Melanoma

SNOWMASS, COLO. – The use of anti–tumor necrosis factor biologics in patients with rheumatoid arthritis, psoriasis, and other serious autoimmune diseases is not associated with increased risk of most forms of cancer, with two highly visible and important exceptions: nonmelanoma skin cancer and malignant melanoma.

That’s the largely reassuring conclusion to be drawn from two large studies conducted by researchers at Stockholm’s Karolinska Institute, according to Dr. Jeffrey R. Curtis, director of the arthritis clinical intervention program at the University of Alabama, Birmingham.

The Swedish group conducted a comprehensive meta-analysis of all 74 pharmaceutical company–sponsored randomized controlled trials of anti-TNF biologics lasting at least 4 weeks. The investigators used individual patient data for 15,418 anti-TNF recipients and 7,486 subjects randomized to methotrexate and other comparators. About half of the randomized trials focused on rheumatoid arthritis (RA) patients; the other half involved patients with the other approved indications for anti-TNF therapy.

The use of individual patient data was a nuance of the meta-analysis that wowed Dr. Curtis.

"This is a really great paper. One of the reasons I was very impressed with it is that getting drug companies to give up any raw person-level data to anybody is difficult. The European Medicines Agency requested it, and that’s probably the only reason it happened," Dr. Curtis observed at the Winter Rheumatology symposium sponsored by the American College of Rheumatology.

The overall relative risk for all forms of cancer, excluding nonmelanoma skin cancer, in patients on anti-TNF biologics was 0.99. Their cancer rate was 641 per 100,000 person-years (Pharmacoepidemiol. Drug Saf. 2011;20:119-30).

"You can tell your patients the risk for cancer is less than 1 in 100 – it’s about 6 per 1,000 – and it’s not increased compared to background therapy," the rheumatologist said.

The exception was nonmelanoma skin cancer. The relative risk for this malignancy among users of all anti-TNF biologics was increased twofold.

In a separate study, the same group used prospectively recorded data from Swedish national registries to investigate the association between anti-TNF therapy and melanoma. This analysis involved 10,878 RA patients treated with anti-TNF biologics, 42,198 others who were not, and 162,743 matched controls from the general population.

Compared with controls, RA patients not on anti-TNF biologics did not have a significantly increased risk of malignant melanoma. However, the 38 first invasive melanomas that occurred in RA patients taking a TNF antagonist signified a 1.5-fold increased risk of this malignancy compared to the general population. This 50% increase in relative risk was statistically significant. The absolute increase in risk was quite small: 20 additional cases per 100,000 person-years. The number needed to harm – that is, the number of patients who needed to be treated with an anti-TNF biologic to cause one additional case of melanoma – was 50,000 (BMJ 2013;346:f1939 [doi: 10.1136/bmj.f1939]).

Dr. Curtis noted that patients who have been urged to consider going on a TNF antagonist often return to the office waving a printout of the product labeling that warns of the possibility of malignancy.

"The bottom line: I tell patients that based on the data that there doesn’t appear to be an increased risk for all types of cancer, including hematologic, with the exceptions of nonmelanoma skin cancer and melanoma. Those are the two we need to advise patients about," he said.

Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.

[email protected]

SNOWMASS, COLO. – The use of anti–tumor necrosis factor biologics in patients with rheumatoid arthritis, psoriasis, and other serious autoimmune diseases is not associated with increased risk of most forms of cancer, with two highly visible and important exceptions: nonmelanoma skin cancer and malignant melanoma.

That’s the largely reassuring conclusion to be drawn from two large studies conducted by researchers at Stockholm’s Karolinska Institute, according to Dr. Jeffrey R. Curtis, director of the arthritis clinical intervention program at the University of Alabama, Birmingham.

The Swedish group conducted a comprehensive meta-analysis of all 74 pharmaceutical company–sponsored randomized controlled trials of anti-TNF biologics lasting at least 4 weeks. The investigators used individual patient data for 15,418 anti-TNF recipients and 7,486 subjects randomized to methotrexate and other comparators. About half of the randomized trials focused on rheumatoid arthritis (RA) patients; the other half involved patients with the other approved indications for anti-TNF therapy.

The use of individual patient data was a nuance of the meta-analysis that wowed Dr. Curtis.

"This is a really great paper. One of the reasons I was very impressed with it is that getting drug companies to give up any raw person-level data to anybody is difficult. The European Medicines Agency requested it, and that’s probably the only reason it happened," Dr. Curtis observed at the Winter Rheumatology symposium sponsored by the American College of Rheumatology.

The overall relative risk for all forms of cancer, excluding nonmelanoma skin cancer, in patients on anti-TNF biologics was 0.99. Their cancer rate was 641 per 100,000 person-years (Pharmacoepidemiol. Drug Saf. 2011;20:119-30).

"You can tell your patients the risk for cancer is less than 1 in 100 – it’s about 6 per 1,000 – and it’s not increased compared to background therapy," the rheumatologist said.

The exception was nonmelanoma skin cancer. The relative risk for this malignancy among users of all anti-TNF biologics was increased twofold.

In a separate study, the same group used prospectively recorded data from Swedish national registries to investigate the association between anti-TNF therapy and melanoma. This analysis involved 10,878 RA patients treated with anti-TNF biologics, 42,198 others who were not, and 162,743 matched controls from the general population.

Compared with controls, RA patients not on anti-TNF biologics did not have a significantly increased risk of malignant melanoma. However, the 38 first invasive melanomas that occurred in RA patients taking a TNF antagonist signified a 1.5-fold increased risk of this malignancy compared to the general population. This 50% increase in relative risk was statistically significant. The absolute increase in risk was quite small: 20 additional cases per 100,000 person-years. The number needed to harm – that is, the number of patients who needed to be treated with an anti-TNF biologic to cause one additional case of melanoma – was 50,000 (BMJ 2013;346:f1939 [doi: 10.1136/bmj.f1939]).

Dr. Curtis noted that patients who have been urged to consider going on a TNF antagonist often return to the office waving a printout of the product labeling that warns of the possibility of malignancy.

"The bottom line: I tell patients that based on the data that there doesn’t appear to be an increased risk for all types of cancer, including hematologic, with the exceptions of nonmelanoma skin cancer and melanoma. Those are the two we need to advise patients about," he said.

Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.

[email protected]

SNOWMASS, COLO. – The use of anti–tumor necrosis factor biologics in patients with rheumatoid arthritis, psoriasis, and other serious autoimmune diseases is not associated with increased risk of most forms of cancer, with two highly visible and important exceptions: nonmelanoma skin cancer and malignant melanoma.

That’s the largely reassuring conclusion to be drawn from two large studies conducted by researchers at Stockholm’s Karolinska Institute, according to Dr. Jeffrey R. Curtis, director of the arthritis clinical intervention program at the University of Alabama, Birmingham.

The Swedish group conducted a comprehensive meta-analysis of all 74 pharmaceutical company–sponsored randomized controlled trials of anti-TNF biologics lasting at least 4 weeks. The investigators used individual patient data for 15,418 anti-TNF recipients and 7,486 subjects randomized to methotrexate and other comparators. About half of the randomized trials focused on rheumatoid arthritis (RA) patients; the other half involved patients with the other approved indications for anti-TNF therapy.

The use of individual patient data was a nuance of the meta-analysis that wowed Dr. Curtis.

"This is a really great paper. One of the reasons I was very impressed with it is that getting drug companies to give up any raw person-level data to anybody is difficult. The European Medicines Agency requested it, and that’s probably the only reason it happened," Dr. Curtis observed at the Winter Rheumatology symposium sponsored by the American College of Rheumatology.

The overall relative risk for all forms of cancer, excluding nonmelanoma skin cancer, in patients on anti-TNF biologics was 0.99. Their cancer rate was 641 per 100,000 person-years (Pharmacoepidemiol. Drug Saf. 2011;20:119-30).

"You can tell your patients the risk for cancer is less than 1 in 100 – it’s about 6 per 1,000 – and it’s not increased compared to background therapy," the rheumatologist said.

The exception was nonmelanoma skin cancer. The relative risk for this malignancy among users of all anti-TNF biologics was increased twofold.

In a separate study, the same group used prospectively recorded data from Swedish national registries to investigate the association between anti-TNF therapy and melanoma. This analysis involved 10,878 RA patients treated with anti-TNF biologics, 42,198 others who were not, and 162,743 matched controls from the general population.

Compared with controls, RA patients not on anti-TNF biologics did not have a significantly increased risk of malignant melanoma. However, the 38 first invasive melanomas that occurred in RA patients taking a TNF antagonist signified a 1.5-fold increased risk of this malignancy compared to the general population. This 50% increase in relative risk was statistically significant. The absolute increase in risk was quite small: 20 additional cases per 100,000 person-years. The number needed to harm – that is, the number of patients who needed to be treated with an anti-TNF biologic to cause one additional case of melanoma – was 50,000 (BMJ 2013;346:f1939 [doi: 10.1136/bmj.f1939]).

Dr. Curtis noted that patients who have been urged to consider going on a TNF antagonist often return to the office waving a printout of the product labeling that warns of the possibility of malignancy.

"The bottom line: I tell patients that based on the data that there doesn’t appear to be an increased risk for all types of cancer, including hematologic, with the exceptions of nonmelanoma skin cancer and melanoma. Those are the two we need to advise patients about," he said.

Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.

[email protected]

Among patients with advanced melanoma who are being considered for ipilimumab therapy, serum vascular endothelial growth factor level may predict who will respond to the treatment and who will not, according to a report published online Feb. 4 in Cancer Immunology Research.

Only a subset of patients with advanced melanoma benefit from the CTLA-4 blocker ipilimumab, but those who do show marked and durable improvement, so there is "a critical need" to identify biomarkers that predict treatment response, said Dr. Jianda Yuan of the Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Cancer Center, New York, and his associates.

The investigators assessed circulating vascular endothelial growth factor (VEGF) levels before and after ipilimumab therapy in 176 patients aged 16-91 years (mean age, 62) who were treated for advanced melanoma at Sloan-Kettering and at Dana-Farber/Harvard Cancer Center, Boston. A total of 78 patients received 10 mg/kg and 98 received 3 mg/kg every 3 weeks for 12 weeks. Those who showed clinical benefit and no dose-limiting toxicity at 24 weeks could continue receiving the drug until the disease progressed, they died, toxicity occurred, or they withdrew from the study.

One-third of the study participants (53 of the 159 patients evaluable at week 24) showed clinical benefit, including 3 complete responders, 13 partial responders, and 37 with stabilization of their disease, the investigators said (Cancer Immunol. Res 2014 Feb. 4 [doi:10.1158/2326-6066.CIR-13-0163]).

Patients with serum VEGF levels higher than 43 pg/mL were significantly less likely to respond to ipilimumab and had significantly shorter overall survival than those with lower levels, regardless of which dose of the drug they were given. Thirty-seven of the 90 patients with low VEGF (41%) showed clinical benefit with ipilimumab, compared with only 16 of the 69 patients with high VEGF (23%).

The findings of this preliminary research show that prospective studies are warranted to assess whether baseline serum VEGF can serve as a predictive biomarker, Dr. Yuan and his associates said.

This study was supported by the National Institutes of Health. Four of Dr. Yuan’s associates reported receiving support from and serving as consultants for Bristol-Myers Squibb, which developed the monoclonal antibody ipilimumab.

Among patients with advanced melanoma who are being considered for ipilimumab therapy, serum vascular endothelial growth factor level may predict who will respond to the treatment and who will not, according to a report published online Feb. 4 in Cancer Immunology Research.

Only a subset of patients with advanced melanoma benefit from the CTLA-4 blocker ipilimumab, but those who do show marked and durable improvement, so there is "a critical need" to identify biomarkers that predict treatment response, said Dr. Jianda Yuan of the Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Cancer Center, New York, and his associates.

The investigators assessed circulating vascular endothelial growth factor (VEGF) levels before and after ipilimumab therapy in 176 patients aged 16-91 years (mean age, 62) who were treated for advanced melanoma at Sloan-Kettering and at Dana-Farber/Harvard Cancer Center, Boston. A total of 78 patients received 10 mg/kg and 98 received 3 mg/kg every 3 weeks for 12 weeks. Those who showed clinical benefit and no dose-limiting toxicity at 24 weeks could continue receiving the drug until the disease progressed, they died, toxicity occurred, or they withdrew from the study.

One-third of the study participants (53 of the 159 patients evaluable at week 24) showed clinical benefit, including 3 complete responders, 13 partial responders, and 37 with stabilization of their disease, the investigators said (Cancer Immunol. Res 2014 Feb. 4 [doi:10.1158/2326-6066.CIR-13-0163]).

Patients with serum VEGF levels higher than 43 pg/mL were significantly less likely to respond to ipilimumab and had significantly shorter overall survival than those with lower levels, regardless of which dose of the drug they were given. Thirty-seven of the 90 patients with low VEGF (41%) showed clinical benefit with ipilimumab, compared with only 16 of the 69 patients with high VEGF (23%).

The findings of this preliminary research show that prospective studies are warranted to assess whether baseline serum VEGF can serve as a predictive biomarker, Dr. Yuan and his associates said.

This study was supported by the National Institutes of Health. Four of Dr. Yuan’s associates reported receiving support from and serving as consultants for Bristol-Myers Squibb, which developed the monoclonal antibody ipilimumab.

Among patients with advanced melanoma who are being considered for ipilimumab therapy, serum vascular endothelial growth factor level may predict who will respond to the treatment and who will not, according to a report published online Feb. 4 in Cancer Immunology Research.

Only a subset of patients with advanced melanoma benefit from the CTLA-4 blocker ipilimumab, but those who do show marked and durable improvement, so there is "a critical need" to identify biomarkers that predict treatment response, said Dr. Jianda Yuan of the Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Cancer Center, New York, and his associates.

The investigators assessed circulating vascular endothelial growth factor (VEGF) levels before and after ipilimumab therapy in 176 patients aged 16-91 years (mean age, 62) who were treated for advanced melanoma at Sloan-Kettering and at Dana-Farber/Harvard Cancer Center, Boston. A total of 78 patients received 10 mg/kg and 98 received 3 mg/kg every 3 weeks for 12 weeks. Those who showed clinical benefit and no dose-limiting toxicity at 24 weeks could continue receiving the drug until the disease progressed, they died, toxicity occurred, or they withdrew from the study.

One-third of the study participants (53 of the 159 patients evaluable at week 24) showed clinical benefit, including 3 complete responders, 13 partial responders, and 37 with stabilization of their disease, the investigators said (Cancer Immunol. Res 2014 Feb. 4 [doi:10.1158/2326-6066.CIR-13-0163]).

Patients with serum VEGF levels higher than 43 pg/mL were significantly less likely to respond to ipilimumab and had significantly shorter overall survival than those with lower levels, regardless of which dose of the drug they were given. Thirty-seven of the 90 patients with low VEGF (41%) showed clinical benefit with ipilimumab, compared with only 16 of the 69 patients with high VEGF (23%).

The findings of this preliminary research show that prospective studies are warranted to assess whether baseline serum VEGF can serve as a predictive biomarker, Dr. Yuan and his associates said.

This study was supported by the National Institutes of Health. Four of Dr. Yuan’s associates reported receiving support from and serving as consultants for Bristol-Myers Squibb, which developed the monoclonal antibody ipilimumab.

Immunosuppressive therapies for inflammatory bowel disease do not appear to be implicated in the increased risk for melanomas and hematologic malignancies seen in these patients, based on the results of a large database analysis and a separate meta-analysis published in the February edition of Clinical Gastroenterology and Hepatology.

The first study, based on a nationwide population-based cohort analysis conducted in Denmark, found that patients with inflammatory bowel disease (IBD) are at increased risk for cancer, in particular hematologic malignancies and melanoma at standardized incidence ratios of 1.9 and 1.4, respectively.

The second study, based on a systematic review and meta-analysis of the medical literature, found a diagnosis of Crohn’s disease or ulcerative colitis was associated with a 37% increase in the risk of developing melanoma. Melanoma risk was higher in studies performed before the introduction of biologic therapies in 1998, but not in those studies performed after 1998.

For the first study, researchers led by Dr. Michael D. Kappelman of the division of pediatric gastroenterology at the University of North Carolina at Chapel Hill used health care databases to identify patients in Denmark with a diagnosis of Crohn’s disease or ulcerative colitis from 1978 through 2010 (doi: 10.1016/j.cgh.2013.03.034). They followed the patients until the first occurrence of cancer, death, or emigration and used standardized incidence ratios (SIRs) to compare cancer incidence in patients with IBD with that expected in the general population.

"If immunosuppressive medications reduce the risk of gastrointestinal malignancy by suppressing intestinal inflammation but increase the risk of extraintestinal malignancies, IBD patients may be trading off one set of risks for another," the researchers wrote. "We therefore sought to evaluate both intestinal and extraintestinal malignancies comprehensively, as well as the occurrence of any invasive cancer, in a nationwide cohort of patients with IBD in Denmark."

The analysis included 13,756 patients with Crohn’s disease and 35,152 patients with ulcerative colitis who were followed up for a mean of nearly 8 years. After the exclusion of cancers diagnosed within 1 year of IBD diagnosis, 772 cases of invasive cancer occurred among patients with Crohn’s disease (SIR 1.3) and 2,331 occurred among patients with ulcerative colitis (SIR 1.1). Diagnosis of Crohn’s disease was weakly associated with gastrointestinal cancers (SIR 1.2) and extraintestinal cancers (SIR 1.3), with the strongest associations for hematologic malignancies (SIR 1.9), smoking-related cancers (SIR 1.5), and melanoma (SIR 1.4). Associations between ulcerative colitis and gastrointestinal and extraintestinal cancers were weaker (SIR of 1.1 for both).

The excess risk of cancer in patients with Crohn’s disease "largely is owing to extraintestinal cancers, particularly hematologic malignancies and melanoma, both of which may be related to immune suppression, and smoking-related cancers," the researchers concluded. They added that their study "provides reassuring data that the decreasing risk for gastrointestinal malignancy observed here ... has not been offset by a concomitant increase in the risk of extraintestinal or hematologic malignancies. These findings suggest that changes in the medical and surgical treatment of IBD and/or other secular trends have not substantially impacted cancer relative risk on a population basis."

The study was supported in part by grants from the National Institute for Diabetes and Digestive and Kidney Diseases, the Karen Elise Jensen Foundation, and the Clinical Epidemiological Research Foundation.

In the second study from the journal, researchers led by Dr. Suddharth Singh of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn., conducted a systematic literature search through March 2013 for cohort studies showing incident melanoma after IBD diagnosis and an estimate of incident rate ratio or standardized incidence rate. Case reports or case series were excluded (doi: 10.1016/j.cgh.2013.04.033).

Of the 838 studies identified, 12 that comprised 172,837 patients with IBD were included in the final analysis. The pooled crude incidence rate of melanoma among patients in the 12 studies was 27.7/100,000 person-years. This translated into a 37% increase in the risk of melanoma (risk ratio of 1.37). The increase was observed independently in the patients with Crohn’s disease (RR 1.51) and in those with ulcerative colitis (RR 1.23). In addition, the risk of melanoma was higher in studies conducted prior to 1998, when biologic therapies were introduced (RR 1.52), but not in those conducted after 1998 (RR 1.08).

"The risk of melanoma has been shown to be increased in immunosuppressed patients, including patients with a prior solid organ transplant, lymphoma, and patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. It is possible that the increased risk of melanoma observed in patients with IBD may be related to underlying immune dysfunction in these patients, resulting in altered tumor surveillance" the researchers wrote.

They hypothesized that immunosuppressive medications may increase the risk of melanoma by "down-regulation of the tumor surveillance mechanisms, increased susceptibility to infection with oncogenic viruses such as melanoma-associated retroviruses, or through direct pharmacologic effects of medications on DNA metabolism. Although thiopurine analogs have been associated with an increased risk of nonmelanoma skin cancers, our pooled analysis did not suggest an increased risk of melanoma, albeit there were a limited number of studies."

Dr. Singh and his associates acknowledged certain limitations of the analysis, including the potential for misclassification bias in the included studies and the fact that studies "did not adjust for known risk factors for melanoma, including personal history of nonmelanoma skin cancers, family history of melanoma, or sun exposure."

For the meta-analysis, one author, Dr. Edward V. Loftus, disclosed that he has consulted for and has received research support from Janssen Biotech, Abbott Laboratories, and UCB Pharma. The others had no relevant conflicts to disclose.

[email protected]

Immunosuppressive therapies for inflammatory bowel disease do not appear to be implicated in the increased risk for melanomas and hematologic malignancies seen in these patients, based on the results of a large database analysis and a separate meta-analysis published in the February edition of Clinical Gastroenterology and Hepatology.

The first study, based on a nationwide population-based cohort analysis conducted in Denmark, found that patients with inflammatory bowel disease (IBD) are at increased risk for cancer, in particular hematologic malignancies and melanoma at standardized incidence ratios of 1.9 and 1.4, respectively.

The second study, based on a systematic review and meta-analysis of the medical literature, found a diagnosis of Crohn’s disease or ulcerative colitis was associated with a 37% increase in the risk of developing melanoma. Melanoma risk was higher in studies performed before the introduction of biologic therapies in 1998, but not in those studies performed after 1998.

For the first study, researchers led by Dr. Michael D. Kappelman of the division of pediatric gastroenterology at the University of North Carolina at Chapel Hill used health care databases to identify patients in Denmark with a diagnosis of Crohn’s disease or ulcerative colitis from 1978 through 2010 (doi: 10.1016/j.cgh.2013.03.034). They followed the patients until the first occurrence of cancer, death, or emigration and used standardized incidence ratios (SIRs) to compare cancer incidence in patients with IBD with that expected in the general population.

"If immunosuppressive medications reduce the risk of gastrointestinal malignancy by suppressing intestinal inflammation but increase the risk of extraintestinal malignancies, IBD patients may be trading off one set of risks for another," the researchers wrote. "We therefore sought to evaluate both intestinal and extraintestinal malignancies comprehensively, as well as the occurrence of any invasive cancer, in a nationwide cohort of patients with IBD in Denmark."

The analysis included 13,756 patients with Crohn’s disease and 35,152 patients with ulcerative colitis who were followed up for a mean of nearly 8 years. After the exclusion of cancers diagnosed within 1 year of IBD diagnosis, 772 cases of invasive cancer occurred among patients with Crohn’s disease (SIR 1.3) and 2,331 occurred among patients with ulcerative colitis (SIR 1.1). Diagnosis of Crohn’s disease was weakly associated with gastrointestinal cancers (SIR 1.2) and extraintestinal cancers (SIR 1.3), with the strongest associations for hematologic malignancies (SIR 1.9), smoking-related cancers (SIR 1.5), and melanoma (SIR 1.4). Associations between ulcerative colitis and gastrointestinal and extraintestinal cancers were weaker (SIR of 1.1 for both).

The excess risk of cancer in patients with Crohn’s disease "largely is owing to extraintestinal cancers, particularly hematologic malignancies and melanoma, both of which may be related to immune suppression, and smoking-related cancers," the researchers concluded. They added that their study "provides reassuring data that the decreasing risk for gastrointestinal malignancy observed here ... has not been offset by a concomitant increase in the risk of extraintestinal or hematologic malignancies. These findings suggest that changes in the medical and surgical treatment of IBD and/or other secular trends have not substantially impacted cancer relative risk on a population basis."

The study was supported in part by grants from the National Institute for Diabetes and Digestive and Kidney Diseases, the Karen Elise Jensen Foundation, and the Clinical Epidemiological Research Foundation.

In the second study from the journal, researchers led by Dr. Suddharth Singh of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn., conducted a systematic literature search through March 2013 for cohort studies showing incident melanoma after IBD diagnosis and an estimate of incident rate ratio or standardized incidence rate. Case reports or case series were excluded (doi: 10.1016/j.cgh.2013.04.033).

Of the 838 studies identified, 12 that comprised 172,837 patients with IBD were included in the final analysis. The pooled crude incidence rate of melanoma among patients in the 12 studies was 27.7/100,000 person-years. This translated into a 37% increase in the risk of melanoma (risk ratio of 1.37). The increase was observed independently in the patients with Crohn’s disease (RR 1.51) and in those with ulcerative colitis (RR 1.23). In addition, the risk of melanoma was higher in studies conducted prior to 1998, when biologic therapies were introduced (RR 1.52), but not in those conducted after 1998 (RR 1.08).

"The risk of melanoma has been shown to be increased in immunosuppressed patients, including patients with a prior solid organ transplant, lymphoma, and patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. It is possible that the increased risk of melanoma observed in patients with IBD may be related to underlying immune dysfunction in these patients, resulting in altered tumor surveillance" the researchers wrote.

They hypothesized that immunosuppressive medications may increase the risk of melanoma by "down-regulation of the tumor surveillance mechanisms, increased susceptibility to infection with oncogenic viruses such as melanoma-associated retroviruses, or through direct pharmacologic effects of medications on DNA metabolism. Although thiopurine analogs have been associated with an increased risk of nonmelanoma skin cancers, our pooled analysis did not suggest an increased risk of melanoma, albeit there were a limited number of studies."

Dr. Singh and his associates acknowledged certain limitations of the analysis, including the potential for misclassification bias in the included studies and the fact that studies "did not adjust for known risk factors for melanoma, including personal history of nonmelanoma skin cancers, family history of melanoma, or sun exposure."

For the meta-analysis, one author, Dr. Edward V. Loftus, disclosed that he has consulted for and has received research support from Janssen Biotech, Abbott Laboratories, and UCB Pharma. The others had no relevant conflicts to disclose.

[email protected]

Immunosuppressive therapies for inflammatory bowel disease do not appear to be implicated in the increased risk for melanomas and hematologic malignancies seen in these patients, based on the results of a large database analysis and a separate meta-analysis published in the February edition of Clinical Gastroenterology and Hepatology.

The first study, based on a nationwide population-based cohort analysis conducted in Denmark, found that patients with inflammatory bowel disease (IBD) are at increased risk for cancer, in particular hematologic malignancies and melanoma at standardized incidence ratios of 1.9 and 1.4, respectively.

The second study, based on a systematic review and meta-analysis of the medical literature, found a diagnosis of Crohn’s disease or ulcerative colitis was associated with a 37% increase in the risk of developing melanoma. Melanoma risk was higher in studies performed before the introduction of biologic therapies in 1998, but not in those studies performed after 1998.

For the first study, researchers led by Dr. Michael D. Kappelman of the division of pediatric gastroenterology at the University of North Carolina at Chapel Hill used health care databases to identify patients in Denmark with a diagnosis of Crohn’s disease or ulcerative colitis from 1978 through 2010 (doi: 10.1016/j.cgh.2013.03.034). They followed the patients until the first occurrence of cancer, death, or emigration and used standardized incidence ratios (SIRs) to compare cancer incidence in patients with IBD with that expected in the general population.

"If immunosuppressive medications reduce the risk of gastrointestinal malignancy by suppressing intestinal inflammation but increase the risk of extraintestinal malignancies, IBD patients may be trading off one set of risks for another," the researchers wrote. "We therefore sought to evaluate both intestinal and extraintestinal malignancies comprehensively, as well as the occurrence of any invasive cancer, in a nationwide cohort of patients with IBD in Denmark."

The analysis included 13,756 patients with Crohn’s disease and 35,152 patients with ulcerative colitis who were followed up for a mean of nearly 8 years. After the exclusion of cancers diagnosed within 1 year of IBD diagnosis, 772 cases of invasive cancer occurred among patients with Crohn’s disease (SIR 1.3) and 2,331 occurred among patients with ulcerative colitis (SIR 1.1). Diagnosis of Crohn’s disease was weakly associated with gastrointestinal cancers (SIR 1.2) and extraintestinal cancers (SIR 1.3), with the strongest associations for hematologic malignancies (SIR 1.9), smoking-related cancers (SIR 1.5), and melanoma (SIR 1.4). Associations between ulcerative colitis and gastrointestinal and extraintestinal cancers were weaker (SIR of 1.1 for both).

The excess risk of cancer in patients with Crohn’s disease "largely is owing to extraintestinal cancers, particularly hematologic malignancies and melanoma, both of which may be related to immune suppression, and smoking-related cancers," the researchers concluded. They added that their study "provides reassuring data that the decreasing risk for gastrointestinal malignancy observed here ... has not been offset by a concomitant increase in the risk of extraintestinal or hematologic malignancies. These findings suggest that changes in the medical and surgical treatment of IBD and/or other secular trends have not substantially impacted cancer relative risk on a population basis."

The study was supported in part by grants from the National Institute for Diabetes and Digestive and Kidney Diseases, the Karen Elise Jensen Foundation, and the Clinical Epidemiological Research Foundation.

In the second study from the journal, researchers led by Dr. Suddharth Singh of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn., conducted a systematic literature search through March 2013 for cohort studies showing incident melanoma after IBD diagnosis and an estimate of incident rate ratio or standardized incidence rate. Case reports or case series were excluded (doi: 10.1016/j.cgh.2013.04.033).

Of the 838 studies identified, 12 that comprised 172,837 patients with IBD were included in the final analysis. The pooled crude incidence rate of melanoma among patients in the 12 studies was 27.7/100,000 person-years. This translated into a 37% increase in the risk of melanoma (risk ratio of 1.37). The increase was observed independently in the patients with Crohn’s disease (RR 1.51) and in those with ulcerative colitis (RR 1.23). In addition, the risk of melanoma was higher in studies conducted prior to 1998, when biologic therapies were introduced (RR 1.52), but not in those conducted after 1998 (RR 1.08).

"The risk of melanoma has been shown to be increased in immunosuppressed patients, including patients with a prior solid organ transplant, lymphoma, and patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. It is possible that the increased risk of melanoma observed in patients with IBD may be related to underlying immune dysfunction in these patients, resulting in altered tumor surveillance" the researchers wrote.

They hypothesized that immunosuppressive medications may increase the risk of melanoma by "down-regulation of the tumor surveillance mechanisms, increased susceptibility to infection with oncogenic viruses such as melanoma-associated retroviruses, or through direct pharmacologic effects of medications on DNA metabolism. Although thiopurine analogs have been associated with an increased risk of nonmelanoma skin cancers, our pooled analysis did not suggest an increased risk of melanoma, albeit there were a limited number of studies."

Dr. Singh and his associates acknowledged certain limitations of the analysis, including the potential for misclassification bias in the included studies and the fact that studies "did not adjust for known risk factors for melanoma, including personal history of nonmelanoma skin cancers, family history of melanoma, or sun exposure."

For the meta-analysis, one author, Dr. Edward V. Loftus, disclosed that he has consulted for and has received research support from Janssen Biotech, Abbott Laboratories, and UCB Pharma. The others had no relevant conflicts to disclose.

[email protected]

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.

Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."

Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.

In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).

"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.

To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."

Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).

Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."

The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).

Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).

A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).

In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).

Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.

Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.

[email protected]

HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.

Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."

Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.

In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).

"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.

To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."

Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).

Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."

The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).

Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).

A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).

In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).

Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.

Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.

[email protected]

HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.

Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."

Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.

In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).

"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.

To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."

Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).

Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."

The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).

Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).

A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).

In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).

Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.

Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.

[email protected]

A combination of two targeted, orally administered drug therapies – trametinib and dabrafenib – has been approved by the Food and Drug Administration for treating patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations, manufacturer GlaxoSmithKline announced on Jan. 9.

An FDA-approved test is used to detect the mutations, according to the company statement.

Trametinib, marketed as Mekinist, and dabrafenib, marketed as Tafinlar, were each approved in May 2013 as separate treatments for metastatic or unresectable melanomas that express the mutations – along with a companion test to detect the mutations. Both are kinase inhibitors.

The GSK statement noted that the accelerated approval of the combination therapy is based on the response rate and median duration of response results in a phase I/II study of 108 patients, which compared the combination (150 mg of dabrafenib twice a day and 2 mg of trametinib once a day) to treatment with dabrafenib alone. The overall response rates, as assessed by the investigators, were 76% among those on the combination and 54% for those on dabrafenib alone. The median duration of response was 10.5 months among those on the combination, vs. 5.6 months among those on dabrafenib alone.

The most common adverse events associated with the combination treatment included fever in 71% of patients, chills in 58%, fatigue in 52%, rash in 45%, nausea in 44%, vomiting in 40%, and diarrhea in 36%. Renal failure, pyrexia, back pain, and hemorrhage were among the most common grade-3 or -4 adverse events among those on the combination.

Serious adverse effects associated with treatment, including some potentially fatal effects, are new primary cutaneous skin cancers, tumor promotion in wild-type BRAF melanoma, and hemorrhagic events, according to GSK.

The FDA approval occurred through an accelerated process based on clinical evidence that the treatment has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Full approval is dependent on the results of an ongoing phase III study, GSK said.

The updated trametinib label states that "improvement in disease-related symptoms or overall survival has not been demonstrated" for the combination treatment.

The prescribing information for Mekinist is available at http://us.gsk.com/products/assets/us_mekinist.pdf. The prescribing information for Tafinlar (which does not yet include the updated information on the combination therapy approval) is available at http://us.gsk.com/products/assets/us_tafinlar.pdf.

[email protected]

A combination of two targeted, orally administered drug therapies – trametinib and dabrafenib – has been approved by the Food and Drug Administration for treating patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations, manufacturer GlaxoSmithKline announced on Jan. 9.

An FDA-approved test is used to detect the mutations, according to the company statement.

Trametinib, marketed as Mekinist, and dabrafenib, marketed as Tafinlar, were each approved in May 2013 as separate treatments for metastatic or unresectable melanomas that express the mutations – along with a companion test to detect the mutations. Both are kinase inhibitors.

The GSK statement noted that the accelerated approval of the combination therapy is based on the response rate and median duration of response results in a phase I/II study of 108 patients, which compared the combination (150 mg of dabrafenib twice a day and 2 mg of trametinib once a day) to treatment with dabrafenib alone. The overall response rates, as assessed by the investigators, were 76% among those on the combination and 54% for those on dabrafenib alone. The median duration of response was 10.5 months among those on the combination, vs. 5.6 months among those on dabrafenib alone.

The most common adverse events associated with the combination treatment included fever in 71% of patients, chills in 58%, fatigue in 52%, rash in 45%, nausea in 44%, vomiting in 40%, and diarrhea in 36%. Renal failure, pyrexia, back pain, and hemorrhage were among the most common grade-3 or -4 adverse events among those on the combination.

Serious adverse effects associated with treatment, including some potentially fatal effects, are new primary cutaneous skin cancers, tumor promotion in wild-type BRAF melanoma, and hemorrhagic events, according to GSK.

The FDA approval occurred through an accelerated process based on clinical evidence that the treatment has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Full approval is dependent on the results of an ongoing phase III study, GSK said.

The updated trametinib label states that "improvement in disease-related symptoms or overall survival has not been demonstrated" for the combination treatment.

The prescribing information for Mekinist is available at http://us.gsk.com/products/assets/us_mekinist.pdf. The prescribing information for Tafinlar (which does not yet include the updated information on the combination therapy approval) is available at http://us.gsk.com/products/assets/us_tafinlar.pdf.

[email protected]

A combination of two targeted, orally administered drug therapies – trametinib and dabrafenib – has been approved by the Food and Drug Administration for treating patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations, manufacturer GlaxoSmithKline announced on Jan. 9.

An FDA-approved test is used to detect the mutations, according to the company statement.

Trametinib, marketed as Mekinist, and dabrafenib, marketed as Tafinlar, were each approved in May 2013 as separate treatments for metastatic or unresectable melanomas that express the mutations – along with a companion test to detect the mutations. Both are kinase inhibitors.

The GSK statement noted that the accelerated approval of the combination therapy is based on the response rate and median duration of response results in a phase I/II study of 108 patients, which compared the combination (150 mg of dabrafenib twice a day and 2 mg of trametinib once a day) to treatment with dabrafenib alone. The overall response rates, as assessed by the investigators, were 76% among those on the combination and 54% for those on dabrafenib alone. The median duration of response was 10.5 months among those on the combination, vs. 5.6 months among those on dabrafenib alone.

The most common adverse events associated with the combination treatment included fever in 71% of patients, chills in 58%, fatigue in 52%, rash in 45%, nausea in 44%, vomiting in 40%, and diarrhea in 36%. Renal failure, pyrexia, back pain, and hemorrhage were among the most common grade-3 or -4 adverse events among those on the combination.

Serious adverse effects associated with treatment, including some potentially fatal effects, are new primary cutaneous skin cancers, tumor promotion in wild-type BRAF melanoma, and hemorrhagic events, according to GSK.

The FDA approval occurred through an accelerated process based on clinical evidence that the treatment has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Full approval is dependent on the results of an ongoing phase III study, GSK said.

The updated trametinib label states that "improvement in disease-related symptoms or overall survival has not been demonstrated" for the combination treatment.

The prescribing information for Mekinist is available at http://us.gsk.com/products/assets/us_mekinist.pdf. The prescribing information for Tafinlar (which does not yet include the updated information on the combination therapy approval) is available at http://us.gsk.com/products/assets/us_tafinlar.pdf.

[email protected]

In an article published online in Maclean’s magazine on October 15, 2013, the concept of developing artificial body parts is discussed. The technology now exists for scientists to grow tissue organs, such as ears, noses, and fingers. Several groups of investigators, including Anthony Atala, MD (Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina) and Alexander Seifalian, PhD (University College London, England), are busy making ears by creating a biodegradable scaffold onto which cells—either stem cells from the patient or cells that have been harvested from the patient’s original organ—are layered and permitted to multiply. The cell-layered scaffold is then placed in a bioreactor for a couple of weeks. Once ready, the new ear is transplanted onto the patient; subsequently, the scaffold melts away.

Dr. Atala’s laboratory also is busy growing fingers. Meanwhile, Dr. Seifalian grew a nose (inside the patient’s own arm) in only 3 months after the patient lost his nose to skin cancer. He made a mold based on the patient’s original nose, created a scaffold composed of nanocomposite material, added the patient’s stem cells to the scaffold, and put the nose in a bioreactor to mature. Meanwhile, he placed a tissue expander in the patient’s arm and subsequently inserted the nose into the arm so that it could become vascularized and covered by skin. The nose was transplanted to the patient’s face; additional surgery is planned to open the nostrils, followed by seeding them with stem cells to return his sense of smell.

Marc Jeschke, MD, PhD (Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario) is developing a bioprinter to create skin. The bioprinter dispenses different types of cells (grown from the patient’s own cells) into a hydrogel matrix in 3 dimensions. Currently, Dr. Jeschke is working with mice; however, in a few years, he anticipates treating human patients. Other investigators, such as Michael C. McAlpine (Princeton University, New Jersey), recently used a commercial 3-dimensional printer to make an ear; the “inks” included calf cells and a silver nanoparticle paste that formed a coiled antenna inside the cartilage that was capable of receiving electromagnetic signals and transmitting them to the brain.

What’s the issue?

The ability to grow tissue organs is going to revolutionize the surgical management of patients who need solid organ replacement; kidneys, lungs, pancreases, spleens, and tracheas have already been successfully grown. Indeed several investigators are making ears and noses. How long will it be before flaps and grafts to repair wound defects following extensive and deforming skin cancer surgery are replaced by ears and noses that are grown from the patient’s own tissue cells or stem cells? Although it seems like science fiction today, how soon will it be before a cutaneous 3-dimensional printer becomes a standard piece of equipment in the dermatologist and dermatologic surgeon’s office for use to create skin to cover postoperative sites that cannot be closed by directly bringing the wound edges together?

We want to know your views. Tell us what you think.

In an article published online in Maclean’s magazine on October 15, 2013, the concept of developing artificial body parts is discussed. The technology now exists for scientists to grow tissue organs, such as ears, noses, and fingers. Several groups of investigators, including Anthony Atala, MD (Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina) and Alexander Seifalian, PhD (University College London, England), are busy making ears by creating a biodegradable scaffold onto which cells—either stem cells from the patient or cells that have been harvested from the patient’s original organ—are layered and permitted to multiply. The cell-layered scaffold is then placed in a bioreactor for a couple of weeks. Once ready, the new ear is transplanted onto the patient; subsequently, the scaffold melts away.

Dr. Atala’s laboratory also is busy growing fingers. Meanwhile, Dr. Seifalian grew a nose (inside the patient’s own arm) in only 3 months after the patient lost his nose to skin cancer. He made a mold based on the patient’s original nose, created a scaffold composed of nanocomposite material, added the patient’s stem cells to the scaffold, and put the nose in a bioreactor to mature. Meanwhile, he placed a tissue expander in the patient’s arm and subsequently inserted the nose into the arm so that it could become vascularized and covered by skin. The nose was transplanted to the patient’s face; additional surgery is planned to open the nostrils, followed by seeding them with stem cells to return his sense of smell.

Marc Jeschke, MD, PhD (Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario) is developing a bioprinter to create skin. The bioprinter dispenses different types of cells (grown from the patient’s own cells) into a hydrogel matrix in 3 dimensions. Currently, Dr. Jeschke is working with mice; however, in a few years, he anticipates treating human patients. Other investigators, such as Michael C. McAlpine (Princeton University, New Jersey), recently used a commercial 3-dimensional printer to make an ear; the “inks” included calf cells and a silver nanoparticle paste that formed a coiled antenna inside the cartilage that was capable of receiving electromagnetic signals and transmitting them to the brain.

What’s the issue?

The ability to grow tissue organs is going to revolutionize the surgical management of patients who need solid organ replacement; kidneys, lungs, pancreases, spleens, and tracheas have already been successfully grown. Indeed several investigators are making ears and noses. How long will it be before flaps and grafts to repair wound defects following extensive and deforming skin cancer surgery are replaced by ears and noses that are grown from the patient’s own tissue cells or stem cells? Although it seems like science fiction today, how soon will it be before a cutaneous 3-dimensional printer becomes a standard piece of equipment in the dermatologist and dermatologic surgeon’s office for use to create skin to cover postoperative sites that cannot be closed by directly bringing the wound edges together?

We want to know your views. Tell us what you think.

In an article published online in Maclean’s magazine on October 15, 2013, the concept of developing artificial body parts is discussed. The technology now exists for scientists to grow tissue organs, such as ears, noses, and fingers. Several groups of investigators, including Anthony Atala, MD (Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina) and Alexander Seifalian, PhD (University College London, England), are busy making ears by creating a biodegradable scaffold onto which cells—either stem cells from the patient or cells that have been harvested from the patient’s original organ—are layered and permitted to multiply. The cell-layered scaffold is then placed in a bioreactor for a couple of weeks. Once ready, the new ear is transplanted onto the patient; subsequently, the scaffold melts away.

Dr. Atala’s laboratory also is busy growing fingers. Meanwhile, Dr. Seifalian grew a nose (inside the patient’s own arm) in only 3 months after the patient lost his nose to skin cancer. He made a mold based on the patient’s original nose, created a scaffold composed of nanocomposite material, added the patient’s stem cells to the scaffold, and put the nose in a bioreactor to mature. Meanwhile, he placed a tissue expander in the patient’s arm and subsequently inserted the nose into the arm so that it could become vascularized and covered by skin. The nose was transplanted to the patient’s face; additional surgery is planned to open the nostrils, followed by seeding them with stem cells to return his sense of smell.

Marc Jeschke, MD, PhD (Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario) is developing a bioprinter to create skin. The bioprinter dispenses different types of cells (grown from the patient’s own cells) into a hydrogel matrix in 3 dimensions. Currently, Dr. Jeschke is working with mice; however, in a few years, he anticipates treating human patients. Other investigators, such as Michael C. McAlpine (Princeton University, New Jersey), recently used a commercial 3-dimensional printer to make an ear; the “inks” included calf cells and a silver nanoparticle paste that formed a coiled antenna inside the cartilage that was capable of receiving electromagnetic signals and transmitting them to the brain.

What’s the issue?

The ability to grow tissue organs is going to revolutionize the surgical management of patients who need solid organ replacement; kidneys, lungs, pancreases, spleens, and tracheas have already been successfully grown. Indeed several investigators are making ears and noses. How long will it be before flaps and grafts to repair wound defects following extensive and deforming skin cancer surgery are replaced by ears and noses that are grown from the patient’s own tissue cells or stem cells? Although it seems like science fiction today, how soon will it be before a cutaneous 3-dimensional printer becomes a standard piece of equipment in the dermatologist and dermatologic surgeon’s office for use to create skin to cover postoperative sites that cannot be closed by directly bringing the wound edges together?

We want to know your views. Tell us what you think.

A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.

Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.

"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.

"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.

The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.

They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.

The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.

The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.

"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."

This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.

Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."

A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.

Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.

"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.

"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.

The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.

They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.

The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.

The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.

"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."

This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.

Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."

A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.

Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.

"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.

"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."

Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.

The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.

They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.

The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.

The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.

"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."

This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.

Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."