AVAHO

A new interim analysis of a large randomized, phase 3 trial provides more evidence that a combination of ibrutinib and rituximab is a better option for younger patients with untreated chronic lymphocytic leukemia (CLL) than the once-standard combination of fludarabine, cyclophosphamide, and rituximab (FCR).

The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).

“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.

There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.

Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”

The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.

According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.

The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.

From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).

Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.

Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.

However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.

In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”

The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)

As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.

All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.

Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).

Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.” 

Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”

He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.

The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.

A new interim analysis of a large randomized, phase 3 trial provides more evidence that a combination of ibrutinib and rituximab is a better option for younger patients with untreated chronic lymphocytic leukemia (CLL) than the once-standard combination of fludarabine, cyclophosphamide, and rituximab (FCR).

The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).

“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.

There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.

Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”

The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.

According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.

The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.

From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).

Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.

Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.

However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.

In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”

The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)

As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.

All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.

Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).

Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.” 

Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”

He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.

The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.

A new interim analysis of a large randomized, phase 3 trial provides more evidence that a combination of ibrutinib and rituximab is a better option for younger patients with untreated chronic lymphocytic leukemia (CLL) than the once-standard combination of fludarabine, cyclophosphamide, and rituximab (FCR).

The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).

“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.

There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.

Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”

The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.

According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.

The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.

From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).

Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.

Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.

However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.

In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”

The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)

As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.

All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.

Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).

Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.” 

Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”

He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.

The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.

Treatment options for patients with cancer that is detected at a late stage are severely limited, which usually leads to an unfavorable prognosis for such patients. Indeed, the options available for patients with metastatic solid cancers are scarcely curative. Therefore, early diagnosis of neoplasia remains a fundamental mainstay for improving outcomes for cancer patients.

Histopathology is the current gold standard for cancer diagnosis. Biopsy is an invasive procedure that provides physicians with further samples to test but that furnishes limited information concerning tumor heterogeneity. Biopsy specimens are usually obtained only when there is clinical evidence of neoplasia, which significantly limits their usefulness in early diagnosis.

Around 20 years ago, it was discovered that the presence of circulating tumor cells (CTC) in patients with metastatic breast cancer who were about to begin a new line of treatment was predictive of overall and progression-free survival. The prognostic value of CTC was independent of the line of treatment (first or second) and was greater than that of the site of metastasis, the type of therapy, and the time to metastasis after complete primary resection. These results support the idea that the presence of CTC could be used to modify the system for staging advanced disease.

Since then, research into liquid biopsy assays has expanded rapidly, and many biomarkers have been studied in various body fluids for their usefulness in assessing solid tumors.
 

Liquid vs. tissue

Liquid biopsy is a minimally invasive tool that is easy to use. It is employed to detect cancer, to assess treatment response, or to monitor disease progression. Liquid biopsy produces test material from primary and metastatic (or micrometastatic) sites and provides a more heterogeneous picture of the entire tumor cell population, compared with specimens obtained with tissue biopsy.

Metastasis

The notion that metastatic lesions are formed from cancer cells that have disseminated from advanced primary tumors has been substantially revised following the identification of disseminated tumor cells (DTC) in the bone marrow of patients with early-stage disease. These results have led researchers to no longer view cancer metastasis as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as metastasizing cells assume new phenotypes while abandoning older behaviors.

The initiation of metastasis is not simply a cell-autonomous event but is heavily influenced by complex tissue microenvironments. Although colonization of distant tissues by DTC is an extremely inefficient process, at times, relatively numerous CTC can be detected in the blood of cancer patients (> 1,000 CTC/mL of blood plasma), whereas the number of clinically detectable metastases is disproportionately low, confirming that tumor cell diffusion can happen at an early stage but usually occurs later on.
 

Early dissemination

Little is currently known about the preference of cancer subtypes for distinct tissues or about the receptiveness of a tissue as a metastatic site. What endures as one of the most confounding clinical phenomena is that patients may undergo tumor resection and remain apparently disease free for months, years, and even decades, only to experience relapse and be diagnosed with late-stage metastatic disease. This course may be a result of cell seeding from minimal residual disease after resection of the primary tumor or of preexisting clinically undetectable micrometastases. It may also arise from early disseminated cells that remain dormant and resistant to therapy until they suddenly reawaken to initiate proliferation into clinically detectable macrometastases.

Dormant DTC could be the main reason for delayed detection of metastases. It is thought that around 40% of patients with prostate cancer who undergo radical prostatectomy present with biochemical recurrence, suggesting that it is likely that hidden DTC or micrometastases are present at the time of the procedure. The finding is consistent with the detection of DTC many years after tumor resection, suggesting they were released before surgical treatment. Nevertheless, research into tumor cell dormancy is limited, owing to the invasive and technically challenging nature of obtaining DTC samples, which are predominantly taken from the bone marrow.
 

CTC metastases

Cancer cells can undergo epithelial-to-mesenchymal transition to facilitate their detachment from the primary tumor and intravasation into the blood circulation (step 1). Dissemination of cancer cells from the primary tumor into circulation can involve either single cells or cell clusters containing multiple CTC as well as immune cells and platelets, known as microemboli. CTC that can survive in circulation (step 2) can exit the bloodstream (step 3) and establish metastatic tumors (step 4), or they can enter dormancy and reside in distant organs, such as the bone marrow.

Use in practice

CTC were discovered over a century ago, but only in recent years has technology been sufficiently advanced to study CTC and to assess their usefulness as biomarkers. Recent evidence suggests that not only do the number of CTC increase during sleep and rest phases but also that these CTC are better able to metastasize, compared to those generated during periods of wakefulness or activity.

CTC clusters (microemboli) are defined as groups of two or more CTC. They can consist of CTC alone (homotypic) or can include various stromal cells, such as cancer-associated fibroblasts or platelets and immune cells (heterotypic). CTC clusters (with or without leukocytes) seem to have greater metastatic capacity, compared with individual CTC.

A multitude of characteristics can be measured in CTC, including genetics and epigenetics, as well as protein levels, which might help in understanding many processes involved in the formation of metastases.

Quantitative assessment of CTC could indicate tumor burden in patients with aggressive cancers, as has been seen in patients with primary lung cancer.
 

Early cancer diagnosis

Early research into CTC didn’t explore their usefulness in diagnosing early-stage tumors because it was thought that CTC were characteristic of advanced-stage disease. This hypothesis was later rejected following evidence of local intravascular invasion of very early cancer cells, even over a period of several hours. This feature may allow CTC to be detected before the clinical diagnosis of cancer.

CTC have been detected in various neoplastic conditions: in breast cancer, seen in 20% of patients with stage I disease, in 26.8% with stage II disease, and 26.7% with stage III disease; in nonmetastatic colorectal cancer, including stage I and II disease; and in prostate cancer, seen in over 50% of patients with localized disease.

The presence of CTC has been proven to be an unfavorable prognostic predictor of overall survival among patients with early-stage non–small cell lung cancer. It distinguishes patients with pancreatic ductal adenocarcinoma from those with noncancerous pancreatic diseases with a sensitivity of 75% and a specificity of 96.3%.

CTC positivity scoring (appropriately defined), combined with serum prostate-specific antigen level, was predictive of a biopsy diagnosis of clinically significant prostate cancer.

All these data support the utility of CTC in early cancer diagnosis. Their link with metastases, and thus with aggressive tumors, gives them an advantage over other (noninvasive or minimally invasive) biomarkers in the early identification of invasive tumors for therapeutic intervention with better cure rates.
 

This article was translated from Univadis Italy. A version appeared on Medscape.com.

Treatment options for patients with cancer that is detected at a late stage are severely limited, which usually leads to an unfavorable prognosis for such patients. Indeed, the options available for patients with metastatic solid cancers are scarcely curative. Therefore, early diagnosis of neoplasia remains a fundamental mainstay for improving outcomes for cancer patients.

Histopathology is the current gold standard for cancer diagnosis. Biopsy is an invasive procedure that provides physicians with further samples to test but that furnishes limited information concerning tumor heterogeneity. Biopsy specimens are usually obtained only when there is clinical evidence of neoplasia, which significantly limits their usefulness in early diagnosis.

Around 20 years ago, it was discovered that the presence of circulating tumor cells (CTC) in patients with metastatic breast cancer who were about to begin a new line of treatment was predictive of overall and progression-free survival. The prognostic value of CTC was independent of the line of treatment (first or second) and was greater than that of the site of metastasis, the type of therapy, and the time to metastasis after complete primary resection. These results support the idea that the presence of CTC could be used to modify the system for staging advanced disease.

Since then, research into liquid biopsy assays has expanded rapidly, and many biomarkers have been studied in various body fluids for their usefulness in assessing solid tumors.
 

Liquid vs. tissue

Liquid biopsy is a minimally invasive tool that is easy to use. It is employed to detect cancer, to assess treatment response, or to monitor disease progression. Liquid biopsy produces test material from primary and metastatic (or micrometastatic) sites and provides a more heterogeneous picture of the entire tumor cell population, compared with specimens obtained with tissue biopsy.

Metastasis

The notion that metastatic lesions are formed from cancer cells that have disseminated from advanced primary tumors has been substantially revised following the identification of disseminated tumor cells (DTC) in the bone marrow of patients with early-stage disease. These results have led researchers to no longer view cancer metastasis as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as metastasizing cells assume new phenotypes while abandoning older behaviors.

The initiation of metastasis is not simply a cell-autonomous event but is heavily influenced by complex tissue microenvironments. Although colonization of distant tissues by DTC is an extremely inefficient process, at times, relatively numerous CTC can be detected in the blood of cancer patients (> 1,000 CTC/mL of blood plasma), whereas the number of clinically detectable metastases is disproportionately low, confirming that tumor cell diffusion can happen at an early stage but usually occurs later on.
 

Early dissemination

Little is currently known about the preference of cancer subtypes for distinct tissues or about the receptiveness of a tissue as a metastatic site. What endures as one of the most confounding clinical phenomena is that patients may undergo tumor resection and remain apparently disease free for months, years, and even decades, only to experience relapse and be diagnosed with late-stage metastatic disease. This course may be a result of cell seeding from minimal residual disease after resection of the primary tumor or of preexisting clinically undetectable micrometastases. It may also arise from early disseminated cells that remain dormant and resistant to therapy until they suddenly reawaken to initiate proliferation into clinically detectable macrometastases.

Dormant DTC could be the main reason for delayed detection of metastases. It is thought that around 40% of patients with prostate cancer who undergo radical prostatectomy present with biochemical recurrence, suggesting that it is likely that hidden DTC or micrometastases are present at the time of the procedure. The finding is consistent with the detection of DTC many years after tumor resection, suggesting they were released before surgical treatment. Nevertheless, research into tumor cell dormancy is limited, owing to the invasive and technically challenging nature of obtaining DTC samples, which are predominantly taken from the bone marrow.
 

CTC metastases

Cancer cells can undergo epithelial-to-mesenchymal transition to facilitate their detachment from the primary tumor and intravasation into the blood circulation (step 1). Dissemination of cancer cells from the primary tumor into circulation can involve either single cells or cell clusters containing multiple CTC as well as immune cells and platelets, known as microemboli. CTC that can survive in circulation (step 2) can exit the bloodstream (step 3) and establish metastatic tumors (step 4), or they can enter dormancy and reside in distant organs, such as the bone marrow.

Use in practice

CTC were discovered over a century ago, but only in recent years has technology been sufficiently advanced to study CTC and to assess their usefulness as biomarkers. Recent evidence suggests that not only do the number of CTC increase during sleep and rest phases but also that these CTC are better able to metastasize, compared to those generated during periods of wakefulness or activity.

CTC clusters (microemboli) are defined as groups of two or more CTC. They can consist of CTC alone (homotypic) or can include various stromal cells, such as cancer-associated fibroblasts or platelets and immune cells (heterotypic). CTC clusters (with or without leukocytes) seem to have greater metastatic capacity, compared with individual CTC.

A multitude of characteristics can be measured in CTC, including genetics and epigenetics, as well as protein levels, which might help in understanding many processes involved in the formation of metastases.

Quantitative assessment of CTC could indicate tumor burden in patients with aggressive cancers, as has been seen in patients with primary lung cancer.
 

Early cancer diagnosis

Early research into CTC didn’t explore their usefulness in diagnosing early-stage tumors because it was thought that CTC were characteristic of advanced-stage disease. This hypothesis was later rejected following evidence of local intravascular invasion of very early cancer cells, even over a period of several hours. This feature may allow CTC to be detected before the clinical diagnosis of cancer.

CTC have been detected in various neoplastic conditions: in breast cancer, seen in 20% of patients with stage I disease, in 26.8% with stage II disease, and 26.7% with stage III disease; in nonmetastatic colorectal cancer, including stage I and II disease; and in prostate cancer, seen in over 50% of patients with localized disease.

The presence of CTC has been proven to be an unfavorable prognostic predictor of overall survival among patients with early-stage non–small cell lung cancer. It distinguishes patients with pancreatic ductal adenocarcinoma from those with noncancerous pancreatic diseases with a sensitivity of 75% and a specificity of 96.3%.

CTC positivity scoring (appropriately defined), combined with serum prostate-specific antigen level, was predictive of a biopsy diagnosis of clinically significant prostate cancer.

All these data support the utility of CTC in early cancer diagnosis. Their link with metastases, and thus with aggressive tumors, gives them an advantage over other (noninvasive or minimally invasive) biomarkers in the early identification of invasive tumors for therapeutic intervention with better cure rates.
 

This article was translated from Univadis Italy. A version appeared on Medscape.com.

Treatment options for patients with cancer that is detected at a late stage are severely limited, which usually leads to an unfavorable prognosis for such patients. Indeed, the options available for patients with metastatic solid cancers are scarcely curative. Therefore, early diagnosis of neoplasia remains a fundamental mainstay for improving outcomes for cancer patients.

Histopathology is the current gold standard for cancer diagnosis. Biopsy is an invasive procedure that provides physicians with further samples to test but that furnishes limited information concerning tumor heterogeneity. Biopsy specimens are usually obtained only when there is clinical evidence of neoplasia, which significantly limits their usefulness in early diagnosis.

Around 20 years ago, it was discovered that the presence of circulating tumor cells (CTC) in patients with metastatic breast cancer who were about to begin a new line of treatment was predictive of overall and progression-free survival. The prognostic value of CTC was independent of the line of treatment (first or second) and was greater than that of the site of metastasis, the type of therapy, and the time to metastasis after complete primary resection. These results support the idea that the presence of CTC could be used to modify the system for staging advanced disease.

Since then, research into liquid biopsy assays has expanded rapidly, and many biomarkers have been studied in various body fluids for their usefulness in assessing solid tumors.
 

Liquid vs. tissue

Liquid biopsy is a minimally invasive tool that is easy to use. It is employed to detect cancer, to assess treatment response, or to monitor disease progression. Liquid biopsy produces test material from primary and metastatic (or micrometastatic) sites and provides a more heterogeneous picture of the entire tumor cell population, compared with specimens obtained with tissue biopsy.

Metastasis

The notion that metastatic lesions are formed from cancer cells that have disseminated from advanced primary tumors has been substantially revised following the identification of disseminated tumor cells (DTC) in the bone marrow of patients with early-stage disease. These results have led researchers to no longer view cancer metastasis as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as metastasizing cells assume new phenotypes while abandoning older behaviors.

The initiation of metastasis is not simply a cell-autonomous event but is heavily influenced by complex tissue microenvironments. Although colonization of distant tissues by DTC is an extremely inefficient process, at times, relatively numerous CTC can be detected in the blood of cancer patients (> 1,000 CTC/mL of blood plasma), whereas the number of clinically detectable metastases is disproportionately low, confirming that tumor cell diffusion can happen at an early stage but usually occurs later on.
 

Early dissemination

Little is currently known about the preference of cancer subtypes for distinct tissues or about the receptiveness of a tissue as a metastatic site. What endures as one of the most confounding clinical phenomena is that patients may undergo tumor resection and remain apparently disease free for months, years, and even decades, only to experience relapse and be diagnosed with late-stage metastatic disease. This course may be a result of cell seeding from minimal residual disease after resection of the primary tumor or of preexisting clinically undetectable micrometastases. It may also arise from early disseminated cells that remain dormant and resistant to therapy until they suddenly reawaken to initiate proliferation into clinically detectable macrometastases.

Dormant DTC could be the main reason for delayed detection of metastases. It is thought that around 40% of patients with prostate cancer who undergo radical prostatectomy present with biochemical recurrence, suggesting that it is likely that hidden DTC or micrometastases are present at the time of the procedure. The finding is consistent with the detection of DTC many years after tumor resection, suggesting they were released before surgical treatment. Nevertheless, research into tumor cell dormancy is limited, owing to the invasive and technically challenging nature of obtaining DTC samples, which are predominantly taken from the bone marrow.
 

CTC metastases

Cancer cells can undergo epithelial-to-mesenchymal transition to facilitate their detachment from the primary tumor and intravasation into the blood circulation (step 1). Dissemination of cancer cells from the primary tumor into circulation can involve either single cells or cell clusters containing multiple CTC as well as immune cells and platelets, known as microemboli. CTC that can survive in circulation (step 2) can exit the bloodstream (step 3) and establish metastatic tumors (step 4), or they can enter dormancy and reside in distant organs, such as the bone marrow.

Use in practice

CTC were discovered over a century ago, but only in recent years has technology been sufficiently advanced to study CTC and to assess their usefulness as biomarkers. Recent evidence suggests that not only do the number of CTC increase during sleep and rest phases but also that these CTC are better able to metastasize, compared to those generated during periods of wakefulness or activity.

CTC clusters (microemboli) are defined as groups of two or more CTC. They can consist of CTC alone (homotypic) or can include various stromal cells, such as cancer-associated fibroblasts or platelets and immune cells (heterotypic). CTC clusters (with or without leukocytes) seem to have greater metastatic capacity, compared with individual CTC.

A multitude of characteristics can be measured in CTC, including genetics and epigenetics, as well as protein levels, which might help in understanding many processes involved in the formation of metastases.

Quantitative assessment of CTC could indicate tumor burden in patients with aggressive cancers, as has been seen in patients with primary lung cancer.
 

Early cancer diagnosis

Early research into CTC didn’t explore their usefulness in diagnosing early-stage tumors because it was thought that CTC were characteristic of advanced-stage disease. This hypothesis was later rejected following evidence of local intravascular invasion of very early cancer cells, even over a period of several hours. This feature may allow CTC to be detected before the clinical diagnosis of cancer.

CTC have been detected in various neoplastic conditions: in breast cancer, seen in 20% of patients with stage I disease, in 26.8% with stage II disease, and 26.7% with stage III disease; in nonmetastatic colorectal cancer, including stage I and II disease; and in prostate cancer, seen in over 50% of patients with localized disease.

The presence of CTC has been proven to be an unfavorable prognostic predictor of overall survival among patients with early-stage non–small cell lung cancer. It distinguishes patients with pancreatic ductal adenocarcinoma from those with noncancerous pancreatic diseases with a sensitivity of 75% and a specificity of 96.3%.

CTC positivity scoring (appropriately defined), combined with serum prostate-specific antigen level, was predictive of a biopsy diagnosis of clinically significant prostate cancer.

All these data support the utility of CTC in early cancer diagnosis. Their link with metastases, and thus with aggressive tumors, gives them an advantage over other (noninvasive or minimally invasive) biomarkers in the early identification of invasive tumors for therapeutic intervention with better cure rates.
 

This article was translated from Univadis Italy. A version appeared on Medscape.com.

This transcript has been edited for clarity.

We need to think about the ways that participating in clinical trials results in increased out-of-pocket costs to our patients and how that limits the ability of marginalized groups to participate. That should be a problem for us.

There are many subtle and some egregious ways that participating in clinical trials can result in increased costs. We may ask patients to come to the clinic more frequently. That may mean costs for transportation, wear and tear on your car, and gas prices. It may also mean that if you work in a job where you don’t have time off, and if you’re not at work, you don’t get paid. That’s a major hit to your take-home pay.

We also need to take a close and more honest look at our study budgets and what we consider standard of care. Now, this becomes a slippery slope because there are clear recommendations that we would all agree, but there are also differences of practice and differences of opinion.

How often should patients with advanced disease, who clinically are doing well, have scans to evaluate their disease status and look for subtle evidence of progression? Are laboratory studies part of the follow-up in patients in the adjuvant setting? Did you really need a urinalysis in somebody who’s going to be starting chemotherapy? Do you need an EKG if you’re going to be giving them a drug that doesn’t have potential cardiac toxicity, for which QTc prolongation is not a problem?

Those are often included in our clinical trials. In some cases, they might be paid for by the trial. In other cases, they’re billed to the insurance provider, which means they’ll contribute to deductibles and copays will apply. It is very likely that they will cost your patient something out of pocket.

Now, this becomes important because many of our consent forms would specifically say that things that are only done for the study are paid for by the study. How we define standard of care becomes vitally important. These issues have not been linked in this way frequently. It is time for us to tackle this problem and think about how we financially support the additional costs of care that can be real barriers for patients to participate in clinical trials.

Clinical trials are how we make progress. The more patients who are able to participate in clinical trials, the better it is for all of us and all our future patients.

Kathy D. Miller, MD, is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. She disclosed no relevant conflicts of interest.
 

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

We need to think about the ways that participating in clinical trials results in increased out-of-pocket costs to our patients and how that limits the ability of marginalized groups to participate. That should be a problem for us.

There are many subtle and some egregious ways that participating in clinical trials can result in increased costs. We may ask patients to come to the clinic more frequently. That may mean costs for transportation, wear and tear on your car, and gas prices. It may also mean that if you work in a job where you don’t have time off, and if you’re not at work, you don’t get paid. That’s a major hit to your take-home pay.

We also need to take a close and more honest look at our study budgets and what we consider standard of care. Now, this becomes a slippery slope because there are clear recommendations that we would all agree, but there are also differences of practice and differences of opinion.

How often should patients with advanced disease, who clinically are doing well, have scans to evaluate their disease status and look for subtle evidence of progression? Are laboratory studies part of the follow-up in patients in the adjuvant setting? Did you really need a urinalysis in somebody who’s going to be starting chemotherapy? Do you need an EKG if you’re going to be giving them a drug that doesn’t have potential cardiac toxicity, for which QTc prolongation is not a problem?

Those are often included in our clinical trials. In some cases, they might be paid for by the trial. In other cases, they’re billed to the insurance provider, which means they’ll contribute to deductibles and copays will apply. It is very likely that they will cost your patient something out of pocket.

Now, this becomes important because many of our consent forms would specifically say that things that are only done for the study are paid for by the study. How we define standard of care becomes vitally important. These issues have not been linked in this way frequently. It is time for us to tackle this problem and think about how we financially support the additional costs of care that can be real barriers for patients to participate in clinical trials.

Clinical trials are how we make progress. The more patients who are able to participate in clinical trials, the better it is for all of us and all our future patients.

Kathy D. Miller, MD, is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. She disclosed no relevant conflicts of interest.
 

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

We need to think about the ways that participating in clinical trials results in increased out-of-pocket costs to our patients and how that limits the ability of marginalized groups to participate. That should be a problem for us.

There are many subtle and some egregious ways that participating in clinical trials can result in increased costs. We may ask patients to come to the clinic more frequently. That may mean costs for transportation, wear and tear on your car, and gas prices. It may also mean that if you work in a job where you don’t have time off, and if you’re not at work, you don’t get paid. That’s a major hit to your take-home pay.

We also need to take a close and more honest look at our study budgets and what we consider standard of care. Now, this becomes a slippery slope because there are clear recommendations that we would all agree, but there are also differences of practice and differences of opinion.

How often should patients with advanced disease, who clinically are doing well, have scans to evaluate their disease status and look for subtle evidence of progression? Are laboratory studies part of the follow-up in patients in the adjuvant setting? Did you really need a urinalysis in somebody who’s going to be starting chemotherapy? Do you need an EKG if you’re going to be giving them a drug that doesn’t have potential cardiac toxicity, for which QTc prolongation is not a problem?

Those are often included in our clinical trials. In some cases, they might be paid for by the trial. In other cases, they’re billed to the insurance provider, which means they’ll contribute to deductibles and copays will apply. It is very likely that they will cost your patient something out of pocket.

Now, this becomes important because many of our consent forms would specifically say that things that are only done for the study are paid for by the study. How we define standard of care becomes vitally important. These issues have not been linked in this way frequently. It is time for us to tackle this problem and think about how we financially support the additional costs of care that can be real barriers for patients to participate in clinical trials.

Clinical trials are how we make progress. The more patients who are able to participate in clinical trials, the better it is for all of us and all our future patients.

Kathy D. Miller, MD, is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. She disclosed no relevant conflicts of interest.
 

A version of this article first appeared on Medscape.com.

I’m Dr. Kenny Lin. I am a family physician and associate director of the Lancaster General Hospital Family Medicine Residency, and I blog at Common Sense Family Doctor.

I’m 47 years old. Two years ago, when the U.S. Preventive Services Task Force (USPSTF) followed the American Cancer Society and lowered the starting age for colorectal cancer (CRC) screening from 50 to 45, my family physician brought up screening options at a health maintenance visit. Although I had expressed some skepticism about this change when the ACS updated its screening guideline in 2018, I generally follow the USPSTF recommendations in my own clinical practice, so I dutifully selected a test that, fortunately, came out negative.

Not everyone in the primary care community, however, is on board with screening average-risk adults in their late 40s for colorectal cancer. The American Academy of Family Physicians (AAFP) published a notable dissent, arguing that the evidence from modeling studies cited by the USPSTF to support lowering the starting age was insufficient. The AAFP also expressed concern that devoting screening resources to younger adults could come at the expense of improving screening rates in older adults who are at higher risk for CRC and increase health care costs without corresponding benefit.

Now, the American College of Physicians has joined the AAFP by releasing an updated guidance statement for CRC screening that discourages screening asymptomatic, average-risk adults between the ages of 45 and 49. In addition to the uncertainty surrounding benefits of screening adults in this age range, the ACP pointed out that starting screening at age 45, compared with age 50, would increase the number of colonoscopies and colonoscopy complications. My colleagues and I recently published a systematic review estimating that for every 10,000 screening colonoscopies performed, 8 people suffer a bowel perforation and 16 to 36 have severe bleeding requiring hospitalization. One in 3 patients undergoing colonoscopies report minor adverse events such as abdominal pain, bloating, and abdominal discomfort in the first 2 weeks following the procedure.

Other aspects of the ACP guidance differ from other colorectal cancer screening guidelines. Unlike the USPSTF, which made no distinctions between various recommended screening tests, the ACP preferentially endorsed fecal immunochemical or high-sensitivity fecal occult blood testing every 2 years, colonoscopy every 10 years, or flexible sigmoidoscopy every 10 years plus a fecal immunochemical test every 2 years. That leaves out stool DNA testing, which my patients increasingly request because they have seen television or online advertisements, and newer blood tests that detect methylation sequences in circulating tumor DNA.

Perhaps most controversial is the ACP’s suggestion that it is probably reasonable for some adults to start screening later than age 50 or undergo screening at longer intervals than currently recommended (for example, colonoscopy every 15 years). Recent data support extending the interval to repeat screening colonoscopy in selected populations; a large cross-sectional study found a low prevalence of advanced adenomas and colorectal cancers in colonoscopies performed 10 or more years after an initial negative colonoscopy, particularly in women and younger patients without gastrointestinal symptoms. A prominent BMJ guideline suggests that patients need not be screened until their estimated 15-year CRC risk is greater than 3% (which most people do not reach until their 60s) and then only need a single sigmoidoscopy or colonoscopy.

Despite some departures from other guidelines, it’s worth emphasizing that the ACP guideline agrees that screening for CRC is generally worthwhile between the ages of 50 and 75 years. On that front, we in primary care have more work to do; the Centers for Disease Control and Prevention estimates that 28% of American adults older than 50 are not up-to-date on CRC screening. And despite some recent debate about the relative benefits and harms of screening colonoscopy, compared with less invasive fecal tests, gastroenterologists and family physicians can agree that the best screening test is the test that gets done.

A version of this article first appeared on Medscape.com.

I’m Dr. Kenny Lin. I am a family physician and associate director of the Lancaster General Hospital Family Medicine Residency, and I blog at Common Sense Family Doctor.

I’m 47 years old. Two years ago, when the U.S. Preventive Services Task Force (USPSTF) followed the American Cancer Society and lowered the starting age for colorectal cancer (CRC) screening from 50 to 45, my family physician brought up screening options at a health maintenance visit. Although I had expressed some skepticism about this change when the ACS updated its screening guideline in 2018, I generally follow the USPSTF recommendations in my own clinical practice, so I dutifully selected a test that, fortunately, came out negative.

Not everyone in the primary care community, however, is on board with screening average-risk adults in their late 40s for colorectal cancer. The American Academy of Family Physicians (AAFP) published a notable dissent, arguing that the evidence from modeling studies cited by the USPSTF to support lowering the starting age was insufficient. The AAFP also expressed concern that devoting screening resources to younger adults could come at the expense of improving screening rates in older adults who are at higher risk for CRC and increase health care costs without corresponding benefit.

Now, the American College of Physicians has joined the AAFP by releasing an updated guidance statement for CRC screening that discourages screening asymptomatic, average-risk adults between the ages of 45 and 49. In addition to the uncertainty surrounding benefits of screening adults in this age range, the ACP pointed out that starting screening at age 45, compared with age 50, would increase the number of colonoscopies and colonoscopy complications. My colleagues and I recently published a systematic review estimating that for every 10,000 screening colonoscopies performed, 8 people suffer a bowel perforation and 16 to 36 have severe bleeding requiring hospitalization. One in 3 patients undergoing colonoscopies report minor adverse events such as abdominal pain, bloating, and abdominal discomfort in the first 2 weeks following the procedure.

Other aspects of the ACP guidance differ from other colorectal cancer screening guidelines. Unlike the USPSTF, which made no distinctions between various recommended screening tests, the ACP preferentially endorsed fecal immunochemical or high-sensitivity fecal occult blood testing every 2 years, colonoscopy every 10 years, or flexible sigmoidoscopy every 10 years plus a fecal immunochemical test every 2 years. That leaves out stool DNA testing, which my patients increasingly request because they have seen television or online advertisements, and newer blood tests that detect methylation sequences in circulating tumor DNA.

Perhaps most controversial is the ACP’s suggestion that it is probably reasonable for some adults to start screening later than age 50 or undergo screening at longer intervals than currently recommended (for example, colonoscopy every 15 years). Recent data support extending the interval to repeat screening colonoscopy in selected populations; a large cross-sectional study found a low prevalence of advanced adenomas and colorectal cancers in colonoscopies performed 10 or more years after an initial negative colonoscopy, particularly in women and younger patients without gastrointestinal symptoms. A prominent BMJ guideline suggests that patients need not be screened until their estimated 15-year CRC risk is greater than 3% (which most people do not reach until their 60s) and then only need a single sigmoidoscopy or colonoscopy.

Despite some departures from other guidelines, it’s worth emphasizing that the ACP guideline agrees that screening for CRC is generally worthwhile between the ages of 50 and 75 years. On that front, we in primary care have more work to do; the Centers for Disease Control and Prevention estimates that 28% of American adults older than 50 are not up-to-date on CRC screening. And despite some recent debate about the relative benefits and harms of screening colonoscopy, compared with less invasive fecal tests, gastroenterologists and family physicians can agree that the best screening test is the test that gets done.

A version of this article first appeared on Medscape.com.

I’m Dr. Kenny Lin. I am a family physician and associate director of the Lancaster General Hospital Family Medicine Residency, and I blog at Common Sense Family Doctor.

I’m 47 years old. Two years ago, when the U.S. Preventive Services Task Force (USPSTF) followed the American Cancer Society and lowered the starting age for colorectal cancer (CRC) screening from 50 to 45, my family physician brought up screening options at a health maintenance visit. Although I had expressed some skepticism about this change when the ACS updated its screening guideline in 2018, I generally follow the USPSTF recommendations in my own clinical practice, so I dutifully selected a test that, fortunately, came out negative.

Not everyone in the primary care community, however, is on board with screening average-risk adults in their late 40s for colorectal cancer. The American Academy of Family Physicians (AAFP) published a notable dissent, arguing that the evidence from modeling studies cited by the USPSTF to support lowering the starting age was insufficient. The AAFP also expressed concern that devoting screening resources to younger adults could come at the expense of improving screening rates in older adults who are at higher risk for CRC and increase health care costs without corresponding benefit.

Now, the American College of Physicians has joined the AAFP by releasing an updated guidance statement for CRC screening that discourages screening asymptomatic, average-risk adults between the ages of 45 and 49. In addition to the uncertainty surrounding benefits of screening adults in this age range, the ACP pointed out that starting screening at age 45, compared with age 50, would increase the number of colonoscopies and colonoscopy complications. My colleagues and I recently published a systematic review estimating that for every 10,000 screening colonoscopies performed, 8 people suffer a bowel perforation and 16 to 36 have severe bleeding requiring hospitalization. One in 3 patients undergoing colonoscopies report minor adverse events such as abdominal pain, bloating, and abdominal discomfort in the first 2 weeks following the procedure.

Other aspects of the ACP guidance differ from other colorectal cancer screening guidelines. Unlike the USPSTF, which made no distinctions between various recommended screening tests, the ACP preferentially endorsed fecal immunochemical or high-sensitivity fecal occult blood testing every 2 years, colonoscopy every 10 years, or flexible sigmoidoscopy every 10 years plus a fecal immunochemical test every 2 years. That leaves out stool DNA testing, which my patients increasingly request because they have seen television or online advertisements, and newer blood tests that detect methylation sequences in circulating tumor DNA.

Perhaps most controversial is the ACP’s suggestion that it is probably reasonable for some adults to start screening later than age 50 or undergo screening at longer intervals than currently recommended (for example, colonoscopy every 15 years). Recent data support extending the interval to repeat screening colonoscopy in selected populations; a large cross-sectional study found a low prevalence of advanced adenomas and colorectal cancers in colonoscopies performed 10 or more years after an initial negative colonoscopy, particularly in women and younger patients without gastrointestinal symptoms. A prominent BMJ guideline suggests that patients need not be screened until their estimated 15-year CRC risk is greater than 3% (which most people do not reach until their 60s) and then only need a single sigmoidoscopy or colonoscopy.

Despite some departures from other guidelines, it’s worth emphasizing that the ACP guideline agrees that screening for CRC is generally worthwhile between the ages of 50 and 75 years. On that front, we in primary care have more work to do; the Centers for Disease Control and Prevention estimates that 28% of American adults older than 50 are not up-to-date on CRC screening. And despite some recent debate about the relative benefits and harms of screening colonoscopy, compared with less invasive fecal tests, gastroenterologists and family physicians can agree that the best screening test is the test that gets done.

A version of this article first appeared on Medscape.com.

Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.

“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.

“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”

While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.

Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.

With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.

The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.

Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.

Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.

Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.

“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.

Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.

The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.

The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.

“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”

The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.

“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”

The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.

“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.

Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.

There are currently no approved anti-DLL4 antibody drugs for use in humans.

“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”

Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.

Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.

“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.

“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”

While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.

Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.

With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.

The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.

Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.

Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.

Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.

“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.

Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.

The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.

The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.

“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”

The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.

“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”

The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.

“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.

Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.

There are currently no approved anti-DLL4 antibody drugs for use in humans.

“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”

Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.

Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.

“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.

“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”

While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.

Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.

With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.

The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.

Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.

Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.

Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.

“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.

Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.

The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.

The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.

“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”

The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.

“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”

The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.

“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.

Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.

There are currently no approved anti-DLL4 antibody drugs for use in humans.

“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”

Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.

TOPLINE:
 

Taking a proton pump inhibitor (PPI) with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib could diminish the full therapeutic benefit of palbociclib in women with breast cancer and lead to worse progression-free survival (PFS) and overall survival, new data suggest.

METHODOLOGY:

• The study retrospectively identified 1,310 women with advanced breast cancer receiving palbociclib using South Korean nationwide claims data.
• Overall, 344 women in the concomitant group, those who were coadministered a PPI for more than one-third of their palbociclib treatment duration, were propensity-score matched to 966 women who did not have PPI exposure: the nonconcomitant group.
• Main outcomes were time to progression and death, presented as PFS and overall survival.

TAKEAWAY:

• Median clinical PFS was significantly shorter by about 15 months in the concomitant PPI group vs. the nonconcomitant group (25.3 vs. 39.8 months; adjusted hazard ratio, 1.76).
• Concomitant PPI use was also associated with shorter overall survival (HR, 2.71).
• Overall, 83.1% of patients in the concomitant group were alive at 1 year vs. 94.0% in the nonconcomitant group (P < .001), and 69.5% vs. 89.3%, respectively, were alive at 2 years (P < .001), though the median overall survival was not reached in either group.
• In a subgroup analysis, concomitant PPI use was associated with shorter clinical PFS (HR, 1.75 for those receiving endocrine-sensitive treatment and 1.82 for those receiving endocrine-resistant treatment), and shorter overall survival (HR, 2.68 in the endocrine-sensitive subgroup and 2.98 in the endocrine-resistant subgroup).

IN PRACTICE:

“The findings suggest that taking PPIs with palbociclib may interrupt the full therapeutic benefits of palbociclib,” the authors conclude. “Physicians should be cautious when prescribing PPIs to patients who are receiving palbociclib.”

SOURCE:

The study, led by Ju-Eun Lee, MS, PharmD, School of Pharmacy, Sungkyunkwan University, South Korea, was published online in JAMA Network Open.

LIMITATIONS:

The study was limited by its retrospective design and use of claims data as well as the inability to confirm whether patients actually took the PPI medication.

DISCLOSURES:

The authors report no relevant financial relationships. The study reported no commercial funding.

A version of this article first appeared on Medscape.com.

TOPLINE:
 

Taking a proton pump inhibitor (PPI) with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib could diminish the full therapeutic benefit of palbociclib in women with breast cancer and lead to worse progression-free survival (PFS) and overall survival, new data suggest.

METHODOLOGY:

• The study retrospectively identified 1,310 women with advanced breast cancer receiving palbociclib using South Korean nationwide claims data.
• Overall, 344 women in the concomitant group, those who were coadministered a PPI for more than one-third of their palbociclib treatment duration, were propensity-score matched to 966 women who did not have PPI exposure: the nonconcomitant group.
• Main outcomes were time to progression and death, presented as PFS and overall survival.

TAKEAWAY:

• Median clinical PFS was significantly shorter by about 15 months in the concomitant PPI group vs. the nonconcomitant group (25.3 vs. 39.8 months; adjusted hazard ratio, 1.76).
• Concomitant PPI use was also associated with shorter overall survival (HR, 2.71).
• Overall, 83.1% of patients in the concomitant group were alive at 1 year vs. 94.0% in the nonconcomitant group (P < .001), and 69.5% vs. 89.3%, respectively, were alive at 2 years (P < .001), though the median overall survival was not reached in either group.
• In a subgroup analysis, concomitant PPI use was associated with shorter clinical PFS (HR, 1.75 for those receiving endocrine-sensitive treatment and 1.82 for those receiving endocrine-resistant treatment), and shorter overall survival (HR, 2.68 in the endocrine-sensitive subgroup and 2.98 in the endocrine-resistant subgroup).

IN PRACTICE:

“The findings suggest that taking PPIs with palbociclib may interrupt the full therapeutic benefits of palbociclib,” the authors conclude. “Physicians should be cautious when prescribing PPIs to patients who are receiving palbociclib.”

SOURCE:

The study, led by Ju-Eun Lee, MS, PharmD, School of Pharmacy, Sungkyunkwan University, South Korea, was published online in JAMA Network Open.

LIMITATIONS:

The study was limited by its retrospective design and use of claims data as well as the inability to confirm whether patients actually took the PPI medication.

DISCLOSURES:

The authors report no relevant financial relationships. The study reported no commercial funding.

A version of this article first appeared on Medscape.com.

TOPLINE:
 

Taking a proton pump inhibitor (PPI) with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib could diminish the full therapeutic benefit of palbociclib in women with breast cancer and lead to worse progression-free survival (PFS) and overall survival, new data suggest.

METHODOLOGY:

• The study retrospectively identified 1,310 women with advanced breast cancer receiving palbociclib using South Korean nationwide claims data.
• Overall, 344 women in the concomitant group, those who were coadministered a PPI for more than one-third of their palbociclib treatment duration, were propensity-score matched to 966 women who did not have PPI exposure: the nonconcomitant group.
• Main outcomes were time to progression and death, presented as PFS and overall survival.

TAKEAWAY:

• Median clinical PFS was significantly shorter by about 15 months in the concomitant PPI group vs. the nonconcomitant group (25.3 vs. 39.8 months; adjusted hazard ratio, 1.76).
• Concomitant PPI use was also associated with shorter overall survival (HR, 2.71).
• Overall, 83.1% of patients in the concomitant group were alive at 1 year vs. 94.0% in the nonconcomitant group (P < .001), and 69.5% vs. 89.3%, respectively, were alive at 2 years (P < .001), though the median overall survival was not reached in either group.
• In a subgroup analysis, concomitant PPI use was associated with shorter clinical PFS (HR, 1.75 for those receiving endocrine-sensitive treatment and 1.82 for those receiving endocrine-resistant treatment), and shorter overall survival (HR, 2.68 in the endocrine-sensitive subgroup and 2.98 in the endocrine-resistant subgroup).

IN PRACTICE:

“The findings suggest that taking PPIs with palbociclib may interrupt the full therapeutic benefits of palbociclib,” the authors conclude. “Physicians should be cautious when prescribing PPIs to patients who are receiving palbociclib.”

SOURCE:

The study, led by Ju-Eun Lee, MS, PharmD, School of Pharmacy, Sungkyunkwan University, South Korea, was published online in JAMA Network Open.

LIMITATIONS:

The study was limited by its retrospective design and use of claims data as well as the inability to confirm whether patients actually took the PPI medication.

DISCLOSURES:

The authors report no relevant financial relationships. The study reported no commercial funding.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Dr. West: Here at ASCO 2023 [American Society of Clinical Oncology] in Chicago, we’ve seen some blockbuster presentations in thoracic oncology. Many of these have brought up some important questions about the clinical implications that we need to discuss further.

At ASCO, as well as in the couple or 3 months preceding ASCO, we’ve gotten more and more data on perioperative approaches. Of course, over the past couple of years, we’ve had some new options of postoperative immunotherapy for a year, say, after chemotherapy or possibly after chemotherapy.

We have also had very influential data, such as the CheckMate 816 trial that gave three cycles of chemotherapy with nivolumab vs. chemotherapy alone to patients with stage IB to IIIA disease, but largely, nearly two thirds, with IIIA disease. That showed a very clear improvement in the pathologic complete response (pCR) rate with nivolumab added to chemotherapy and also a highly significant improvement in event-free survival and a strong trend toward improved overall survival. This is FDA approved and has been increasingly adopted, I would say, maybe with some variability by geography and center, but really a good amount of enthusiasm.

Now, we have a bunch of trials that give chemotherapy with immunotherapy. We’ve got the AEGEAN trial with durvalumab. We have Neotorch with chemotherapy and toripalimab. At ASCO 2023, we had a highly prominent presentation of KEYNOTE-671, giving four cycles of chemotherapy with pembrolizumab vs. chemotherapy and placebo.

Then there’s the built-in postoperative component of a year of immunotherapy as well, in all these trials. The data for KEYNOTE-671 look quite good. Of course, the other trials also were significant. I would say the comparator now is not nothing or chemotherapy alone anymore; it’s really against what is the best current standard of care.

The real question is, if we were happy to do chemoimmunotherapy neoadjuvant with chemotherapy/nivolumab, do we want or need to add the year of immunotherapy? It certainly adds some cost, it adds some risk for toxicity, and it adds a year of a patient coming into the clinic and getting IV infusions all this time to get a treatment that the patient has already had for four cycles in most of these trials.

If your cancer is resistant, is there going to be an incremental benefit to giving more of it? What are your thoughts about the risk and benefit? Going to a patient in your own clinic, how are you going to counsel your patients? Will anything change after the presentation of all these data and how you approach preoperatively?

Dr. Rotow: I agree. In some sense, it’s an embarrassment of riches, right?

Dr. West: Yes.

Dr. Rotow: We have so many positive studies looking at perioperative immunotherapy for our patients. They all show improved outcomes, but of course, they all compare with the old control arm of chemotherapy alone in some form, and this is no longer a useful control in this space. The open question is, do you use neoadjuvant, do you use adjuvant, or do you use both?

My high-level takeaway from these data is that the neoadjuvant component appears to be important. I think the overall trend, comparing across studies, of course, is that outcomes seem to be better with the neoadjuvant component. You also get the advantage of potential downstaging and potential greater ease of surgical resection. We know they have lower morbidity resection and shorter surgeries. You can comment on that. You also get your pathologic response data.

Dr. West: You get the feedback.

Dr. Rotow: Exactly.

Dr. West: The deliverability is also a big issue. You know you can much more reliably deliver your intended treatment by doing neoadjuvant followed by surgery.

Dr. Rotow: Exactly.

Dr. West: We know there’s major drop-off if patients have surgery, and in the recovery room they hear you got it all, and then they need to come back and maybe get chemotherapy and immunotherapy for a year. They’d ask, “What for? I can’t see anything.”

Dr. Rotow: Exactly. I think there are many advantages to that neoadjuvant component. I think all or many of us now have integrated this into our routine practice. Now the question is, do you need the adjuvant element or not on top? That is challenging because no trial has compared adjuvant to nonadjuvant. I think we all advocate for the need for this trial to answer this in a more randomized, prospective fashion. Of course, that doesn’t help our clinic practice tomorrow when we see a patient.

Dr. West: Or for the next 4 years.

Dr. Rotow: Or for the next 4 years – exactly. There’s going to be the open question of who really needs this? In some sense, we may be guided by the path response during the surgery itself. I think there may be those who claim that if you have a pCR, do you really need additional therapy? We don’t know the answer, but it’s tempting to say we know the outcomes in event-free survival are extremely good with a pCR.

Dr. West: Which is only 20% or 25% of patients, so it’s not most.

Dr. Rotow: It’s not most, but it’s better than the 2% or so with chemotherapy alone. That’s real progress, and it’s nice to have that readout. For that 80% without a pCR, what to do? I suspect there will be variation from provider to provider and from patient to patient, depending on tolerability to prior therapy, the patient’s wishes around the goals of care, and the patient’s risk for autoimmune toxicities.

Maybe there’s a patient with underlying autoimmune disease who’s gotten their neoadjuvant therapy and done well. You don’t want to risk that ongoing risk of exposure. Perhaps a patient with no risk factors who desires very aggressive treatment might be interested in more treatment.

In KEYNOTE-671, I was interested in the PD-L1 subgroups. These did trend the way you expect, with better responses in PD-L1 high, but there were also good outcomes and benefit to immunotherapy with the perioperative strategy in PD-L1–negative patients.

Dr. West: That didn’t really exclude anybody.

Dr. Rotow: It didn’t exclude anybody. In CheckMate 816, everyone benefited, but the benefit was less with those PD-L1–negative patients.

Dr. West: True.

Dr. Rotow: Absent further data to guide me or any prospective data here comparing these strategies, I might lean toward a longer course of immunotherapy in that population in hopes of triggering a response. I suspect that there will be variation from clinician to clinician in that space.

Dr. West: This is a setting where I feel like I have equipoise. I really feel that the incremental benefit is pretty small.

Dr. Rotow: Small. I agree.

Dr. West: It’s, frankly, somewhat dubious. On the other hand, you’re in a situation where if you know that three of four patients will experience a relapse and less-than-amazing outcomes, it’s hard to leave something that’s FDA approved and studied and a well-sanctioned option on the table if this patient may have relapse later.

In the end, I feel like I’d like to offer this and discuss it with all my patients. I think it’s a great place for shared decision-making because if a patient hears about that and decides they’re not interested, I’ll be fine with that. I think that’s a very sensible approach, but I don’t want to make it unilaterally. Other patients may say they want every opportunity, and if it comes back, at least I’ll know I did everything we could.

Dr. Rotow: Exactly. I agree with your statement about equipoise. I truly think that this is present here in the situation, and that there’s room for discussion in both directions with patients.

Now, one caveat I’d like to add to all these data is that the data should not apply to patients with some of our classic nonsmoking-associated driver mutations. This is another piece to the neoadjuvant data that I think is worth commenting on – the need to get appropriate testing before initiation of therapy and the pitfalls of starting this kind of treatment without knowing full biomarker testing. I think that’s something we have to watch for in our clinical practice as well.

Dr. West: Perhaps especially if we’re talking about doing a year of postoperative and someone has an ALK rearrangement or an EGFR mutation and we didn’t know it. That is a group where we’re worried about a rapid transition and potentially prohibitive, even life-threatening, toxicities from not planning in advance for this. This is something you don’t want to give concurrently or one right on top of the other. You don’t want to give immunotherapy and then transition right to targeted therapy. It’s dangerous.

Dr. Rotow: Exactly. The stakes were already high with neoadjuvant alone, but at least you had that gap of the presurgical period, surgical recovery, and then initiation of adjuvant therapy, if needed, or at relapse. With a postoperative long adjuvant period, those stakes are elevated because the immunotherapy exposure continues, so it’s something to be mindful of.

Dr. West: We have a general sense that many, but not all, of the targets that we’re talking about are associated with low benefit from immunotherapy. It’s not that well studied. I think this is another place for individualized discussion of the pros and cons. They were included in the trial, but they probably benefit less.

Dr. Rotow: Exactly. I think with the best established, EGFR and ALK probably are not benefiting much. They were actually included in the trial. Many of the neoadjuvant studies do not allow them to enroll if they’re known. On the other end of that spectrum, I think KRAS is just fine to treat with immunotherapy.

Dr. West: Sure.

Dr. Rotow: It’s an actionable driver. It’s not a traditional nonsmoking-associated driver, and those do just fine.

Dr. West: The studies show that these patients benefit just as much, at least, as the other patients.

Dr. Rotow: Exactly. I would never withhold this form of therapy for a KRAS driver mutation. The others, I think, are still in a gray zone. Depending on the patient demographics and tobacco use, I may elicit more or less caution in that space.

Dr. West: Well, I think we’re going to have much to still tease apart, with room for judgment here without a strong sense of the data telling us exactly what to do.

Dr. Rotow: Exactly.

Dr. West: There’s a large amount of excitement and interest in these new data, but there are still many open questions. I hope we continue to mull it over as we get more data and more insight to shape our plans.

Dr. West is an associate professor at City of Hope Comprehensive Cancer Center in Duarte, Calif., and vice president of network strategy at AccessHope in Los Angeles. Dr. Rotow is the clinical director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston. Dr. West reported conflicts of interest with Ariad/Takeda, Bristol Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly. Dr. Rotow reported conflicts of interest with Genentech, AstraZeneca,Guardant, and Janssen.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Dr. West: Here at ASCO 2023 [American Society of Clinical Oncology] in Chicago, we’ve seen some blockbuster presentations in thoracic oncology. Many of these have brought up some important questions about the clinical implications that we need to discuss further.

At ASCO, as well as in the couple or 3 months preceding ASCO, we’ve gotten more and more data on perioperative approaches. Of course, over the past couple of years, we’ve had some new options of postoperative immunotherapy for a year, say, after chemotherapy or possibly after chemotherapy.

We have also had very influential data, such as the CheckMate 816 trial that gave three cycles of chemotherapy with nivolumab vs. chemotherapy alone to patients with stage IB to IIIA disease, but largely, nearly two thirds, with IIIA disease. That showed a very clear improvement in the pathologic complete response (pCR) rate with nivolumab added to chemotherapy and also a highly significant improvement in event-free survival and a strong trend toward improved overall survival. This is FDA approved and has been increasingly adopted, I would say, maybe with some variability by geography and center, but really a good amount of enthusiasm.

Now, we have a bunch of trials that give chemotherapy with immunotherapy. We’ve got the AEGEAN trial with durvalumab. We have Neotorch with chemotherapy and toripalimab. At ASCO 2023, we had a highly prominent presentation of KEYNOTE-671, giving four cycles of chemotherapy with pembrolizumab vs. chemotherapy and placebo.

Then there’s the built-in postoperative component of a year of immunotherapy as well, in all these trials. The data for KEYNOTE-671 look quite good. Of course, the other trials also were significant. I would say the comparator now is not nothing or chemotherapy alone anymore; it’s really against what is the best current standard of care.

The real question is, if we were happy to do chemoimmunotherapy neoadjuvant with chemotherapy/nivolumab, do we want or need to add the year of immunotherapy? It certainly adds some cost, it adds some risk for toxicity, and it adds a year of a patient coming into the clinic and getting IV infusions all this time to get a treatment that the patient has already had for four cycles in most of these trials.

If your cancer is resistant, is there going to be an incremental benefit to giving more of it? What are your thoughts about the risk and benefit? Going to a patient in your own clinic, how are you going to counsel your patients? Will anything change after the presentation of all these data and how you approach preoperatively?

Dr. Rotow: I agree. In some sense, it’s an embarrassment of riches, right?

Dr. West: Yes.

Dr. Rotow: We have so many positive studies looking at perioperative immunotherapy for our patients. They all show improved outcomes, but of course, they all compare with the old control arm of chemotherapy alone in some form, and this is no longer a useful control in this space. The open question is, do you use neoadjuvant, do you use adjuvant, or do you use both?

My high-level takeaway from these data is that the neoadjuvant component appears to be important. I think the overall trend, comparing across studies, of course, is that outcomes seem to be better with the neoadjuvant component. You also get the advantage of potential downstaging and potential greater ease of surgical resection. We know they have lower morbidity resection and shorter surgeries. You can comment on that. You also get your pathologic response data.

Dr. West: You get the feedback.

Dr. Rotow: Exactly.

Dr. West: The deliverability is also a big issue. You know you can much more reliably deliver your intended treatment by doing neoadjuvant followed by surgery.

Dr. Rotow: Exactly.

Dr. West: We know there’s major drop-off if patients have surgery, and in the recovery room they hear you got it all, and then they need to come back and maybe get chemotherapy and immunotherapy for a year. They’d ask, “What for? I can’t see anything.”

Dr. Rotow: Exactly. I think there are many advantages to that neoadjuvant component. I think all or many of us now have integrated this into our routine practice. Now the question is, do you need the adjuvant element or not on top? That is challenging because no trial has compared adjuvant to nonadjuvant. I think we all advocate for the need for this trial to answer this in a more randomized, prospective fashion. Of course, that doesn’t help our clinic practice tomorrow when we see a patient.

Dr. West: Or for the next 4 years.

Dr. Rotow: Or for the next 4 years – exactly. There’s going to be the open question of who really needs this? In some sense, we may be guided by the path response during the surgery itself. I think there may be those who claim that if you have a pCR, do you really need additional therapy? We don’t know the answer, but it’s tempting to say we know the outcomes in event-free survival are extremely good with a pCR.

Dr. West: Which is only 20% or 25% of patients, so it’s not most.

Dr. Rotow: It’s not most, but it’s better than the 2% or so with chemotherapy alone. That’s real progress, and it’s nice to have that readout. For that 80% without a pCR, what to do? I suspect there will be variation from provider to provider and from patient to patient, depending on tolerability to prior therapy, the patient’s wishes around the goals of care, and the patient’s risk for autoimmune toxicities.

Maybe there’s a patient with underlying autoimmune disease who’s gotten their neoadjuvant therapy and done well. You don’t want to risk that ongoing risk of exposure. Perhaps a patient with no risk factors who desires very aggressive treatment might be interested in more treatment.

In KEYNOTE-671, I was interested in the PD-L1 subgroups. These did trend the way you expect, with better responses in PD-L1 high, but there were also good outcomes and benefit to immunotherapy with the perioperative strategy in PD-L1–negative patients.

Dr. West: That didn’t really exclude anybody.

Dr. Rotow: It didn’t exclude anybody. In CheckMate 816, everyone benefited, but the benefit was less with those PD-L1–negative patients.

Dr. West: True.

Dr. Rotow: Absent further data to guide me or any prospective data here comparing these strategies, I might lean toward a longer course of immunotherapy in that population in hopes of triggering a response. I suspect that there will be variation from clinician to clinician in that space.

Dr. West: This is a setting where I feel like I have equipoise. I really feel that the incremental benefit is pretty small.

Dr. Rotow: Small. I agree.

Dr. West: It’s, frankly, somewhat dubious. On the other hand, you’re in a situation where if you know that three of four patients will experience a relapse and less-than-amazing outcomes, it’s hard to leave something that’s FDA approved and studied and a well-sanctioned option on the table if this patient may have relapse later.

In the end, I feel like I’d like to offer this and discuss it with all my patients. I think it’s a great place for shared decision-making because if a patient hears about that and decides they’re not interested, I’ll be fine with that. I think that’s a very sensible approach, but I don’t want to make it unilaterally. Other patients may say they want every opportunity, and if it comes back, at least I’ll know I did everything we could.

Dr. Rotow: Exactly. I agree with your statement about equipoise. I truly think that this is present here in the situation, and that there’s room for discussion in both directions with patients.

Now, one caveat I’d like to add to all these data is that the data should not apply to patients with some of our classic nonsmoking-associated driver mutations. This is another piece to the neoadjuvant data that I think is worth commenting on – the need to get appropriate testing before initiation of therapy and the pitfalls of starting this kind of treatment without knowing full biomarker testing. I think that’s something we have to watch for in our clinical practice as well.

Dr. West: Perhaps especially if we’re talking about doing a year of postoperative and someone has an ALK rearrangement or an EGFR mutation and we didn’t know it. That is a group where we’re worried about a rapid transition and potentially prohibitive, even life-threatening, toxicities from not planning in advance for this. This is something you don’t want to give concurrently or one right on top of the other. You don’t want to give immunotherapy and then transition right to targeted therapy. It’s dangerous.

Dr. Rotow: Exactly. The stakes were already high with neoadjuvant alone, but at least you had that gap of the presurgical period, surgical recovery, and then initiation of adjuvant therapy, if needed, or at relapse. With a postoperative long adjuvant period, those stakes are elevated because the immunotherapy exposure continues, so it’s something to be mindful of.

Dr. West: We have a general sense that many, but not all, of the targets that we’re talking about are associated with low benefit from immunotherapy. It’s not that well studied. I think this is another place for individualized discussion of the pros and cons. They were included in the trial, but they probably benefit less.

Dr. Rotow: Exactly. I think with the best established, EGFR and ALK probably are not benefiting much. They were actually included in the trial. Many of the neoadjuvant studies do not allow them to enroll if they’re known. On the other end of that spectrum, I think KRAS is just fine to treat with immunotherapy.

Dr. West: Sure.

Dr. Rotow: It’s an actionable driver. It’s not a traditional nonsmoking-associated driver, and those do just fine.

Dr. West: The studies show that these patients benefit just as much, at least, as the other patients.

Dr. Rotow: Exactly. I would never withhold this form of therapy for a KRAS driver mutation. The others, I think, are still in a gray zone. Depending on the patient demographics and tobacco use, I may elicit more or less caution in that space.

Dr. West: Well, I think we’re going to have much to still tease apart, with room for judgment here without a strong sense of the data telling us exactly what to do.

Dr. Rotow: Exactly.

Dr. West: There’s a large amount of excitement and interest in these new data, but there are still many open questions. I hope we continue to mull it over as we get more data and more insight to shape our plans.

Dr. West is an associate professor at City of Hope Comprehensive Cancer Center in Duarte, Calif., and vice president of network strategy at AccessHope in Los Angeles. Dr. Rotow is the clinical director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston. Dr. West reported conflicts of interest with Ariad/Takeda, Bristol Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly. Dr. Rotow reported conflicts of interest with Genentech, AstraZeneca,Guardant, and Janssen.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Dr. West: Here at ASCO 2023 [American Society of Clinical Oncology] in Chicago, we’ve seen some blockbuster presentations in thoracic oncology. Many of these have brought up some important questions about the clinical implications that we need to discuss further.

At ASCO, as well as in the couple or 3 months preceding ASCO, we’ve gotten more and more data on perioperative approaches. Of course, over the past couple of years, we’ve had some new options of postoperative immunotherapy for a year, say, after chemotherapy or possibly after chemotherapy.

We have also had very influential data, such as the CheckMate 816 trial that gave three cycles of chemotherapy with nivolumab vs. chemotherapy alone to patients with stage IB to IIIA disease, but largely, nearly two thirds, with IIIA disease. That showed a very clear improvement in the pathologic complete response (pCR) rate with nivolumab added to chemotherapy and also a highly significant improvement in event-free survival and a strong trend toward improved overall survival. This is FDA approved and has been increasingly adopted, I would say, maybe with some variability by geography and center, but really a good amount of enthusiasm.

Now, we have a bunch of trials that give chemotherapy with immunotherapy. We’ve got the AEGEAN trial with durvalumab. We have Neotorch with chemotherapy and toripalimab. At ASCO 2023, we had a highly prominent presentation of KEYNOTE-671, giving four cycles of chemotherapy with pembrolizumab vs. chemotherapy and placebo.

Then there’s the built-in postoperative component of a year of immunotherapy as well, in all these trials. The data for KEYNOTE-671 look quite good. Of course, the other trials also were significant. I would say the comparator now is not nothing or chemotherapy alone anymore; it’s really against what is the best current standard of care.

The real question is, if we were happy to do chemoimmunotherapy neoadjuvant with chemotherapy/nivolumab, do we want or need to add the year of immunotherapy? It certainly adds some cost, it adds some risk for toxicity, and it adds a year of a patient coming into the clinic and getting IV infusions all this time to get a treatment that the patient has already had for four cycles in most of these trials.

If your cancer is resistant, is there going to be an incremental benefit to giving more of it? What are your thoughts about the risk and benefit? Going to a patient in your own clinic, how are you going to counsel your patients? Will anything change after the presentation of all these data and how you approach preoperatively?

Dr. Rotow: I agree. In some sense, it’s an embarrassment of riches, right?

Dr. West: Yes.

Dr. Rotow: We have so many positive studies looking at perioperative immunotherapy for our patients. They all show improved outcomes, but of course, they all compare with the old control arm of chemotherapy alone in some form, and this is no longer a useful control in this space. The open question is, do you use neoadjuvant, do you use adjuvant, or do you use both?

My high-level takeaway from these data is that the neoadjuvant component appears to be important. I think the overall trend, comparing across studies, of course, is that outcomes seem to be better with the neoadjuvant component. You also get the advantage of potential downstaging and potential greater ease of surgical resection. We know they have lower morbidity resection and shorter surgeries. You can comment on that. You also get your pathologic response data.

Dr. West: You get the feedback.

Dr. Rotow: Exactly.

Dr. West: The deliverability is also a big issue. You know you can much more reliably deliver your intended treatment by doing neoadjuvant followed by surgery.

Dr. Rotow: Exactly.

Dr. West: We know there’s major drop-off if patients have surgery, and in the recovery room they hear you got it all, and then they need to come back and maybe get chemotherapy and immunotherapy for a year. They’d ask, “What for? I can’t see anything.”

Dr. Rotow: Exactly. I think there are many advantages to that neoadjuvant component. I think all or many of us now have integrated this into our routine practice. Now the question is, do you need the adjuvant element or not on top? That is challenging because no trial has compared adjuvant to nonadjuvant. I think we all advocate for the need for this trial to answer this in a more randomized, prospective fashion. Of course, that doesn’t help our clinic practice tomorrow when we see a patient.

Dr. West: Or for the next 4 years.

Dr. Rotow: Or for the next 4 years – exactly. There’s going to be the open question of who really needs this? In some sense, we may be guided by the path response during the surgery itself. I think there may be those who claim that if you have a pCR, do you really need additional therapy? We don’t know the answer, but it’s tempting to say we know the outcomes in event-free survival are extremely good with a pCR.

Dr. West: Which is only 20% or 25% of patients, so it’s not most.

Dr. Rotow: It’s not most, but it’s better than the 2% or so with chemotherapy alone. That’s real progress, and it’s nice to have that readout. For that 80% without a pCR, what to do? I suspect there will be variation from provider to provider and from patient to patient, depending on tolerability to prior therapy, the patient’s wishes around the goals of care, and the patient’s risk for autoimmune toxicities.

Maybe there’s a patient with underlying autoimmune disease who’s gotten their neoadjuvant therapy and done well. You don’t want to risk that ongoing risk of exposure. Perhaps a patient with no risk factors who desires very aggressive treatment might be interested in more treatment.

In KEYNOTE-671, I was interested in the PD-L1 subgroups. These did trend the way you expect, with better responses in PD-L1 high, but there were also good outcomes and benefit to immunotherapy with the perioperative strategy in PD-L1–negative patients.

Dr. West: That didn’t really exclude anybody.

Dr. Rotow: It didn’t exclude anybody. In CheckMate 816, everyone benefited, but the benefit was less with those PD-L1–negative patients.

Dr. West: True.

Dr. Rotow: Absent further data to guide me or any prospective data here comparing these strategies, I might lean toward a longer course of immunotherapy in that population in hopes of triggering a response. I suspect that there will be variation from clinician to clinician in that space.

Dr. West: This is a setting where I feel like I have equipoise. I really feel that the incremental benefit is pretty small.

Dr. Rotow: Small. I agree.

Dr. West: It’s, frankly, somewhat dubious. On the other hand, you’re in a situation where if you know that three of four patients will experience a relapse and less-than-amazing outcomes, it’s hard to leave something that’s FDA approved and studied and a well-sanctioned option on the table if this patient may have relapse later.

In the end, I feel like I’d like to offer this and discuss it with all my patients. I think it’s a great place for shared decision-making because if a patient hears about that and decides they’re not interested, I’ll be fine with that. I think that’s a very sensible approach, but I don’t want to make it unilaterally. Other patients may say they want every opportunity, and if it comes back, at least I’ll know I did everything we could.

Dr. Rotow: Exactly. I agree with your statement about equipoise. I truly think that this is present here in the situation, and that there’s room for discussion in both directions with patients.

Now, one caveat I’d like to add to all these data is that the data should not apply to patients with some of our classic nonsmoking-associated driver mutations. This is another piece to the neoadjuvant data that I think is worth commenting on – the need to get appropriate testing before initiation of therapy and the pitfalls of starting this kind of treatment without knowing full biomarker testing. I think that’s something we have to watch for in our clinical practice as well.

Dr. West: Perhaps especially if we’re talking about doing a year of postoperative and someone has an ALK rearrangement or an EGFR mutation and we didn’t know it. That is a group where we’re worried about a rapid transition and potentially prohibitive, even life-threatening, toxicities from not planning in advance for this. This is something you don’t want to give concurrently or one right on top of the other. You don’t want to give immunotherapy and then transition right to targeted therapy. It’s dangerous.

Dr. Rotow: Exactly. The stakes were already high with neoadjuvant alone, but at least you had that gap of the presurgical period, surgical recovery, and then initiation of adjuvant therapy, if needed, or at relapse. With a postoperative long adjuvant period, those stakes are elevated because the immunotherapy exposure continues, so it’s something to be mindful of.

Dr. West: We have a general sense that many, but not all, of the targets that we’re talking about are associated with low benefit from immunotherapy. It’s not that well studied. I think this is another place for individualized discussion of the pros and cons. They were included in the trial, but they probably benefit less.

Dr. Rotow: Exactly. I think with the best established, EGFR and ALK probably are not benefiting much. They were actually included in the trial. Many of the neoadjuvant studies do not allow them to enroll if they’re known. On the other end of that spectrum, I think KRAS is just fine to treat with immunotherapy.

Dr. West: Sure.

Dr. Rotow: It’s an actionable driver. It’s not a traditional nonsmoking-associated driver, and those do just fine.

Dr. West: The studies show that these patients benefit just as much, at least, as the other patients.

Dr. Rotow: Exactly. I would never withhold this form of therapy for a KRAS driver mutation. The others, I think, are still in a gray zone. Depending on the patient demographics and tobacco use, I may elicit more or less caution in that space.

Dr. West: Well, I think we’re going to have much to still tease apart, with room for judgment here without a strong sense of the data telling us exactly what to do.

Dr. Rotow: Exactly.

Dr. West: There’s a large amount of excitement and interest in these new data, but there are still many open questions. I hope we continue to mull it over as we get more data and more insight to shape our plans.

Dr. West is an associate professor at City of Hope Comprehensive Cancer Center in Duarte, Calif., and vice president of network strategy at AccessHope in Los Angeles. Dr. Rotow is the clinical director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston. Dr. West reported conflicts of interest with Ariad/Takeda, Bristol Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly. Dr. Rotow reported conflicts of interest with Genentech, AstraZeneca,Guardant, and Janssen.

A version of this article first appeared on Medscape.com.

TOPLINE:

Long-term and recurrent use of antibiotics early in life may raise the risk of early-onset colorectal cancer (CRC) and adenomas, particularly in people with a variant in a specific gut microbiota regulatory gene, a new analysis found.

METHODOLOGY:

• Researchers analyzed data from UK Biobank participants who were recruited between 2006 and 2010 and were followed up to February 2022.
• They evaluated associations between early-life factors and early-onset CRC risk overall, focusing on long-term and recurrent antibiotic use.
• The team also estimated associations between long-term and recurrent antibiotic use in early life and CRC risk by polygenic risk score using 127 CRC-related genetic variants, as well as a particular gut microbiota regulatory gene FUT2.
• Associations for early-onset colorectal adenomas, as precursor to CRC, were also evaluated.
• The study included 113,256 participants. There were 165 early-onset CRC cases and 719 early-onset adenoma cases.

TAKEAWAY:

• Early-life, long-term, and recurrent antibiotic use was “nominally” associated with an increased risk of early-onset CRC (odds ratio, 1.48; P = .046) and adenomas (OR, 1.40; P < .001).
• Regarding variants of FUT2, the risk of early-onset CRC appeared to be greater for individuals with the rs281377 TT genotype (OR, 2.74) in comparison with those with the CT and TT genotypes, but none of the estimates reached statistical significance.
• The researchers found a strong positive association between long-term and recurrent antibiotic use and adenomas, largely in patients with rs281377 TT (OR, 1.75) and CT genotypes (OR, 1.51).
• Individuals with a high polygenic risk score were at higher risk of early-onset CRC (OR, 1.72; P = .019), while those with low polygenic risk scores were not at higher risk (OR, 1.05; P = .889). The association between antibiotic use and early-onset CRC risk by family history was also higher (OR, 2.34).

IN PRACTICE:

“Our findings suggested that individuals with genetic risk factors (i.e., family history of CRC) who have experienced early-life antibiotics use on a long-term basis are probably at increased early-onset CRC risk,” the authors concluded. “Given that antibiotics remain valuable in the management of bacterial infections during early life, investigating the pros and cons of early-life antibiotic use is of great significance.”

SOURCE:

The study, led by Fangyuan Jiang, with Zhejiang University, Hangzhou, China, was published online in the International Journal of Cancer.

LIMITATIONS:

The study relied on participants’ recall of early-life antibiotics use, which could introduce recall bias and misclassification of this exposure.

DISCLOSURES:

No conflicts of interest were reported.

A version of this article first appeared on Medscape.com.

TOPLINE:

Long-term and recurrent use of antibiotics early in life may raise the risk of early-onset colorectal cancer (CRC) and adenomas, particularly in people with a variant in a specific gut microbiota regulatory gene, a new analysis found.

METHODOLOGY:

• Researchers analyzed data from UK Biobank participants who were recruited between 2006 and 2010 and were followed up to February 2022.
• They evaluated associations between early-life factors and early-onset CRC risk overall, focusing on long-term and recurrent antibiotic use.
• The team also estimated associations between long-term and recurrent antibiotic use in early life and CRC risk by polygenic risk score using 127 CRC-related genetic variants, as well as a particular gut microbiota regulatory gene FUT2.
• Associations for early-onset colorectal adenomas, as precursor to CRC, were also evaluated.
• The study included 113,256 participants. There were 165 early-onset CRC cases and 719 early-onset adenoma cases.

TAKEAWAY:

• Early-life, long-term, and recurrent antibiotic use was “nominally” associated with an increased risk of early-onset CRC (odds ratio, 1.48; P = .046) and adenomas (OR, 1.40; P < .001).
• Regarding variants of FUT2, the risk of early-onset CRC appeared to be greater for individuals with the rs281377 TT genotype (OR, 2.74) in comparison with those with the CT and TT genotypes, but none of the estimates reached statistical significance.
• The researchers found a strong positive association between long-term and recurrent antibiotic use and adenomas, largely in patients with rs281377 TT (OR, 1.75) and CT genotypes (OR, 1.51).
• Individuals with a high polygenic risk score were at higher risk of early-onset CRC (OR, 1.72; P = .019), while those with low polygenic risk scores were not at higher risk (OR, 1.05; P = .889). The association between antibiotic use and early-onset CRC risk by family history was also higher (OR, 2.34).

IN PRACTICE:

“Our findings suggested that individuals with genetic risk factors (i.e., family history of CRC) who have experienced early-life antibiotics use on a long-term basis are probably at increased early-onset CRC risk,” the authors concluded. “Given that antibiotics remain valuable in the management of bacterial infections during early life, investigating the pros and cons of early-life antibiotic use is of great significance.”

SOURCE:

The study, led by Fangyuan Jiang, with Zhejiang University, Hangzhou, China, was published online in the International Journal of Cancer.

LIMITATIONS:

The study relied on participants’ recall of early-life antibiotics use, which could introduce recall bias and misclassification of this exposure.

DISCLOSURES:

No conflicts of interest were reported.

A version of this article first appeared on Medscape.com.

TOPLINE:

Long-term and recurrent use of antibiotics early in life may raise the risk of early-onset colorectal cancer (CRC) and adenomas, particularly in people with a variant in a specific gut microbiota regulatory gene, a new analysis found.

METHODOLOGY:

• Researchers analyzed data from UK Biobank participants who were recruited between 2006 and 2010 and were followed up to February 2022.
• They evaluated associations between early-life factors and early-onset CRC risk overall, focusing on long-term and recurrent antibiotic use.
• The team also estimated associations between long-term and recurrent antibiotic use in early life and CRC risk by polygenic risk score using 127 CRC-related genetic variants, as well as a particular gut microbiota regulatory gene FUT2.
• Associations for early-onset colorectal adenomas, as precursor to CRC, were also evaluated.
• The study included 113,256 participants. There were 165 early-onset CRC cases and 719 early-onset adenoma cases.

TAKEAWAY:

• Early-life, long-term, and recurrent antibiotic use was “nominally” associated with an increased risk of early-onset CRC (odds ratio, 1.48; P = .046) and adenomas (OR, 1.40; P < .001).
• Regarding variants of FUT2, the risk of early-onset CRC appeared to be greater for individuals with the rs281377 TT genotype (OR, 2.74) in comparison with those with the CT and TT genotypes, but none of the estimates reached statistical significance.
• The researchers found a strong positive association between long-term and recurrent antibiotic use and adenomas, largely in patients with rs281377 TT (OR, 1.75) and CT genotypes (OR, 1.51).
• Individuals with a high polygenic risk score were at higher risk of early-onset CRC (OR, 1.72; P = .019), while those with low polygenic risk scores were not at higher risk (OR, 1.05; P = .889). The association between antibiotic use and early-onset CRC risk by family history was also higher (OR, 2.34).

IN PRACTICE:

“Our findings suggested that individuals with genetic risk factors (i.e., family history of CRC) who have experienced early-life antibiotics use on a long-term basis are probably at increased early-onset CRC risk,” the authors concluded. “Given that antibiotics remain valuable in the management of bacterial infections during early life, investigating the pros and cons of early-life antibiotic use is of great significance.”

SOURCE:

The study, led by Fangyuan Jiang, with Zhejiang University, Hangzhou, China, was published online in the International Journal of Cancer.

LIMITATIONS:

The study relied on participants’ recall of early-life antibiotics use, which could introduce recall bias and misclassification of this exposure.

DISCLOSURES:

No conflicts of interest were reported.

A version of this article first appeared on Medscape.com.

Deanna Denham Hughes was stunned when she was diagnosed with ovarian cancer in 2022. She was only 32. She had no family history of cancer, and tests found no genetic link. Ms. Hughes wondered why she, an otherwise healthy Black mother of two, would develop a malignancy known as a “silent killer.”

After emergency surgery to remove the mass, along with her ovaries, uterus, fallopian tubes, and appendix, Ms. Hughes said, she saw an Instagram post in which a woman with uterine cancer linked her condition to chemical hair straighteners.

“I almost fell over,” she said from her home in Smyrna, Ga.

When Ms. Hughes was about 4, her mother began applying a chemical straightener, or relaxer, to her hair every 6-8 weeks. “It burned, and it smelled awful,” Ms. Hughes recalled. “But it was just part of our routine to ‘deal with my hair.’ ”

The routine continued until she went to college and met other Black women who wore their hair naturally. Soon, Ms. Hughes quit relaxers.

Social and economic pressures have long compelled Black girls and women to straighten their hair to conform to Eurocentric beauty standards. But chemical straighteners are stinky and costly and sometimes cause painful scalp burns. Mounting evidence now shows they could be a health hazard.

Relaxers can contain carcinogens, such as formaldehyde-releasing agents, phthalates, and other endocrine-disrupting compounds, according to National Institutes of Health studies. The compounds can mimic the body’s hormones and have been linked to breast, uterine, and ovarian cancers, studies show.

African American women’s often frequent and lifelong application of chemical relaxers to their hair and scalp might explain why hormone-related cancers kill disproportionately more Black than White women, say researchers and cancer doctors.

“What’s in these products is harmful,” said Tamarra James-Todd, PhD, an epidemiology professor at Harvard T.H. Chan School of Public Health, Boston, who has studied straightening products for the past 20 years.

She believes manufacturers, policymakers, and physicians should warn consumers that relaxers might cause cancer and other health problems.

But regulators have been slow to act, physicians have been reluctant to take up the cause, and racism continues to dictate fashion standards that make it tough for women to quit relaxers, products so addictive they’re known as “creamy crack.”

Michelle Obama straightened her hair when Barack Obama served as president because she believed Americans were “not ready” to see her in braids, the former first lady said after leaving the White House. The U.S. military still prohibited popular Black hairstyles such as dreadlocks and twists while the nation’s first Black president was in office.

California in 2019 became the first of nearly two dozen states to ban race-based hair discrimination. Last year, the U.S. House of Representatives passed similar legislation, known as the CROWN Act, for Creating a Respectful and Open World for Natural Hair. But the bill failed in the Senate.

The need for legislation underscores the challenges Black girls and women face at school and in the workplace.

“You have to pick your struggles,” said Atlanta-based surgical oncologist Ryland J. Gore, MD. She informs her breast cancer patients about the increased cancer risk from relaxers. Despite her knowledge, however, Dr. Gore continues to use chemical straighteners on her own hair, as she has since she was about 7 years old.

“Your hair tells a story,” she said.

In conversations with patients, Dr. Gore sometimes talks about how African American women once wove messages into their braids about the route to take on the Underground Railroad as they sought freedom from slavery.

“It’s just a deep discussion,” one that touches on culture, history, and research into current hairstyling practices, she said. “The data is out there. So patients should be warned, and then they can make a decision.”

The first hint of a connection between hair products and health issues surfaced in the 1990s. Doctors began seeing signs of sexual maturation in Black babies and young girls who developed breasts and pubic hair after using shampoo containing estrogen or placental extract. When the girls stopped using the shampoo, the hair and breast development receded, according to a study published in the journal Clinical Pediatrics in 1998.

Since then, Dr. James-Todd and other researchers have linked chemicals in hair products to a variety of health issues more prevalent among Black women – from early puberty to preterm birth, obesity, and diabetes.

In recent years, researchers have focused on a possible connection between ingredients in chemical relaxers and hormone-related cancers, like the one Ms. Hughes developed, which tend to be more aggressive and deadly in Black women.

A 2017 study found White women who used chemical relaxers were nearly twice as likely to develop breast cancer as those who did not use them. Because the vast majority of the Black study participants used relaxers, researchers could not effectively test the association in Black women, said lead author Adana Llanos, PhD, associate professor of epidemiology at Columbia University’s Mailman School of Public Health, New York.

Researchers did test it in 2020.

The so-called Sister Study, a landmark National Institute of Environmental Health Sciences investigation into the causes of breast cancer and related diseases, followed 50,000 U.S. women whose sisters had been diagnosed with breast cancer and who were cancer-free when they enrolled. Regardless of race, women who reported using relaxers in the prior year were 18% more likely to be diagnosed with breast cancer. Those who used relaxers at least every 5-8 weeks had a 31% higher breast cancer risk.

Nearly 75% of the Black sisters used relaxers in the prior year, compared with 3% of the non-Hispanic White sisters. Three-quarters of Black women self-reported using the straighteners as adolescents, and frequent use of chemical straighteners during adolescence raised the risk of premenopausal breast cancer, a 2021 NIH-funded study in the International Journal of Cancer found.

Another 2021 analysis of the Sister Study data showed sisters who self-reported that they frequently used relaxers or pressing products doubled their ovarian cancer risk. In 2022, another study found frequent use more than doubled uterine cancer risk.

After researchers discovered the link with uterine cancer, some called for policy changes and other measures to reduce exposure to chemical relaxers.

“It is time to intervene,” Dr. Llanos and her colleagues wrote in a Journal of the National Cancer Institute editorial accompanying the uterine cancer analysis. While acknowledging the need for more research, they issued a “call for action.”

No one can say that using permanent hair straighteners will give you cancer, Dr. Llanos said in an interview. “That’s not how cancer works,” she said, noting that some smokers never develop lung cancer, despite tobacco use being a known risk factor.

The body of research linking hair straighteners and cancer is more limited, said Dr. Llanos, who quit using chemical relaxers 15 years ago. But, she asked rhetorically, “Do we need to do the research for 50 more years to know that chemical relaxers are harmful?”

Charlotte R. Gamble, MD, a gynecological oncologist whose Washington, D.C., practice includes Black women with uterine and ovarian cancer, said she and her colleagues see the uterine cancer study findings as worthy of further exploration – but not yet worthy of discussion with patients.

“The jury’s out for me personally,” she said. “There’s so much more data that’s needed.”

Meanwhile, Dr. James-Todd and other researchers believe they have built a solid body of evidence.

“There are enough things we do know to begin taking action, developing interventions, providing useful information to clinicians and patients and the general public,” said Traci N. Bethea, PhD, assistant professor in the Office of Minority Health and Health Disparities Research at Georgetown University.

Responsibility for regulating personal-care products, including chemical hair straighteners and hair dyes – which also have been linked to hormone-related cancers – lies with the Food and Drug Administration. But the FDA does not subject personal-care products to the same approval process it uses for food and drugs. The FDA restricts only 11 categories of chemicals used in cosmetics, while concerns about health effects have prompted the European Union to restrict the use of at least 2,400 substances.

In March, Reps. Ayanna Pressley (D-Mass.) and Shontel Brown (D-Ohio) asked the FDA to investigate the potential health threat posed by chemical relaxers. An FDA representative said the agency would look into it.

Natural hairstyles are enjoying a resurgence among Black girls and women, but many continue to rely on the creamy crack, said Dede Teteh, DrPH, assistant professor of public health at Chapman University, Irvine, Calif.

She had her first straightening perm at 8 and has struggled to withdraw from relaxers as an adult, said Dr. Teteh, who now wears locs. Not long ago, she considered chemically straightening her hair for an academic job interview because she didn’t want her hair to “be a hindrance” when she appeared before White professors.

Dr. Teteh led “The Cost of Beauty,” a hair-health research project published in 2017. She and her team interviewed 91 Black women in Southern California. Some became “combative” at the idea of quitting relaxers and claimed “everything can cause cancer.”

Their reactions speak to the challenges Black women face in America, Dr. Teteh said.

“It’s not that people do not want to hear the information related to their health,” she said. “But they want people to share the information in a way that it’s really empathetic to the plight of being Black here in the United States.”
 

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – the independent source for health policy research, polling, and journalism.

Deanna Denham Hughes was stunned when she was diagnosed with ovarian cancer in 2022. She was only 32. She had no family history of cancer, and tests found no genetic link. Ms. Hughes wondered why she, an otherwise healthy Black mother of two, would develop a malignancy known as a “silent killer.”

After emergency surgery to remove the mass, along with her ovaries, uterus, fallopian tubes, and appendix, Ms. Hughes said, she saw an Instagram post in which a woman with uterine cancer linked her condition to chemical hair straighteners.

“I almost fell over,” she said from her home in Smyrna, Ga.

When Ms. Hughes was about 4, her mother began applying a chemical straightener, or relaxer, to her hair every 6-8 weeks. “It burned, and it smelled awful,” Ms. Hughes recalled. “But it was just part of our routine to ‘deal with my hair.’ ”

The routine continued until she went to college and met other Black women who wore their hair naturally. Soon, Ms. Hughes quit relaxers.

Social and economic pressures have long compelled Black girls and women to straighten their hair to conform to Eurocentric beauty standards. But chemical straighteners are stinky and costly and sometimes cause painful scalp burns. Mounting evidence now shows they could be a health hazard.

Relaxers can contain carcinogens, such as formaldehyde-releasing agents, phthalates, and other endocrine-disrupting compounds, according to National Institutes of Health studies. The compounds can mimic the body’s hormones and have been linked to breast, uterine, and ovarian cancers, studies show.

African American women’s often frequent and lifelong application of chemical relaxers to their hair and scalp might explain why hormone-related cancers kill disproportionately more Black than White women, say researchers and cancer doctors.

“What’s in these products is harmful,” said Tamarra James-Todd, PhD, an epidemiology professor at Harvard T.H. Chan School of Public Health, Boston, who has studied straightening products for the past 20 years.

She believes manufacturers, policymakers, and physicians should warn consumers that relaxers might cause cancer and other health problems.

But regulators have been slow to act, physicians have been reluctant to take up the cause, and racism continues to dictate fashion standards that make it tough for women to quit relaxers, products so addictive they’re known as “creamy crack.”

Michelle Obama straightened her hair when Barack Obama served as president because she believed Americans were “not ready” to see her in braids, the former first lady said after leaving the White House. The U.S. military still prohibited popular Black hairstyles such as dreadlocks and twists while the nation’s first Black president was in office.

California in 2019 became the first of nearly two dozen states to ban race-based hair discrimination. Last year, the U.S. House of Representatives passed similar legislation, known as the CROWN Act, for Creating a Respectful and Open World for Natural Hair. But the bill failed in the Senate.

The need for legislation underscores the challenges Black girls and women face at school and in the workplace.

“You have to pick your struggles,” said Atlanta-based surgical oncologist Ryland J. Gore, MD. She informs her breast cancer patients about the increased cancer risk from relaxers. Despite her knowledge, however, Dr. Gore continues to use chemical straighteners on her own hair, as she has since she was about 7 years old.

“Your hair tells a story,” she said.

In conversations with patients, Dr. Gore sometimes talks about how African American women once wove messages into their braids about the route to take on the Underground Railroad as they sought freedom from slavery.

“It’s just a deep discussion,” one that touches on culture, history, and research into current hairstyling practices, she said. “The data is out there. So patients should be warned, and then they can make a decision.”

The first hint of a connection between hair products and health issues surfaced in the 1990s. Doctors began seeing signs of sexual maturation in Black babies and young girls who developed breasts and pubic hair after using shampoo containing estrogen or placental extract. When the girls stopped using the shampoo, the hair and breast development receded, according to a study published in the journal Clinical Pediatrics in 1998.

Since then, Dr. James-Todd and other researchers have linked chemicals in hair products to a variety of health issues more prevalent among Black women – from early puberty to preterm birth, obesity, and diabetes.

In recent years, researchers have focused on a possible connection between ingredients in chemical relaxers and hormone-related cancers, like the one Ms. Hughes developed, which tend to be more aggressive and deadly in Black women.

A 2017 study found White women who used chemical relaxers were nearly twice as likely to develop breast cancer as those who did not use them. Because the vast majority of the Black study participants used relaxers, researchers could not effectively test the association in Black women, said lead author Adana Llanos, PhD, associate professor of epidemiology at Columbia University’s Mailman School of Public Health, New York.

Researchers did test it in 2020.

The so-called Sister Study, a landmark National Institute of Environmental Health Sciences investigation into the causes of breast cancer and related diseases, followed 50,000 U.S. women whose sisters had been diagnosed with breast cancer and who were cancer-free when they enrolled. Regardless of race, women who reported using relaxers in the prior year were 18% more likely to be diagnosed with breast cancer. Those who used relaxers at least every 5-8 weeks had a 31% higher breast cancer risk.

Nearly 75% of the Black sisters used relaxers in the prior year, compared with 3% of the non-Hispanic White sisters. Three-quarters of Black women self-reported using the straighteners as adolescents, and frequent use of chemical straighteners during adolescence raised the risk of premenopausal breast cancer, a 2021 NIH-funded study in the International Journal of Cancer found.

Another 2021 analysis of the Sister Study data showed sisters who self-reported that they frequently used relaxers or pressing products doubled their ovarian cancer risk. In 2022, another study found frequent use more than doubled uterine cancer risk.

After researchers discovered the link with uterine cancer, some called for policy changes and other measures to reduce exposure to chemical relaxers.

“It is time to intervene,” Dr. Llanos and her colleagues wrote in a Journal of the National Cancer Institute editorial accompanying the uterine cancer analysis. While acknowledging the need for more research, they issued a “call for action.”

No one can say that using permanent hair straighteners will give you cancer, Dr. Llanos said in an interview. “That’s not how cancer works,” she said, noting that some smokers never develop lung cancer, despite tobacco use being a known risk factor.

The body of research linking hair straighteners and cancer is more limited, said Dr. Llanos, who quit using chemical relaxers 15 years ago. But, she asked rhetorically, “Do we need to do the research for 50 more years to know that chemical relaxers are harmful?”

Charlotte R. Gamble, MD, a gynecological oncologist whose Washington, D.C., practice includes Black women with uterine and ovarian cancer, said she and her colleagues see the uterine cancer study findings as worthy of further exploration – but not yet worthy of discussion with patients.

“The jury’s out for me personally,” she said. “There’s so much more data that’s needed.”

Meanwhile, Dr. James-Todd and other researchers believe they have built a solid body of evidence.

“There are enough things we do know to begin taking action, developing interventions, providing useful information to clinicians and patients and the general public,” said Traci N. Bethea, PhD, assistant professor in the Office of Minority Health and Health Disparities Research at Georgetown University.

Responsibility for regulating personal-care products, including chemical hair straighteners and hair dyes – which also have been linked to hormone-related cancers – lies with the Food and Drug Administration. But the FDA does not subject personal-care products to the same approval process it uses for food and drugs. The FDA restricts only 11 categories of chemicals used in cosmetics, while concerns about health effects have prompted the European Union to restrict the use of at least 2,400 substances.

In March, Reps. Ayanna Pressley (D-Mass.) and Shontel Brown (D-Ohio) asked the FDA to investigate the potential health threat posed by chemical relaxers. An FDA representative said the agency would look into it.

Natural hairstyles are enjoying a resurgence among Black girls and women, but many continue to rely on the creamy crack, said Dede Teteh, DrPH, assistant professor of public health at Chapman University, Irvine, Calif.

She had her first straightening perm at 8 and has struggled to withdraw from relaxers as an adult, said Dr. Teteh, who now wears locs. Not long ago, she considered chemically straightening her hair for an academic job interview because she didn’t want her hair to “be a hindrance” when she appeared before White professors.

Dr. Teteh led “The Cost of Beauty,” a hair-health research project published in 2017. She and her team interviewed 91 Black women in Southern California. Some became “combative” at the idea of quitting relaxers and claimed “everything can cause cancer.”

Their reactions speak to the challenges Black women face in America, Dr. Teteh said.

“It’s not that people do not want to hear the information related to their health,” she said. “But they want people to share the information in a way that it’s really empathetic to the plight of being Black here in the United States.”
 

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – the independent source for health policy research, polling, and journalism.

Deanna Denham Hughes was stunned when she was diagnosed with ovarian cancer in 2022. She was only 32. She had no family history of cancer, and tests found no genetic link. Ms. Hughes wondered why she, an otherwise healthy Black mother of two, would develop a malignancy known as a “silent killer.”

After emergency surgery to remove the mass, along with her ovaries, uterus, fallopian tubes, and appendix, Ms. Hughes said, she saw an Instagram post in which a woman with uterine cancer linked her condition to chemical hair straighteners.

“I almost fell over,” she said from her home in Smyrna, Ga.

When Ms. Hughes was about 4, her mother began applying a chemical straightener, or relaxer, to her hair every 6-8 weeks. “It burned, and it smelled awful,” Ms. Hughes recalled. “But it was just part of our routine to ‘deal with my hair.’ ”

The routine continued until she went to college and met other Black women who wore their hair naturally. Soon, Ms. Hughes quit relaxers.

Social and economic pressures have long compelled Black girls and women to straighten their hair to conform to Eurocentric beauty standards. But chemical straighteners are stinky and costly and sometimes cause painful scalp burns. Mounting evidence now shows they could be a health hazard.

Relaxers can contain carcinogens, such as formaldehyde-releasing agents, phthalates, and other endocrine-disrupting compounds, according to National Institutes of Health studies. The compounds can mimic the body’s hormones and have been linked to breast, uterine, and ovarian cancers, studies show.

African American women’s often frequent and lifelong application of chemical relaxers to their hair and scalp might explain why hormone-related cancers kill disproportionately more Black than White women, say researchers and cancer doctors.

“What’s in these products is harmful,” said Tamarra James-Todd, PhD, an epidemiology professor at Harvard T.H. Chan School of Public Health, Boston, who has studied straightening products for the past 20 years.

She believes manufacturers, policymakers, and physicians should warn consumers that relaxers might cause cancer and other health problems.

But regulators have been slow to act, physicians have been reluctant to take up the cause, and racism continues to dictate fashion standards that make it tough for women to quit relaxers, products so addictive they’re known as “creamy crack.”

Michelle Obama straightened her hair when Barack Obama served as president because she believed Americans were “not ready” to see her in braids, the former first lady said after leaving the White House. The U.S. military still prohibited popular Black hairstyles such as dreadlocks and twists while the nation’s first Black president was in office.

California in 2019 became the first of nearly two dozen states to ban race-based hair discrimination. Last year, the U.S. House of Representatives passed similar legislation, known as the CROWN Act, for Creating a Respectful and Open World for Natural Hair. But the bill failed in the Senate.

The need for legislation underscores the challenges Black girls and women face at school and in the workplace.

“You have to pick your struggles,” said Atlanta-based surgical oncologist Ryland J. Gore, MD. She informs her breast cancer patients about the increased cancer risk from relaxers. Despite her knowledge, however, Dr. Gore continues to use chemical straighteners on her own hair, as she has since she was about 7 years old.

“Your hair tells a story,” she said.

In conversations with patients, Dr. Gore sometimes talks about how African American women once wove messages into their braids about the route to take on the Underground Railroad as they sought freedom from slavery.

“It’s just a deep discussion,” one that touches on culture, history, and research into current hairstyling practices, she said. “The data is out there. So patients should be warned, and then they can make a decision.”

The first hint of a connection between hair products and health issues surfaced in the 1990s. Doctors began seeing signs of sexual maturation in Black babies and young girls who developed breasts and pubic hair after using shampoo containing estrogen or placental extract. When the girls stopped using the shampoo, the hair and breast development receded, according to a study published in the journal Clinical Pediatrics in 1998.

Since then, Dr. James-Todd and other researchers have linked chemicals in hair products to a variety of health issues more prevalent among Black women – from early puberty to preterm birth, obesity, and diabetes.

In recent years, researchers have focused on a possible connection between ingredients in chemical relaxers and hormone-related cancers, like the one Ms. Hughes developed, which tend to be more aggressive and deadly in Black women.

A 2017 study found White women who used chemical relaxers were nearly twice as likely to develop breast cancer as those who did not use them. Because the vast majority of the Black study participants used relaxers, researchers could not effectively test the association in Black women, said lead author Adana Llanos, PhD, associate professor of epidemiology at Columbia University’s Mailman School of Public Health, New York.

Researchers did test it in 2020.

The so-called Sister Study, a landmark National Institute of Environmental Health Sciences investigation into the causes of breast cancer and related diseases, followed 50,000 U.S. women whose sisters had been diagnosed with breast cancer and who were cancer-free when they enrolled. Regardless of race, women who reported using relaxers in the prior year were 18% more likely to be diagnosed with breast cancer. Those who used relaxers at least every 5-8 weeks had a 31% higher breast cancer risk.

Nearly 75% of the Black sisters used relaxers in the prior year, compared with 3% of the non-Hispanic White sisters. Three-quarters of Black women self-reported using the straighteners as adolescents, and frequent use of chemical straighteners during adolescence raised the risk of premenopausal breast cancer, a 2021 NIH-funded study in the International Journal of Cancer found.

Another 2021 analysis of the Sister Study data showed sisters who self-reported that they frequently used relaxers or pressing products doubled their ovarian cancer risk. In 2022, another study found frequent use more than doubled uterine cancer risk.

After researchers discovered the link with uterine cancer, some called for policy changes and other measures to reduce exposure to chemical relaxers.

“It is time to intervene,” Dr. Llanos and her colleagues wrote in a Journal of the National Cancer Institute editorial accompanying the uterine cancer analysis. While acknowledging the need for more research, they issued a “call for action.”

No one can say that using permanent hair straighteners will give you cancer, Dr. Llanos said in an interview. “That’s not how cancer works,” she said, noting that some smokers never develop lung cancer, despite tobacco use being a known risk factor.

The body of research linking hair straighteners and cancer is more limited, said Dr. Llanos, who quit using chemical relaxers 15 years ago. But, she asked rhetorically, “Do we need to do the research for 50 more years to know that chemical relaxers are harmful?”

Charlotte R. Gamble, MD, a gynecological oncologist whose Washington, D.C., practice includes Black women with uterine and ovarian cancer, said she and her colleagues see the uterine cancer study findings as worthy of further exploration – but not yet worthy of discussion with patients.

“The jury’s out for me personally,” she said. “There’s so much more data that’s needed.”

Meanwhile, Dr. James-Todd and other researchers believe they have built a solid body of evidence.

“There are enough things we do know to begin taking action, developing interventions, providing useful information to clinicians and patients and the general public,” said Traci N. Bethea, PhD, assistant professor in the Office of Minority Health and Health Disparities Research at Georgetown University.

Responsibility for regulating personal-care products, including chemical hair straighteners and hair dyes – which also have been linked to hormone-related cancers – lies with the Food and Drug Administration. But the FDA does not subject personal-care products to the same approval process it uses for food and drugs. The FDA restricts only 11 categories of chemicals used in cosmetics, while concerns about health effects have prompted the European Union to restrict the use of at least 2,400 substances.

In March, Reps. Ayanna Pressley (D-Mass.) and Shontel Brown (D-Ohio) asked the FDA to investigate the potential health threat posed by chemical relaxers. An FDA representative said the agency would look into it.

Natural hairstyles are enjoying a resurgence among Black girls and women, but many continue to rely on the creamy crack, said Dede Teteh, DrPH, assistant professor of public health at Chapman University, Irvine, Calif.

She had her first straightening perm at 8 and has struggled to withdraw from relaxers as an adult, said Dr. Teteh, who now wears locs. Not long ago, she considered chemically straightening her hair for an academic job interview because she didn’t want her hair to “be a hindrance” when she appeared before White professors.

Dr. Teteh led “The Cost of Beauty,” a hair-health research project published in 2017. She and her team interviewed 91 Black women in Southern California. Some became “combative” at the idea of quitting relaxers and claimed “everything can cause cancer.”

Their reactions speak to the challenges Black women face in America, Dr. Teteh said.

“It’s not that people do not want to hear the information related to their health,” she said. “But they want people to share the information in a way that it’s really empathetic to the plight of being Black here in the United States.”
 

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – the independent source for health policy research, polling, and journalism.

TOPLINE:

Five scleroderma immune responses have associations with cancer risk and could be used to stratify patients, researchers argue.

METHODOLOGY:

• Included patients from the Johns Hopkins Scleroderma Center Research Registry and the University of Pittsburgh Scleroderma Center, Pittsburgh.
• A total of 676 patients with scleroderma and a history of cancer were compared with 687 control patients with scleroderma but without a history of cancer.
• Serum tested via line blot and enzyme-linked immunosorbent assay for an array of scleroderma autoantibodies.
• Examined association between autoantibodies and overall cancer risk.

TAKEAWAYS:

• Anti-POLR3 and monospecific anti-Ro52 were associated with significantly increased overall cancer risk.
• Anti-centromere and anti-U1RNP were associated with a decreased cancer risk.
• These associations remained when looking specifically at cancer-associated scleroderma.
• Patients positive for anti-Ro52 in combination with either anti-U1RNP or anti-Th/To had a decreased risk of cancer, compared with those who had anti-Ro52 alone.

IN PRACTICE:

This study is too preliminary to have practice application.

SOURCE:

Ji Soo Kim, PhD, of John Hopkins University, Baltimore, was the first author of the study, published in Arthritis & Rheumatology on July 24, 2023. Fellow Johns Hopkins researchers Livia Casciola-Rosen, PhD, and Ami A. Shah, MD, were joint senior authors.

DISCLOSURES:

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Martha McCrory Professorship, and the Johns Hopkins inHealth initiative. The authors disclosed the following patents or patent applications: Autoimmune Antigens and Cancer, Materials and Methods for Assessing Cancer Risk and Treating Cancer.

A version of this article appeared on Medscape.com.

TOPLINE:

Five scleroderma immune responses have associations with cancer risk and could be used to stratify patients, researchers argue.

METHODOLOGY:

• Included patients from the Johns Hopkins Scleroderma Center Research Registry and the University of Pittsburgh Scleroderma Center, Pittsburgh.
• A total of 676 patients with scleroderma and a history of cancer were compared with 687 control patients with scleroderma but without a history of cancer.
• Serum tested via line blot and enzyme-linked immunosorbent assay for an array of scleroderma autoantibodies.
• Examined association between autoantibodies and overall cancer risk.

TAKEAWAYS:

• Anti-POLR3 and monospecific anti-Ro52 were associated with significantly increased overall cancer risk.
• Anti-centromere and anti-U1RNP were associated with a decreased cancer risk.
• These associations remained when looking specifically at cancer-associated scleroderma.
• Patients positive for anti-Ro52 in combination with either anti-U1RNP or anti-Th/To had a decreased risk of cancer, compared with those who had anti-Ro52 alone.

IN PRACTICE:

This study is too preliminary to have practice application.

SOURCE:

Ji Soo Kim, PhD, of John Hopkins University, Baltimore, was the first author of the study, published in Arthritis & Rheumatology on July 24, 2023. Fellow Johns Hopkins researchers Livia Casciola-Rosen, PhD, and Ami A. Shah, MD, were joint senior authors.

DISCLOSURES:

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Martha McCrory Professorship, and the Johns Hopkins inHealth initiative. The authors disclosed the following patents or patent applications: Autoimmune Antigens and Cancer, Materials and Methods for Assessing Cancer Risk and Treating Cancer.

A version of this article appeared on Medscape.com.

TOPLINE:

Five scleroderma immune responses have associations with cancer risk and could be used to stratify patients, researchers argue.

METHODOLOGY:

• Included patients from the Johns Hopkins Scleroderma Center Research Registry and the University of Pittsburgh Scleroderma Center, Pittsburgh.
• A total of 676 patients with scleroderma and a history of cancer were compared with 687 control patients with scleroderma but without a history of cancer.
• Serum tested via line blot and enzyme-linked immunosorbent assay for an array of scleroderma autoantibodies.
• Examined association between autoantibodies and overall cancer risk.

TAKEAWAYS:

• Anti-POLR3 and monospecific anti-Ro52 were associated with significantly increased overall cancer risk.
• Anti-centromere and anti-U1RNP were associated with a decreased cancer risk.
• These associations remained when looking specifically at cancer-associated scleroderma.
• Patients positive for anti-Ro52 in combination with either anti-U1RNP or anti-Th/To had a decreased risk of cancer, compared with those who had anti-Ro52 alone.

IN PRACTICE:

This study is too preliminary to have practice application.

SOURCE:

Ji Soo Kim, PhD, of John Hopkins University, Baltimore, was the first author of the study, published in Arthritis & Rheumatology on July 24, 2023. Fellow Johns Hopkins researchers Livia Casciola-Rosen, PhD, and Ami A. Shah, MD, were joint senior authors.

DISCLOSURES:

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Martha McCrory Professorship, and the Johns Hopkins inHealth initiative. The authors disclosed the following patents or patent applications: Autoimmune Antigens and Cancer, Materials and Methods for Assessing Cancer Risk and Treating Cancer.

A version of this article appeared on Medscape.com.