tissue is often a consideration. Proximity to vital structures such as large blood vessels or the potential for significant morbidity in the event of a complication (liver or lung biopsies, particularly in patients on anticoagulation medications) may make the risk/benefit ratio too high. The inability to conduct somatic testing has been reported to often be due to inadequate tissue sampling.26 ctDNA is an attractive alternative but should typically be drawn when a tumor is progressing with a reasonable tumor burden that is more likely to be shedding DNA. Performing ctDNA analysis in patients without obvious radiographic metastasis or in patients whose tumor is under good control is unlikely to produce interpretable results.
Interpreting the Results
The intent of sequencing tumor tissue is to identify alterations that are biologically important and may provide a point of therapeutic leverage. However, deciding which alterations are relevant is not always straightforward. For example, any normal individual genome contains around 10,000 missense variants, hundreds of insertion/deletion variants, and dozens of protein-truncating variants. Distinguishing these alterations, which are part of the individual, from those that are tumor-specific and have functional significance can be difficult in the absence of paired sequencing of both normal and tissue samples.
Specific Alterations
Although most commercial vendors provide important information in sequencing reports to assist oncology HCPs in deciding which alterations are relevant, the reports are not always clear. In many cases the report will specifically indicate whether the alteration has been reported previously as pathogenic or benign. However, some platforms will report alterations that are not known to be drivers of tumor biology. It is critical to be aware that if variants are not reported as pathogenic, they should not be assumed to be pathogenic simply because they are included in the report. Alterations more likely to be drivers of relevant biology are those that change gene and protein structure and include frameshift (fs*), nonsense (denoted by sequence ending in “X” or “*”), or specific fusions or insertions/deletions (indel) that occur in important domains of the gene.
For some genes, only specific alterations are targetable and not all alterations have the same effect on protein function. Although overexpression of certain genes and proteins are actionable (eg, HER2), amplification of a gene does not necessarily indicate that it is targetable. In NSCLC, specific alterations convey sensitivity to targeted therapies. For example, in EGFR-mutated NSCLC, the sensitizing mutations to EGFR TKIs are exon19 deletions and exon 21 L858R point mutations (the most common mutations), as well as less common mutations found in exon 18-21. Exon 20 mutations, however, are not responsive to EGFR TKIs with a few exceptions.27 Patients who have tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI. In a variety of solid tumors, gene fusions of the NTRK 1/2/3, act as oncogenic drivers. The chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and upstream amino-terminal partners lead to overexpression of the chimeric proteins tropomyosin receptor kinase (TRK) A/B/C, resulting in constitutively active, ligand-independent downstream signaling. In patients with NTRK 1/2/3 gene fusions, larotrectinib and entrectinib, small molecule inhibitors to TRK, have shown antitumor activity.28,29 No alterations beyond these fusions are known to be targetable.
Allele Fraction
Knowing the fraction (or proportion) of the alteration of interest in the sequenced tissue relative to the estimated tumor content can assist in decision making. Not all platforms will provide this information, which is referred to as mutation allele fraction (MAF) or variant allele fraction (VAF), but sometimes will provide it on request. Platforms will usually provide an estimate of the percent tumor in the tissue being sampled if it is from a biopsy. If the MAF is around 50% in the sequenced tissue (including ctDNA), then there is a reasonable chance that it is a germline variant. However, there are nuances as germline alterations in some genes, such as BRCA1/2, can be accompanied by loss of the other allele of the gene (LOH). In that case, if most of the circulating DNA is from tumor, then the MAF can be > 50%.
If there are 2 alterations of the same gene with MAF percentages that are each half of the total percent tumor, there is a high likelihood of biallelic alteration. These sorts of paired alterations or one mutation with apparent LOH or copy loss would again indicate a high likelihood that the alteration is in fact pathogenic and a relevant driver. Not all pathogenic alterations have to be biallelic to be driver mutations but in BRCA1/2, or mismatch repair deficiency genes, the presence of biallelic alterations increases the likelihood of their being pathogenic.
Tumors that are hypermutated—containing sometimes hundreds of mutations per megabyte of DNA—can be particularly complicated to interpret, because the likelihood increases that many of the alterations are a function of the hypermutation and not a driver mutation. This is particularly important when there are concurrent mutations in mismatch repair genes and genes, such as BRCA1/2. If the tumor is
Confounders
In some situations, interpretation can be particularly challenging. For example, several alterations for which there are FDA on-label indications (such as ATM or BRCA2) can be detected in ctDNA that may not be due to the tumor but to CHIP. CHIP represents hematopoietic clones that are dysplastic as a result of exposure to DNA-damaging agents (eg, platinum chemotherapy) or as a result of aging and arise when mutations in hematopoietic stem cells provide a competitive advantage.31 The most common CHIP clones that can be detected are DNMT3A, ASXL1, or TET2; because these alterations are not targetable, their importance lies primarily in whether patients have evidence of hematologic abnormality, which might represent an evolving hematopoietic disorder. Because CHIP alterations can overlap with somatic alterations for which FDA-approved drugs exist, such as ATM or CHEK2 (olaparib for prostate cancer) and BRCA2 (poly-ADP-ribose polymerase inhibitors in a range of indications) there is concern that CHIP might result in patient harm from inappropriate treatment of CHIP rather than the tumor, with no likelihood that the treatment would affect the tumor, causing treatment delays.32 General considerations for deciding whether an alteration represents CHIP include excluding alteration in which the VAF is < 1% and when the VAF in the alteration of interest is < 20% of the estimated tumor fraction in the sample. Exceptions to this are found in patients with true myelodysplasia or chronic lymphocytic leukemia, in whom the VAF can be well over 50% because of circulating tumor burden. The only way to be certain that an alteration detected on ctDNA reflects tumor rather than CHIP is to utilize an assay with matched tumor-normal sequencing.
Resources for Assistance
For oncology HCPs, perhaps the best resource to help in selecting and interpreting the appropriate testing is through a dedicated molecular oncology tumor board and subject matter experts who contribute to those tumor boards. In the US Department of Veterans Affairs, the national precision oncology program and its affiliated clinical services, such as the option to order a national consultation and molecular tumor board education, are easily accessible to all HCPs (www.cancer.va.gov). Many commercial vendors provide support to assist with questions of interpretation and to inform clinical decision-making. Other resources that can assist with deciding whether an alteration is pathogenic include extensive curated databases such as ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the Human Genetic Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) for germline alterations or COSMIC (cancer.sanger.ac.uk/cosmic) for somatic alterations. OncoKB (www.oncokb.org) is a resource for assistance in defining levels of evidence for the use of agents to target specific alterations and to assist in assigning pathogenicity to specific alterations. Additional educational resources for training in genomics and genetics are also included in the Appendix.
The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for men and women dealing with malignancy and our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.
Acknowledgments
Dedicated to Neil Spector.
The ability to find and target specific biomarkers in the DNA of advanced cancers is rapidly changing options and outcomes for patients with locally advanced and metastatic solid tumors. This strategy is the basis for precision oncology, defined here as using predictive biomarkers from tumor and/or germline sequencing to guide therapies. This article focuses specifically on the use of DNA sequencing to find those biomarkers and provides guidance about which test is optimal in a specific situation, as well as interpretation of the results. We emphasize the identification of biomarkers that provide adult patients with advanced solid tumors access to therapies that would not be an option had sequencing not been performed and that have the potential for significant clinical benefit. The best approach is to have an expert team with experience in precision oncology to assist in the interpretation of results.
Which test?
Deciding what test of the array of assays available to use and which tissue to test can be overwhelming, and uncertainty may prevent oncology practitioners from ordering germline or somatic sequencing. For the purposes of this article, we will focus on DNA sequencing for inherited/germline alterations (including mutations, copy number changes, or fusions), which may inform treatment, or alterations that arise in the process of carcinogenesis and tumor evolution (somatic alterations in tumor DNA). This focus is not meant to exclude any specific test but to focus on DNA-based tests in patients with locally advanced or metastatic malignancy.
Germline Testing
Germline testing is the sequencing of inherited DNA in noncancerous cells to find alterations that may play a role in the development of cancers and are actionable in some cases. Germline alterations can inform therapeutic decisions, predict future cancer risk, and provide information that can help family members to better manage their risks of malignancy. Detailed discussions of the importance of germline testing to inform cancer surveillance, risk-reducing interventions, and the testing of relatives to determine who carries inherited alterations (cascade testing) is extremely important with several advantages and is covered in a number of excellent reviews elsewhere.1-3 Testing of germline DNA in patients with a metastatic malignancy can provide treatment options otherwise not available for patients, particularly for BRCA1/2 and Lynch syndrome–related cancers. Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration.4,5
Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations. Germline testing is also less susceptible to the rare situations in which artifacts occur in formalin-fixed tissues and obscure relevant alterations.
The cost of germline testing varies, but most commercial vendor assays for germline testing are significantly less expensive than the cost of somatic testing. The disadvantages include the inability of germline testing to find any alterations that arise solely in tumor tissue and the smaller gene panels included in germline testing as compared to somatic testing panels. Other considerations relate to the inherited nature of pathogenic germline variants and its implications for family members that may affect the patient’s psychosocial health and potentially change the family dynamics.
Deciding who is appropriate for germline testing and when to perform the testing should be individualized to the patient’s wishes and disease status. Treatment planning may be less complicated if testing has been performed and germline status is known. In some cases urgent germline testing is indicated to inform pending procedures and/or surgical decisions for risk reduction, including more extensive tissue resection, such as the removal of additional organs or contralateral tissue. A minor point regarding germline testing is that the DNA of patients with hematologic malignancies may be difficult to sequence because of sample contamination by the circulating malignancy. For this reason, most laboratories will not accept peripheral blood or saliva samples for germline testing in patients with active hematologic malignancies; they often require DNA from another source such as fibroblasts from a skin biopsy or cells from a muscle biopsy. Germline testing is recommended for all patients with metastatic prostate cancer, as well as any patient with any stage of pancreatic cancer or ovarian cancer and patients with breast cancer diagnosed at age ≤ 45 years. More detailed criteria for who is appropriate for germline testing outside of these groups can be found in the appropriate National Comprehensive Cancer Network (NCCN) guidelines.6-8 In patients with some malignancies such as prostate and pancreatic cancer, approximately half of patients who have a BRCA-related cancer developed that malignancy because of a germline BRCA alteration.9-11 Testing germline DNA is therefore an easy way to quickly find almost half of all targetable alterations with a treatment approved by the US Food and Drug Administration (FDA) and at low cost, with the added benefit of providing critical information for families who may be unaware that members carry a relevant pathogenic germline alteration. In those families, cascade testing can provide surveillance and intervention strategies that can be lifesaving.
A related and particularly relevant question is when should a result found on a somatic testing panel prompt follow-up germline testing? Some institutions have algorithms in place to automate referral for germline testing based on specific genetic criteria.12 Excellent reviews are available that outline the following considerations in more detail.13 Typically, somatic testing results that would trigger follow-up germline testing would be truncating or deleterious or likely deleterious mutations per germline datasets in high-risk genes associated with highly penetrant autosomal dominant conditions (BRCA1, BRCA2, PALB2, MLH1, MSH2, and MSH6), selected moderate-risk genes (BRIP1, RAD51C, and RAD51D), and specific variants with a high probability of being germline because they are common germline founder mutations. Although the actionability and significance of specific genes remains a matter of some discussion, generally finding a somatic pathogenic sequencing result included in the 59-gene list of the American College of Medical Genetics and Genomics (ACMG) guidelines would be an indication for germline testing. Another indication for germline testing would be finding genes with germline mutations for which the NCCN has specific management guidelines, or the presence of alterations consistent with known founder mutations.14 When a patient’s tumor has microsatellite instability or is hypermutated (defined as > 10 mutations per megabase), a search for germline alterations is warranted given that about 15% of these patients with these tumors carry a Lynch syndrome gene.15 Genes that are commonly found as somatic alterations alone (eg, TP53 or APC) are generally not an indication for germline testing unless family history is compelling.
Although some clinicians use the variant allele fraction in the somatic sequencing report to decide whether to conduct germline testing, this approach is suboptimal, as allele fraction may be confounded by assay conditions and a high allele fraction may be found in pure tumors with loss of heterozygosity (LOH) of the other allele. There is also evidence that for a variety of reasons, somatic sequencing panels do not always detect germline alterations in somatic tissues.16 Reasons for this may include discordance between the genes being tested in the germline vs the somatic panel, technical differences such as interference of formalin-fixed paraffin-embedded (FFPE) artifact with detecting the germline variant, lack of expertise in germline variant interpretation among laboratories doing tumor-only sequencing, and, in rare cases, large deletions in tumor tissue masking a germline point mutation.
Variant Interpretation of Germline Testing
A general understanding of the terminology used for germline variant interpretation allows for the ordering health care practitioner (HCP) to provide the best quality care and an appreciation for the limitations of current molecular testing. Not all variants are associated with disease; the clinical significance of a genetic variant falls on a spectrum. The criteria for determining pathogenicity differ between molecular laboratories, but most are influenced by the standards and guidelines set forth by the ACMG.14 The clinical molecular laboratory determines variant classification, and a detailed discussion is beyond the scope of this primer. In brief, variant classification is based on evidence of varying strength in different categories including population data, computational and predictive data, functional data, segregation data, de novo data, allelic data, and information from various databases. The ACMG has proposed a 5-tiered classification system, by which most molecular laboratories adhere to in their genetic test reports (Table 1).14
Pathogenic and likely pathogenic variants are clinically actionable, whereas variants of uncertain significance (VUS) require additional data and/or functional studies before making clinical decisions. Depending on the clinical context and existing supporting evidence, it may be prudent to continue monitoring for worsening or new signs of disease in patients with one or more VUS while additional efforts are underway to understand the variant’s significance.
In some cases, variants are reclassified, which may alter the management and treatment of patients. Reclassification can occur with VUS, and in rare instances, can also occur with variants previously classified as pathogenic/likely pathogenic or benign/likely benign. In such a case, the reporting laboratory will typically make concerted efforts to alert the ordering HCP. However, variant reclassifications are not always communicated to the care team. Thus, it is important to periodically contact the molecular laboratory of interest to obtain updated test interpretations.
Somatic Testing
Testing of somatic (tumor) tissue is critical and is the approach most commonly taken in medical oncology (Table 2).
The advantages of primary tumor are that it is usually in hand as a diagnostic biopsy, acquisition is standard of care, and several targetable alterations are truncal, defined as driver mutations present at the time of tumor development. Also, the potential that the tumor arose in the background of a predisposing germline alteration can be suggested by sequencing primary tumor as discussed above. Moreover, sequencing the primary tumor can be done at any time unless the biopsy sample is considered too old or degraded (per specific platform requirements). The information gained can be used to anticipate additional treatment options that are relevant when patients experience disease progression. Disadvantages include the problem that primary specimens may be old or have limited tumor content, both of which increase the likelihood that sequencing will not be technically successful.
Alterations that are targetable and arise as a result of either treatment pressure or clonal evolution are considered evolutionary. If evolutionary alterations are the main focus for sequencing, then metastasis biopsy or ctDNA are better choices. The advantages of a metastasis biopsy are that tissue is contemporary, tumor content may be higher than in primary tumor, and both truncal and evolutionary alterations can be detected.
For specific tumors, continued analysis of evolving genomic alterations can play a critical role in management. In non–small cell lung cancer (NSCLC), somatic testing is conducted again at progression on repeat biopsies to evaluate for emerging resistance mutations. In epidermal growth factor receptor (EGFR)–mutated lung cancer, the resistance mutation, exon 20 p.T790M (point mutation), can present in patients after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKI). Even in patients who are treated with the third-generation EGFR TKI osimertinib that can treat T790M-mutated lung cancer, multiple possible evolutionary mutations can occur at progression, including other EGFR mutations, MET/HER2 amplification, and BRAF V600E, to name a few.20 Resistance mechanisms develop due to treatment selection pressure and the molecular heterogeneity seen in lung cancer.
Disadvantages for metastatic biopsy include the inability to safely access a metastatic site, the time considerations for preauthorization and arrangement of biopsy, and a lower-than-average likelihood of successful sequencing from sites such as bone.21,22 In addition, there is some concern that a single metastatic site may not capture all relevant alterations for multiple reasons, including tumor heterogeneity.
Significant advances in the past decade have dramatically improved the ability to use ctDNA to guide therapy. Advantages include ease of acquisition as acquiring a sample requires only a blood draw, and the potential that the pool of ctDNA is a better reflection of the relevant biology as it potentially reflects all metastatic tissues. Disadvantages are that sequencing attempts may not be productive if the sample is acquired at a time when the tumor is either quiescent or tumor burden is so low that only limited amounts of DNA are being shed. Performing ctDNA analysis when a tumor is not progressing is less likely to be productive for a number of tumor types.23,24 Sequencing ctDNA is also more susceptible than sequencing tumor biopsies to detection of alterations that are not from the tumor of interest but from clonal hematopoiesis of indeterminate potential (CHIP) or other clonal hematopoietic disorders (see Confounders section below).
Selecting the Tissue
Deciding on the tissue to analyze is a critical part of the decision process (Table 3). If the primary tumor tissue is old the likelihood of productive sequencing is lower, although age alone is not the only consideration and the methods of fixation may be just as relevant.
For prostate cancer in particular, the ability to successfully sequence primary tumor tissue decreases as the amount of tumor decreases in low-volume biopsies such as prostate needle biopsies. Generally, if tumor content is < 10% of the biopsy specimen, then sequencing is less likely to be productive.25 Also, if the alteration of interest is not known to be truncal, then a relevant target might be missed by sequencing tissue that does not reflect current biology. Metastasis biopsy may be the most appropriate tissue, particularly if this specimen has already been acquired. As above, a metastasis biopsy may have a higher tumor content, and it should reflect relevant biology if it is recent. However, bone biopsies have a relatively low yield for successful sequencing, so a soft tissue lesion (eg, liver or lymph node metastasis) is generally preferred.
The inability to safely access tissue is often a consideration. Proximity to vital structures such as large blood vessels or the potential for significant morbidity in the event of a complication (liver or lung biopsies, particularly in patients on anticoagulation medications) may make the risk/benefit ratio too high. The inability to conduct somatic testing has been reported to often be due to inadequate tissue sampling.26 ctDNA is an attractive alternative but should typically be drawn when a tumor is progressing with a reasonable tumor burden that is more likely to be shedding DNA. Performing ctDNA analysis in patients without obvious radiographic metastasis or in patients whose tumor is under good control is unlikely to produce interpretable results.
Interpreting the Results
The intent of sequencing tumor tissue is to identify alterations that are biologically important and may provide a point of therapeutic leverage. However, deciding which alterations are relevant is not always straightforward. For example, any normal individual genome contains around 10,000 missense variants, hundreds of insertion/deletion variants, and dozens of protein-truncating variants. Distinguishing these alterations, which are part of the individual, from those that are tumor-specific and have functional significance can be difficult in the absence of paired sequencing of both normal and tissue samples.
Specific Alterations
Although most commercial vendors provide important information in sequencing reports to assist oncology HCPs in deciding which alterations are relevant, the reports are not always clear. In many cases the report will specifically indicate whether the alteration has been reported previously as pathogenic or benign. However, some platforms will report alterations that are not known to be drivers of tumor biology. It is critical to be aware that if variants are not reported as pathogenic, they should not be assumed to be pathogenic simply because they are included in the report. Alterations more likely to be drivers of relevant biology are those that change gene and protein structure and include frameshift (fs*), nonsense (denoted by sequence ending in “X” or “*”), or specific fusions or insertions/deletions (indel) that occur in important domains of the gene.
For some genes, only specific alterations are targetable and not all alterations have the same effect on protein function. Although overexpression of certain genes and proteins are actionable (eg, HER2), amplification of a gene does not necessarily indicate that it is targetable. In NSCLC, specific alterations convey sensitivity to targeted therapies. For example, in EGFR-mutated NSCLC, the sensitizing mutations to EGFR TKIs are exon19 deletions and exon 21 L858R point mutations (the most common mutations), as well as less common mutations found in exon 18-21. Exon 20 mutations, however, are not responsive to EGFR TKIs with a few exceptions.27 Patients who have tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI. In a variety of solid tumors, gene fusions of the NTRK 1/2/3, act as oncogenic drivers. The chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and upstream amino-terminal partners lead to overexpression of the chimeric proteins tropomyosin receptor kinase (TRK) A/B/C, resulting in constitutively active, ligand-independent downstream signaling. In patients with NTRK 1/2/3 gene fusions, larotrectinib and entrectinib, small molecule inhibitors to TRK, have shown antitumor activity.28,29 No alterations beyond these fusions are known to be targetable.
Allele Fraction
Knowing the fraction (or proportion) of the alteration of interest in the sequenced tissue relative to the estimated tumor content can assist in decision making. Not all platforms will provide this information, which is referred to as mutation allele fraction (MAF) or variant allele fraction (VAF), but sometimes will provide it on request. Platforms will usually provide an estimate of the percent tumor in the tissue being sampled if it is from a biopsy. If the MAF is around 50% in the sequenced tissue (including ctDNA), then there is a reasonable chance that it is a germline variant. However, there are nuances as germline alterations in some genes, such as BRCA1/2, can be accompanied by loss of the other allele of the gene (LOH). In that case, if most of the circulating DNA is from tumor, then the MAF can be > 50%.
If there are 2 alterations of the same gene with MAF percentages that are each half of the total percent tumor, there is a high likelihood of biallelic alteration. These sorts of paired alterations or one mutation with apparent LOH or copy loss would again indicate a high likelihood that the alteration is in fact pathogenic and a relevant driver. Not all pathogenic alterations have to be biallelic to be driver mutations but in BRCA1/2, or mismatch repair deficiency genes, the presence of biallelic alterations increases the likelihood of their being pathogenic.
Tumors that are hypermutated—containing sometimes hundreds of mutations per megabyte of DNA—can be particularly complicated to interpret, because the likelihood increases that many of the alterations are a function of the hypermutation and not a driver mutation. This is particularly important when there are concurrent mutations in mismatch repair genes and genes, such as BRCA1/2. If the tumor is
Confounders
In some situations, interpretation can be particularly challenging. For example, several alterations for which there are FDA on-label indications (such as ATM or BRCA2) can be detected in ctDNA that may not be due to the tumor but to CHIP. CHIP represents hematopoietic clones that are dysplastic as a result of exposure to DNA-damaging agents (eg, platinum chemotherapy) or as a result of aging and arise when mutations in hematopoietic stem cells provide a competitive advantage.31 The most common CHIP clones that can be detected are DNMT3A, ASXL1, or TET2; because these alterations are not targetable, their importance lies primarily in whether patients have evidence of hematologic abnormality, which might represent an evolving hematopoietic disorder. Because CHIP alterations can overlap with somatic alterations for which FDA-approved drugs exist, such as ATM or CHEK2 (olaparib for prostate cancer) and BRCA2 (poly-ADP-ribose polymerase inhibitors in a range of indications) there is concern that CHIP might result in patient harm from inappropriate treatment of CHIP rather than the tumor, with no likelihood that the treatment would affect the tumor, causing treatment delays.32 General considerations for deciding whether an alteration represents CHIP include excluding alteration in which the VAF is < 1% and when the VAF in the alteration of interest is < 20% of the estimated tumor fraction in the sample. Exceptions to this are found in patients with true myelodysplasia or chronic lymphocytic leukemia, in whom the VAF can be well over 50% because of circulating tumor burden. The only way to be certain that an alteration detected on ctDNA reflects tumor rather than CHIP is to utilize an assay with matched tumor-normal sequencing.
Resources for Assistance
For oncology HCPs, perhaps the best resource to help in selecting and interpreting the appropriate testing is through a dedicated molecular oncology tumor board and subject matter experts who contribute to those tumor boards. In the US Department of Veterans Affairs, the national precision oncology program and its affiliated clinical services, such as the option to order a national consultation and molecular tumor board education, are easily accessible to all HCPs (www.cancer.va.gov). Many commercial vendors provide support to assist with questions of interpretation and to inform clinical decision-making. Other resources that can assist with deciding whether an alteration is pathogenic include extensive curated databases such as ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the Human Genetic Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) for germline alterations or COSMIC (cancer.sanger.ac.uk/cosmic) for somatic alterations. OncoKB (www.oncokb.org) is a resource for assistance in defining levels of evidence for the use of agents to target specific alterations and to assist in assigning pathogenicity to specific alterations. Additional educational resources for training in genomics and genetics are also included in the Appendix.
The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for men and women dealing with malignancy and our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.
Acknowledgments
Dedicated to Neil Spector.
1. Domchek SM, Mardis E, Carlisle JW, Owonikoko TK. Integrating genetic and genomic testing into oncology practice. Am Soc Clin Oncol Educ Book. 2020;40:e259-e263. doi:10.1200/EDBK_280607
2. Stoffel EM, Carethers JM. Current approaches to germline cancer genetic testing. Annu Rev Med. 2020;71:85-102. doi:10.1146/annurev-med-052318-101009
3. Lappalainen T, Scott AJ, Brandt M, Hall IM. Genomic analysis in the age of human genome sequencing. Cell. 2019;177(1):70-84. doi:10.1016/j.cell.2019.02.032
4. Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol. 2021;7(2):230-237. doi:10.1001/jamaoncol.2020.6252
5. Schneider BP, Stout L, Philips S, et al. Implications of incidental germline findings identified in the context of clinical whole exome sequencing for guiding cancer therapy. JCO Precis Oncol. 2020;4:1109-1121. doi:10.1200/PO.19.00354
6. National Comprehensive Cancer Network. Pancreatic cancer (Version 1.2022). Updated February 24, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
7. National Comprehensive Cancer Network. Prostate cancer (Version 3.2022). Updated January 10, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
8. National Comprehensive Cancer Network. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic (Version 2.2022). Updated March 9, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
9. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001
10. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144
11. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 2017;32(2):185-203.e13. doi:10.1016/j.ccell.2017.07.007
12. Clark DF, Maxwell KN, Powers J, et al. Identification and confirmation of potentially actionable germline mutations in tumor-only genomic sequencing. JCO Precis Oncol. 2019;3:PO.19.00076. doi:10.1200/PO.19.00076
13. DeLeonardis K, Hogan L, Cannistra SA, Rangachari D, Tung N. When should tumor genomic profiling prompt consideration of germline testing? J Oncol Pract. 2019;15(9):465-473. doi:10.1200/JOP.19.00201
14. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30
15. Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J Clin Oncol. 2019;37(4):286-295. doi:10.1200/JCO.18.00283
16. Lincoln SE, Nussbaum RL, Kurian AW, et al. Yield and utility of germline testing following tumor sequencing in patients with cancer. JAMA Netw Open. 2020;3(10):e2019452. doi:10.1001/jamanetworkopen.2020.19452
17. National Comprehensive Cancer Network. Non-small cell lung cancer (Version: 3.2022). Updated March 16, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
18. National Comprehensive Cancer Network. Colon cancer (Version 1.2022). February 25, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
19. National Comprehensive Cancer Network. Melanoma: cutaneous (Version 3.2022). April 11, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf
20. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725-737. doi:10.1038/s41416-019-0573-8
21. Zheng G, Lin MT, Lokhandwala PM, et al. Clinical mutational profiling of bone metastases of lung and colon carcinoma and malignant melanoma using next-generation sequencing. Cancer Cytopathol. 2016;124(10):744-753. doi:10.1002/cncy.21743
22. Spritzer CE, Afonso PD, Vinson EN, et al. Bone marrow biopsy: RNA isolation with expression profiling in men with metastatic castration-resistant prostate cancer—factors affecting diagnostic success. Radiology. 2013;269(3):816-823. doi:10.1148/radiol.13121782
23. Schweizer MT, Gulati R, Beightol M, et al. Clinical determinants for successful circulating tumor DNA analysis in prostate cancer. Prostate. 2019;79(7):701-708. doi:10.1002/pros.23778
24. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra224. doi:10.1126/scitranslmed.3007094
25. Pritchard CC, Salipante SJ, Koehler K, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. J Mol Diagn. 2014;16(1):56-67. doi:10.1016/j.jmoldx.2013.08.004
26. Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer. 2017;18(6):651-659. doi:10.1016/j.cllc.2017.04.004
27. Malapelle U, Pilotto S, Passiglia F, et al. Dealing with NSCLC EGFR mutation testing and treatment: a comprehensive review with an Italian real-world perspective. Crit Rev Oncol Hematol. 2021;160:103300. doi:10.1016/j.critrevonc.2021.103300
28. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448
29. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. doi:10.1016/S1470-2045(19)30691-6
30. Jonsson P, Bandlamudi C, Cheng ML, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019;571(7766):576-579. doi:10.1038/s41586-019-1382-1
31. Steensma DP. Clinical consequences of clonal hematopoiesis of indeterminate potential. Hematology Am Soc Hematol Educ Program. 2018;2018(1):264-269. doi:10.1182/asheducation-2018.1.264
32. Jensen K, Konnick EQ, Schweizer MT, et al. Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. JAMA Oncol. 2021;7(1):107-110. doi:10.1001/jamaoncol.2020.5161
1. Domchek SM, Mardis E, Carlisle JW, Owonikoko TK. Integrating genetic and genomic testing into oncology practice. Am Soc Clin Oncol Educ Book. 2020;40:e259-e263. doi:10.1200/EDBK_280607
2. Stoffel EM, Carethers JM. Current approaches to germline cancer genetic testing. Annu Rev Med. 2020;71:85-102. doi:10.1146/annurev-med-052318-101009
3. Lappalainen T, Scott AJ, Brandt M, Hall IM. Genomic analysis in the age of human genome sequencing. Cell. 2019;177(1):70-84. doi:10.1016/j.cell.2019.02.032
4. Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol. 2021;7(2):230-237. doi:10.1001/jamaoncol.2020.6252
5. Schneider BP, Stout L, Philips S, et al. Implications of incidental germline findings identified in the context of clinical whole exome sequencing for guiding cancer therapy. JCO Precis Oncol. 2020;4:1109-1121. doi:10.1200/PO.19.00354
6. National Comprehensive Cancer Network. Pancreatic cancer (Version 1.2022). Updated February 24, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
7. National Comprehensive Cancer Network. Prostate cancer (Version 3.2022). Updated January 10, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
8. National Comprehensive Cancer Network. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic (Version 2.2022). Updated March 9, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
9. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001
10. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144
11. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 2017;32(2):185-203.e13. doi:10.1016/j.ccell.2017.07.007
12. Clark DF, Maxwell KN, Powers J, et al. Identification and confirmation of potentially actionable germline mutations in tumor-only genomic sequencing. JCO Precis Oncol. 2019;3:PO.19.00076. doi:10.1200/PO.19.00076
13. DeLeonardis K, Hogan L, Cannistra SA, Rangachari D, Tung N. When should tumor genomic profiling prompt consideration of germline testing? J Oncol Pract. 2019;15(9):465-473. doi:10.1200/JOP.19.00201
14. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30
15. Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J Clin Oncol. 2019;37(4):286-295. doi:10.1200/JCO.18.00283
16. Lincoln SE, Nussbaum RL, Kurian AW, et al. Yield and utility of germline testing following tumor sequencing in patients with cancer. JAMA Netw Open. 2020;3(10):e2019452. doi:10.1001/jamanetworkopen.2020.19452
17. National Comprehensive Cancer Network. Non-small cell lung cancer (Version: 3.2022). Updated March 16, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
18. National Comprehensive Cancer Network. Colon cancer (Version 1.2022). February 25, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
19. National Comprehensive Cancer Network. Melanoma: cutaneous (Version 3.2022). April 11, 2022. Accessed April 13, 2022. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf
20. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725-737. doi:10.1038/s41416-019-0573-8
21. Zheng G, Lin MT, Lokhandwala PM, et al. Clinical mutational profiling of bone metastases of lung and colon carcinoma and malignant melanoma using next-generation sequencing. Cancer Cytopathol. 2016;124(10):744-753. doi:10.1002/cncy.21743
22. Spritzer CE, Afonso PD, Vinson EN, et al. Bone marrow biopsy: RNA isolation with expression profiling in men with metastatic castration-resistant prostate cancer—factors affecting diagnostic success. Radiology. 2013;269(3):816-823. doi:10.1148/radiol.13121782
23. Schweizer MT, Gulati R, Beightol M, et al. Clinical determinants for successful circulating tumor DNA analysis in prostate cancer. Prostate. 2019;79(7):701-708. doi:10.1002/pros.23778
24. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra224. doi:10.1126/scitranslmed.3007094
25. Pritchard CC, Salipante SJ, Koehler K, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. J Mol Diagn. 2014;16(1):56-67. doi:10.1016/j.jmoldx.2013.08.004
26. Gutierrez ME, Choi K, Lanman RB, et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer. 2017;18(6):651-659. doi:10.1016/j.cllc.2017.04.004
27. Malapelle U, Pilotto S, Passiglia F, et al. Dealing with NSCLC EGFR mutation testing and treatment: a comprehensive review with an Italian real-world perspective. Crit Rev Oncol Hematol. 2021;160:103300. doi:10.1016/j.critrevonc.2021.103300
28. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448
29. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. doi:10.1016/S1470-2045(19)30691-6
30. Jonsson P, Bandlamudi C, Cheng ML, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019;571(7766):576-579. doi:10.1038/s41586-019-1382-1
31. Steensma DP. Clinical consequences of clonal hematopoiesis of indeterminate potential. Hematology Am Soc Hematol Educ Program. 2018;2018(1):264-269. doi:10.1182/asheducation-2018.1.264
32. Jensen K, Konnick EQ, Schweizer MT, et al. Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. JAMA Oncol. 2021;7(1):107-110. doi:10.1001/jamaoncol.2020.5161
Applicability of the USPSTF Lung Cancer Screening Guidelines in a Predominantly Black Veteran Population
Lung cancer is the leading cause of cancer death in the United States.1 The 2011 National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography (LDCT) screening provided a 20% relative reduction in lung cancer–specific mortality.2 Based on these findings, the United States Preventive Services Task Force (USPSTF) published lung cancer screening guidelines in 2013 recommending an annual LDCT of the thorax in patients aged 55 to 80 years with a 30 pack-year smoking history and who currently smoke or quit within the past 15 years.
In 2021, the USPSTF updated its recommendations by reducing the qualifications for annual screening to a 20 pack-year smoking history.3 The updated guidelines recognized the increased risk of lung cancer for Black individuals.4,5 Evidence suggests the 2013 screening criteria was too conservative for this population.6,7
Similarly, US Department of Veteran Affairs (VA) patients are a population at higher risk for lung cancer due to a male predominance, presence of comorbidities, exposure to carcinogenic agents, and possibly a higher prevalence of tobacco smoking.8 This study sought to examine the applicability of the USPSTF guidelines in a VA health care system with a predominantly Black population.
Methods
A retrospective chart review of adult patients who were diagnosed and treated with early-stage small cell or non–small cell lung cancer (stage I or II) was performed within the Southeast Louisiana Veterans Health Care System (SLVHCS) in New Orleans. The review used data from the VA Cancer Registry from January 1, 2005, through December 31, 2017. Patients were grouped by whether they met 2013 USPSTF screening criteria at time of diagnosis vs those that did not. Data collected included type and stage of lung cancer at time of diagnosis, context of diagnosis (incidental, screening, symptomatic), diagnostic method, smoking history, and presence of chronic obstructive pulmonary disease (COPD). Patients without a clear smoking history documented in the health record were excluded.
Statistical analyses were performed with GraphPad Prism 8.0. Student t test and Fischer exact test were performed for most of the statistical analyses, with differences between groups noted to be statistically significant at a P < .05.
Results
A total of 182 patient charts were reviewed and 13 patients were excluded for missing information related to the USPSTF screening criteria. Of the 169 patients included, 122 (72%) met USPSTF screening criteria while 47 (28%) patients did not. The reasons for not meeting screening criteria were 14 patients were too young at and 9 patients were too old at time of diagnosis, 7 had a < 20 pack-year smoking history, 7 patients had quit > 15 years previously, and 12 patients met multiple exclusion criteria. The study population was 96% male and there was an overall predominance of Black patients (58%) within the sample (Table).
There was a significantly higher proportion of Black patients in the group that did not meet screening criteria compared with the group that met screening criteria (68% vs 54%, P = .04). Cancer type and stage at diagnosis were similar in both patient populations. There was a statistically significant difference in COPD diagnosis between the groups, with a larger proportion of COPD patients in the met screening criteria group (74% vs 45%, P < .001). The mean smoking history was 61.4 pack-years in the met criteria group and 43.3 pack-years in the did not meet criteria group.
Five additional patients in the group that did not meet the 2013 USPSTF screening criteria would have met criteria if the 2021 USPSTF guidelines were applied. All 5 were Black patients. Using the 2021 guidelines, Black patients would have made up 56% of the patients who met screening criteria and 54% of the patients who did not meet screening criteria at time of diagnosis.
Discussion
This study sought to determine the hypothetical effectiveness of national lung cancer screening guidelines in detecting early-stage lung cancer for a high-risk population. Patients diagnosed with early-stage lung cancer were selected as these patients have improved outcomes with treatment, and thus would theoretically benefit from early detection through screening. As expected, the study population had a majority of Black veterans (58%), with a higher proportion of Black patients in the did not meet screening criteria group compared with the met screening criteria group (68% vs 54%, P = .04). This difference highlights the concern that Black individuals were being underscreened with the 2013 USPSTF guidelines.7 This is not all surprising as the NLST, from which the initial screening guidelines were based, included a majority White population with only 4.4% of their population being Black.2 The USPSTF also cites the NELSON trial as evidence to support annual lung cancer screening, a trial that was performed in the Netherlands with a very different population compared with that of southeast Louisiana.9
Given concern that the old criteria were underscreening certain populations, the updated 2021 USPSTF guidelines sought to expand the screening population. In this study, the implementation of these new guidelines resulted in more Black patients meeting screening criteria.
Racial and ethnic disparities in health care in the US are no secret, as Black individuals consistently have increased disease and death rates, higher rates of unemployment, and decreased access to preventive medical care compared to White individuals.10 Despite the updated USPSTF guidelines, additional modifications to the screening criteria could improve the ability to identify high-risk patients. A modified model using data from the Prostate, Lung, Colorectal, and Ovarian Screening Trial (PLCO) incorporating COPD history, race and ethnicity, and personal history of cancer increased the sensitivity for high-risk Black ever-smokers.11 Additional models and analyses also support the utility of incorporating race and ethnicity in lung cancer screening criteria.7,12 Using race and ethnicity to guide screening criteria for cancer is not unheard of; in 2017, the US Multi-Society Task Force recommended that Black individuals start colon cancer screening at age 45 years rather than the typical age of 50 years, before updating the guidelines again in 2021 to recommend that all adults start at age 45 years.13,14
Limitations
This study had the inherent weakness of being a retrospective study at a single institution. Additionally, the 7th edition of the International Association for the Study of Lung Cancer was published in 2010, during the 2005 to 2017 time frame from which our data was collected, leading to possible inconsistencies in staging between patients before and after 2010.15 However, these changes in staging are unlikely to significantly impact the results for in this study, since the vast majority of the patients diagnosed with lung cancer stage I or II before 2010 would still be in the those 2 stages in the 2010 edition. Finally, specific to our patient population, it was often difficult to ascertain an accurate smoking history for each patient, especially in the early years of the data set, likely due to the disruption of care caused by Hurricane Katrina.
Conclusions
In this retrospective study performed at the SLVHCS in New Orleans, a significantly higher proportion of Black patients compared with White patients with early-stage lung cancer did not meet the 2013 USPSTF lung cancer screening guidelines at time of diagnosis, highlighting the concern that this population was being underscreened. These findings demonstrate the challenges and failures of applying national guidelines to a unique, high-risk population. An individualized, risk-based screening model incorporating race and ethnicity could be more effective at diagnosing early-stage lung cancer and requires more investigation. Centralized lung cancer screening programs within the VA system could also be beneficial for early detection and treatment, as well as provide insight into the increased risk within the veteran population.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7-30. doi:10.3322/caac.21590
2. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa110287
3. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for lung cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(10):962-970. doi:10.1001/jama.2021.1117
4. Jonas DE, Reuland DS, Reddy SM, et al. Screening for lung cancer with low-dose computed tomography: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2021;325(10):971-987. doi:10.1001/jama.2021.0377
5. Haiman CA, Stram DO, Wilkens LR, et al. Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med. 2006;354(4):333-342. doi:10.1056/NEJMoa033250
6. DeSantis CE, Miller KD, Goding Sauer A, Jemal A, Siegel RL. Cancer statistics for African Americans, 2019. CA Cancer J Clin. 2019;69(3):211-233. doi:10.3322/caac.21555
7. Aldrich MC, Mercaldo SF, Sandler KL, Blot WJ, Grogan EL, Blume JD. Evaluation of USPSTF Lung Cancer Screening Guidelines among African American adult smokers. JAMA Oncol. 2019;5(9):1318-1324. doi:10.1001/jamaoncol.2019.1402
8. Brown DW. Smoking prevalence among US veterans. J Gen Intern Med. 2010;25(2):147-149. doi:10.1007/s11606-009-1160-0
9. de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020;382(6):503-513. doi:10.1056/NEJMoa1911793
10. Williams DR, Rucker TD. Understanding and addressing racial disparities in health care. Health Care Financ Rev. 2000;21(4):75-90.
11. Pasquinelli MM, Tammemägi MC, Kovitz KL, et al. Risk prediction model versus United States Preventive Services Task Force lung cancer screening eligibility criteria: reducing race disparities. J Thorac Oncol. 2020;15(11):1738-1747. doi:10.1016/j.jtho.2020.08.006
12. Ten Haaf K, Bastani M, Cao P, et al. A comparative modeling analysis of risk-based lung cancer screening strategies. J Natl Cancer Inst. 2020;112(5):466-479. doi:10.1093/jnci/djz164
13. Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and patients from the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;153(1):307-323. doi:10.1053/j.gastro.2017.05.013
14. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238
15. Mirsadraee S, Oswal D, Alizadeh Y, Caulo A, van Beek E Jr. The 7th lung cancer TNM classification and staging system: review of the changes and implications. World J Radiol. 2012;4(4):128-134. doi:10.4329/wjr.v4.i4.128
Lung cancer is the leading cause of cancer death in the United States.1 The 2011 National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography (LDCT) screening provided a 20% relative reduction in lung cancer–specific mortality.2 Based on these findings, the United States Preventive Services Task Force (USPSTF) published lung cancer screening guidelines in 2013 recommending an annual LDCT of the thorax in patients aged 55 to 80 years with a 30 pack-year smoking history and who currently smoke or quit within the past 15 years.
In 2021, the USPSTF updated its recommendations by reducing the qualifications for annual screening to a 20 pack-year smoking history.3 The updated guidelines recognized the increased risk of lung cancer for Black individuals.4,5 Evidence suggests the 2013 screening criteria was too conservative for this population.6,7
Similarly, US Department of Veteran Affairs (VA) patients are a population at higher risk for lung cancer due to a male predominance, presence of comorbidities, exposure to carcinogenic agents, and possibly a higher prevalence of tobacco smoking.8 This study sought to examine the applicability of the USPSTF guidelines in a VA health care system with a predominantly Black population.
Methods
A retrospective chart review of adult patients who were diagnosed and treated with early-stage small cell or non–small cell lung cancer (stage I or II) was performed within the Southeast Louisiana Veterans Health Care System (SLVHCS) in New Orleans. The review used data from the VA Cancer Registry from January 1, 2005, through December 31, 2017. Patients were grouped by whether they met 2013 USPSTF screening criteria at time of diagnosis vs those that did not. Data collected included type and stage of lung cancer at time of diagnosis, context of diagnosis (incidental, screening, symptomatic), diagnostic method, smoking history, and presence of chronic obstructive pulmonary disease (COPD). Patients without a clear smoking history documented in the health record were excluded.
Statistical analyses were performed with GraphPad Prism 8.0. Student t test and Fischer exact test were performed for most of the statistical analyses, with differences between groups noted to be statistically significant at a P < .05.
Results
A total of 182 patient charts were reviewed and 13 patients were excluded for missing information related to the USPSTF screening criteria. Of the 169 patients included, 122 (72%) met USPSTF screening criteria while 47 (28%) patients did not. The reasons for not meeting screening criteria were 14 patients were too young at and 9 patients were too old at time of diagnosis, 7 had a < 20 pack-year smoking history, 7 patients had quit > 15 years previously, and 12 patients met multiple exclusion criteria. The study population was 96% male and there was an overall predominance of Black patients (58%) within the sample (Table).
There was a significantly higher proportion of Black patients in the group that did not meet screening criteria compared with the group that met screening criteria (68% vs 54%, P = .04). Cancer type and stage at diagnosis were similar in both patient populations. There was a statistically significant difference in COPD diagnosis between the groups, with a larger proportion of COPD patients in the met screening criteria group (74% vs 45%, P < .001). The mean smoking history was 61.4 pack-years in the met criteria group and 43.3 pack-years in the did not meet criteria group.
Five additional patients in the group that did not meet the 2013 USPSTF screening criteria would have met criteria if the 2021 USPSTF guidelines were applied. All 5 were Black patients. Using the 2021 guidelines, Black patients would have made up 56% of the patients who met screening criteria and 54% of the patients who did not meet screening criteria at time of diagnosis.
Discussion
This study sought to determine the hypothetical effectiveness of national lung cancer screening guidelines in detecting early-stage lung cancer for a high-risk population. Patients diagnosed with early-stage lung cancer were selected as these patients have improved outcomes with treatment, and thus would theoretically benefit from early detection through screening. As expected, the study population had a majority of Black veterans (58%), with a higher proportion of Black patients in the did not meet screening criteria group compared with the met screening criteria group (68% vs 54%, P = .04). This difference highlights the concern that Black individuals were being underscreened with the 2013 USPSTF guidelines.7 This is not all surprising as the NLST, from which the initial screening guidelines were based, included a majority White population with only 4.4% of their population being Black.2 The USPSTF also cites the NELSON trial as evidence to support annual lung cancer screening, a trial that was performed in the Netherlands with a very different population compared with that of southeast Louisiana.9
Given concern that the old criteria were underscreening certain populations, the updated 2021 USPSTF guidelines sought to expand the screening population. In this study, the implementation of these new guidelines resulted in more Black patients meeting screening criteria.
Racial and ethnic disparities in health care in the US are no secret, as Black individuals consistently have increased disease and death rates, higher rates of unemployment, and decreased access to preventive medical care compared to White individuals.10 Despite the updated USPSTF guidelines, additional modifications to the screening criteria could improve the ability to identify high-risk patients. A modified model using data from the Prostate, Lung, Colorectal, and Ovarian Screening Trial (PLCO) incorporating COPD history, race and ethnicity, and personal history of cancer increased the sensitivity for high-risk Black ever-smokers.11 Additional models and analyses also support the utility of incorporating race and ethnicity in lung cancer screening criteria.7,12 Using race and ethnicity to guide screening criteria for cancer is not unheard of; in 2017, the US Multi-Society Task Force recommended that Black individuals start colon cancer screening at age 45 years rather than the typical age of 50 years, before updating the guidelines again in 2021 to recommend that all adults start at age 45 years.13,14
Limitations
This study had the inherent weakness of being a retrospective study at a single institution. Additionally, the 7th edition of the International Association for the Study of Lung Cancer was published in 2010, during the 2005 to 2017 time frame from which our data was collected, leading to possible inconsistencies in staging between patients before and after 2010.15 However, these changes in staging are unlikely to significantly impact the results for in this study, since the vast majority of the patients diagnosed with lung cancer stage I or II before 2010 would still be in the those 2 stages in the 2010 edition. Finally, specific to our patient population, it was often difficult to ascertain an accurate smoking history for each patient, especially in the early years of the data set, likely due to the disruption of care caused by Hurricane Katrina.
Conclusions
In this retrospective study performed at the SLVHCS in New Orleans, a significantly higher proportion of Black patients compared with White patients with early-stage lung cancer did not meet the 2013 USPSTF lung cancer screening guidelines at time of diagnosis, highlighting the concern that this population was being underscreened. These findings demonstrate the challenges and failures of applying national guidelines to a unique, high-risk population. An individualized, risk-based screening model incorporating race and ethnicity could be more effective at diagnosing early-stage lung cancer and requires more investigation. Centralized lung cancer screening programs within the VA system could also be beneficial for early detection and treatment, as well as provide insight into the increased risk within the veteran population.
Lung cancer is the leading cause of cancer death in the United States.1 The 2011 National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography (LDCT) screening provided a 20% relative reduction in lung cancer–specific mortality.2 Based on these findings, the United States Preventive Services Task Force (USPSTF) published lung cancer screening guidelines in 2013 recommending an annual LDCT of the thorax in patients aged 55 to 80 years with a 30 pack-year smoking history and who currently smoke or quit within the past 15 years.
In 2021, the USPSTF updated its recommendations by reducing the qualifications for annual screening to a 20 pack-year smoking history.3 The updated guidelines recognized the increased risk of lung cancer for Black individuals.4,5 Evidence suggests the 2013 screening criteria was too conservative for this population.6,7
Similarly, US Department of Veteran Affairs (VA) patients are a population at higher risk for lung cancer due to a male predominance, presence of comorbidities, exposure to carcinogenic agents, and possibly a higher prevalence of tobacco smoking.8 This study sought to examine the applicability of the USPSTF guidelines in a VA health care system with a predominantly Black population.
Methods
A retrospective chart review of adult patients who were diagnosed and treated with early-stage small cell or non–small cell lung cancer (stage I or II) was performed within the Southeast Louisiana Veterans Health Care System (SLVHCS) in New Orleans. The review used data from the VA Cancer Registry from January 1, 2005, through December 31, 2017. Patients were grouped by whether they met 2013 USPSTF screening criteria at time of diagnosis vs those that did not. Data collected included type and stage of lung cancer at time of diagnosis, context of diagnosis (incidental, screening, symptomatic), diagnostic method, smoking history, and presence of chronic obstructive pulmonary disease (COPD). Patients without a clear smoking history documented in the health record were excluded.
Statistical analyses were performed with GraphPad Prism 8.0. Student t test and Fischer exact test were performed for most of the statistical analyses, with differences between groups noted to be statistically significant at a P < .05.
Results
A total of 182 patient charts were reviewed and 13 patients were excluded for missing information related to the USPSTF screening criteria. Of the 169 patients included, 122 (72%) met USPSTF screening criteria while 47 (28%) patients did not. The reasons for not meeting screening criteria were 14 patients were too young at and 9 patients were too old at time of diagnosis, 7 had a < 20 pack-year smoking history, 7 patients had quit > 15 years previously, and 12 patients met multiple exclusion criteria. The study population was 96% male and there was an overall predominance of Black patients (58%) within the sample (Table).
There was a significantly higher proportion of Black patients in the group that did not meet screening criteria compared with the group that met screening criteria (68% vs 54%, P = .04). Cancer type and stage at diagnosis were similar in both patient populations. There was a statistically significant difference in COPD diagnosis between the groups, with a larger proportion of COPD patients in the met screening criteria group (74% vs 45%, P < .001). The mean smoking history was 61.4 pack-years in the met criteria group and 43.3 pack-years in the did not meet criteria group.
Five additional patients in the group that did not meet the 2013 USPSTF screening criteria would have met criteria if the 2021 USPSTF guidelines were applied. All 5 were Black patients. Using the 2021 guidelines, Black patients would have made up 56% of the patients who met screening criteria and 54% of the patients who did not meet screening criteria at time of diagnosis.
Discussion
This study sought to determine the hypothetical effectiveness of national lung cancer screening guidelines in detecting early-stage lung cancer for a high-risk population. Patients diagnosed with early-stage lung cancer were selected as these patients have improved outcomes with treatment, and thus would theoretically benefit from early detection through screening. As expected, the study population had a majority of Black veterans (58%), with a higher proportion of Black patients in the did not meet screening criteria group compared with the met screening criteria group (68% vs 54%, P = .04). This difference highlights the concern that Black individuals were being underscreened with the 2013 USPSTF guidelines.7 This is not all surprising as the NLST, from which the initial screening guidelines were based, included a majority White population with only 4.4% of their population being Black.2 The USPSTF also cites the NELSON trial as evidence to support annual lung cancer screening, a trial that was performed in the Netherlands with a very different population compared with that of southeast Louisiana.9
Given concern that the old criteria were underscreening certain populations, the updated 2021 USPSTF guidelines sought to expand the screening population. In this study, the implementation of these new guidelines resulted in more Black patients meeting screening criteria.
Racial and ethnic disparities in health care in the US are no secret, as Black individuals consistently have increased disease and death rates, higher rates of unemployment, and decreased access to preventive medical care compared to White individuals.10 Despite the updated USPSTF guidelines, additional modifications to the screening criteria could improve the ability to identify high-risk patients. A modified model using data from the Prostate, Lung, Colorectal, and Ovarian Screening Trial (PLCO) incorporating COPD history, race and ethnicity, and personal history of cancer increased the sensitivity for high-risk Black ever-smokers.11 Additional models and analyses also support the utility of incorporating race and ethnicity in lung cancer screening criteria.7,12 Using race and ethnicity to guide screening criteria for cancer is not unheard of; in 2017, the US Multi-Society Task Force recommended that Black individuals start colon cancer screening at age 45 years rather than the typical age of 50 years, before updating the guidelines again in 2021 to recommend that all adults start at age 45 years.13,14
Limitations
This study had the inherent weakness of being a retrospective study at a single institution. Additionally, the 7th edition of the International Association for the Study of Lung Cancer was published in 2010, during the 2005 to 2017 time frame from which our data was collected, leading to possible inconsistencies in staging between patients before and after 2010.15 However, these changes in staging are unlikely to significantly impact the results for in this study, since the vast majority of the patients diagnosed with lung cancer stage I or II before 2010 would still be in the those 2 stages in the 2010 edition. Finally, specific to our patient population, it was often difficult to ascertain an accurate smoking history for each patient, especially in the early years of the data set, likely due to the disruption of care caused by Hurricane Katrina.
Conclusions
In this retrospective study performed at the SLVHCS in New Orleans, a significantly higher proportion of Black patients compared with White patients with early-stage lung cancer did not meet the 2013 USPSTF lung cancer screening guidelines at time of diagnosis, highlighting the concern that this population was being underscreened. These findings demonstrate the challenges and failures of applying national guidelines to a unique, high-risk population. An individualized, risk-based screening model incorporating race and ethnicity could be more effective at diagnosing early-stage lung cancer and requires more investigation. Centralized lung cancer screening programs within the VA system could also be beneficial for early detection and treatment, as well as provide insight into the increased risk within the veteran population.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7-30. doi:10.3322/caac.21590
2. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa110287
3. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for lung cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(10):962-970. doi:10.1001/jama.2021.1117
4. Jonas DE, Reuland DS, Reddy SM, et al. Screening for lung cancer with low-dose computed tomography: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2021;325(10):971-987. doi:10.1001/jama.2021.0377
5. Haiman CA, Stram DO, Wilkens LR, et al. Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med. 2006;354(4):333-342. doi:10.1056/NEJMoa033250
6. DeSantis CE, Miller KD, Goding Sauer A, Jemal A, Siegel RL. Cancer statistics for African Americans, 2019. CA Cancer J Clin. 2019;69(3):211-233. doi:10.3322/caac.21555
7. Aldrich MC, Mercaldo SF, Sandler KL, Blot WJ, Grogan EL, Blume JD. Evaluation of USPSTF Lung Cancer Screening Guidelines among African American adult smokers. JAMA Oncol. 2019;5(9):1318-1324. doi:10.1001/jamaoncol.2019.1402
8. Brown DW. Smoking prevalence among US veterans. J Gen Intern Med. 2010;25(2):147-149. doi:10.1007/s11606-009-1160-0
9. de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020;382(6):503-513. doi:10.1056/NEJMoa1911793
10. Williams DR, Rucker TD. Understanding and addressing racial disparities in health care. Health Care Financ Rev. 2000;21(4):75-90.
11. Pasquinelli MM, Tammemägi MC, Kovitz KL, et al. Risk prediction model versus United States Preventive Services Task Force lung cancer screening eligibility criteria: reducing race disparities. J Thorac Oncol. 2020;15(11):1738-1747. doi:10.1016/j.jtho.2020.08.006
12. Ten Haaf K, Bastani M, Cao P, et al. A comparative modeling analysis of risk-based lung cancer screening strategies. J Natl Cancer Inst. 2020;112(5):466-479. doi:10.1093/jnci/djz164
13. Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and patients from the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;153(1):307-323. doi:10.1053/j.gastro.2017.05.013
14. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238
15. Mirsadraee S, Oswal D, Alizadeh Y, Caulo A, van Beek E Jr. The 7th lung cancer TNM classification and staging system: review of the changes and implications. World J Radiol. 2012;4(4):128-134. doi:10.4329/wjr.v4.i4.128
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7-30. doi:10.3322/caac.21590
2. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa110287
3. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for lung cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(10):962-970. doi:10.1001/jama.2021.1117
4. Jonas DE, Reuland DS, Reddy SM, et al. Screening for lung cancer with low-dose computed tomography: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2021;325(10):971-987. doi:10.1001/jama.2021.0377
5. Haiman CA, Stram DO, Wilkens LR, et al. Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med. 2006;354(4):333-342. doi:10.1056/NEJMoa033250
6. DeSantis CE, Miller KD, Goding Sauer A, Jemal A, Siegel RL. Cancer statistics for African Americans, 2019. CA Cancer J Clin. 2019;69(3):211-233. doi:10.3322/caac.21555
7. Aldrich MC, Mercaldo SF, Sandler KL, Blot WJ, Grogan EL, Blume JD. Evaluation of USPSTF Lung Cancer Screening Guidelines among African American adult smokers. JAMA Oncol. 2019;5(9):1318-1324. doi:10.1001/jamaoncol.2019.1402
8. Brown DW. Smoking prevalence among US veterans. J Gen Intern Med. 2010;25(2):147-149. doi:10.1007/s11606-009-1160-0
9. de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020;382(6):503-513. doi:10.1056/NEJMoa1911793
10. Williams DR, Rucker TD. Understanding and addressing racial disparities in health care. Health Care Financ Rev. 2000;21(4):75-90.
11. Pasquinelli MM, Tammemägi MC, Kovitz KL, et al. Risk prediction model versus United States Preventive Services Task Force lung cancer screening eligibility criteria: reducing race disparities. J Thorac Oncol. 2020;15(11):1738-1747. doi:10.1016/j.jtho.2020.08.006
12. Ten Haaf K, Bastani M, Cao P, et al. A comparative modeling analysis of risk-based lung cancer screening strategies. J Natl Cancer Inst. 2020;112(5):466-479. doi:10.1093/jnci/djz164
13. Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and patients from the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;153(1):307-323. doi:10.1053/j.gastro.2017.05.013
14. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238
15. Mirsadraee S, Oswal D, Alizadeh Y, Caulo A, van Beek E Jr. The 7th lung cancer TNM classification and staging system: review of the changes and implications. World J Radiol. 2012;4(4):128-134. doi:10.4329/wjr.v4.i4.128
Leiomyosarcoma of the Penis: A Case Report and Re-Appraisal
Penile cancer is rare with a worldwide incidence of 0.8 cases per 100,000 men.1 The most common type is squamous cell carcinoma (SCC) followed by soft tissue sarcoma (STS) and Kaposi sarcoma.2 Leiomyosarcoma (LMS) is the second most common STS subtype at this location.3 Approximately 50 cases of penile LMS have been reported in the English literature, most as isolated case reports while Fetsch and colleagues reported 14 cases from a single institute.4 We present a case of penile LMS with a review of 31 cases. We also describe presentation, treatment options, and recurrence pattern of this rare malignancy.
Case Presentation
A patient aged 70 years presented to the urology clinic with 1-year history of a slowly enlarging penile mass associated with phimosis. He reported no pain, dysuria, or hesitancy. On examination a 2 × 2-cm smooth, mobile, nonulcerating mass was seen on the tip of his left glans without inguinal lymphadenopathy. He underwent circumcision and excision biopsy that revealed an encapsulated tan-white mass measuring 3 × 2.2 × 1.5 cm under the surface of the foreskin. Histology showed a spindle cell tumor with areas of increased cellularity, prominent atypia, and pleomorphism, focal necrosis, and scattered mitoses, including atypical forms. The tumor stained positive for smooth muscle actin and desmin. Ki-67 staining showed foci with a very high proliferation index (Figure). Resection margins were negative. Final Fédération Nationale des Centres de Lutte Contre Le Cancer score was grade 2 (differentiation, 1; mitotic, 3; necrosis, 1). Computed tomography of the chest, abdomen, and pelvis did not show evidence of metastasis. The tumor was classified as superficial, stage IIA (pT1cN0cM0). Local excision with negative margins was deemed adequate treatment.
Discussion
Penile LMS is rare and arises from smooth muscles, which in the penis can be from dartos fascia, erector pili in the skin covering the shaft, or from tunica media of the superficial vessels and cavernosa.5 It commonly presents as a nodule or ulcer that might be accompanied by paraphimosis, phimosis, erectile dysfunction, and lower urinary tract symptoms depending on the extent of local tissue involvement. In our review of 31 cases, the age at presentation ranged from 38 to 85 years, with 1 case report of LMS in a 6-year-old. The highest incidence was in the 6th decade. Tumor behavior can be indolent or aggressive. Most patients in our review had asymptomatic, slow-growing lesions for 6 to 24 months before presentation—including our patient—while others had an aggressive tumor with symptoms for a few weeks followed by rapid metastatic spread.6,7
Histology and Staging
Diagnosis requires biopsy followed by histologic examination and immunohistochemistry of the lesion. Typically, LMS shows fascicles of spindle cells with varying degrees of nuclear atypia, pleomorphisms, and necrotic regions. Mitotic rate is variable and usually > 5 per high power field. Cells stain positive for smooth muscle actin, desmin, and h-caldesmon.8 TNM (tumor, nodes, metastasis) stage is determined by the American Joint Committee on Cancer guidelines for STS.
Pratt and colleagues were the first to categorize penile LMS as superficial or deep.9 The former includes all lesions superficial to tunica albuginea while the latter run deep to this layer. Anatomical distinction is an important factor in tumor behavior, treatment selection, and prognosis. In our review, we found 14 cases of superficial and 17 cases of deep LMS.
Treatment
There are no established guidelines on optimum treatment of penile LMS. However, we can extrapolate principles from current guidelines on penile cancer, cutaneous leiomyosarcoma, and limb sarcomas. At present, the first-line treatment for superficial penile LMS is wide local excision to achieve negative margins. Circumcision alone might be sufficient for tumors of the distal prepuce, as in our case.10 Radical resection generally is not required for these early-stage tumors. In our review, no patient in this category developed recurrence or metastasis regardless of initial surgery type (Table 1).6,11,12
For deep lesions, partial—if functional penile stump and negative margins can be achieved—or total penectomy is required.10 In our review, more conservative approaches to deep tumors were associated with local recurrences.7,13,14 Lymphatic spread is rare for LMS. Additionally, involvement of local lymph nodes usually coincides with distant spread. Inguinal lymph node dissection is not indicated if initial negative surgical margins are achieved.
For STS at other sites in the body, radiation therapy is recommended postoperatively for high-grade lesions, which can be extrapolated to penile LMS as well. The benefit of preoperative radiation therapy is less certain. In limb sarcomas, radiation is associated with better local control for large-sized tumors and is used for patients with initial unresectable tumors.15 Similar recommendation could be extended to penile LMS with local spread to inguinal lymph nodes, scrotum, or abdominal wall. In our review, postoperative radiation therapy was used in 3 patients with deep tumors.16-18 Of these, short-term relapse occurred in 1 patient.
Chemotherapy for LMS remains controversial. The tumor generally is resistant to chemotherapy and systemic therapy, if employed, is for palliative purpose. The most promising results for adjuvant chemotherapy for resectable STS is seen in limb and uterine sarcomas with high-grade, metastatic, or relapsed tumors but improvement in overall survival has been marginal.19,20Single and multidrug regimens based on doxorubicin, ifosfamide, and gemcitabine have been studied with results showing no efficacy or a slight benefit.8,21 Immunotherapy and targeted therapy for penile STS have not been studied. In our review, postoperative chemotherapy was used for 2 patients with deep tumors and 1 patient with a superficial tumor while preoperative chemotherapy was used for 1 patient.16,18,22 Short-term relapse was seen in 2 of 4 of these patients (Table 2).
Metastatic Disease
LMS tends to metastasize hematogenously and lymphatic spread is uncommon. In our review, 7 patients developed metastasis. These patients had deep tumors at presentation with tumor size > 3 cm. Five of 7 patients had involvement of corpora cavernosa at presentation. The lung was the most common site of metastasis, followed by local extension to lower abdominal wall and scrotum. Of the 7 patients, 3 were treated with initial limited excision or partial penectomy and then experienced local recurrence or distant metastasis.7,13,14,23 This supports the use of radical surgery in large, deep tumors. In an additional 4 cases, metastasis occurred despite initial treatment with total penectomy and use of adjuvant chemoradiation therapy.
In most cases penile LMS is a de novo tumor, however, on occasion it could be accompanied by another epithelial malignancy. Similarly, penile LMS might be a site of recurrence for a primary LMS at another site, as seen in 3 of the reviewed cases. In the first, a patient presented with a nodule on the glans suspicious for SCC, second with synchronous SCC and LMS, and a third case where a patient presented with penile LMS 9 years after being treated for similar tumor in the epididymis.17,24,25
Prognosis
Penile LMS prognosis is difficult to ascertain because reported cases are rare. In our review, the longest documented disease-free survival was 3.5 years for a patient with superficial LMS treated with local excision.26 In cases of distant metastasis, average survival was 4.6 months, while the longest survival since initial presentation and last documented local recurrence was 16 years.14 Five-year survival has not been reported.
Conclusions
LMS of the penis is a rare and potentially aggressive malignancy. It can be classified as superficial or deep based on tumor relation to the tunica albuginea. Deep tumors, those > 3 cm, high-grade lesions, and tumors with involvement of corpora cavernosa, tend to spread locally, metastasize to distant areas, and require more radical surgery with or without postoperative radiation therapy. In comparison, superficial lesions can be treated with local excision only. Both superficial and deep tumors require close follow-up.
1. Montes Cardona CE, García-Perdomo HA. Incidence of penile cancer worldwide: systematic review and meta-analysis. Rev Panam Salud Publica. 2017;41:e117. Published 2017 Nov 30. doi:10.26633/RPSP.2017.117
2. Volker HU, Zettl A, Haralambieva E, et al. Leiomyosarcoma of the larynx as a local relapse of squamous cell carcinoma—report of an unusual case. Head Neck. 2010;32(5):679-683. doi:10.1002/hed.21127
3. Wollina U, Steinbach F, Verma S, et al. Penile tumours: a review. J Eur Acad Dermatol Venereol. 2014;28(10):1267-1276. doi:10.1111/jdv.12491
4. Fetsch JF, Davis CJ Jr, Miettinen M, Sesterhenn IA. Leiomyosarcoma of the penis: a clinicopathologic study of 14 cases with review of the literature and discussion of the differential diagnosis. Am J Surg Pathol. 2004;28(1):115-125. doi:10.1097/00000478-200401000-00014
5. Sundersingh S, Majhi U, Narayanaswamy K, Balasubramanian S. Primary leiomyosarcoma of the penis. Indian J Pathol Microbiol. 2009;52(3):447-448. doi:10.4103/0377-4929.55028
6. Mendis D, Bott SR, Davies JH. Subcutaneous leiomyosarcoma of the frenulum. Scientific World J. 2005;5:571-575. doi:10.1100/tsw.2005.76
7. Elem B, Nieslanik J. Leiomyosarcoma of the penis. Br J Urol. 1979;51(1):46. doi:10.1111/j.1464-410x.1979.tb04244.x
8. Serrano C, George S. Leiomyosarcoma. Hematol Oncol Clin North Am. 2013;27(5):957-974. doi:10.1016/j.hoc.2013.07.002
9. Pratt RM, Ross RT. Leiomyosarcoma of the penis. A report of a case. Br J Surg. 1969;56(11):870-872. doi:10.1002/bjs.1800561122
10. National Comprehensive Cancer Network. Penile cancer. NCCN evidence blocks. Version 2.2022 Updated January 26, 2022. Accessed March 16, 2022. https://www.nccn.org/professionals/physician_gls/pdf/penile_blocks.pdf
11. Ashley DJ, Edwards EC. Sarcoma of the penis; leiomyosarcoma of the penis: report of a case with a review of the literature on sarcoma of the penis. Br J Surg. 1957;45(190):170-179. doi:10.1002/bjs.18004519011
12. Pow-Sang MR, Orihuela E. Leiomyosarcoma of the penis. J Urol. 1994;151(6):1643-1645. doi:10.1016/s0022-5347(17)35328-413. Isa SS, Almaraz R, Magovern J. Leiomyosarcoma of the penis. Case report and review of the literature. Cancer. 1984;54(5):939-942. doi:10.1002/1097-0142(19840901)54:5<939::aid-cncr2820540533>3.0.co;2-y
14. Hutcheson JB, Wittaker WW, Fronstin MH. Leiomyosarcoma of the penis: case report and review of literature. J Urol. 1969;101(6):874-875. doi:10.1016/s0022-5347(17)62446-7
15. Grimer R, Judson I, Peake D, et al. Guidelines for the management of soft tissue sarcomas. Sarcoma. 2010;2010:506182. doi:10.1155/2010/506182
16. McDonald MW, O’Connell JR, Manning JT, Benjamin RS. Leiomyosarcoma of the penis. J Urol. 1983;130(4):788-789. doi:10.1016/s0022-5347(17)51464-0
17. Planz B, Brunner K, Kalem T, Schlick RW, Kind M. Primary leiomyosarcoma of the epididymis and late recurrence on the penis. J Urol. 1998;159(2):508. doi:10.1016/s0022-5347(01)63966-1
18. Smart RH. Leiomyosarcoma of the penis. J Urol. 1984;132(2):356-357. doi:10.1016/s0022-5347(17)49624-8
19. Patrikidou A, Domont J, Cioffi A, Le Cesne A. Treating soft tissue sarcomas with adjuvant chemotherapy. Curr Treat Options Oncol. 2011;12(1):21-31. doi:10.1007/s11864-011-0145-5
20. Italiano A, Delva F, Mathoulin-Pelissier S, et al. Effect of adjuvant chemotherapy on survival in FNCLCC grade 3 soft tissue sarcomas: a multivariate analysis of the French Sarcoma Group Database. Ann Oncol. 2010;21(12):2436-2441. doi:10.1093/annonc/mdq238
21. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113(3):573-581. doi:10.1002/cncr.23592
22. Lacarrière E, Galliot I, Gobet F, Sibert L. Leiomyosarcoma of the corpus cavernosum mimicking a Peyronie’s plaque. Urology. 2012;79(4):e53-e54. doi:10.1016/j.urology.2011.07.1410
23. Hamal PB. Leiomyosarcoma of penis—case report and review of the literature. Br J Urol. 1975;47(3):319-324. doi:10.1111/j.1464-410x.1975.tb03974.x
24. Greenwood N, Fox H, Edwards EC. Leiomyosarcoma of the penis. Cancer. 1972;29(2):481-483. doi:10.1002/1097-0142(197202)29:2<481::aid -cncr2820290237>3.0.co;2-q
25. Koizumi H, Nagano K, Kosaka S. A case of penile tumor: combination of leiomyosarcoma and squamous cell carcinoma. Hinyokika Kiyo. 1987;33(9):1489-1491.
26. Romero Gonzalez EJ, Marenco Jimenez JL, Mayorga Pineda MP, Martínez Morán A, Castiñeiras Fernández J. Leiomyosarcoma of the penis, an exceptional entity. Urol Case Rep. 2015;3(3):63-64. doi:10.1016/j.eucr.2014.12.007
Penile cancer is rare with a worldwide incidence of 0.8 cases per 100,000 men.1 The most common type is squamous cell carcinoma (SCC) followed by soft tissue sarcoma (STS) and Kaposi sarcoma.2 Leiomyosarcoma (LMS) is the second most common STS subtype at this location.3 Approximately 50 cases of penile LMS have been reported in the English literature, most as isolated case reports while Fetsch and colleagues reported 14 cases from a single institute.4 We present a case of penile LMS with a review of 31 cases. We also describe presentation, treatment options, and recurrence pattern of this rare malignancy.
Case Presentation
A patient aged 70 years presented to the urology clinic with 1-year history of a slowly enlarging penile mass associated with phimosis. He reported no pain, dysuria, or hesitancy. On examination a 2 × 2-cm smooth, mobile, nonulcerating mass was seen on the tip of his left glans without inguinal lymphadenopathy. He underwent circumcision and excision biopsy that revealed an encapsulated tan-white mass measuring 3 × 2.2 × 1.5 cm under the surface of the foreskin. Histology showed a spindle cell tumor with areas of increased cellularity, prominent atypia, and pleomorphism, focal necrosis, and scattered mitoses, including atypical forms. The tumor stained positive for smooth muscle actin and desmin. Ki-67 staining showed foci with a very high proliferation index (Figure). Resection margins were negative. Final Fédération Nationale des Centres de Lutte Contre Le Cancer score was grade 2 (differentiation, 1; mitotic, 3; necrosis, 1). Computed tomography of the chest, abdomen, and pelvis did not show evidence of metastasis. The tumor was classified as superficial, stage IIA (pT1cN0cM0). Local excision with negative margins was deemed adequate treatment.
Discussion
Penile LMS is rare and arises from smooth muscles, which in the penis can be from dartos fascia, erector pili in the skin covering the shaft, or from tunica media of the superficial vessels and cavernosa.5 It commonly presents as a nodule or ulcer that might be accompanied by paraphimosis, phimosis, erectile dysfunction, and lower urinary tract symptoms depending on the extent of local tissue involvement. In our review of 31 cases, the age at presentation ranged from 38 to 85 years, with 1 case report of LMS in a 6-year-old. The highest incidence was in the 6th decade. Tumor behavior can be indolent or aggressive. Most patients in our review had asymptomatic, slow-growing lesions for 6 to 24 months before presentation—including our patient—while others had an aggressive tumor with symptoms for a few weeks followed by rapid metastatic spread.6,7
Histology and Staging
Diagnosis requires biopsy followed by histologic examination and immunohistochemistry of the lesion. Typically, LMS shows fascicles of spindle cells with varying degrees of nuclear atypia, pleomorphisms, and necrotic regions. Mitotic rate is variable and usually > 5 per high power field. Cells stain positive for smooth muscle actin, desmin, and h-caldesmon.8 TNM (tumor, nodes, metastasis) stage is determined by the American Joint Committee on Cancer guidelines for STS.
Pratt and colleagues were the first to categorize penile LMS as superficial or deep.9 The former includes all lesions superficial to tunica albuginea while the latter run deep to this layer. Anatomical distinction is an important factor in tumor behavior, treatment selection, and prognosis. In our review, we found 14 cases of superficial and 17 cases of deep LMS.
Treatment
There are no established guidelines on optimum treatment of penile LMS. However, we can extrapolate principles from current guidelines on penile cancer, cutaneous leiomyosarcoma, and limb sarcomas. At present, the first-line treatment for superficial penile LMS is wide local excision to achieve negative margins. Circumcision alone might be sufficient for tumors of the distal prepuce, as in our case.10 Radical resection generally is not required for these early-stage tumors. In our review, no patient in this category developed recurrence or metastasis regardless of initial surgery type (Table 1).6,11,12
For deep lesions, partial—if functional penile stump and negative margins can be achieved—or total penectomy is required.10 In our review, more conservative approaches to deep tumors were associated with local recurrences.7,13,14 Lymphatic spread is rare for LMS. Additionally, involvement of local lymph nodes usually coincides with distant spread. Inguinal lymph node dissection is not indicated if initial negative surgical margins are achieved.
For STS at other sites in the body, radiation therapy is recommended postoperatively for high-grade lesions, which can be extrapolated to penile LMS as well. The benefit of preoperative radiation therapy is less certain. In limb sarcomas, radiation is associated with better local control for large-sized tumors and is used for patients with initial unresectable tumors.15 Similar recommendation could be extended to penile LMS with local spread to inguinal lymph nodes, scrotum, or abdominal wall. In our review, postoperative radiation therapy was used in 3 patients with deep tumors.16-18 Of these, short-term relapse occurred in 1 patient.
Chemotherapy for LMS remains controversial. The tumor generally is resistant to chemotherapy and systemic therapy, if employed, is for palliative purpose. The most promising results for adjuvant chemotherapy for resectable STS is seen in limb and uterine sarcomas with high-grade, metastatic, or relapsed tumors but improvement in overall survival has been marginal.19,20Single and multidrug regimens based on doxorubicin, ifosfamide, and gemcitabine have been studied with results showing no efficacy or a slight benefit.8,21 Immunotherapy and targeted therapy for penile STS have not been studied. In our review, postoperative chemotherapy was used for 2 patients with deep tumors and 1 patient with a superficial tumor while preoperative chemotherapy was used for 1 patient.16,18,22 Short-term relapse was seen in 2 of 4 of these patients (Table 2).
Metastatic Disease
LMS tends to metastasize hematogenously and lymphatic spread is uncommon. In our review, 7 patients developed metastasis. These patients had deep tumors at presentation with tumor size > 3 cm. Five of 7 patients had involvement of corpora cavernosa at presentation. The lung was the most common site of metastasis, followed by local extension to lower abdominal wall and scrotum. Of the 7 patients, 3 were treated with initial limited excision or partial penectomy and then experienced local recurrence or distant metastasis.7,13,14,23 This supports the use of radical surgery in large, deep tumors. In an additional 4 cases, metastasis occurred despite initial treatment with total penectomy and use of adjuvant chemoradiation therapy.
In most cases penile LMS is a de novo tumor, however, on occasion it could be accompanied by another epithelial malignancy. Similarly, penile LMS might be a site of recurrence for a primary LMS at another site, as seen in 3 of the reviewed cases. In the first, a patient presented with a nodule on the glans suspicious for SCC, second with synchronous SCC and LMS, and a third case where a patient presented with penile LMS 9 years after being treated for similar tumor in the epididymis.17,24,25
Prognosis
Penile LMS prognosis is difficult to ascertain because reported cases are rare. In our review, the longest documented disease-free survival was 3.5 years for a patient with superficial LMS treated with local excision.26 In cases of distant metastasis, average survival was 4.6 months, while the longest survival since initial presentation and last documented local recurrence was 16 years.14 Five-year survival has not been reported.
Conclusions
LMS of the penis is a rare and potentially aggressive malignancy. It can be classified as superficial or deep based on tumor relation to the tunica albuginea. Deep tumors, those > 3 cm, high-grade lesions, and tumors with involvement of corpora cavernosa, tend to spread locally, metastasize to distant areas, and require more radical surgery with or without postoperative radiation therapy. In comparison, superficial lesions can be treated with local excision only. Both superficial and deep tumors require close follow-up.
Penile cancer is rare with a worldwide incidence of 0.8 cases per 100,000 men.1 The most common type is squamous cell carcinoma (SCC) followed by soft tissue sarcoma (STS) and Kaposi sarcoma.2 Leiomyosarcoma (LMS) is the second most common STS subtype at this location.3 Approximately 50 cases of penile LMS have been reported in the English literature, most as isolated case reports while Fetsch and colleagues reported 14 cases from a single institute.4 We present a case of penile LMS with a review of 31 cases. We also describe presentation, treatment options, and recurrence pattern of this rare malignancy.
Case Presentation
A patient aged 70 years presented to the urology clinic with 1-year history of a slowly enlarging penile mass associated with phimosis. He reported no pain, dysuria, or hesitancy. On examination a 2 × 2-cm smooth, mobile, nonulcerating mass was seen on the tip of his left glans without inguinal lymphadenopathy. He underwent circumcision and excision biopsy that revealed an encapsulated tan-white mass measuring 3 × 2.2 × 1.5 cm under the surface of the foreskin. Histology showed a spindle cell tumor with areas of increased cellularity, prominent atypia, and pleomorphism, focal necrosis, and scattered mitoses, including atypical forms. The tumor stained positive for smooth muscle actin and desmin. Ki-67 staining showed foci with a very high proliferation index (Figure). Resection margins were negative. Final Fédération Nationale des Centres de Lutte Contre Le Cancer score was grade 2 (differentiation, 1; mitotic, 3; necrosis, 1). Computed tomography of the chest, abdomen, and pelvis did not show evidence of metastasis. The tumor was classified as superficial, stage IIA (pT1cN0cM0). Local excision with negative margins was deemed adequate treatment.
Discussion
Penile LMS is rare and arises from smooth muscles, which in the penis can be from dartos fascia, erector pili in the skin covering the shaft, or from tunica media of the superficial vessels and cavernosa.5 It commonly presents as a nodule or ulcer that might be accompanied by paraphimosis, phimosis, erectile dysfunction, and lower urinary tract symptoms depending on the extent of local tissue involvement. In our review of 31 cases, the age at presentation ranged from 38 to 85 years, with 1 case report of LMS in a 6-year-old. The highest incidence was in the 6th decade. Tumor behavior can be indolent or aggressive. Most patients in our review had asymptomatic, slow-growing lesions for 6 to 24 months before presentation—including our patient—while others had an aggressive tumor with symptoms for a few weeks followed by rapid metastatic spread.6,7
Histology and Staging
Diagnosis requires biopsy followed by histologic examination and immunohistochemistry of the lesion. Typically, LMS shows fascicles of spindle cells with varying degrees of nuclear atypia, pleomorphisms, and necrotic regions. Mitotic rate is variable and usually > 5 per high power field. Cells stain positive for smooth muscle actin, desmin, and h-caldesmon.8 TNM (tumor, nodes, metastasis) stage is determined by the American Joint Committee on Cancer guidelines for STS.
Pratt and colleagues were the first to categorize penile LMS as superficial or deep.9 The former includes all lesions superficial to tunica albuginea while the latter run deep to this layer. Anatomical distinction is an important factor in tumor behavior, treatment selection, and prognosis. In our review, we found 14 cases of superficial and 17 cases of deep LMS.
Treatment
There are no established guidelines on optimum treatment of penile LMS. However, we can extrapolate principles from current guidelines on penile cancer, cutaneous leiomyosarcoma, and limb sarcomas. At present, the first-line treatment for superficial penile LMS is wide local excision to achieve negative margins. Circumcision alone might be sufficient for tumors of the distal prepuce, as in our case.10 Radical resection generally is not required for these early-stage tumors. In our review, no patient in this category developed recurrence or metastasis regardless of initial surgery type (Table 1).6,11,12
For deep lesions, partial—if functional penile stump and negative margins can be achieved—or total penectomy is required.10 In our review, more conservative approaches to deep tumors were associated with local recurrences.7,13,14 Lymphatic spread is rare for LMS. Additionally, involvement of local lymph nodes usually coincides with distant spread. Inguinal lymph node dissection is not indicated if initial negative surgical margins are achieved.
For STS at other sites in the body, radiation therapy is recommended postoperatively for high-grade lesions, which can be extrapolated to penile LMS as well. The benefit of preoperative radiation therapy is less certain. In limb sarcomas, radiation is associated with better local control for large-sized tumors and is used for patients with initial unresectable tumors.15 Similar recommendation could be extended to penile LMS with local spread to inguinal lymph nodes, scrotum, or abdominal wall. In our review, postoperative radiation therapy was used in 3 patients with deep tumors.16-18 Of these, short-term relapse occurred in 1 patient.
Chemotherapy for LMS remains controversial. The tumor generally is resistant to chemotherapy and systemic therapy, if employed, is for palliative purpose. The most promising results for adjuvant chemotherapy for resectable STS is seen in limb and uterine sarcomas with high-grade, metastatic, or relapsed tumors but improvement in overall survival has been marginal.19,20Single and multidrug regimens based on doxorubicin, ifosfamide, and gemcitabine have been studied with results showing no efficacy or a slight benefit.8,21 Immunotherapy and targeted therapy for penile STS have not been studied. In our review, postoperative chemotherapy was used for 2 patients with deep tumors and 1 patient with a superficial tumor while preoperative chemotherapy was used for 1 patient.16,18,22 Short-term relapse was seen in 2 of 4 of these patients (Table 2).
Metastatic Disease
LMS tends to metastasize hematogenously and lymphatic spread is uncommon. In our review, 7 patients developed metastasis. These patients had deep tumors at presentation with tumor size > 3 cm. Five of 7 patients had involvement of corpora cavernosa at presentation. The lung was the most common site of metastasis, followed by local extension to lower abdominal wall and scrotum. Of the 7 patients, 3 were treated with initial limited excision or partial penectomy and then experienced local recurrence or distant metastasis.7,13,14,23 This supports the use of radical surgery in large, deep tumors. In an additional 4 cases, metastasis occurred despite initial treatment with total penectomy and use of adjuvant chemoradiation therapy.
In most cases penile LMS is a de novo tumor, however, on occasion it could be accompanied by another epithelial malignancy. Similarly, penile LMS might be a site of recurrence for a primary LMS at another site, as seen in 3 of the reviewed cases. In the first, a patient presented with a nodule on the glans suspicious for SCC, second with synchronous SCC and LMS, and a third case where a patient presented with penile LMS 9 years after being treated for similar tumor in the epididymis.17,24,25
Prognosis
Penile LMS prognosis is difficult to ascertain because reported cases are rare. In our review, the longest documented disease-free survival was 3.5 years for a patient with superficial LMS treated with local excision.26 In cases of distant metastasis, average survival was 4.6 months, while the longest survival since initial presentation and last documented local recurrence was 16 years.14 Five-year survival has not been reported.
Conclusions
LMS of the penis is a rare and potentially aggressive malignancy. It can be classified as superficial or deep based on tumor relation to the tunica albuginea. Deep tumors, those > 3 cm, high-grade lesions, and tumors with involvement of corpora cavernosa, tend to spread locally, metastasize to distant areas, and require more radical surgery with or without postoperative radiation therapy. In comparison, superficial lesions can be treated with local excision only. Both superficial and deep tumors require close follow-up.
1. Montes Cardona CE, García-Perdomo HA. Incidence of penile cancer worldwide: systematic review and meta-analysis. Rev Panam Salud Publica. 2017;41:e117. Published 2017 Nov 30. doi:10.26633/RPSP.2017.117
2. Volker HU, Zettl A, Haralambieva E, et al. Leiomyosarcoma of the larynx as a local relapse of squamous cell carcinoma—report of an unusual case. Head Neck. 2010;32(5):679-683. doi:10.1002/hed.21127
3. Wollina U, Steinbach F, Verma S, et al. Penile tumours: a review. J Eur Acad Dermatol Venereol. 2014;28(10):1267-1276. doi:10.1111/jdv.12491
4. Fetsch JF, Davis CJ Jr, Miettinen M, Sesterhenn IA. Leiomyosarcoma of the penis: a clinicopathologic study of 14 cases with review of the literature and discussion of the differential diagnosis. Am J Surg Pathol. 2004;28(1):115-125. doi:10.1097/00000478-200401000-00014
5. Sundersingh S, Majhi U, Narayanaswamy K, Balasubramanian S. Primary leiomyosarcoma of the penis. Indian J Pathol Microbiol. 2009;52(3):447-448. doi:10.4103/0377-4929.55028
6. Mendis D, Bott SR, Davies JH. Subcutaneous leiomyosarcoma of the frenulum. Scientific World J. 2005;5:571-575. doi:10.1100/tsw.2005.76
7. Elem B, Nieslanik J. Leiomyosarcoma of the penis. Br J Urol. 1979;51(1):46. doi:10.1111/j.1464-410x.1979.tb04244.x
8. Serrano C, George S. Leiomyosarcoma. Hematol Oncol Clin North Am. 2013;27(5):957-974. doi:10.1016/j.hoc.2013.07.002
9. Pratt RM, Ross RT. Leiomyosarcoma of the penis. A report of a case. Br J Surg. 1969;56(11):870-872. doi:10.1002/bjs.1800561122
10. National Comprehensive Cancer Network. Penile cancer. NCCN evidence blocks. Version 2.2022 Updated January 26, 2022. Accessed March 16, 2022. https://www.nccn.org/professionals/physician_gls/pdf/penile_blocks.pdf
11. Ashley DJ, Edwards EC. Sarcoma of the penis; leiomyosarcoma of the penis: report of a case with a review of the literature on sarcoma of the penis. Br J Surg. 1957;45(190):170-179. doi:10.1002/bjs.18004519011
12. Pow-Sang MR, Orihuela E. Leiomyosarcoma of the penis. J Urol. 1994;151(6):1643-1645. doi:10.1016/s0022-5347(17)35328-413. Isa SS, Almaraz R, Magovern J. Leiomyosarcoma of the penis. Case report and review of the literature. Cancer. 1984;54(5):939-942. doi:10.1002/1097-0142(19840901)54:5<939::aid-cncr2820540533>3.0.co;2-y
14. Hutcheson JB, Wittaker WW, Fronstin MH. Leiomyosarcoma of the penis: case report and review of literature. J Urol. 1969;101(6):874-875. doi:10.1016/s0022-5347(17)62446-7
15. Grimer R, Judson I, Peake D, et al. Guidelines for the management of soft tissue sarcomas. Sarcoma. 2010;2010:506182. doi:10.1155/2010/506182
16. McDonald MW, O’Connell JR, Manning JT, Benjamin RS. Leiomyosarcoma of the penis. J Urol. 1983;130(4):788-789. doi:10.1016/s0022-5347(17)51464-0
17. Planz B, Brunner K, Kalem T, Schlick RW, Kind M. Primary leiomyosarcoma of the epididymis and late recurrence on the penis. J Urol. 1998;159(2):508. doi:10.1016/s0022-5347(01)63966-1
18. Smart RH. Leiomyosarcoma of the penis. J Urol. 1984;132(2):356-357. doi:10.1016/s0022-5347(17)49624-8
19. Patrikidou A, Domont J, Cioffi A, Le Cesne A. Treating soft tissue sarcomas with adjuvant chemotherapy. Curr Treat Options Oncol. 2011;12(1):21-31. doi:10.1007/s11864-011-0145-5
20. Italiano A, Delva F, Mathoulin-Pelissier S, et al. Effect of adjuvant chemotherapy on survival in FNCLCC grade 3 soft tissue sarcomas: a multivariate analysis of the French Sarcoma Group Database. Ann Oncol. 2010;21(12):2436-2441. doi:10.1093/annonc/mdq238
21. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113(3):573-581. doi:10.1002/cncr.23592
22. Lacarrière E, Galliot I, Gobet F, Sibert L. Leiomyosarcoma of the corpus cavernosum mimicking a Peyronie’s plaque. Urology. 2012;79(4):e53-e54. doi:10.1016/j.urology.2011.07.1410
23. Hamal PB. Leiomyosarcoma of penis—case report and review of the literature. Br J Urol. 1975;47(3):319-324. doi:10.1111/j.1464-410x.1975.tb03974.x
24. Greenwood N, Fox H, Edwards EC. Leiomyosarcoma of the penis. Cancer. 1972;29(2):481-483. doi:10.1002/1097-0142(197202)29:2<481::aid -cncr2820290237>3.0.co;2-q
25. Koizumi H, Nagano K, Kosaka S. A case of penile tumor: combination of leiomyosarcoma and squamous cell carcinoma. Hinyokika Kiyo. 1987;33(9):1489-1491.
26. Romero Gonzalez EJ, Marenco Jimenez JL, Mayorga Pineda MP, Martínez Morán A, Castiñeiras Fernández J. Leiomyosarcoma of the penis, an exceptional entity. Urol Case Rep. 2015;3(3):63-64. doi:10.1016/j.eucr.2014.12.007
1. Montes Cardona CE, García-Perdomo HA. Incidence of penile cancer worldwide: systematic review and meta-analysis. Rev Panam Salud Publica. 2017;41:e117. Published 2017 Nov 30. doi:10.26633/RPSP.2017.117
2. Volker HU, Zettl A, Haralambieva E, et al. Leiomyosarcoma of the larynx as a local relapse of squamous cell carcinoma—report of an unusual case. Head Neck. 2010;32(5):679-683. doi:10.1002/hed.21127
3. Wollina U, Steinbach F, Verma S, et al. Penile tumours: a review. J Eur Acad Dermatol Venereol. 2014;28(10):1267-1276. doi:10.1111/jdv.12491
4. Fetsch JF, Davis CJ Jr, Miettinen M, Sesterhenn IA. Leiomyosarcoma of the penis: a clinicopathologic study of 14 cases with review of the literature and discussion of the differential diagnosis. Am J Surg Pathol. 2004;28(1):115-125. doi:10.1097/00000478-200401000-00014
5. Sundersingh S, Majhi U, Narayanaswamy K, Balasubramanian S. Primary leiomyosarcoma of the penis. Indian J Pathol Microbiol. 2009;52(3):447-448. doi:10.4103/0377-4929.55028
6. Mendis D, Bott SR, Davies JH. Subcutaneous leiomyosarcoma of the frenulum. Scientific World J. 2005;5:571-575. doi:10.1100/tsw.2005.76
7. Elem B, Nieslanik J. Leiomyosarcoma of the penis. Br J Urol. 1979;51(1):46. doi:10.1111/j.1464-410x.1979.tb04244.x
8. Serrano C, George S. Leiomyosarcoma. Hematol Oncol Clin North Am. 2013;27(5):957-974. doi:10.1016/j.hoc.2013.07.002
9. Pratt RM, Ross RT. Leiomyosarcoma of the penis. A report of a case. Br J Surg. 1969;56(11):870-872. doi:10.1002/bjs.1800561122
10. National Comprehensive Cancer Network. Penile cancer. NCCN evidence blocks. Version 2.2022 Updated January 26, 2022. Accessed March 16, 2022. https://www.nccn.org/professionals/physician_gls/pdf/penile_blocks.pdf
11. Ashley DJ, Edwards EC. Sarcoma of the penis; leiomyosarcoma of the penis: report of a case with a review of the literature on sarcoma of the penis. Br J Surg. 1957;45(190):170-179. doi:10.1002/bjs.18004519011
12. Pow-Sang MR, Orihuela E. Leiomyosarcoma of the penis. J Urol. 1994;151(6):1643-1645. doi:10.1016/s0022-5347(17)35328-413. Isa SS, Almaraz R, Magovern J. Leiomyosarcoma of the penis. Case report and review of the literature. Cancer. 1984;54(5):939-942. doi:10.1002/1097-0142(19840901)54:5<939::aid-cncr2820540533>3.0.co;2-y
14. Hutcheson JB, Wittaker WW, Fronstin MH. Leiomyosarcoma of the penis: case report and review of literature. J Urol. 1969;101(6):874-875. doi:10.1016/s0022-5347(17)62446-7
15. Grimer R, Judson I, Peake D, et al. Guidelines for the management of soft tissue sarcomas. Sarcoma. 2010;2010:506182. doi:10.1155/2010/506182
16. McDonald MW, O’Connell JR, Manning JT, Benjamin RS. Leiomyosarcoma of the penis. J Urol. 1983;130(4):788-789. doi:10.1016/s0022-5347(17)51464-0
17. Planz B, Brunner K, Kalem T, Schlick RW, Kind M. Primary leiomyosarcoma of the epididymis and late recurrence on the penis. J Urol. 1998;159(2):508. doi:10.1016/s0022-5347(01)63966-1
18. Smart RH. Leiomyosarcoma of the penis. J Urol. 1984;132(2):356-357. doi:10.1016/s0022-5347(17)49624-8
19. Patrikidou A, Domont J, Cioffi A, Le Cesne A. Treating soft tissue sarcomas with adjuvant chemotherapy. Curr Treat Options Oncol. 2011;12(1):21-31. doi:10.1007/s11864-011-0145-5
20. Italiano A, Delva F, Mathoulin-Pelissier S, et al. Effect of adjuvant chemotherapy on survival in FNCLCC grade 3 soft tissue sarcomas: a multivariate analysis of the French Sarcoma Group Database. Ann Oncol. 2010;21(12):2436-2441. doi:10.1093/annonc/mdq238
21. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113(3):573-581. doi:10.1002/cncr.23592
22. Lacarrière E, Galliot I, Gobet F, Sibert L. Leiomyosarcoma of the corpus cavernosum mimicking a Peyronie’s plaque. Urology. 2012;79(4):e53-e54. doi:10.1016/j.urology.2011.07.1410
23. Hamal PB. Leiomyosarcoma of penis—case report and review of the literature. Br J Urol. 1975;47(3):319-324. doi:10.1111/j.1464-410x.1975.tb03974.x
24. Greenwood N, Fox H, Edwards EC. Leiomyosarcoma of the penis. Cancer. 1972;29(2):481-483. doi:10.1002/1097-0142(197202)29:2<481::aid -cncr2820290237>3.0.co;2-q
25. Koizumi H, Nagano K, Kosaka S. A case of penile tumor: combination of leiomyosarcoma and squamous cell carcinoma. Hinyokika Kiyo. 1987;33(9):1489-1491.
26. Romero Gonzalez EJ, Marenco Jimenez JL, Mayorga Pineda MP, Martínez Morán A, Castiñeiras Fernández J. Leiomyosarcoma of the penis, an exceptional entity. Urol Case Rep. 2015;3(3):63-64. doi:10.1016/j.eucr.2014.12.007
Psychosocial Barriers and Their Impact on Hepatocellular Carcinoma Care in US Veterans: Tumor Board Model of Care
Hepatocellular carcinoma (HCC) remains a major global health problem and is the third leading cause of cancer-related mortality worldwide.1 Management of HCC is complex; as it largely occurs in the background of chronic liver disease, its management must simultaneously address challenges related to the patient’s tumor burden, as well as their underlying liver dysfunction and performance status. HCC is universally fatal without treatment, with a 5-year survival < 10%.2 However, if detected early HCC is potentially curable, with treatments such as hepatic resection, ablation, and/or liver transplantation, which are associated with 5-year survival rates as high as 70%.2 HCC-specific palliative treatments, including intra-arterial therapies (eg, trans-arterial chemoembolization, radioembolization) and systemic chemotherapy, have also been shown to prolong survival in patients with advanced HCC. Therefore, a key driver of patient survival is receipt of HCC-specific therapy.
There is rising incidence and mortality related to HCC in the US veteran population, largely attributed to acquisition of chronic hepatitis C virus (HCV) infection decades prior.3 There is also a high prevalence of psychosocial barriers in this population, such as low socioeconomic status, homelessness, alcohol and substance use disorders, and psychiatric disorders which can negatively influence receipt of medical treatment, including cancer care.4,5 Given the complexity of managing HCC, as well as the plethora of potential treatment options available, it is widely accepted that a multidisciplinary team approach, such as the multidisciplinary tumor board (MDTB) provides optimal care to patients with HCC.2,6 The aim of the present study was to identify in a population of veterans diagnosed with HCC the prevalence of psychosocial barriers to care and assess their impact and the role of an MDTB on receipt of HCC-specific care.
Methods
In June 2007, a joint institutional MDTB was established for patients with primary liver tumors receiving care at the William S. Middleton Memorial Veterans’ Hospital (WSMMVH) in Madison, Wisconsin. As we have described elsewhere, individual cases with their corresponding imaging studies were reviewed at a weekly conference attended by transplant hepatologists, medical oncologists, hepatobiliary and transplant surgeons, pathologists, diagnostic and interventional radiologists, and nurse coordinators.6 Potential therapies offered included surgical resection, liver transplantation (LT), thermal ablation, intra-arterial therapies (chemo and/or radioembolization), systemic chemotherapy, stereotactic radiation, and best supportive care. Decisions regarding the appropriate treatment modality were made based on patient factors, review of their cross-sectional imaging studies and/or histopathology, and context of their underlying liver dysfunction. The tumor board discussion was summarized in meeting minutes as well as tumor board encounters recorded in each patient’s health record. Although patients with benign tumors were presented at the MDTB, only patients with a diagnosis of HCC were included in this study.
A database analysis was conducted of all veteran patients with HCC managed through the WSMMVH MDTB, since its inception up to December 31, 2016, with follow-up until December 31, 2018. Data for analysis included demographics, laboratory parameters at time of diagnosis and treatment, imaging findings, histopathology and/or surgical pathology, treatment rendered, and follow-up information. The primary outcome measured in this study included receipt of any therapy and secondarily, patient survival.
Discrete variables were analyzed with χ2 statistics or Fisher exact test and continuous variables with the student t test. Multivariable analyses were carried out with logistic regression. Variables with a P < .05 were considered statistically significant. Analyses were carried out using IBM SPSS v24.0.
As a quality-improvement initiative for the care and management of veterans with HCC, this study was determined to be exempt from review by the WSMMVH and University of Wisconsin School of Medicine and Public Health Institutional Review Board.
Results
From January 1, 2007, through December 31, 2016, 149 patients with HCC were managed through the MDTB. Baseline demographic data, Model for End-stage Liver Disease (MELD) score and Child-Turcotte-Pugh class, and baseline HCC characteristics of the cohort are shown in Tables 1 and 2.
There was a high prevalence of psychosocial barriers in our study cohort, including alcohol or substance use disorder, mental illness diagnosis, and low socioeconomic status (Table 3). The mean distance traveled to WSMMVH for HCC-specific care was 206 km. Fifty patients in the cohort utilized travel assistance and 33 patients accessed lodging assistance.
HCC Treatments
There was a high rate of receipt of treatment in our study cohort with 127 (85%) patients receiving at least one HCC-specific therapy. Care was individualized and coordinated through our institutional MDTB, with both curative and palliative treatment modalities utilized (Table 4).
Curative treatment, which includes LT, ablation, or resection, was offered to 78 (52%) patients who were within T2 stage. Of these 78 patients who were potential candidates for LT as a curative treatment for HCC, 31 were not deemed suitable transplant candidates. Psychosocial barriers precluded consideration for LT in 7 of the 31 patients due to active substance use, homelessness in 1 patient, and severe mental illness in 3 patients. Medical comorbidities, advanced patient age, and patient preference accounted for the remainder.
In a univariate analysis of the cohort of 149 patients, factors that decreased the likelihood of receipt of curative HCC therapy included T2 stage or higher at diagnosis and a diagnosis of depression, whereas provision for lodging was associated with increased likelihood of receiving HCC-specific care (Table 5). Other factors that influenced receipt of any treatment included patient’s MELD score, total bilirubin, and serum α-fetoprotein, a surrogate marker for tumor stage. In the multivariable analysis, predictors of receiving curative therapy included absence of substance use, within T2 stage of tumor, and Child-Turcotte-Pugh class A cirrhosis. The presence of psychosocial barriers apart from substance use did not predict a lower chance of receiving curative HCC therapy (including homelessness, distance traveled to center, mental health disorder, and low income).
Median survival was 727 (95% CI, 488-966) days from diagnosis. Survival from HCC diagnosis in study cohort was 72% at 1 year, 50% at 2 years, 39% at 3 years, and 36% at 5 years. Death occurred in 71 (48%) patients; HCC accounted for death in 52 (73%) patients, complications of end-stage liver disease in 13 (18%) patients, and other causes for the remainder of patients.
Discussion
Increases in prevalence and mortality related to cirrhosis and HCC have been reported among the US veteran population.3 This is in large part attributable to the burden of chronic HCV infection in this population. As mirrored in the US population in general, we may be at a turning point regarding the gradual increase in prevalence in HCC.7 The prevalence of cirrhosis and viral-related HCC related to HCV infection will decline with availability of effective antiviral therapy. Alcoholic liver disease remains a main etiological factor for development of cirrhosis and HCC. Nonalcoholic fatty liver disease is becoming a more prevalent cause for development of cirrhosis, indication for liver transplantation, and development of HCC, and indeed may lead to HCC even in the absence of cirrhosis.8
HCC remains a challenging clinical problem.2 As the vast majority of cases arise in the context of cirrhosis, management of HCC not only must address the cancer stage at diagnosis, but also the patient’s underlying liver dysfunction and performance status. Receipt of HCC-specific therapy is a key driver of patient outcome, with curative therapies available for those diagnosed with early-stage disease. We and others have shown that a multidisciplinary approach to coordinate, individualize, and optimize care for these complex patients can improve the rate of treatment utilization, reduce treatment delays, and improve patient survival.6,9,10
Patient psychosocial barriers, such as low socioeconomic status, homelessness, alcohol and substance use, and psychiatric disorders, are more prevalent among the veteran population and have the potential to negatively influence successful health care delivery. One retrospective study of 100 veterans at a US Department of Veterans Affairs (VA) medical center treated for HCC from 2009 to 2014 showed a majority of the patients lived on a meager income, a high prevalence of homelessness, substance use history in 96% of their cohort, and psychiatric illness in 65% of patients.11 Other studies have documented similar findings in the veteran population, with alcohol, substance use, as well as other uncontrolled comorbidities as barriers to providing care, such as antiviral therapy for chronic HCV infection.12
Herein, we present a cohort of veterans with HCC managed through our MDTB from 2007 to 2016, for whom chronic HCV infection and/or alcoholic liver disease were the main causes of cirrhosis. Our cohort had a high burden of alcohol and substance use disorders while other psychiatric illnesses were also common. Our cohort includes patients who were poor, and even some veterans who lacked a stable home. This profile of poverty and social deprivation among veterans is matched in national data.13-15 Using a tumor board model of nurse navigation and multidisciplinary care, we were able to provide travel and lodging assistance to 50 (34%) and 33 (22%) patients, respectively, in order to facilitate their care.
Our data demonstrate that the impact of psychosocial barriers on our capacity to deliver care varies with the nature of the treatment under consideration: curative vs cancer control. For example, active substance use disorder, homelessness, and severe established mental illness were often considered insurmountable when the treatment in question was LT. Nevertheless, despite the high prevalence in our study group of barriers, such as lack of transport while living far from a VA medical center, or alcohol use disorder, a curative treatment with either LT, tumor ablation, or resection could be offered to over half of our cohort. When noncurative therapies are included, most patients (85%) received HCC-specific care, with good relative survival.
Our reported high receipt of HCC-specific care and patient survival is in contrast to previously reported low rates of HCC-specific care in in a national survey of management of 1296 veteran patients infected with HCV who developed HCC from 1998 to 2006. In this population, HCC-specific treatment was provided to 34%.16 However our data are consistent with our previously published data of patients with HCC managed through an institutional MDTB.6 Indeed, as shown by a univariate analysis in our present study, individualizing care to address modifiable patient barriers, such as providing provisions for lodging if needed, was associated with an increased likelihood of receiving HCC-specific care. On the other hand, advanced tumor stage (> T2) at diagnosis and a diagnosis of depression, which was the most common psychiatric diagnosis in our cohort, were both associated with decreased likelihood of receiving HCC-specific care. Clinical factors such as MELD score, total bilirubin, and serum AFP all affected the likelihood of providing HCC-specific care. In a multivariate analysis, factors that predicted ability to receive curative therapy included absence of substance use, T2 stage of tumor, and Child-Turcotte-Pugh class A cirrhosis. This is expected as patients with HCC within T2 stage (or Milan criteria) with compensated cirrhosis are most likely to receive curative therapies, such as resection, ablation, or LT.2
Conclusions
Our study demonstrates a high burden of psychosocial challenges in veterans with HCC. These accounted for a significant barrier to receive HCC-specific care. Despite the presence of these patient barriers, high rates of HCC-specific treatment are attainable through individualization and coordination of patient care in the context of a MDTB model with nurse navigation. Provision of targeted social support to ameliorate these modifiable factors improves patient outcomes.
1. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73(suppl 1):4-13. doi:10.1002/hep.31288.
2. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723-750. doi:10.1002/hep.29913
3. Beste LA, Leipertz SL, Green PK, Dominitz JA, Ross D, Ioannou GN. Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001-2013. Gastroenterology. 2015;149(6):1471-e18. doi:10.1053/j.gastro.2015.07.056
4. Kazis LE, Miller DR, Clark J, et al. Health-related quality of life in patients served by the Department of Veterans Affairs: results from the Veterans Health Study. Arch Intern Med. 1998;158(6):626-632. doi:10.1001/archinte.158.6.626
5. Slind LM, Keating TM, Fisher AG, Rose TG. A patient navigation model for veterans traveling for cancer care. Fed Pract. 2016;33(suppl 1):40S-45S.
6. Agarwal PD, Phillips P, Hillman L, et al. Multidisciplinary management of hepatocellular carcinoma improves access to therapy and patient survival. J Clin Gastroenterol. 2017;51(9):845-849. doi:10.1097/MCG.0000000000000825
7. White DL, Thrift AP, Kanwal F, Davila J, El-Serag HB. Incidence of hepatocellular carcinoma in all 50 United States, From 2000 Through 2012. Gastroenterology. 2017;152(4):812-820.e5. doi:10.1053/j.gastro.2016.11.020
8. Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology. 2018;155(6):1828-1837.e2. doi:10.1053/j.gastro.2018.08.024
9. Yopp AC, Mansour JC, Beg MS, et al. Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome. Ann Surg Oncol. 2014;21(4):1287-1295. doi:10.1245/s10434-013-3413-8
10. Chang TT, Sawhney R, Monto A, et al. Implementation of a multidisciplinary treatment team for hepatocellular cancer at a Veterans Affairs Medical Center improves survival. HPB (Oxford). 2008;10(6):405-411. doi:10.1080/13651820802356572
11. Hwa KJ, Dua MM, Wren SM, Visser BC. Missing the obvious: psychosocial obstacles in veterans with hepatocellular carcinoma. HPB (Oxford). 2015;17(12):1124-1129. doi:10.1111/hpb.12508
12. Taylor J, Carr-Lopez S, Robinson A, et al. Determinants of treatment eligibility in veterans with hepatitis C viral infection. Clin Ther. 2017;39(1):130-137. doi:10.1016/j.clinthera.2016.11.019
13. Fargo J, Metraux S, Byrne T, et al. Prevalence and risk of homelessness among US veterans. Prev Chronic Dis. 2012;9:E45.
14. Tsai J, Rosenheck RA. Risk factors for homelessness among US veterans. Epidemiol Rev. 2015;37:177-195. doi:10.1093/epirev/mxu004
15. Tsai J, Link B, Rosenheck RA, Pietrzak RH. Homelessness among a nationally representative sample of US veterans: prevalence, service utilization, and correlates. Soc Psychiatry Psychiatr Epidemiol. 2016;51(6):907-916. doi:10.1007/s00127-016-1210-y
16. Davila JA, Kramer JR, Duan Z, et al. Referral and receipt of treatment for hepatocellular carcinoma in United States veterans: effect of patient and nonpatient factors. Hepatology. 2013;57(5):1858-1868. doi:10.1002/hep.26287
Hepatocellular carcinoma (HCC) remains a major global health problem and is the third leading cause of cancer-related mortality worldwide.1 Management of HCC is complex; as it largely occurs in the background of chronic liver disease, its management must simultaneously address challenges related to the patient’s tumor burden, as well as their underlying liver dysfunction and performance status. HCC is universally fatal without treatment, with a 5-year survival < 10%.2 However, if detected early HCC is potentially curable, with treatments such as hepatic resection, ablation, and/or liver transplantation, which are associated with 5-year survival rates as high as 70%.2 HCC-specific palliative treatments, including intra-arterial therapies (eg, trans-arterial chemoembolization, radioembolization) and systemic chemotherapy, have also been shown to prolong survival in patients with advanced HCC. Therefore, a key driver of patient survival is receipt of HCC-specific therapy.
There is rising incidence and mortality related to HCC in the US veteran population, largely attributed to acquisition of chronic hepatitis C virus (HCV) infection decades prior.3 There is also a high prevalence of psychosocial barriers in this population, such as low socioeconomic status, homelessness, alcohol and substance use disorders, and psychiatric disorders which can negatively influence receipt of medical treatment, including cancer care.4,5 Given the complexity of managing HCC, as well as the plethora of potential treatment options available, it is widely accepted that a multidisciplinary team approach, such as the multidisciplinary tumor board (MDTB) provides optimal care to patients with HCC.2,6 The aim of the present study was to identify in a population of veterans diagnosed with HCC the prevalence of psychosocial barriers to care and assess their impact and the role of an MDTB on receipt of HCC-specific care.
Methods
In June 2007, a joint institutional MDTB was established for patients with primary liver tumors receiving care at the William S. Middleton Memorial Veterans’ Hospital (WSMMVH) in Madison, Wisconsin. As we have described elsewhere, individual cases with their corresponding imaging studies were reviewed at a weekly conference attended by transplant hepatologists, medical oncologists, hepatobiliary and transplant surgeons, pathologists, diagnostic and interventional radiologists, and nurse coordinators.6 Potential therapies offered included surgical resection, liver transplantation (LT), thermal ablation, intra-arterial therapies (chemo and/or radioembolization), systemic chemotherapy, stereotactic radiation, and best supportive care. Decisions regarding the appropriate treatment modality were made based on patient factors, review of their cross-sectional imaging studies and/or histopathology, and context of their underlying liver dysfunction. The tumor board discussion was summarized in meeting minutes as well as tumor board encounters recorded in each patient’s health record. Although patients with benign tumors were presented at the MDTB, only patients with a diagnosis of HCC were included in this study.
A database analysis was conducted of all veteran patients with HCC managed through the WSMMVH MDTB, since its inception up to December 31, 2016, with follow-up until December 31, 2018. Data for analysis included demographics, laboratory parameters at time of diagnosis and treatment, imaging findings, histopathology and/or surgical pathology, treatment rendered, and follow-up information. The primary outcome measured in this study included receipt of any therapy and secondarily, patient survival.
Discrete variables were analyzed with χ2 statistics or Fisher exact test and continuous variables with the student t test. Multivariable analyses were carried out with logistic regression. Variables with a P < .05 were considered statistically significant. Analyses were carried out using IBM SPSS v24.0.
As a quality-improvement initiative for the care and management of veterans with HCC, this study was determined to be exempt from review by the WSMMVH and University of Wisconsin School of Medicine and Public Health Institutional Review Board.
Results
From January 1, 2007, through December 31, 2016, 149 patients with HCC were managed through the MDTB. Baseline demographic data, Model for End-stage Liver Disease (MELD) score and Child-Turcotte-Pugh class, and baseline HCC characteristics of the cohort are shown in Tables 1 and 2.
There was a high prevalence of psychosocial barriers in our study cohort, including alcohol or substance use disorder, mental illness diagnosis, and low socioeconomic status (Table 3). The mean distance traveled to WSMMVH for HCC-specific care was 206 km. Fifty patients in the cohort utilized travel assistance and 33 patients accessed lodging assistance.
HCC Treatments
There was a high rate of receipt of treatment in our study cohort with 127 (85%) patients receiving at least one HCC-specific therapy. Care was individualized and coordinated through our institutional MDTB, with both curative and palliative treatment modalities utilized (Table 4).
Curative treatment, which includes LT, ablation, or resection, was offered to 78 (52%) patients who were within T2 stage. Of these 78 patients who were potential candidates for LT as a curative treatment for HCC, 31 were not deemed suitable transplant candidates. Psychosocial barriers precluded consideration for LT in 7 of the 31 patients due to active substance use, homelessness in 1 patient, and severe mental illness in 3 patients. Medical comorbidities, advanced patient age, and patient preference accounted for the remainder.
In a univariate analysis of the cohort of 149 patients, factors that decreased the likelihood of receipt of curative HCC therapy included T2 stage or higher at diagnosis and a diagnosis of depression, whereas provision for lodging was associated with increased likelihood of receiving HCC-specific care (Table 5). Other factors that influenced receipt of any treatment included patient’s MELD score, total bilirubin, and serum α-fetoprotein, a surrogate marker for tumor stage. In the multivariable analysis, predictors of receiving curative therapy included absence of substance use, within T2 stage of tumor, and Child-Turcotte-Pugh class A cirrhosis. The presence of psychosocial barriers apart from substance use did not predict a lower chance of receiving curative HCC therapy (including homelessness, distance traveled to center, mental health disorder, and low income).
Median survival was 727 (95% CI, 488-966) days from diagnosis. Survival from HCC diagnosis in study cohort was 72% at 1 year, 50% at 2 years, 39% at 3 years, and 36% at 5 years. Death occurred in 71 (48%) patients; HCC accounted for death in 52 (73%) patients, complications of end-stage liver disease in 13 (18%) patients, and other causes for the remainder of patients.
Discussion
Increases in prevalence and mortality related to cirrhosis and HCC have been reported among the US veteran population.3 This is in large part attributable to the burden of chronic HCV infection in this population. As mirrored in the US population in general, we may be at a turning point regarding the gradual increase in prevalence in HCC.7 The prevalence of cirrhosis and viral-related HCC related to HCV infection will decline with availability of effective antiviral therapy. Alcoholic liver disease remains a main etiological factor for development of cirrhosis and HCC. Nonalcoholic fatty liver disease is becoming a more prevalent cause for development of cirrhosis, indication for liver transplantation, and development of HCC, and indeed may lead to HCC even in the absence of cirrhosis.8
HCC remains a challenging clinical problem.2 As the vast majority of cases arise in the context of cirrhosis, management of HCC not only must address the cancer stage at diagnosis, but also the patient’s underlying liver dysfunction and performance status. Receipt of HCC-specific therapy is a key driver of patient outcome, with curative therapies available for those diagnosed with early-stage disease. We and others have shown that a multidisciplinary approach to coordinate, individualize, and optimize care for these complex patients can improve the rate of treatment utilization, reduce treatment delays, and improve patient survival.6,9,10
Patient psychosocial barriers, such as low socioeconomic status, homelessness, alcohol and substance use, and psychiatric disorders, are more prevalent among the veteran population and have the potential to negatively influence successful health care delivery. One retrospective study of 100 veterans at a US Department of Veterans Affairs (VA) medical center treated for HCC from 2009 to 2014 showed a majority of the patients lived on a meager income, a high prevalence of homelessness, substance use history in 96% of their cohort, and psychiatric illness in 65% of patients.11 Other studies have documented similar findings in the veteran population, with alcohol, substance use, as well as other uncontrolled comorbidities as barriers to providing care, such as antiviral therapy for chronic HCV infection.12
Herein, we present a cohort of veterans with HCC managed through our MDTB from 2007 to 2016, for whom chronic HCV infection and/or alcoholic liver disease were the main causes of cirrhosis. Our cohort had a high burden of alcohol and substance use disorders while other psychiatric illnesses were also common. Our cohort includes patients who were poor, and even some veterans who lacked a stable home. This profile of poverty and social deprivation among veterans is matched in national data.13-15 Using a tumor board model of nurse navigation and multidisciplinary care, we were able to provide travel and lodging assistance to 50 (34%) and 33 (22%) patients, respectively, in order to facilitate their care.
Our data demonstrate that the impact of psychosocial barriers on our capacity to deliver care varies with the nature of the treatment under consideration: curative vs cancer control. For example, active substance use disorder, homelessness, and severe established mental illness were often considered insurmountable when the treatment in question was LT. Nevertheless, despite the high prevalence in our study group of barriers, such as lack of transport while living far from a VA medical center, or alcohol use disorder, a curative treatment with either LT, tumor ablation, or resection could be offered to over half of our cohort. When noncurative therapies are included, most patients (85%) received HCC-specific care, with good relative survival.
Our reported high receipt of HCC-specific care and patient survival is in contrast to previously reported low rates of HCC-specific care in in a national survey of management of 1296 veteran patients infected with HCV who developed HCC from 1998 to 2006. In this population, HCC-specific treatment was provided to 34%.16 However our data are consistent with our previously published data of patients with HCC managed through an institutional MDTB.6 Indeed, as shown by a univariate analysis in our present study, individualizing care to address modifiable patient barriers, such as providing provisions for lodging if needed, was associated with an increased likelihood of receiving HCC-specific care. On the other hand, advanced tumor stage (> T2) at diagnosis and a diagnosis of depression, which was the most common psychiatric diagnosis in our cohort, were both associated with decreased likelihood of receiving HCC-specific care. Clinical factors such as MELD score, total bilirubin, and serum AFP all affected the likelihood of providing HCC-specific care. In a multivariate analysis, factors that predicted ability to receive curative therapy included absence of substance use, T2 stage of tumor, and Child-Turcotte-Pugh class A cirrhosis. This is expected as patients with HCC within T2 stage (or Milan criteria) with compensated cirrhosis are most likely to receive curative therapies, such as resection, ablation, or LT.2
Conclusions
Our study demonstrates a high burden of psychosocial challenges in veterans with HCC. These accounted for a significant barrier to receive HCC-specific care. Despite the presence of these patient barriers, high rates of HCC-specific treatment are attainable through individualization and coordination of patient care in the context of a MDTB model with nurse navigation. Provision of targeted social support to ameliorate these modifiable factors improves patient outcomes.
Hepatocellular carcinoma (HCC) remains a major global health problem and is the third leading cause of cancer-related mortality worldwide.1 Management of HCC is complex; as it largely occurs in the background of chronic liver disease, its management must simultaneously address challenges related to the patient’s tumor burden, as well as their underlying liver dysfunction and performance status. HCC is universally fatal without treatment, with a 5-year survival < 10%.2 However, if detected early HCC is potentially curable, with treatments such as hepatic resection, ablation, and/or liver transplantation, which are associated with 5-year survival rates as high as 70%.2 HCC-specific palliative treatments, including intra-arterial therapies (eg, trans-arterial chemoembolization, radioembolization) and systemic chemotherapy, have also been shown to prolong survival in patients with advanced HCC. Therefore, a key driver of patient survival is receipt of HCC-specific therapy.
There is rising incidence and mortality related to HCC in the US veteran population, largely attributed to acquisition of chronic hepatitis C virus (HCV) infection decades prior.3 There is also a high prevalence of psychosocial barriers in this population, such as low socioeconomic status, homelessness, alcohol and substance use disorders, and psychiatric disorders which can negatively influence receipt of medical treatment, including cancer care.4,5 Given the complexity of managing HCC, as well as the plethora of potential treatment options available, it is widely accepted that a multidisciplinary team approach, such as the multidisciplinary tumor board (MDTB) provides optimal care to patients with HCC.2,6 The aim of the present study was to identify in a population of veterans diagnosed with HCC the prevalence of psychosocial barriers to care and assess their impact and the role of an MDTB on receipt of HCC-specific care.
Methods
In June 2007, a joint institutional MDTB was established for patients with primary liver tumors receiving care at the William S. Middleton Memorial Veterans’ Hospital (WSMMVH) in Madison, Wisconsin. As we have described elsewhere, individual cases with their corresponding imaging studies were reviewed at a weekly conference attended by transplant hepatologists, medical oncologists, hepatobiliary and transplant surgeons, pathologists, diagnostic and interventional radiologists, and nurse coordinators.6 Potential therapies offered included surgical resection, liver transplantation (LT), thermal ablation, intra-arterial therapies (chemo and/or radioembolization), systemic chemotherapy, stereotactic radiation, and best supportive care. Decisions regarding the appropriate treatment modality were made based on patient factors, review of their cross-sectional imaging studies and/or histopathology, and context of their underlying liver dysfunction. The tumor board discussion was summarized in meeting minutes as well as tumor board encounters recorded in each patient’s health record. Although patients with benign tumors were presented at the MDTB, only patients with a diagnosis of HCC were included in this study.
A database analysis was conducted of all veteran patients with HCC managed through the WSMMVH MDTB, since its inception up to December 31, 2016, with follow-up until December 31, 2018. Data for analysis included demographics, laboratory parameters at time of diagnosis and treatment, imaging findings, histopathology and/or surgical pathology, treatment rendered, and follow-up information. The primary outcome measured in this study included receipt of any therapy and secondarily, patient survival.
Discrete variables were analyzed with χ2 statistics or Fisher exact test and continuous variables with the student t test. Multivariable analyses were carried out with logistic regression. Variables with a P < .05 were considered statistically significant. Analyses were carried out using IBM SPSS v24.0.
As a quality-improvement initiative for the care and management of veterans with HCC, this study was determined to be exempt from review by the WSMMVH and University of Wisconsin School of Medicine and Public Health Institutional Review Board.
Results
From January 1, 2007, through December 31, 2016, 149 patients with HCC were managed through the MDTB. Baseline demographic data, Model for End-stage Liver Disease (MELD) score and Child-Turcotte-Pugh class, and baseline HCC characteristics of the cohort are shown in Tables 1 and 2.
There was a high prevalence of psychosocial barriers in our study cohort, including alcohol or substance use disorder, mental illness diagnosis, and low socioeconomic status (Table 3). The mean distance traveled to WSMMVH for HCC-specific care was 206 km. Fifty patients in the cohort utilized travel assistance and 33 patients accessed lodging assistance.
HCC Treatments
There was a high rate of receipt of treatment in our study cohort with 127 (85%) patients receiving at least one HCC-specific therapy. Care was individualized and coordinated through our institutional MDTB, with both curative and palliative treatment modalities utilized (Table 4).
Curative treatment, which includes LT, ablation, or resection, was offered to 78 (52%) patients who were within T2 stage. Of these 78 patients who were potential candidates for LT as a curative treatment for HCC, 31 were not deemed suitable transplant candidates. Psychosocial barriers precluded consideration for LT in 7 of the 31 patients due to active substance use, homelessness in 1 patient, and severe mental illness in 3 patients. Medical comorbidities, advanced patient age, and patient preference accounted for the remainder.
In a univariate analysis of the cohort of 149 patients, factors that decreased the likelihood of receipt of curative HCC therapy included T2 stage or higher at diagnosis and a diagnosis of depression, whereas provision for lodging was associated with increased likelihood of receiving HCC-specific care (Table 5). Other factors that influenced receipt of any treatment included patient’s MELD score, total bilirubin, and serum α-fetoprotein, a surrogate marker for tumor stage. In the multivariable analysis, predictors of receiving curative therapy included absence of substance use, within T2 stage of tumor, and Child-Turcotte-Pugh class A cirrhosis. The presence of psychosocial barriers apart from substance use did not predict a lower chance of receiving curative HCC therapy (including homelessness, distance traveled to center, mental health disorder, and low income).
Median survival was 727 (95% CI, 488-966) days from diagnosis. Survival from HCC diagnosis in study cohort was 72% at 1 year, 50% at 2 years, 39% at 3 years, and 36% at 5 years. Death occurred in 71 (48%) patients; HCC accounted for death in 52 (73%) patients, complications of end-stage liver disease in 13 (18%) patients, and other causes for the remainder of patients.
Discussion
Increases in prevalence and mortality related to cirrhosis and HCC have been reported among the US veteran population.3 This is in large part attributable to the burden of chronic HCV infection in this population. As mirrored in the US population in general, we may be at a turning point regarding the gradual increase in prevalence in HCC.7 The prevalence of cirrhosis and viral-related HCC related to HCV infection will decline with availability of effective antiviral therapy. Alcoholic liver disease remains a main etiological factor for development of cirrhosis and HCC. Nonalcoholic fatty liver disease is becoming a more prevalent cause for development of cirrhosis, indication for liver transplantation, and development of HCC, and indeed may lead to HCC even in the absence of cirrhosis.8
HCC remains a challenging clinical problem.2 As the vast majority of cases arise in the context of cirrhosis, management of HCC not only must address the cancer stage at diagnosis, but also the patient’s underlying liver dysfunction and performance status. Receipt of HCC-specific therapy is a key driver of patient outcome, with curative therapies available for those diagnosed with early-stage disease. We and others have shown that a multidisciplinary approach to coordinate, individualize, and optimize care for these complex patients can improve the rate of treatment utilization, reduce treatment delays, and improve patient survival.6,9,10
Patient psychosocial barriers, such as low socioeconomic status, homelessness, alcohol and substance use, and psychiatric disorders, are more prevalent among the veteran population and have the potential to negatively influence successful health care delivery. One retrospective study of 100 veterans at a US Department of Veterans Affairs (VA) medical center treated for HCC from 2009 to 2014 showed a majority of the patients lived on a meager income, a high prevalence of homelessness, substance use history in 96% of their cohort, and psychiatric illness in 65% of patients.11 Other studies have documented similar findings in the veteran population, with alcohol, substance use, as well as other uncontrolled comorbidities as barriers to providing care, such as antiviral therapy for chronic HCV infection.12
Herein, we present a cohort of veterans with HCC managed through our MDTB from 2007 to 2016, for whom chronic HCV infection and/or alcoholic liver disease were the main causes of cirrhosis. Our cohort had a high burden of alcohol and substance use disorders while other psychiatric illnesses were also common. Our cohort includes patients who were poor, and even some veterans who lacked a stable home. This profile of poverty and social deprivation among veterans is matched in national data.13-15 Using a tumor board model of nurse navigation and multidisciplinary care, we were able to provide travel and lodging assistance to 50 (34%) and 33 (22%) patients, respectively, in order to facilitate their care.
Our data demonstrate that the impact of psychosocial barriers on our capacity to deliver care varies with the nature of the treatment under consideration: curative vs cancer control. For example, active substance use disorder, homelessness, and severe established mental illness were often considered insurmountable when the treatment in question was LT. Nevertheless, despite the high prevalence in our study group of barriers, such as lack of transport while living far from a VA medical center, or alcohol use disorder, a curative treatment with either LT, tumor ablation, or resection could be offered to over half of our cohort. When noncurative therapies are included, most patients (85%) received HCC-specific care, with good relative survival.
Our reported high receipt of HCC-specific care and patient survival is in contrast to previously reported low rates of HCC-specific care in in a national survey of management of 1296 veteran patients infected with HCV who developed HCC from 1998 to 2006. In this population, HCC-specific treatment was provided to 34%.16 However our data are consistent with our previously published data of patients with HCC managed through an institutional MDTB.6 Indeed, as shown by a univariate analysis in our present study, individualizing care to address modifiable patient barriers, such as providing provisions for lodging if needed, was associated with an increased likelihood of receiving HCC-specific care. On the other hand, advanced tumor stage (> T2) at diagnosis and a diagnosis of depression, which was the most common psychiatric diagnosis in our cohort, were both associated with decreased likelihood of receiving HCC-specific care. Clinical factors such as MELD score, total bilirubin, and serum AFP all affected the likelihood of providing HCC-specific care. In a multivariate analysis, factors that predicted ability to receive curative therapy included absence of substance use, T2 stage of tumor, and Child-Turcotte-Pugh class A cirrhosis. This is expected as patients with HCC within T2 stage (or Milan criteria) with compensated cirrhosis are most likely to receive curative therapies, such as resection, ablation, or LT.2
Conclusions
Our study demonstrates a high burden of psychosocial challenges in veterans with HCC. These accounted for a significant barrier to receive HCC-specific care. Despite the presence of these patient barriers, high rates of HCC-specific treatment are attainable through individualization and coordination of patient care in the context of a MDTB model with nurse navigation. Provision of targeted social support to ameliorate these modifiable factors improves patient outcomes.
1. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73(suppl 1):4-13. doi:10.1002/hep.31288.
2. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723-750. doi:10.1002/hep.29913
3. Beste LA, Leipertz SL, Green PK, Dominitz JA, Ross D, Ioannou GN. Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001-2013. Gastroenterology. 2015;149(6):1471-e18. doi:10.1053/j.gastro.2015.07.056
4. Kazis LE, Miller DR, Clark J, et al. Health-related quality of life in patients served by the Department of Veterans Affairs: results from the Veterans Health Study. Arch Intern Med. 1998;158(6):626-632. doi:10.1001/archinte.158.6.626
5. Slind LM, Keating TM, Fisher AG, Rose TG. A patient navigation model for veterans traveling for cancer care. Fed Pract. 2016;33(suppl 1):40S-45S.
6. Agarwal PD, Phillips P, Hillman L, et al. Multidisciplinary management of hepatocellular carcinoma improves access to therapy and patient survival. J Clin Gastroenterol. 2017;51(9):845-849. doi:10.1097/MCG.0000000000000825
7. White DL, Thrift AP, Kanwal F, Davila J, El-Serag HB. Incidence of hepatocellular carcinoma in all 50 United States, From 2000 Through 2012. Gastroenterology. 2017;152(4):812-820.e5. doi:10.1053/j.gastro.2016.11.020
8. Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology. 2018;155(6):1828-1837.e2. doi:10.1053/j.gastro.2018.08.024
9. Yopp AC, Mansour JC, Beg MS, et al. Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome. Ann Surg Oncol. 2014;21(4):1287-1295. doi:10.1245/s10434-013-3413-8
10. Chang TT, Sawhney R, Monto A, et al. Implementation of a multidisciplinary treatment team for hepatocellular cancer at a Veterans Affairs Medical Center improves survival. HPB (Oxford). 2008;10(6):405-411. doi:10.1080/13651820802356572
11. Hwa KJ, Dua MM, Wren SM, Visser BC. Missing the obvious: psychosocial obstacles in veterans with hepatocellular carcinoma. HPB (Oxford). 2015;17(12):1124-1129. doi:10.1111/hpb.12508
12. Taylor J, Carr-Lopez S, Robinson A, et al. Determinants of treatment eligibility in veterans with hepatitis C viral infection. Clin Ther. 2017;39(1):130-137. doi:10.1016/j.clinthera.2016.11.019
13. Fargo J, Metraux S, Byrne T, et al. Prevalence and risk of homelessness among US veterans. Prev Chronic Dis. 2012;9:E45.
14. Tsai J, Rosenheck RA. Risk factors for homelessness among US veterans. Epidemiol Rev. 2015;37:177-195. doi:10.1093/epirev/mxu004
15. Tsai J, Link B, Rosenheck RA, Pietrzak RH. Homelessness among a nationally representative sample of US veterans: prevalence, service utilization, and correlates. Soc Psychiatry Psychiatr Epidemiol. 2016;51(6):907-916. doi:10.1007/s00127-016-1210-y
16. Davila JA, Kramer JR, Duan Z, et al. Referral and receipt of treatment for hepatocellular carcinoma in United States veterans: effect of patient and nonpatient factors. Hepatology. 2013;57(5):1858-1868. doi:10.1002/hep.26287
1. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73(suppl 1):4-13. doi:10.1002/hep.31288.
2. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723-750. doi:10.1002/hep.29913
3. Beste LA, Leipertz SL, Green PK, Dominitz JA, Ross D, Ioannou GN. Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001-2013. Gastroenterology. 2015;149(6):1471-e18. doi:10.1053/j.gastro.2015.07.056
4. Kazis LE, Miller DR, Clark J, et al. Health-related quality of life in patients served by the Department of Veterans Affairs: results from the Veterans Health Study. Arch Intern Med. 1998;158(6):626-632. doi:10.1001/archinte.158.6.626
5. Slind LM, Keating TM, Fisher AG, Rose TG. A patient navigation model for veterans traveling for cancer care. Fed Pract. 2016;33(suppl 1):40S-45S.
6. Agarwal PD, Phillips P, Hillman L, et al. Multidisciplinary management of hepatocellular carcinoma improves access to therapy and patient survival. J Clin Gastroenterol. 2017;51(9):845-849. doi:10.1097/MCG.0000000000000825
7. White DL, Thrift AP, Kanwal F, Davila J, El-Serag HB. Incidence of hepatocellular carcinoma in all 50 United States, From 2000 Through 2012. Gastroenterology. 2017;152(4):812-820.e5. doi:10.1053/j.gastro.2016.11.020
8. Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology. 2018;155(6):1828-1837.e2. doi:10.1053/j.gastro.2018.08.024
9. Yopp AC, Mansour JC, Beg MS, et al. Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome. Ann Surg Oncol. 2014;21(4):1287-1295. doi:10.1245/s10434-013-3413-8
10. Chang TT, Sawhney R, Monto A, et al. Implementation of a multidisciplinary treatment team for hepatocellular cancer at a Veterans Affairs Medical Center improves survival. HPB (Oxford). 2008;10(6):405-411. doi:10.1080/13651820802356572
11. Hwa KJ, Dua MM, Wren SM, Visser BC. Missing the obvious: psychosocial obstacles in veterans with hepatocellular carcinoma. HPB (Oxford). 2015;17(12):1124-1129. doi:10.1111/hpb.12508
12. Taylor J, Carr-Lopez S, Robinson A, et al. Determinants of treatment eligibility in veterans with hepatitis C viral infection. Clin Ther. 2017;39(1):130-137. doi:10.1016/j.clinthera.2016.11.019
13. Fargo J, Metraux S, Byrne T, et al. Prevalence and risk of homelessness among US veterans. Prev Chronic Dis. 2012;9:E45.
14. Tsai J, Rosenheck RA. Risk factors for homelessness among US veterans. Epidemiol Rev. 2015;37:177-195. doi:10.1093/epirev/mxu004
15. Tsai J, Link B, Rosenheck RA, Pietrzak RH. Homelessness among a nationally representative sample of US veterans: prevalence, service utilization, and correlates. Soc Psychiatry Psychiatr Epidemiol. 2016;51(6):907-916. doi:10.1007/s00127-016-1210-y
16. Davila JA, Kramer JR, Duan Z, et al. Referral and receipt of treatment for hepatocellular carcinoma in United States veterans: effect of patient and nonpatient factors. Hepatology. 2013;57(5):1858-1868. doi:10.1002/hep.26287
Women with lung cancer live longer than men
“In this first Australian prospective study of lung cancer survival comparing men and women, we found that men had a 43% greater risk of dying from their lung cancer than women,” comments lead author Xue Qin Yu, PhD, the Daffodil Centre, the University of Sydney, and colleagues.
“[However], when all prognostic factors were considered together, most of the survival differential disappeared,” they add.
“These results suggest that sex differences in lung cancer survival can be largely explained by known prognostic factors,” Dr. Yu and colleagues emphasize.
The study was published in the May issue of the Journal of Thoracic Oncology.
The ‘45 and up’ study
The findings come from the Sax Institute’s 45 and Up Study, an ongoing trial involving over 267,000 participants aged 45 years and older living in New South Wales, Australia. Patients were recruited to the study between 2006 and 2009. At the time of recruitment, patients were cancer free.
A total of 1,130 participants were diagnosed with having lung cancer during follow-up – 488 women and 642 men. Compared with men, women were, on average, younger at the time of diagnosis, had fewer comorbidities, and were more likely to be never-smokers or to have been exposed to passive smoke.
Women were also more likely to be diagnosed with adenocarcinoma than men and to receive surgery within 6 months of their diagnosis.
“Lung cancer survival was significantly higher for women,” the authors report, at a median of 1.28 years versus 0.77 years for men (P < .0001).
Within each subgroup of major prognostic factors – histologic subtype, cancer stage, cancer treatment, and smoking status – women again survived significantly longer than men.
Interestingly, the authors note that “women with adenocarcinoma had significantly better survival than men with adenocarcinoma independent of smoking status,” (P = .0009). This suggests that sex differences in tumor biology may play a role in explaining the sex survival differential between men and women, they commented. That said, never-smokers had a 16% lower risk for lung cancer death than ever-smokers after adjusting for age, the authors point out.
The authors also note that approximately half of the disparity in survival between the sexes could be explained by differences in the receipt of anticancer therapy within 6 months of the diagnosis. “This could partly be due to a lower proportion of men having surgery within 6 months than women,” investigators speculate, at 17% versus 25%, respectively.
Men were also older than women at the time of diagnosis, were less likely to be never-smokers, and had more comorbidities, all of which might also have prevented them from having surgery. Women with lung cancer may also respond better to chemotherapy than men, although the sex disparity in survival persisted even among patients who did not receive any treatment for their cancer within 6 months of their diagnosis, investigators point out.
Furthermore, “smoking history at baseline was identified as a significant contributing factor to the sex survival disparity, explaining approximately 28% of the overall disparity,” Dr. Yu and colleagues observe.
Only 8% of men diagnosed with lung cancer were never-smokers, compared with 23% of women. The authors note that never-smokers are more likely to receive aggressive or complete treatment and respond well to treatment.
Similarly, tumor-related factors together explained about one-quarter of the overall sex disparity in survival.
Screening guidelines
Commenting on the findings in an accompanying editorial, Claudia Poleri, MD, Hospital María Ferrer, Buenos Aires, says that this Australian study provides “valuable information.”
“The risk of dying from lung cancer was significantly higher for men than for women,” she writes. “Differences in treatment-related factors explained 50% of the sex survival differential, followed by lifestyle and tumor-related factors (28% and 26%, respectively).
“Nevertheless, these differences alone do not explain the higher survival in women,” she comments.
“Does it matter to analyze the differences by sex in lung cancer?” Dr. Poleri asks in the editorial, and then answers herself: “It matters.”
“It is necessary to implement screening programs and build artificial intelligence diagnostic algorithms considering the role of sex and gender equity to ensure that innovative technologies do not induce disparities in clinical care,” she writes.
“It is crucial to conduct education and health public programs that consider these differences, optimizing the use of available resources, [and] it is essential to improve the accuracy of research design and clinical trials,” she adds.
Dr. Yu and Dr. Poleri declared no relevant financial interests.
A version of this article first appeared on Medscape.com.
“In this first Australian prospective study of lung cancer survival comparing men and women, we found that men had a 43% greater risk of dying from their lung cancer than women,” comments lead author Xue Qin Yu, PhD, the Daffodil Centre, the University of Sydney, and colleagues.
“[However], when all prognostic factors were considered together, most of the survival differential disappeared,” they add.
“These results suggest that sex differences in lung cancer survival can be largely explained by known prognostic factors,” Dr. Yu and colleagues emphasize.
The study was published in the May issue of the Journal of Thoracic Oncology.
The ‘45 and up’ study
The findings come from the Sax Institute’s 45 and Up Study, an ongoing trial involving over 267,000 participants aged 45 years and older living in New South Wales, Australia. Patients were recruited to the study between 2006 and 2009. At the time of recruitment, patients were cancer free.
A total of 1,130 participants were diagnosed with having lung cancer during follow-up – 488 women and 642 men. Compared with men, women were, on average, younger at the time of diagnosis, had fewer comorbidities, and were more likely to be never-smokers or to have been exposed to passive smoke.
Women were also more likely to be diagnosed with adenocarcinoma than men and to receive surgery within 6 months of their diagnosis.
“Lung cancer survival was significantly higher for women,” the authors report, at a median of 1.28 years versus 0.77 years for men (P < .0001).
Within each subgroup of major prognostic factors – histologic subtype, cancer stage, cancer treatment, and smoking status – women again survived significantly longer than men.
Interestingly, the authors note that “women with adenocarcinoma had significantly better survival than men with adenocarcinoma independent of smoking status,” (P = .0009). This suggests that sex differences in tumor biology may play a role in explaining the sex survival differential between men and women, they commented. That said, never-smokers had a 16% lower risk for lung cancer death than ever-smokers after adjusting for age, the authors point out.
The authors also note that approximately half of the disparity in survival between the sexes could be explained by differences in the receipt of anticancer therapy within 6 months of the diagnosis. “This could partly be due to a lower proportion of men having surgery within 6 months than women,” investigators speculate, at 17% versus 25%, respectively.
Men were also older than women at the time of diagnosis, were less likely to be never-smokers, and had more comorbidities, all of which might also have prevented them from having surgery. Women with lung cancer may also respond better to chemotherapy than men, although the sex disparity in survival persisted even among patients who did not receive any treatment for their cancer within 6 months of their diagnosis, investigators point out.
Furthermore, “smoking history at baseline was identified as a significant contributing factor to the sex survival disparity, explaining approximately 28% of the overall disparity,” Dr. Yu and colleagues observe.
Only 8% of men diagnosed with lung cancer were never-smokers, compared with 23% of women. The authors note that never-smokers are more likely to receive aggressive or complete treatment and respond well to treatment.
Similarly, tumor-related factors together explained about one-quarter of the overall sex disparity in survival.
Screening guidelines
Commenting on the findings in an accompanying editorial, Claudia Poleri, MD, Hospital María Ferrer, Buenos Aires, says that this Australian study provides “valuable information.”
“The risk of dying from lung cancer was significantly higher for men than for women,” she writes. “Differences in treatment-related factors explained 50% of the sex survival differential, followed by lifestyle and tumor-related factors (28% and 26%, respectively).
“Nevertheless, these differences alone do not explain the higher survival in women,” she comments.
“Does it matter to analyze the differences by sex in lung cancer?” Dr. Poleri asks in the editorial, and then answers herself: “It matters.”
“It is necessary to implement screening programs and build artificial intelligence diagnostic algorithms considering the role of sex and gender equity to ensure that innovative technologies do not induce disparities in clinical care,” she writes.
“It is crucial to conduct education and health public programs that consider these differences, optimizing the use of available resources, [and] it is essential to improve the accuracy of research design and clinical trials,” she adds.
Dr. Yu and Dr. Poleri declared no relevant financial interests.
A version of this article first appeared on Medscape.com.
“In this first Australian prospective study of lung cancer survival comparing men and women, we found that men had a 43% greater risk of dying from their lung cancer than women,” comments lead author Xue Qin Yu, PhD, the Daffodil Centre, the University of Sydney, and colleagues.
“[However], when all prognostic factors were considered together, most of the survival differential disappeared,” they add.
“These results suggest that sex differences in lung cancer survival can be largely explained by known prognostic factors,” Dr. Yu and colleagues emphasize.
The study was published in the May issue of the Journal of Thoracic Oncology.
The ‘45 and up’ study
The findings come from the Sax Institute’s 45 and Up Study, an ongoing trial involving over 267,000 participants aged 45 years and older living in New South Wales, Australia. Patients were recruited to the study between 2006 and 2009. At the time of recruitment, patients were cancer free.
A total of 1,130 participants were diagnosed with having lung cancer during follow-up – 488 women and 642 men. Compared with men, women were, on average, younger at the time of diagnosis, had fewer comorbidities, and were more likely to be never-smokers or to have been exposed to passive smoke.
Women were also more likely to be diagnosed with adenocarcinoma than men and to receive surgery within 6 months of their diagnosis.
“Lung cancer survival was significantly higher for women,” the authors report, at a median of 1.28 years versus 0.77 years for men (P < .0001).
Within each subgroup of major prognostic factors – histologic subtype, cancer stage, cancer treatment, and smoking status – women again survived significantly longer than men.
Interestingly, the authors note that “women with adenocarcinoma had significantly better survival than men with adenocarcinoma independent of smoking status,” (P = .0009). This suggests that sex differences in tumor biology may play a role in explaining the sex survival differential between men and women, they commented. That said, never-smokers had a 16% lower risk for lung cancer death than ever-smokers after adjusting for age, the authors point out.
The authors also note that approximately half of the disparity in survival between the sexes could be explained by differences in the receipt of anticancer therapy within 6 months of the diagnosis. “This could partly be due to a lower proportion of men having surgery within 6 months than women,” investigators speculate, at 17% versus 25%, respectively.
Men were also older than women at the time of diagnosis, were less likely to be never-smokers, and had more comorbidities, all of which might also have prevented them from having surgery. Women with lung cancer may also respond better to chemotherapy than men, although the sex disparity in survival persisted even among patients who did not receive any treatment for their cancer within 6 months of their diagnosis, investigators point out.
Furthermore, “smoking history at baseline was identified as a significant contributing factor to the sex survival disparity, explaining approximately 28% of the overall disparity,” Dr. Yu and colleagues observe.
Only 8% of men diagnosed with lung cancer were never-smokers, compared with 23% of women. The authors note that never-smokers are more likely to receive aggressive or complete treatment and respond well to treatment.
Similarly, tumor-related factors together explained about one-quarter of the overall sex disparity in survival.
Screening guidelines
Commenting on the findings in an accompanying editorial, Claudia Poleri, MD, Hospital María Ferrer, Buenos Aires, says that this Australian study provides “valuable information.”
“The risk of dying from lung cancer was significantly higher for men than for women,” she writes. “Differences in treatment-related factors explained 50% of the sex survival differential, followed by lifestyle and tumor-related factors (28% and 26%, respectively).
“Nevertheless, these differences alone do not explain the higher survival in women,” she comments.
“Does it matter to analyze the differences by sex in lung cancer?” Dr. Poleri asks in the editorial, and then answers herself: “It matters.”
“It is necessary to implement screening programs and build artificial intelligence diagnostic algorithms considering the role of sex and gender equity to ensure that innovative technologies do not induce disparities in clinical care,” she writes.
“It is crucial to conduct education and health public programs that consider these differences, optimizing the use of available resources, [and] it is essential to improve the accuracy of research design and clinical trials,” she adds.
Dr. Yu and Dr. Poleri declared no relevant financial interests.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THORACIC ONCOLOGY