AVAHO

In contrast to other recent studies, androgen deprivation therapy (ADT) had no link to dementia in a observational cohort study of more than 45,000 men with prostate cancer who received definitive radiotherapy, investigators have reported.

No significant associations were found between ADT and Alzheimer’s disease or vascular dementia, or between shorter or longer courses of ADT and any dementia studied, according to Rishi Deka, PhD, of Veterans Affairs San Diego Health Care System, La Jolla, Calif., and coinvestigators.

“These results may mitigate concerns regarding the long-term risks of ADT on cognitive health in the treatment of prostate cancer,” Dr. Deka and colleagues wrote in JAMA Oncology.

Two other recent studies showed strong, statistically significant associations between ADT and dementia in prostate cancer. However, those studies combined patients with local and metastatic disease, receiving ADT in the upfront or recurrent settings, while the present study looked specifically at men with nonmetastatic prostate cancer who received radiotherapy.

“Different treatment modalities and disease stages are associated with substantial selection bias that may predispose results to false associations,” noted Dr. Deka and coauthors.

Their observational cohort study comprised 45,218 men diagnosed with nonmetastatic prostate cancer at the U.S. Department of Veterans Affairs who underwent radiotherapy with or without ADT. The investigators excluded men who had a diagnosis of dementia within 1 year of the prostate cancer diagnosis or who had prior diagnoses of dementia, stroke, or cognitive impairment.

A total of 1,497 patients were diagnosed with dementia over a median of 6.8 years of follow-up: 404 with Alzheimer disease, 335 with vascular dementia, and 758 with other types or unclassified dementias.

The investigators found no significant association between use of ADT and development of any dementia, the primary outcome of the analysis (subdistribution hazard ratio [SHR], 1.04; 95% confidence interval, 0.94-1.16; P = .43).

Likewise, there was no association between ADT and vascular dementia, specifically, with an SHR of 1.20 (95% CI, 0.97-1.50; P = .10) or Alzheimer’s disease, with an SHR of 1.11 (95% CI, 0.91-1.36; P = .29).

Duration of ADT longer than 1 year was not significantly associated with dementia, nor was duration shorter than 1 year, with SHRs, of 1.08 and 1.01 respectively, the analysis shows.

The SHRs in these and other analysis reported ranged from 1.00 to 1.21. That is substantially lower than hazard ratios of 1.66 to 2.32 in one previous study linking ADT to dementia, according to the investigators, suggesting that the results of the current analysis were not due to inadequate power to detect differences.

Nevertheless, the findings may not be generalizable to some other populations, they cautioned, since it was focused demographically on veterans, and was limited to radiotherapy-treated patients.

Dr. Deka and coauthors reported no conflict of interest. Their study was funded by grants from the University of California San Diego Center for Precision Radiation Medicine.

SOURCE: Deka R et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4423.

In contrast to other recent studies, androgen deprivation therapy (ADT) had no link to dementia in a observational cohort study of more than 45,000 men with prostate cancer who received definitive radiotherapy, investigators have reported.

No significant associations were found between ADT and Alzheimer’s disease or vascular dementia, or between shorter or longer courses of ADT and any dementia studied, according to Rishi Deka, PhD, of Veterans Affairs San Diego Health Care System, La Jolla, Calif., and coinvestigators.

“These results may mitigate concerns regarding the long-term risks of ADT on cognitive health in the treatment of prostate cancer,” Dr. Deka and colleagues wrote in JAMA Oncology.

Two other recent studies showed strong, statistically significant associations between ADT and dementia in prostate cancer. However, those studies combined patients with local and metastatic disease, receiving ADT in the upfront or recurrent settings, while the present study looked specifically at men with nonmetastatic prostate cancer who received radiotherapy.

“Different treatment modalities and disease stages are associated with substantial selection bias that may predispose results to false associations,” noted Dr. Deka and coauthors.

Their observational cohort study comprised 45,218 men diagnosed with nonmetastatic prostate cancer at the U.S. Department of Veterans Affairs who underwent radiotherapy with or without ADT. The investigators excluded men who had a diagnosis of dementia within 1 year of the prostate cancer diagnosis or who had prior diagnoses of dementia, stroke, or cognitive impairment.

A total of 1,497 patients were diagnosed with dementia over a median of 6.8 years of follow-up: 404 with Alzheimer disease, 335 with vascular dementia, and 758 with other types or unclassified dementias.

The investigators found no significant association between use of ADT and development of any dementia, the primary outcome of the analysis (subdistribution hazard ratio [SHR], 1.04; 95% confidence interval, 0.94-1.16; P = .43).

Likewise, there was no association between ADT and vascular dementia, specifically, with an SHR of 1.20 (95% CI, 0.97-1.50; P = .10) or Alzheimer’s disease, with an SHR of 1.11 (95% CI, 0.91-1.36; P = .29).

Duration of ADT longer than 1 year was not significantly associated with dementia, nor was duration shorter than 1 year, with SHRs, of 1.08 and 1.01 respectively, the analysis shows.

The SHRs in these and other analysis reported ranged from 1.00 to 1.21. That is substantially lower than hazard ratios of 1.66 to 2.32 in one previous study linking ADT to dementia, according to the investigators, suggesting that the results of the current analysis were not due to inadequate power to detect differences.

Nevertheless, the findings may not be generalizable to some other populations, they cautioned, since it was focused demographically on veterans, and was limited to radiotherapy-treated patients.

Dr. Deka and coauthors reported no conflict of interest. Their study was funded by grants from the University of California San Diego Center for Precision Radiation Medicine.

SOURCE: Deka R et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4423.

In contrast to other recent studies, androgen deprivation therapy (ADT) had no link to dementia in a observational cohort study of more than 45,000 men with prostate cancer who received definitive radiotherapy, investigators have reported.

No significant associations were found between ADT and Alzheimer’s disease or vascular dementia, or between shorter or longer courses of ADT and any dementia studied, according to Rishi Deka, PhD, of Veterans Affairs San Diego Health Care System, La Jolla, Calif., and coinvestigators.

“These results may mitigate concerns regarding the long-term risks of ADT on cognitive health in the treatment of prostate cancer,” Dr. Deka and colleagues wrote in JAMA Oncology.

Two other recent studies showed strong, statistically significant associations between ADT and dementia in prostate cancer. However, those studies combined patients with local and metastatic disease, receiving ADT in the upfront or recurrent settings, while the present study looked specifically at men with nonmetastatic prostate cancer who received radiotherapy.

“Different treatment modalities and disease stages are associated with substantial selection bias that may predispose results to false associations,” noted Dr. Deka and coauthors.

Their observational cohort study comprised 45,218 men diagnosed with nonmetastatic prostate cancer at the U.S. Department of Veterans Affairs who underwent radiotherapy with or without ADT. The investigators excluded men who had a diagnosis of dementia within 1 year of the prostate cancer diagnosis or who had prior diagnoses of dementia, stroke, or cognitive impairment.

A total of 1,497 patients were diagnosed with dementia over a median of 6.8 years of follow-up: 404 with Alzheimer disease, 335 with vascular dementia, and 758 with other types or unclassified dementias.

The investigators found no significant association between use of ADT and development of any dementia, the primary outcome of the analysis (subdistribution hazard ratio [SHR], 1.04; 95% confidence interval, 0.94-1.16; P = .43).

Likewise, there was no association between ADT and vascular dementia, specifically, with an SHR of 1.20 (95% CI, 0.97-1.50; P = .10) or Alzheimer’s disease, with an SHR of 1.11 (95% CI, 0.91-1.36; P = .29).

Duration of ADT longer than 1 year was not significantly associated with dementia, nor was duration shorter than 1 year, with SHRs, of 1.08 and 1.01 respectively, the analysis shows.

The SHRs in these and other analysis reported ranged from 1.00 to 1.21. That is substantially lower than hazard ratios of 1.66 to 2.32 in one previous study linking ADT to dementia, according to the investigators, suggesting that the results of the current analysis were not due to inadequate power to detect differences.

Nevertheless, the findings may not be generalizable to some other populations, they cautioned, since it was focused demographically on veterans, and was limited to radiotherapy-treated patients.

Dr. Deka and coauthors reported no conflict of interest. Their study was funded by grants from the University of California San Diego Center for Precision Radiation Medicine.

SOURCE: Deka R et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4423.

Checkpoint inhibitors are so new that not enough patients have received them to allow clinicians to predict who will benefit most. But researchers from the National Cancer Institute, Center for Cancer Institute; Harvard University in Cambridge, Massachusetts; University of Pennsylvania in Philadelphia; and University of Maryland in College Park may have found a clue: A gene expression predictor.

They began by looking at neuroblastoma cases where the immune system seemed to mount “an unprompted, successful immune response” to cancer, causing spontaneous tumor regression. The researchers were able to define gene expression features that separated regressing from nonregressing disease.

The researchers then computed Immuno-PREdictive Scores (IMPRES) for each patient sample. The higher the score, the more likely was spontaneous regression. Analyzing 297 samples from several studies, they found the predictor identified nearly all patients who responded to the inhibitors and more than half of those who did not. “Importantly,” the researchers say, their predictor was accurate across many different melanoma patient datasets.

Checkpoint inhibitors are so new that not enough patients have received them to allow clinicians to predict who will benefit most. But researchers from the National Cancer Institute, Center for Cancer Institute; Harvard University in Cambridge, Massachusetts; University of Pennsylvania in Philadelphia; and University of Maryland in College Park may have found a clue: A gene expression predictor.

They began by looking at neuroblastoma cases where the immune system seemed to mount “an unprompted, successful immune response” to cancer, causing spontaneous tumor regression. The researchers were able to define gene expression features that separated regressing from nonregressing disease.

The researchers then computed Immuno-PREdictive Scores (IMPRES) for each patient sample. The higher the score, the more likely was spontaneous regression. Analyzing 297 samples from several studies, they found the predictor identified nearly all patients who responded to the inhibitors and more than half of those who did not. “Importantly,” the researchers say, their predictor was accurate across many different melanoma patient datasets.

Checkpoint inhibitors are so new that not enough patients have received them to allow clinicians to predict who will benefit most. But researchers from the National Cancer Institute, Center for Cancer Institute; Harvard University in Cambridge, Massachusetts; University of Pennsylvania in Philadelphia; and University of Maryland in College Park may have found a clue: A gene expression predictor.

They began by looking at neuroblastoma cases where the immune system seemed to mount “an unprompted, successful immune response” to cancer, causing spontaneous tumor regression. The researchers were able to define gene expression features that separated regressing from nonregressing disease.

The researchers then computed Immuno-PREdictive Scores (IMPRES) for each patient sample. The higher the score, the more likely was spontaneous regression. Analyzing 297 samples from several studies, they found the predictor identified nearly all patients who responded to the inhibitors and more than half of those who did not. “Importantly,” the researchers say, their predictor was accurate across many different melanoma patient datasets.

Obesity and weight gain are linked to increased risk of colorectal cancer in younger women, according to an analysis of a large, prospective U.S. cohort study.

Young women who were obese had a nearly twofold increase in risk of early-onset colorectal cancer, compared with women of normal weight, authors of the study reported in JAMA Oncology.

The findings suggest body weight could be used to “personalize and complement” early cancer screening strategies among adults younger than 50 years, said investigator Po-Hong Liu, MD, of Washington University, St. Louis, and coauthors.

“Given that most of these younger cases are diagnosed symptomatically with more advanced tumors and with a significant influence on years of life lost, our findings reinforce the benefits of maintaining a healthy weight throughout life,” Dr. Liu and coinvestigators said in their report.

Their analysis was based on the ongoing Nurses Health Study II, which began in 1989 and enrolled a total of 116,430 women between the ages of 25 and 42 years in 14 U.S. states. Women completed questionnaires on demographics, medical and health information, and lifestyle factors every 2 years after enrollment.

Dr. Liu and colleagues were able to document 114 cases of colorectal cancer over a median of 13.9 years of follow-up in 85,256 women who had no cancer or inflammatory bowel disease when they were enrolled in the study. The median age at diagnosis for these cancers was 45 years.

Obesity was independently associated with increased risk of these early-onset colorectal cancers, the investigators found in multivariable analysis.

Women with a body mass index of 30 kg/m² or higher had a relative risk of 1.93 (95% confidence interval, 1.15-3.25) versus women with normal BMIs in the 18.5-22.9 kg/m² range, according to results of the analysis, they reported.

There was an apparent linear trend between increasing weight and increasing colorectal cancer risk, they added in their report.

They also found links between BMI in early adulthood and risk of early-onset colorectal cancer, including a relative risk of 1.63 for women who reported a BMI of 23 kg/m² or higher at 18 years of age, versus women with a BMI of 18.5-20.9 kg/m² at that age.

Similarly, increase in weight since early adulthood was associated with increased cancer risk, they reported.

While the link between excess weight and colorectal cancer incidence and mortality is well established in previous studies, this study is one of few reports looking at the association in younger individuals, according to Dr. Liu and colleagues.

This is thought to be the first prospective study looking at the link between obesity and risk of colorectal cancer diagnosed before the age of 50, they added.

The study was funded by grants from the National Institutes of Health. Dr. Liu had no conflict of interest disclosures related to the study. One coauthor reported consulting fees from Bayer Pharma AG, Janssen, and Pfizer.

SOURCE: Liu P-H et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4280.

Obesity and weight gain are linked to increased risk of colorectal cancer in younger women, according to an analysis of a large, prospective U.S. cohort study.

Young women who were obese had a nearly twofold increase in risk of early-onset colorectal cancer, compared with women of normal weight, authors of the study reported in JAMA Oncology.

The findings suggest body weight could be used to “personalize and complement” early cancer screening strategies among adults younger than 50 years, said investigator Po-Hong Liu, MD, of Washington University, St. Louis, and coauthors.

“Given that most of these younger cases are diagnosed symptomatically with more advanced tumors and with a significant influence on years of life lost, our findings reinforce the benefits of maintaining a healthy weight throughout life,” Dr. Liu and coinvestigators said in their report.

Their analysis was based on the ongoing Nurses Health Study II, which began in 1989 and enrolled a total of 116,430 women between the ages of 25 and 42 years in 14 U.S. states. Women completed questionnaires on demographics, medical and health information, and lifestyle factors every 2 years after enrollment.

Dr. Liu and colleagues were able to document 114 cases of colorectal cancer over a median of 13.9 years of follow-up in 85,256 women who had no cancer or inflammatory bowel disease when they were enrolled in the study. The median age at diagnosis for these cancers was 45 years.

Obesity was independently associated with increased risk of these early-onset colorectal cancers, the investigators found in multivariable analysis.

Women with a body mass index of 30 kg/m² or higher had a relative risk of 1.93 (95% confidence interval, 1.15-3.25) versus women with normal BMIs in the 18.5-22.9 kg/m² range, according to results of the analysis, they reported.

There was an apparent linear trend between increasing weight and increasing colorectal cancer risk, they added in their report.

They also found links between BMI in early adulthood and risk of early-onset colorectal cancer, including a relative risk of 1.63 for women who reported a BMI of 23 kg/m² or higher at 18 years of age, versus women with a BMI of 18.5-20.9 kg/m² at that age.

Similarly, increase in weight since early adulthood was associated with increased cancer risk, they reported.

While the link between excess weight and colorectal cancer incidence and mortality is well established in previous studies, this study is one of few reports looking at the association in younger individuals, according to Dr. Liu and colleagues.

This is thought to be the first prospective study looking at the link between obesity and risk of colorectal cancer diagnosed before the age of 50, they added.

The study was funded by grants from the National Institutes of Health. Dr. Liu had no conflict of interest disclosures related to the study. One coauthor reported consulting fees from Bayer Pharma AG, Janssen, and Pfizer.

SOURCE: Liu P-H et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4280.

Obesity and weight gain are linked to increased risk of colorectal cancer in younger women, according to an analysis of a large, prospective U.S. cohort study.

Young women who were obese had a nearly twofold increase in risk of early-onset colorectal cancer, compared with women of normal weight, authors of the study reported in JAMA Oncology.

The findings suggest body weight could be used to “personalize and complement” early cancer screening strategies among adults younger than 50 years, said investigator Po-Hong Liu, MD, of Washington University, St. Louis, and coauthors.

“Given that most of these younger cases are diagnosed symptomatically with more advanced tumors and with a significant influence on years of life lost, our findings reinforce the benefits of maintaining a healthy weight throughout life,” Dr. Liu and coinvestigators said in their report.

Their analysis was based on the ongoing Nurses Health Study II, which began in 1989 and enrolled a total of 116,430 women between the ages of 25 and 42 years in 14 U.S. states. Women completed questionnaires on demographics, medical and health information, and lifestyle factors every 2 years after enrollment.

Dr. Liu and colleagues were able to document 114 cases of colorectal cancer over a median of 13.9 years of follow-up in 85,256 women who had no cancer or inflammatory bowel disease when they were enrolled in the study. The median age at diagnosis for these cancers was 45 years.

Obesity was independently associated with increased risk of these early-onset colorectal cancers, the investigators found in multivariable analysis.

Women with a body mass index of 30 kg/m² or higher had a relative risk of 1.93 (95% confidence interval, 1.15-3.25) versus women with normal BMIs in the 18.5-22.9 kg/m² range, according to results of the analysis, they reported.

There was an apparent linear trend between increasing weight and increasing colorectal cancer risk, they added in their report.

They also found links between BMI in early adulthood and risk of early-onset colorectal cancer, including a relative risk of 1.63 for women who reported a BMI of 23 kg/m² or higher at 18 years of age, versus women with a BMI of 18.5-20.9 kg/m² at that age.

Similarly, increase in weight since early adulthood was associated with increased cancer risk, they reported.

While the link between excess weight and colorectal cancer incidence and mortality is well established in previous studies, this study is one of few reports looking at the association in younger individuals, according to Dr. Liu and colleagues.

This is thought to be the first prospective study looking at the link between obesity and risk of colorectal cancer diagnosed before the age of 50, they added.

The study was funded by grants from the National Institutes of Health. Dr. Liu had no conflict of interest disclosures related to the study. One coauthor reported consulting fees from Bayer Pharma AG, Janssen, and Pfizer.

SOURCE: Liu P-H et al. JAMA Oncol. 2018 Oct 11. doi: 10.1001/jamaoncol.2018.4280.

Cancer geneticists have identified 21 clusters of complex chromosomal rearrangements in breast cancers that contain both known oncogenes and potential new driver loci.

A systematic analysis of chromosomal rearrangements in tissues from 560 patients with breast cancer identified 21 “hotspots,” some of which contain known oncogene chromosomal loci, and others of which contain genes not typically associated with breast cancer, reported Serena Nik-Zainal, PhD, of the University of Cambridge, England, and her colleagues.

“Detailed analysis of rearrangements at these hotspots highlights chromosomal aberrations likely driven by selection, and reveal underlying mutational processes,” they wrote in a study published online in Annals of Oncology.

The investigators sought insight into mutational mechanisms of gene amplifications by examining clustered rearrangements – somatic breakpoints occurring in high densities – in individual patients.

To see whether these rearrangements were associated with breast cancer, they identified the aforementioned chromosomal hotspots where clustered rearrangements were seen in samples from different patients.

They identified 624 cluster rearrangements in the 560 breast cancer genomes, including 17,247 within-chromosome rearrangements, and 6,509 between-chromosome translocations.

Of the 560 samples, 372 had at least one rearrangement cluster, with the frequency of clusters similar between some breast cancer types. For example, there were 0.96 rearrangements clusters per sample from patients with triple negative breast cancers, and 1.00 per sample from women with estrogen receptor–positive tumors.

“To identify loci where clusters of rearrangements recur across multiple independent tumor samples, we pooled all breakpoints in the ‘clustered’ category and sorted them according to position in the reference genome,” the investigators explained.

They used a Piecewise-Constant-Fitting algorithm to identify genome sequences where there were short inter-mutation distances between rearrangement clusters, suggesting the presence of hotspots.

In the 21 hotspots they identified, they found, as expected, common driver amplification regions (e.g., CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC), but also several hotspots near oncogenes that are not typically associated with breast cancer.

Notably, they saw simultaneous amplification of regions on chromosomes 8 and 11 (chr8:ZNF703/FGFR1 and chr11:CCND1). Amplification of these regions are frequent in estrogen receptor–positive breast cancers. The investigators propose a pathogenic model in which a chromosome 8 to chromosome 11 translocation is an early, critical event leading to breast tumor development.

“Clustered rearrangements are common in breast cancer genomes, and often associated with gene amplifications that drive oncogenesis. Understanding the process of amplicon formation, an example of which we present here for the chr8:ZNF703/FGFR1 and chr11:CCND1 co-amplifications, will be important for our understanding of the origins of a subset of breast cancers,” they concluded.

The study was supported by an award from the Wellcome Trust. Dr. Nik-Zainal and coauthor Dominik Glodzik are inventors on several patent applications. All remaining authors declared no conflicts of interest.
 

SOURCE: Glodzik D et al. Ann Oncol. 2018 Sept 25. doi: 10.1093/annonc/mdy404.

Cancer geneticists have identified 21 clusters of complex chromosomal rearrangements in breast cancers that contain both known oncogenes and potential new driver loci.

A systematic analysis of chromosomal rearrangements in tissues from 560 patients with breast cancer identified 21 “hotspots,” some of which contain known oncogene chromosomal loci, and others of which contain genes not typically associated with breast cancer, reported Serena Nik-Zainal, PhD, of the University of Cambridge, England, and her colleagues.

“Detailed analysis of rearrangements at these hotspots highlights chromosomal aberrations likely driven by selection, and reveal underlying mutational processes,” they wrote in a study published online in Annals of Oncology.

The investigators sought insight into mutational mechanisms of gene amplifications by examining clustered rearrangements – somatic breakpoints occurring in high densities – in individual patients.

To see whether these rearrangements were associated with breast cancer, they identified the aforementioned chromosomal hotspots where clustered rearrangements were seen in samples from different patients.

They identified 624 cluster rearrangements in the 560 breast cancer genomes, including 17,247 within-chromosome rearrangements, and 6,509 between-chromosome translocations.

Of the 560 samples, 372 had at least one rearrangement cluster, with the frequency of clusters similar between some breast cancer types. For example, there were 0.96 rearrangements clusters per sample from patients with triple negative breast cancers, and 1.00 per sample from women with estrogen receptor–positive tumors.

“To identify loci where clusters of rearrangements recur across multiple independent tumor samples, we pooled all breakpoints in the ‘clustered’ category and sorted them according to position in the reference genome,” the investigators explained.

They used a Piecewise-Constant-Fitting algorithm to identify genome sequences where there were short inter-mutation distances between rearrangement clusters, suggesting the presence of hotspots.

In the 21 hotspots they identified, they found, as expected, common driver amplification regions (e.g., CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC), but also several hotspots near oncogenes that are not typically associated with breast cancer.

Notably, they saw simultaneous amplification of regions on chromosomes 8 and 11 (chr8:ZNF703/FGFR1 and chr11:CCND1). Amplification of these regions are frequent in estrogen receptor–positive breast cancers. The investigators propose a pathogenic model in which a chromosome 8 to chromosome 11 translocation is an early, critical event leading to breast tumor development.

“Clustered rearrangements are common in breast cancer genomes, and often associated with gene amplifications that drive oncogenesis. Understanding the process of amplicon formation, an example of which we present here for the chr8:ZNF703/FGFR1 and chr11:CCND1 co-amplifications, will be important for our understanding of the origins of a subset of breast cancers,” they concluded.

The study was supported by an award from the Wellcome Trust. Dr. Nik-Zainal and coauthor Dominik Glodzik are inventors on several patent applications. All remaining authors declared no conflicts of interest.
 

SOURCE: Glodzik D et al. Ann Oncol. 2018 Sept 25. doi: 10.1093/annonc/mdy404.

Cancer geneticists have identified 21 clusters of complex chromosomal rearrangements in breast cancers that contain both known oncogenes and potential new driver loci.

A systematic analysis of chromosomal rearrangements in tissues from 560 patients with breast cancer identified 21 “hotspots,” some of which contain known oncogene chromosomal loci, and others of which contain genes not typically associated with breast cancer, reported Serena Nik-Zainal, PhD, of the University of Cambridge, England, and her colleagues.

“Detailed analysis of rearrangements at these hotspots highlights chromosomal aberrations likely driven by selection, and reveal underlying mutational processes,” they wrote in a study published online in Annals of Oncology.

The investigators sought insight into mutational mechanisms of gene amplifications by examining clustered rearrangements – somatic breakpoints occurring in high densities – in individual patients.

To see whether these rearrangements were associated with breast cancer, they identified the aforementioned chromosomal hotspots where clustered rearrangements were seen in samples from different patients.

They identified 624 cluster rearrangements in the 560 breast cancer genomes, including 17,247 within-chromosome rearrangements, and 6,509 between-chromosome translocations.

Of the 560 samples, 372 had at least one rearrangement cluster, with the frequency of clusters similar between some breast cancer types. For example, there were 0.96 rearrangements clusters per sample from patients with triple negative breast cancers, and 1.00 per sample from women with estrogen receptor–positive tumors.

“To identify loci where clusters of rearrangements recur across multiple independent tumor samples, we pooled all breakpoints in the ‘clustered’ category and sorted them according to position in the reference genome,” the investigators explained.

They used a Piecewise-Constant-Fitting algorithm to identify genome sequences where there were short inter-mutation distances between rearrangement clusters, suggesting the presence of hotspots.

In the 21 hotspots they identified, they found, as expected, common driver amplification regions (e.g., CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC), but also several hotspots near oncogenes that are not typically associated with breast cancer.

Notably, they saw simultaneous amplification of regions on chromosomes 8 and 11 (chr8:ZNF703/FGFR1 and chr11:CCND1). Amplification of these regions are frequent in estrogen receptor–positive breast cancers. The investigators propose a pathogenic model in which a chromosome 8 to chromosome 11 translocation is an early, critical event leading to breast tumor development.

“Clustered rearrangements are common in breast cancer genomes, and often associated with gene amplifications that drive oncogenesis. Understanding the process of amplicon formation, an example of which we present here for the chr8:ZNF703/FGFR1 and chr11:CCND1 co-amplifications, will be important for our understanding of the origins of a subset of breast cancers,” they concluded.

The study was supported by an award from the Wellcome Trust. Dr. Nik-Zainal and coauthor Dominik Glodzik are inventors on several patent applications. All remaining authors declared no conflicts of interest.
 

SOURCE: Glodzik D et al. Ann Oncol. 2018 Sept 25. doi: 10.1093/annonc/mdy404.

Key leadership in research and oncology addressed attendees of the recent AVAHO annual meeting in Chicago. Carolyn Clancy, MD, deputy undersecretary for health discovery, education and affiliated networks, discussed the important role of cancer in the VA’s research and clinical mission. Neil Spector, MD, director of the National Precision Oncology Program (NPOP) outlined the significant growth in the use of tumor sequencing by NPOP, while Michael Kelley, MD, director of operations for National Oncology discussed the significant strides in opening up access to clinical trials at the VA.

Dr. Clancy addressed AVAHO for the first time and remarked upon the impressive array of research conducted by AVAHO members. “I love the idea of telehealth for genomics,” she remarked about the Genomic Medicine Service Uses Group Telehealth Appointments poster abstract, “it’s brilliant and it’s only the beginning.” The VA’s unique blend of clinical care and research puts it in a unique position to provide cutting edge care to its patients.

Clancy also addressed the larger shift in the VA as it moves from a closed integrated health care system to a high performing network. “We are closer than most systems in this country—public or private—to having a research enterprise that is integral to our mission of providing veterans with great care,” she said. “The magic of bringing [research and clinical] groups together is to enhance the visibility. But frankly it’s also to enhance our capability to take advantage of these assets strategically.” That means providing veterans with “cutting-edge care, and what could be better than that? When we do great things in how we deliver health care that helps your work,” she told attendees.

This shift, as outlined by the VA’s new leadership under Secretary Robert Wilkie and Richard A. Stone, MD, executive in charge of the Veterans Health Administration (VHA), is designed to restore veterans’ trust and confidence in the system, foster an environment of continuous learning to improve quality, and transform the VHA into a “high-reliability organization,” to reduce medical errors. The goal, according to Dr. Clancy, is to develop a culture—like the National Aeronautics and Space Administration or air traffic control systems—where all members of the organization search for and eliminate potential problems. Improving safety, she insisted, has to be a top priority for everyone.

Dr. Clancy also reported that 700,000 veterans enrolled in the VA’s Million Veteran Program (MVP) “We not only have the largest repository of genomic information on people but we also have their clinical data” Later, she told AVAHO members “I am hugely optimistic about the work that is being done in oncology research.” In July, the VA made an arrangement with the National Cancer Institute to allows veterans access to clinical trials. “We need to do more of that, she said, “this is only the beginning of the exciting work we will be doing in cancer research.”

Dr. Spector reported on the progress made by NPOP over the previous year. Currently, NPOP is sequencing solid tumors with a recent biopsy (liquid biopsies are acceptable), but hopes to begin examination of sarcomas and hematologic malignancies. NPOP has grown from about 100 samples analyzed monthly in January 2017 to nearly 350 in June 2018 with a goal of reaching 600 monthly samples across the VA. “You should be sending tumor tissues to be sequenced,” he explained. “It’s free, sequencing tumor tissue is the standard of care, and we need to be sequencing our patients to provide them with an opportunity to get patients onto clinical trials.”

Although the initial analysis can take up to 21 days, the program offers a 72-hour turn-around time for e-consultations. Depending on the quality of trial data, patients may be eligible for treatment even if there is no FDA-approved treatment. According to Spector, the goal of the program is to get patients on the right treatment and avoid costly treatment that will not work for a patient’s cancer type. “We do not want to be giving an expensive drug to someone who will not respond,” he explained.

Multiple efforts are underway to streamline and increase access to oncology care in the VA, according to Dr. Kelley. The development of a national cancer strategy is “long overdue” he admitted, but multiple efforts are underway to including the Fast Track to VA Cancer Care, a single national point of entry for VA cancer care, mechanisms to streamline enrolling patients in non-VA clinical trials, virtual tumor boards, and oncology-specific dashboards. “We have to be transparent and show not only to ourselves, but the whole worlds that we are doing a great job,” he told attendees.

One of the biggest challenges the VA faces will be the roll out of a new electronic health record system. While the new Cerner system has an oncology package, it does not have a cancer registry. According to Kelley, the VA is searching for a commercial system that can interface with Cerner to provide a cancer registry.

Kelley also focused on Annie, a new VA texting platform that allow patients to report on symptoms and get advice The Annie system is automated and allows patients to provide self-care. Already, cancer care providers are experimenting with Annie and Kelley expects the program to develop further.

Key leadership in research and oncology addressed attendees of the recent AVAHO annual meeting in Chicago. Carolyn Clancy, MD, deputy undersecretary for health discovery, education and affiliated networks, discussed the important role of cancer in the VA’s research and clinical mission. Neil Spector, MD, director of the National Precision Oncology Program (NPOP) outlined the significant growth in the use of tumor sequencing by NPOP, while Michael Kelley, MD, director of operations for National Oncology discussed the significant strides in opening up access to clinical trials at the VA.

Dr. Clancy addressed AVAHO for the first time and remarked upon the impressive array of research conducted by AVAHO members. “I love the idea of telehealth for genomics,” she remarked about the Genomic Medicine Service Uses Group Telehealth Appointments poster abstract, “it’s brilliant and it’s only the beginning.” The VA’s unique blend of clinical care and research puts it in a unique position to provide cutting edge care to its patients.

Clancy also addressed the larger shift in the VA as it moves from a closed integrated health care system to a high performing network. “We are closer than most systems in this country—public or private—to having a research enterprise that is integral to our mission of providing veterans with great care,” she said. “The magic of bringing [research and clinical] groups together is to enhance the visibility. But frankly it’s also to enhance our capability to take advantage of these assets strategically.” That means providing veterans with “cutting-edge care, and what could be better than that? When we do great things in how we deliver health care that helps your work,” she told attendees.

This shift, as outlined by the VA’s new leadership under Secretary Robert Wilkie and Richard A. Stone, MD, executive in charge of the Veterans Health Administration (VHA), is designed to restore veterans’ trust and confidence in the system, foster an environment of continuous learning to improve quality, and transform the VHA into a “high-reliability organization,” to reduce medical errors. The goal, according to Dr. Clancy, is to develop a culture—like the National Aeronautics and Space Administration or air traffic control systems—where all members of the organization search for and eliminate potential problems. Improving safety, she insisted, has to be a top priority for everyone.

Dr. Clancy also reported that 700,000 veterans enrolled in the VA’s Million Veteran Program (MVP) “We not only have the largest repository of genomic information on people but we also have their clinical data” Later, she told AVAHO members “I am hugely optimistic about the work that is being done in oncology research.” In July, the VA made an arrangement with the National Cancer Institute to allows veterans access to clinical trials. “We need to do more of that, she said, “this is only the beginning of the exciting work we will be doing in cancer research.”

Dr. Spector reported on the progress made by NPOP over the previous year. Currently, NPOP is sequencing solid tumors with a recent biopsy (liquid biopsies are acceptable), but hopes to begin examination of sarcomas and hematologic malignancies. NPOP has grown from about 100 samples analyzed monthly in January 2017 to nearly 350 in June 2018 with a goal of reaching 600 monthly samples across the VA. “You should be sending tumor tissues to be sequenced,” he explained. “It’s free, sequencing tumor tissue is the standard of care, and we need to be sequencing our patients to provide them with an opportunity to get patients onto clinical trials.”

Although the initial analysis can take up to 21 days, the program offers a 72-hour turn-around time for e-consultations. Depending on the quality of trial data, patients may be eligible for treatment even if there is no FDA-approved treatment. According to Spector, the goal of the program is to get patients on the right treatment and avoid costly treatment that will not work for a patient’s cancer type. “We do not want to be giving an expensive drug to someone who will not respond,” he explained.

Multiple efforts are underway to streamline and increase access to oncology care in the VA, according to Dr. Kelley. The development of a national cancer strategy is “long overdue” he admitted, but multiple efforts are underway to including the Fast Track to VA Cancer Care, a single national point of entry for VA cancer care, mechanisms to streamline enrolling patients in non-VA clinical trials, virtual tumor boards, and oncology-specific dashboards. “We have to be transparent and show not only to ourselves, but the whole worlds that we are doing a great job,” he told attendees.

One of the biggest challenges the VA faces will be the roll out of a new electronic health record system. While the new Cerner system has an oncology package, it does not have a cancer registry. According to Kelley, the VA is searching for a commercial system that can interface with Cerner to provide a cancer registry.

Kelley also focused on Annie, a new VA texting platform that allow patients to report on symptoms and get advice The Annie system is automated and allows patients to provide self-care. Already, cancer care providers are experimenting with Annie and Kelley expects the program to develop further.

Key leadership in research and oncology addressed attendees of the recent AVAHO annual meeting in Chicago. Carolyn Clancy, MD, deputy undersecretary for health discovery, education and affiliated networks, discussed the important role of cancer in the VA’s research and clinical mission. Neil Spector, MD, director of the National Precision Oncology Program (NPOP) outlined the significant growth in the use of tumor sequencing by NPOP, while Michael Kelley, MD, director of operations for National Oncology discussed the significant strides in opening up access to clinical trials at the VA.

Dr. Clancy addressed AVAHO for the first time and remarked upon the impressive array of research conducted by AVAHO members. “I love the idea of telehealth for genomics,” she remarked about the Genomic Medicine Service Uses Group Telehealth Appointments poster abstract, “it’s brilliant and it’s only the beginning.” The VA’s unique blend of clinical care and research puts it in a unique position to provide cutting edge care to its patients.

Clancy also addressed the larger shift in the VA as it moves from a closed integrated health care system to a high performing network. “We are closer than most systems in this country—public or private—to having a research enterprise that is integral to our mission of providing veterans with great care,” she said. “The magic of bringing [research and clinical] groups together is to enhance the visibility. But frankly it’s also to enhance our capability to take advantage of these assets strategically.” That means providing veterans with “cutting-edge care, and what could be better than that? When we do great things in how we deliver health care that helps your work,” she told attendees.

This shift, as outlined by the VA’s new leadership under Secretary Robert Wilkie and Richard A. Stone, MD, executive in charge of the Veterans Health Administration (VHA), is designed to restore veterans’ trust and confidence in the system, foster an environment of continuous learning to improve quality, and transform the VHA into a “high-reliability organization,” to reduce medical errors. The goal, according to Dr. Clancy, is to develop a culture—like the National Aeronautics and Space Administration or air traffic control systems—where all members of the organization search for and eliminate potential problems. Improving safety, she insisted, has to be a top priority for everyone.

Dr. Clancy also reported that 700,000 veterans enrolled in the VA’s Million Veteran Program (MVP) “We not only have the largest repository of genomic information on people but we also have their clinical data” Later, she told AVAHO members “I am hugely optimistic about the work that is being done in oncology research.” In July, the VA made an arrangement with the National Cancer Institute to allows veterans access to clinical trials. “We need to do more of that, she said, “this is only the beginning of the exciting work we will be doing in cancer research.”

Dr. Spector reported on the progress made by NPOP over the previous year. Currently, NPOP is sequencing solid tumors with a recent biopsy (liquid biopsies are acceptable), but hopes to begin examination of sarcomas and hematologic malignancies. NPOP has grown from about 100 samples analyzed monthly in January 2017 to nearly 350 in June 2018 with a goal of reaching 600 monthly samples across the VA. “You should be sending tumor tissues to be sequenced,” he explained. “It’s free, sequencing tumor tissue is the standard of care, and we need to be sequencing our patients to provide them with an opportunity to get patients onto clinical trials.”

Although the initial analysis can take up to 21 days, the program offers a 72-hour turn-around time for e-consultations. Depending on the quality of trial data, patients may be eligible for treatment even if there is no FDA-approved treatment. According to Spector, the goal of the program is to get patients on the right treatment and avoid costly treatment that will not work for a patient’s cancer type. “We do not want to be giving an expensive drug to someone who will not respond,” he explained.

Multiple efforts are underway to streamline and increase access to oncology care in the VA, according to Dr. Kelley. The development of a national cancer strategy is “long overdue” he admitted, but multiple efforts are underway to including the Fast Track to VA Cancer Care, a single national point of entry for VA cancer care, mechanisms to streamline enrolling patients in non-VA clinical trials, virtual tumor boards, and oncology-specific dashboards. “We have to be transparent and show not only to ourselves, but the whole worlds that we are doing a great job,” he told attendees.

One of the biggest challenges the VA faces will be the roll out of a new electronic health record system. While the new Cerner system has an oncology package, it does not have a cancer registry. According to Kelley, the VA is searching for a commercial system that can interface with Cerner to provide a cancer registry.

Kelley also focused on Annie, a new VA texting platform that allow patients to report on symptoms and get advice The Annie system is automated and allows patients to provide self-care. Already, cancer care providers are experimenting with Annie and Kelley expects the program to develop further.

NEW YORK – Four-drug combinations are looking promising for the treatment of multiple myeloma, though data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, Madison.

“The outlook for myeloma patients is quite good,” Dr. Callander said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

“Triplet therapy is the standard, and quad therapy may be in the future.”

The study that set the standard for triplets in myeloma, according to Dr. Callander, is SWOG 0777, an open-label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.

Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable (Lancet. 2017 Feb 4;389[10068]:519-27).

The median progression-free survival was 43 months for the triplet, versus 30 months for the two-drug regimen (P = .0018); likewise, median overall survival was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P = .025).

“Very convincingly, just receiving that short exposure to bortezomib ended up causing a substantial increase of progression-free and overall survival,” Dr. Callander said.

The efficacy of multiple triplet regimens has been documented, including the combination of carfilzomib, lenalidomide, and dexamethasone (KRd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and more recently, ixazomib, lenalidomide, and dexamethasone (IRd). These regimens have “excellent” response rates and survival data, Dr. Callander said.

Data is now emerging on the potential role of four-drug combinations, she added. The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology.

Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data presented at ASCO in 2017, with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.

Even so, “it remains to be seen whether four drugs will be the new standard,” Dr. Callander told the NCCN attendees.

Four- versus three-drug strategies are being evaluated in ongoing randomized clinical trials, including patients with previously untreated myeloma, she said. Those studies include Cassiopeia, which is evaluating bortezomib, thalidomide, and dexamethasone (with or without daratumumab), and GRIFFIN, which is looking at VRd (with or without daratumumab).

Daratumumab recently received an additional indication in the treatment of myeloma, this time as part of a four-drug regimen, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.

The Food and Drug Administration approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.

That approval was based on results of the multicenter phase 3 ALCYONE study, showing an 18-month progression-free survival rate of 71.6% for the four-drug combination versus 50.2% for VMP alone (N Engl J Med. 2018;378:518-28).

Dr. Callander reported having no relevant financial disclosures.

NEW YORK – Four-drug combinations are looking promising for the treatment of multiple myeloma, though data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, Madison.

“The outlook for myeloma patients is quite good,” Dr. Callander said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

“Triplet therapy is the standard, and quad therapy may be in the future.”

The study that set the standard for triplets in myeloma, according to Dr. Callander, is SWOG 0777, an open-label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.

Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable (Lancet. 2017 Feb 4;389[10068]:519-27).

The median progression-free survival was 43 months for the triplet, versus 30 months for the two-drug regimen (P = .0018); likewise, median overall survival was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P = .025).

“Very convincingly, just receiving that short exposure to bortezomib ended up causing a substantial increase of progression-free and overall survival,” Dr. Callander said.

The efficacy of multiple triplet regimens has been documented, including the combination of carfilzomib, lenalidomide, and dexamethasone (KRd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and more recently, ixazomib, lenalidomide, and dexamethasone (IRd). These regimens have “excellent” response rates and survival data, Dr. Callander said.

Data is now emerging on the potential role of four-drug combinations, she added. The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology.

Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data presented at ASCO in 2017, with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.

Even so, “it remains to be seen whether four drugs will be the new standard,” Dr. Callander told the NCCN attendees.

Four- versus three-drug strategies are being evaluated in ongoing randomized clinical trials, including patients with previously untreated myeloma, she said. Those studies include Cassiopeia, which is evaluating bortezomib, thalidomide, and dexamethasone (with or without daratumumab), and GRIFFIN, which is looking at VRd (with or without daratumumab).

Daratumumab recently received an additional indication in the treatment of myeloma, this time as part of a four-drug regimen, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.

The Food and Drug Administration approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.

That approval was based on results of the multicenter phase 3 ALCYONE study, showing an 18-month progression-free survival rate of 71.6% for the four-drug combination versus 50.2% for VMP alone (N Engl J Med. 2018;378:518-28).

Dr. Callander reported having no relevant financial disclosures.

NEW YORK – Four-drug combinations are looking promising for the treatment of multiple myeloma, though data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, Madison.

“The outlook for myeloma patients is quite good,” Dr. Callander said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

“Triplet therapy is the standard, and quad therapy may be in the future.”

The study that set the standard for triplets in myeloma, according to Dr. Callander, is SWOG 0777, an open-label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.

Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable (Lancet. 2017 Feb 4;389[10068]:519-27).

The median progression-free survival was 43 months for the triplet, versus 30 months for the two-drug regimen (P = .0018); likewise, median overall survival was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P = .025).

“Very convincingly, just receiving that short exposure to bortezomib ended up causing a substantial increase of progression-free and overall survival,” Dr. Callander said.

The efficacy of multiple triplet regimens has been documented, including the combination of carfilzomib, lenalidomide, and dexamethasone (KRd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and more recently, ixazomib, lenalidomide, and dexamethasone (IRd). These regimens have “excellent” response rates and survival data, Dr. Callander said.

Data is now emerging on the potential role of four-drug combinations, she added. The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology.

Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data presented at ASCO in 2017, with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.

Even so, “it remains to be seen whether four drugs will be the new standard,” Dr. Callander told the NCCN attendees.

Four- versus three-drug strategies are being evaluated in ongoing randomized clinical trials, including patients with previously untreated myeloma, she said. Those studies include Cassiopeia, which is evaluating bortezomib, thalidomide, and dexamethasone (with or without daratumumab), and GRIFFIN, which is looking at VRd (with or without daratumumab).

Daratumumab recently received an additional indication in the treatment of myeloma, this time as part of a four-drug regimen, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.

The Food and Drug Administration approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.

That approval was based on results of the multicenter phase 3 ALCYONE study, showing an 18-month progression-free survival rate of 71.6% for the four-drug combination versus 50.2% for VMP alone (N Engl J Med. 2018;378:518-28).

Dr. Callander reported having no relevant financial disclosures.

ORLANDO – The moderately increased risk of breast cancer among women with type 2 diabetes mellitus appears to be associated with adiposity rather than with diabetes or insulin treatment, findings from meta-analyses suggest.

Vasilis Varsakelis/Fotolia

In one meta-analysis of data from 21 prospective studies with a total of nearly 15.2 million women, 325,117 breast cancer cases, and a mean follow-up time of 8 years (nearly 33 million person-years), the risk of breast cancer was significantly greater among patients with diabetes than it was among patients without diabetes (summary relative risk, 1.11), Maria Bota reported at the annual scientific sessions of the American Diabetes Association.

However, there was substantial unexplained heterogeneity of results across the individual studies (I² = 82%), said Ms. Bota, a faculty member at the International Prevention Research Institute, Lyon, France.

“When the analysis was restricted to the 12 studies that adjusted for [body mass index], the summary relative risk decreased to 1.09 and the heterogeneity also decreased to a moderate value of 32%; when the analysis was restricted to the 9 studies that did not adjust for BMI, the summary relative risk increased to 1.14 again, and the heterogeneity increased even more to 91%,” she said.

In an analysis that combined the results of the nine studies that did not adjust for BMI along with crude relative risks from studies that reported both crude and BMI-adjusted relative risks (17 studies in all), the SRR was 1.12, and heterogeneity among the studies was high at 84%.

Additionally, an analysis by menopausal status based on four studies that reported breast cancer in both pre- and postmenopausal women showed SRRs for breast cancer of 0.97 (a 3% decrease in risk) and 1.14 among diabetic vs. nondiabetic premenopausal women and postmenopausal women, respectively, she said, noting that heterogeneity was low (I² = 0%) among the premenopausal breast cancer study groups and high (I² = 70%) among the postmenopausal study groups.

The findings provide evidence for a moderately increased risk of breast cancer in women with T2DM, Ms. Bota said.

“However, the effect of the adjustment or lack of adjustment on the heterogeneity suggests that the higher risk of breast cancer in women with diabetes may not be due to diabetes itself, but to adiposity,” she said, adding that “this hypothesis is equally supported by our subgroup analysis according to menopausal status because we saw that the risk of breast cancer was only associated with diabetes in postmenopausal women and this pattern resembles the pattern of the risk of breast cancer associated with adiposity, which is also only increased in postmenopausal women.”

This study was limited by insufficient data for investigating the sources of heterogeneity, she said.

“Therefore we propose ... future pooled analyses based on individual data from good quality prospective studies in order to increase the study power and to do some detailed analysis of the links between adiposity, diabetes, and breast cancer,” she concluded, adding that new studies to examine those relationships only in premenopausal women are also needed

In a separate meta-analysis, she and her colleagues, including Peter Boyle, PhD, president of the International Prevention Research Institute, assessed the association between insulin treatment and breast cancer risk in patients with diabetes.

“The long-acting insulin analogues glargine and detemir have been shown in some studies to be associated with increased risk of breast cancer, and other studies have shown no association between the use of these two compounds and the risk of breast cancer,” Dr. Boyle said in a separate presentation at the ADA meeting. “It was important to sort out a little bit what was going on in the literature.”

Overall, the meta-analysis of data from 12 longitudinal cohort studies – including more than 6,000 cases of breast cancer – showed a slight increase in breast cancer risk in patients taking long-acting insulin (SRR, 1.13) with “a relatively reasonable” level of heterogeneity (I² = 23%).

“But we see that the story is not that simple,” he said.

For example, some studies included only patients who were prescribed insulin for the first time after the study began (new users), some included only patients who were prescribed insulin before the study began (prevalent users), and some included both (ever users), which may have introduced bias in the results, he explained.

Studies of glargine included 4,168 breast cancer cases over a total of 1,418,743 person-years of observation, and studies of detemir included fewer than 2,047 breast cancer cases (not all studies reported case numbers). Among both new users of glargine and detemir, the SRR was 1.12, suggesting no real association between either glargine or detemir use and breast cancer, he said.

“One important take-home message is that you have to be careful that these pharmaco-epidemiological studies, even when working with the same database, may have conflicting results ... so we still need more robust standards in methods for [such] studies,” he concluded.

Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.

sworcester@mdedge.com

SOURCE: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.

ORLANDO – The moderately increased risk of breast cancer among women with type 2 diabetes mellitus appears to be associated with adiposity rather than with diabetes or insulin treatment, findings from meta-analyses suggest.

Vasilis Varsakelis/Fotolia

In one meta-analysis of data from 21 prospective studies with a total of nearly 15.2 million women, 325,117 breast cancer cases, and a mean follow-up time of 8 years (nearly 33 million person-years), the risk of breast cancer was significantly greater among patients with diabetes than it was among patients without diabetes (summary relative risk, 1.11), Maria Bota reported at the annual scientific sessions of the American Diabetes Association.

However, there was substantial unexplained heterogeneity of results across the individual studies (I² = 82%), said Ms. Bota, a faculty member at the International Prevention Research Institute, Lyon, France.

“When the analysis was restricted to the 12 studies that adjusted for [body mass index], the summary relative risk decreased to 1.09 and the heterogeneity also decreased to a moderate value of 32%; when the analysis was restricted to the 9 studies that did not adjust for BMI, the summary relative risk increased to 1.14 again, and the heterogeneity increased even more to 91%,” she said.

In an analysis that combined the results of the nine studies that did not adjust for BMI along with crude relative risks from studies that reported both crude and BMI-adjusted relative risks (17 studies in all), the SRR was 1.12, and heterogeneity among the studies was high at 84%.

Additionally, an analysis by menopausal status based on four studies that reported breast cancer in both pre- and postmenopausal women showed SRRs for breast cancer of 0.97 (a 3% decrease in risk) and 1.14 among diabetic vs. nondiabetic premenopausal women and postmenopausal women, respectively, she said, noting that heterogeneity was low (I² = 0%) among the premenopausal breast cancer study groups and high (I² = 70%) among the postmenopausal study groups.

The findings provide evidence for a moderately increased risk of breast cancer in women with T2DM, Ms. Bota said.

“However, the effect of the adjustment or lack of adjustment on the heterogeneity suggests that the higher risk of breast cancer in women with diabetes may not be due to diabetes itself, but to adiposity,” she said, adding that “this hypothesis is equally supported by our subgroup analysis according to menopausal status because we saw that the risk of breast cancer was only associated with diabetes in postmenopausal women and this pattern resembles the pattern of the risk of breast cancer associated with adiposity, which is also only increased in postmenopausal women.”

This study was limited by insufficient data for investigating the sources of heterogeneity, she said.

“Therefore we propose ... future pooled analyses based on individual data from good quality prospective studies in order to increase the study power and to do some detailed analysis of the links between adiposity, diabetes, and breast cancer,” she concluded, adding that new studies to examine those relationships only in premenopausal women are also needed

In a separate meta-analysis, she and her colleagues, including Peter Boyle, PhD, president of the International Prevention Research Institute, assessed the association between insulin treatment and breast cancer risk in patients with diabetes.

“The long-acting insulin analogues glargine and detemir have been shown in some studies to be associated with increased risk of breast cancer, and other studies have shown no association between the use of these two compounds and the risk of breast cancer,” Dr. Boyle said in a separate presentation at the ADA meeting. “It was important to sort out a little bit what was going on in the literature.”

Overall, the meta-analysis of data from 12 longitudinal cohort studies – including more than 6,000 cases of breast cancer – showed a slight increase in breast cancer risk in patients taking long-acting insulin (SRR, 1.13) with “a relatively reasonable” level of heterogeneity (I² = 23%).

“But we see that the story is not that simple,” he said.

For example, some studies included only patients who were prescribed insulin for the first time after the study began (new users), some included only patients who were prescribed insulin before the study began (prevalent users), and some included both (ever users), which may have introduced bias in the results, he explained.

Studies of glargine included 4,168 breast cancer cases over a total of 1,418,743 person-years of observation, and studies of detemir included fewer than 2,047 breast cancer cases (not all studies reported case numbers). Among both new users of glargine and detemir, the SRR was 1.12, suggesting no real association between either glargine or detemir use and breast cancer, he said.

“One important take-home message is that you have to be careful that these pharmaco-epidemiological studies, even when working with the same database, may have conflicting results ... so we still need more robust standards in methods for [such] studies,” he concluded.

Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.

sworcester@mdedge.com

SOURCE: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.

ORLANDO – The moderately increased risk of breast cancer among women with type 2 diabetes mellitus appears to be associated with adiposity rather than with diabetes or insulin treatment, findings from meta-analyses suggest.

Vasilis Varsakelis/Fotolia

In one meta-analysis of data from 21 prospective studies with a total of nearly 15.2 million women, 325,117 breast cancer cases, and a mean follow-up time of 8 years (nearly 33 million person-years), the risk of breast cancer was significantly greater among patients with diabetes than it was among patients without diabetes (summary relative risk, 1.11), Maria Bota reported at the annual scientific sessions of the American Diabetes Association.

However, there was substantial unexplained heterogeneity of results across the individual studies (I² = 82%), said Ms. Bota, a faculty member at the International Prevention Research Institute, Lyon, France.

“When the analysis was restricted to the 12 studies that adjusted for [body mass index], the summary relative risk decreased to 1.09 and the heterogeneity also decreased to a moderate value of 32%; when the analysis was restricted to the 9 studies that did not adjust for BMI, the summary relative risk increased to 1.14 again, and the heterogeneity increased even more to 91%,” she said.

In an analysis that combined the results of the nine studies that did not adjust for BMI along with crude relative risks from studies that reported both crude and BMI-adjusted relative risks (17 studies in all), the SRR was 1.12, and heterogeneity among the studies was high at 84%.

Additionally, an analysis by menopausal status based on four studies that reported breast cancer in both pre- and postmenopausal women showed SRRs for breast cancer of 0.97 (a 3% decrease in risk) and 1.14 among diabetic vs. nondiabetic premenopausal women and postmenopausal women, respectively, she said, noting that heterogeneity was low (I² = 0%) among the premenopausal breast cancer study groups and high (I² = 70%) among the postmenopausal study groups.

The findings provide evidence for a moderately increased risk of breast cancer in women with T2DM, Ms. Bota said.

“However, the effect of the adjustment or lack of adjustment on the heterogeneity suggests that the higher risk of breast cancer in women with diabetes may not be due to diabetes itself, but to adiposity,” she said, adding that “this hypothesis is equally supported by our subgroup analysis according to menopausal status because we saw that the risk of breast cancer was only associated with diabetes in postmenopausal women and this pattern resembles the pattern of the risk of breast cancer associated with adiposity, which is also only increased in postmenopausal women.”

This study was limited by insufficient data for investigating the sources of heterogeneity, she said.

“Therefore we propose ... future pooled analyses based on individual data from good quality prospective studies in order to increase the study power and to do some detailed analysis of the links between adiposity, diabetes, and breast cancer,” she concluded, adding that new studies to examine those relationships only in premenopausal women are also needed

In a separate meta-analysis, she and her colleagues, including Peter Boyle, PhD, president of the International Prevention Research Institute, assessed the association between insulin treatment and breast cancer risk in patients with diabetes.

“The long-acting insulin analogues glargine and detemir have been shown in some studies to be associated with increased risk of breast cancer, and other studies have shown no association between the use of these two compounds and the risk of breast cancer,” Dr. Boyle said in a separate presentation at the ADA meeting. “It was important to sort out a little bit what was going on in the literature.”

Overall, the meta-analysis of data from 12 longitudinal cohort studies – including more than 6,000 cases of breast cancer – showed a slight increase in breast cancer risk in patients taking long-acting insulin (SRR, 1.13) with “a relatively reasonable” level of heterogeneity (I² = 23%).

“But we see that the story is not that simple,” he said.

For example, some studies included only patients who were prescribed insulin for the first time after the study began (new users), some included only patients who were prescribed insulin before the study began (prevalent users), and some included both (ever users), which may have introduced bias in the results, he explained.

Studies of glargine included 4,168 breast cancer cases over a total of 1,418,743 person-years of observation, and studies of detemir included fewer than 2,047 breast cancer cases (not all studies reported case numbers). Among both new users of glargine and detemir, the SRR was 1.12, suggesting no real association between either glargine or detemir use and breast cancer, he said.

“One important take-home message is that you have to be careful that these pharmaco-epidemiological studies, even when working with the same database, may have conflicting results ... so we still need more robust standards in methods for [such] studies,” he concluded.

Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.

sworcester@mdedge.com

SOURCE: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.

Two researchers who made groundbreaking discoveries leading to the development of immune checkpoint therapy have jointly received the 2018 Nobel Prize in Physiology or Medicine.

James P. Allison, PhD, and Tasuku Honjo, MD, PhD, share the prize for their work in showing how strategies for “inhibiting the brakes” on T cells can be used in the treatment of cancer, the Nobel Assembly at Karolinska Institutet, Stockholm, said in a news release.

The discoveries of Dr. Allison and Dr. Honjo represent a landmark in the fight against cancer, according to the Nobel Assembly.

“This new form of immunotherapy unleashes a vigorous, and often durable, immune response directed against essentially any tumor already recognized by the immune system,” members of the Nobel Committee and Assembly said in a simultaneously published manuscript explaining the scientific background behind the discovery.

The “unprecedented” research activity in the immune checkpoint field demonstrates how influential the discoveries of Dr. Allison and Dr. Honjo have been, molecular genetics professor C. I. Edvard Smith, MD, PhD, and coauthors said in the manuscript.

Their findings have “conferred great benefit on mankind” and add a “new pillar” to existing cancer treatments, Dr. Smith and coauthors said in their report.

Dr. Allison was one of several scientists to observe that the cytotoxic T-lymphocyte antigen 4 (CTLA4) protein functions as a brake on T cells, the Nobel Assembly said in the press release. He developed an antibody that could bind to CTLA4 and block its function, and demonstrated its activity in experiments taking place near the end of 1994.

The “spectacular” results showed that, in mice, the antibodies could inhibit the brake and unlock antitumor T-cell activity, according to the release.

Studies of CTLA-4 blockade in humans from several research groups yielded promising results, and in 2010, a major breakthrough came, according to the Nobel Assembly, when it was reported that the CTLA4 blocker ipilimumab improved survival in patients with metastatic melanoma.

Dr. Honjo discovered the programmed cell death protein (PD-1) in 1992, a few years before Dr. Allison’s discovery, and explored its function in experiments carried out over many years at his laboratory at Kyoto University.

Dr. Honjo’s experiments showed that PD-1 functioned as a T-cell brake, but by a different mechanism than CTLA4, paving the way for studying PD-1 as a target of cancer treatment.

That led to a considerable amount of clinical development, including a key 2012 study showing that patients treated with the anti-PD-1 antibody nivolumab led to long-term remissions and possible cures in some patients, the assembly said in their press release.

Scientists have attempted to harness the immune system in the fight against cancer for more than 100 years, according to the assembly. “Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”

Two researchers who made groundbreaking discoveries leading to the development of immune checkpoint therapy have jointly received the 2018 Nobel Prize in Physiology or Medicine.

James P. Allison, PhD, and Tasuku Honjo, MD, PhD, share the prize for their work in showing how strategies for “inhibiting the brakes” on T cells can be used in the treatment of cancer, the Nobel Assembly at Karolinska Institutet, Stockholm, said in a news release.

The discoveries of Dr. Allison and Dr. Honjo represent a landmark in the fight against cancer, according to the Nobel Assembly.

“This new form of immunotherapy unleashes a vigorous, and often durable, immune response directed against essentially any tumor already recognized by the immune system,” members of the Nobel Committee and Assembly said in a simultaneously published manuscript explaining the scientific background behind the discovery.

The “unprecedented” research activity in the immune checkpoint field demonstrates how influential the discoveries of Dr. Allison and Dr. Honjo have been, molecular genetics professor C. I. Edvard Smith, MD, PhD, and coauthors said in the manuscript.

Their findings have “conferred great benefit on mankind” and add a “new pillar” to existing cancer treatments, Dr. Smith and coauthors said in their report.

Dr. Allison was one of several scientists to observe that the cytotoxic T-lymphocyte antigen 4 (CTLA4) protein functions as a brake on T cells, the Nobel Assembly said in the press release. He developed an antibody that could bind to CTLA4 and block its function, and demonstrated its activity in experiments taking place near the end of 1994.

The “spectacular” results showed that, in mice, the antibodies could inhibit the brake and unlock antitumor T-cell activity, according to the release.

Studies of CTLA-4 blockade in humans from several research groups yielded promising results, and in 2010, a major breakthrough came, according to the Nobel Assembly, when it was reported that the CTLA4 blocker ipilimumab improved survival in patients with metastatic melanoma.

Dr. Honjo discovered the programmed cell death protein (PD-1) in 1992, a few years before Dr. Allison’s discovery, and explored its function in experiments carried out over many years at his laboratory at Kyoto University.

Dr. Honjo’s experiments showed that PD-1 functioned as a T-cell brake, but by a different mechanism than CTLA4, paving the way for studying PD-1 as a target of cancer treatment.

That led to a considerable amount of clinical development, including a key 2012 study showing that patients treated with the anti-PD-1 antibody nivolumab led to long-term remissions and possible cures in some patients, the assembly said in their press release.

Scientists have attempted to harness the immune system in the fight against cancer for more than 100 years, according to the assembly. “Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”

Two researchers who made groundbreaking discoveries leading to the development of immune checkpoint therapy have jointly received the 2018 Nobel Prize in Physiology or Medicine.

James P. Allison, PhD, and Tasuku Honjo, MD, PhD, share the prize for their work in showing how strategies for “inhibiting the brakes” on T cells can be used in the treatment of cancer, the Nobel Assembly at Karolinska Institutet, Stockholm, said in a news release.

The discoveries of Dr. Allison and Dr. Honjo represent a landmark in the fight against cancer, according to the Nobel Assembly.

“This new form of immunotherapy unleashes a vigorous, and often durable, immune response directed against essentially any tumor already recognized by the immune system,” members of the Nobel Committee and Assembly said in a simultaneously published manuscript explaining the scientific background behind the discovery.

The “unprecedented” research activity in the immune checkpoint field demonstrates how influential the discoveries of Dr. Allison and Dr. Honjo have been, molecular genetics professor C. I. Edvard Smith, MD, PhD, and coauthors said in the manuscript.

Their findings have “conferred great benefit on mankind” and add a “new pillar” to existing cancer treatments, Dr. Smith and coauthors said in their report.

Dr. Allison was one of several scientists to observe that the cytotoxic T-lymphocyte antigen 4 (CTLA4) protein functions as a brake on T cells, the Nobel Assembly said in the press release. He developed an antibody that could bind to CTLA4 and block its function, and demonstrated its activity in experiments taking place near the end of 1994.

The “spectacular” results showed that, in mice, the antibodies could inhibit the brake and unlock antitumor T-cell activity, according to the release.

Studies of CTLA-4 blockade in humans from several research groups yielded promising results, and in 2010, a major breakthrough came, according to the Nobel Assembly, when it was reported that the CTLA4 blocker ipilimumab improved survival in patients with metastatic melanoma.

Dr. Honjo discovered the programmed cell death protein (PD-1) in 1992, a few years before Dr. Allison’s discovery, and explored its function in experiments carried out over many years at his laboratory at Kyoto University.

Dr. Honjo’s experiments showed that PD-1 functioned as a T-cell brake, but by a different mechanism than CTLA4, paving the way for studying PD-1 as a target of cancer treatment.

That led to a considerable amount of clinical development, including a key 2012 study showing that patients treated with the anti-PD-1 antibody nivolumab led to long-term remissions and possible cures in some patients, the assembly said in their press release.

Scientists have attempted to harness the immune system in the fight against cancer for more than 100 years, according to the assembly. “Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”

The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.

The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.

The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.

The Food and Drug Administration has approved dacomitinib tablets (VIZIMPRO) for the first-line treatment of metastatic non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.

The second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) has a recommended dose of 45 mg once daily with or without food.

The approval is based on the randomized, active-controlled 452-patient ARCHER 1050 trial, in which the drug showed improvement in progression-free survival (PFS) versus gefitinib. The median PFS was 14.7 in the dacomitinib arm, compared with 9.2 months in the gefitinib arm (hazard ratio 0.59).

ARCHER 1050 trial participants had good performance status, no prior therapy for metastatic disease or recurrent disease and were disease-free for at least 12 months following systemic non-EGFR TKI-containing therapy. Dacomitinib and gefitinib were given once-daily at 45 mg and 250 mg oral doses, respectively, until disease progression or unacceptable toxicity.

No improvement was seen in overall response rate or overall survival with dacomitinib vs. gefitinib.

Of 394 patients who received dacomitinib, 27% experienced serious adverse reactions – most often diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus, according to the FDA. Those that most often lead to discontinuation were diarrhea and interstitial lung disease. Prescribing information for dacomitinib contains warnings and precautions for interstitial lung disease, diarrhea, and dermatologic adverse reactions.

sworcester@mdedge.com

The Food and Drug Administration has approved dacomitinib tablets (VIZIMPRO) for the first-line treatment of metastatic non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.

The second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) has a recommended dose of 45 mg once daily with or without food.

The approval is based on the randomized, active-controlled 452-patient ARCHER 1050 trial, in which the drug showed improvement in progression-free survival (PFS) versus gefitinib. The median PFS was 14.7 in the dacomitinib arm, compared with 9.2 months in the gefitinib arm (hazard ratio 0.59).

ARCHER 1050 trial participants had good performance status, no prior therapy for metastatic disease or recurrent disease and were disease-free for at least 12 months following systemic non-EGFR TKI-containing therapy. Dacomitinib and gefitinib were given once-daily at 45 mg and 250 mg oral doses, respectively, until disease progression or unacceptable toxicity.

No improvement was seen in overall response rate or overall survival with dacomitinib vs. gefitinib.

Of 394 patients who received dacomitinib, 27% experienced serious adverse reactions – most often diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus, according to the FDA. Those that most often lead to discontinuation were diarrhea and interstitial lung disease. Prescribing information for dacomitinib contains warnings and precautions for interstitial lung disease, diarrhea, and dermatologic adverse reactions.

sworcester@mdedge.com

The Food and Drug Administration has approved dacomitinib tablets (VIZIMPRO) for the first-line treatment of metastatic non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.

The second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) has a recommended dose of 45 mg once daily with or without food.

The approval is based on the randomized, active-controlled 452-patient ARCHER 1050 trial, in which the drug showed improvement in progression-free survival (PFS) versus gefitinib. The median PFS was 14.7 in the dacomitinib arm, compared with 9.2 months in the gefitinib arm (hazard ratio 0.59).

ARCHER 1050 trial participants had good performance status, no prior therapy for metastatic disease or recurrent disease and were disease-free for at least 12 months following systemic non-EGFR TKI-containing therapy. Dacomitinib and gefitinib were given once-daily at 45 mg and 250 mg oral doses, respectively, until disease progression or unacceptable toxicity.

No improvement was seen in overall response rate or overall survival with dacomitinib vs. gefitinib.

Of 394 patients who received dacomitinib, 27% experienced serious adverse reactions – most often diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus, according to the FDA. Those that most often lead to discontinuation were diarrhea and interstitial lung disease. Prescribing information for dacomitinib contains warnings and precautions for interstitial lung disease, diarrhea, and dermatologic adverse reactions.

sworcester@mdedge.com