Melanoma

Smartphone applications (apps) using so-called artificial intelligence (AI) aimed at the general public for use on suspicious skin lesions are unreliable, said U.K. researchers reporting a systematic review.
 

These apps are providing information that could lead to “potentially life-or-death decisions,” commented co-lead author Hywel C. Williams, MD, from the Centre of Evidence Based Dermatology, University of Nottingham (England).

“The one thing you mustn’t do in a situation where early diagnosis can make a difference between life and death is you mustn’t miss the melanoma,” he said in an interview.

“These apps were missing melanomas, and that’s very worrisome,” he commented.

The review included nine studies of skin cancer smartphone apps, including two apps, SkinScan and SkinVision, that have been given Conformit Europenne (CE) marks, allowing them to be marketed across Europe. These apps are also available in Australia and New Zealand, but not in the United States.

The review found that SkinScan was not able to identify any melanomas in the one study that assessed this app, while SkinVision had a relatively low sensitivity and specificity, with 12% of cancerous or precancerous lesions missed and 21% of benign lesions wrongly identified as cancerous.

This means that among 1,000 people with a melanoma prevalence of 3%, 4 of 30 melanomas would be missed, and 200 people would be incorrectly told that a mole was of high concern, the authors estimated.

The research was published by The BMJ on Feb. 10.

“Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps,” Dr. Williams commented in a statement.

Coauthor Jac Dinnes, PhD, from the Institute of Applied Health Research at the University of Birmingham (England), added it is “really disappointing that there is not better quality evidence available to judge the efficacy of these apps.”

“It is vital that health care professionals are aware of the current limitations both in the technologies and in their evaluations,” she added.

The results also highlight the limitations of the regulatory system governing smartphone apps in that they are currently not subject to assessment by bodies such as the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), the authors commented.

“Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create,” said co-lead author Jonathan J. Deeks, PhD, also at the Institute of Applied Health Research.

“We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Speaking in an interview, Williams lamented the poor quality of the research that had been conducted. “These studies were not good enough,” he said, adding that “there’s no excuse for really poor study design and poor reporting.”

He would like to see the regulations tightened around AI apps purporting to inform decision making for the general public and suggests that these devices should be assessed by the MHRA. “I really do think a CE mark is not enough,” he said.

The team noted that the skin cancer apps “all include disclaimers that the results should only be used as a guide and cannot replace health care advice,” through which the manufacturers “attempt to evade any responsibility for negative outcomes experienced by users.”

Nevertheless, the “poor and variable performance” of the apps revealed by their review indicates that they “have not yet shown sufficient promise to recommend their use,” they concluded.

The “official approval” implied by a CE mark “will give consumers the impression that the apps have been assessed as effective and safe,” wrote Ben Goldacre, DataLab director, Nuffield Department of Primary Care, University of Oxford (England), and colleagues in an accompanying editorial.

“The implicit assumption is that apps are similarly low-risk technology” to devices such as sticking plasters and reading glasses, they comment.

“But shortcomings in diagnostic apps can have serious implications,” they warn. The “risks include psychological harm from health anxiety or ‘cyberchondria,’ and physical harm from misdiagnosis or overdiagnosis; for clinicians there is a risk of increased workload, and changes to ethical or legal responsibilities around triage, referral, diagnosis, and treatment.” There is also potential for “inappropriate resource use, and even loss of credibility for digital technology in general.”

Details of the review

For their review, the authors searched the Cochrane Central Register on Controlled Trials, the MEDLNE, Embase, Cumulative Index to Nursing and Allied Health Literature, Conference Proceedings Citation index, Zetoc, and Science Citation Index databases, and online trial registers for studies published between August 2016 and April 2019.

From 80 studies identified, 9 met the eligibility criteria.

Of those, six studies, evaluating a total of 725 skin lesions, determined the accuracy of smartphone apps in risk stratifying suspicious skin lesions by comparing them against a histopathological reference standard diagnosis or expert follow-up.

Five of these studies aimed to detect only melanoma, while one sought to differentiate between malignant or premalignant lesions (including melanoma, basal cell carcinoma, and squamous cell carcinoma) and benign lesions.

The three remaining studies, which evaluated 407 lesions in all, compared smartphone app recommendations against a reference standard of expert recommendations for further investigation or intervention.

The researchers found the studies had a string of potential biases and limitations.

For example, only four studies recruited a consecutive sample of study participants and lesions, and only two included lesions selected by study participants, whereas five studies used lesions that had been selected by a clinician.

Three studies reported that it took 5-10 attempts to obtain an adequate image. In seven studies, it was the researchers and not the patients who used the app to photograph the lesions, and two studies used images obtained from dermatology databases.

This “raised concerns that the results of the studies were unlikely to be representative of real life use,” the authors comment.

In addition, the exclusion of unevaluable images “might have systematically inflated the diagnostic performance of the tested apps,” they add.

The independent research was supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham and is an update of one of a collection of reviews funded by the NIHR through its Cochrane Systematic Review Programme Grant.
 

This article first appeared on Medscape.com.

Smartphone applications (apps) using so-called artificial intelligence (AI) aimed at the general public for use on suspicious skin lesions are unreliable, said U.K. researchers reporting a systematic review.
 

These apps are providing information that could lead to “potentially life-or-death decisions,” commented co-lead author Hywel C. Williams, MD, from the Centre of Evidence Based Dermatology, University of Nottingham (England).

“The one thing you mustn’t do in a situation where early diagnosis can make a difference between life and death is you mustn’t miss the melanoma,” he said in an interview.

“These apps were missing melanomas, and that’s very worrisome,” he commented.

The review included nine studies of skin cancer smartphone apps, including two apps, SkinScan and SkinVision, that have been given Conformit Europenne (CE) marks, allowing them to be marketed across Europe. These apps are also available in Australia and New Zealand, but not in the United States.

The review found that SkinScan was not able to identify any melanomas in the one study that assessed this app, while SkinVision had a relatively low sensitivity and specificity, with 12% of cancerous or precancerous lesions missed and 21% of benign lesions wrongly identified as cancerous.

This means that among 1,000 people with a melanoma prevalence of 3%, 4 of 30 melanomas would be missed, and 200 people would be incorrectly told that a mole was of high concern, the authors estimated.

The research was published by The BMJ on Feb. 10.

“Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps,” Dr. Williams commented in a statement.

Coauthor Jac Dinnes, PhD, from the Institute of Applied Health Research at the University of Birmingham (England), added it is “really disappointing that there is not better quality evidence available to judge the efficacy of these apps.”

“It is vital that health care professionals are aware of the current limitations both in the technologies and in their evaluations,” she added.

The results also highlight the limitations of the regulatory system governing smartphone apps in that they are currently not subject to assessment by bodies such as the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), the authors commented.

“Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create,” said co-lead author Jonathan J. Deeks, PhD, also at the Institute of Applied Health Research.

“We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Speaking in an interview, Williams lamented the poor quality of the research that had been conducted. “These studies were not good enough,” he said, adding that “there’s no excuse for really poor study design and poor reporting.”

He would like to see the regulations tightened around AI apps purporting to inform decision making for the general public and suggests that these devices should be assessed by the MHRA. “I really do think a CE mark is not enough,” he said.

The team noted that the skin cancer apps “all include disclaimers that the results should only be used as a guide and cannot replace health care advice,” through which the manufacturers “attempt to evade any responsibility for negative outcomes experienced by users.”

Nevertheless, the “poor and variable performance” of the apps revealed by their review indicates that they “have not yet shown sufficient promise to recommend their use,” they concluded.

The “official approval” implied by a CE mark “will give consumers the impression that the apps have been assessed as effective and safe,” wrote Ben Goldacre, DataLab director, Nuffield Department of Primary Care, University of Oxford (England), and colleagues in an accompanying editorial.

“The implicit assumption is that apps are similarly low-risk technology” to devices such as sticking plasters and reading glasses, they comment.

“But shortcomings in diagnostic apps can have serious implications,” they warn. The “risks include psychological harm from health anxiety or ‘cyberchondria,’ and physical harm from misdiagnosis or overdiagnosis; for clinicians there is a risk of increased workload, and changes to ethical or legal responsibilities around triage, referral, diagnosis, and treatment.” There is also potential for “inappropriate resource use, and even loss of credibility for digital technology in general.”

Details of the review

For their review, the authors searched the Cochrane Central Register on Controlled Trials, the MEDLNE, Embase, Cumulative Index to Nursing and Allied Health Literature, Conference Proceedings Citation index, Zetoc, and Science Citation Index databases, and online trial registers for studies published between August 2016 and April 2019.

From 80 studies identified, 9 met the eligibility criteria.

Of those, six studies, evaluating a total of 725 skin lesions, determined the accuracy of smartphone apps in risk stratifying suspicious skin lesions by comparing them against a histopathological reference standard diagnosis or expert follow-up.

Five of these studies aimed to detect only melanoma, while one sought to differentiate between malignant or premalignant lesions (including melanoma, basal cell carcinoma, and squamous cell carcinoma) and benign lesions.

The three remaining studies, which evaluated 407 lesions in all, compared smartphone app recommendations against a reference standard of expert recommendations for further investigation or intervention.

The researchers found the studies had a string of potential biases and limitations.

For example, only four studies recruited a consecutive sample of study participants and lesions, and only two included lesions selected by study participants, whereas five studies used lesions that had been selected by a clinician.

Three studies reported that it took 5-10 attempts to obtain an adequate image. In seven studies, it was the researchers and not the patients who used the app to photograph the lesions, and two studies used images obtained from dermatology databases.

This “raised concerns that the results of the studies were unlikely to be representative of real life use,” the authors comment.

In addition, the exclusion of unevaluable images “might have systematically inflated the diagnostic performance of the tested apps,” they add.

The independent research was supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham and is an update of one of a collection of reviews funded by the NIHR through its Cochrane Systematic Review Programme Grant.
 

This article first appeared on Medscape.com.

Smartphone applications (apps) using so-called artificial intelligence (AI) aimed at the general public for use on suspicious skin lesions are unreliable, said U.K. researchers reporting a systematic review.
 

These apps are providing information that could lead to “potentially life-or-death decisions,” commented co-lead author Hywel C. Williams, MD, from the Centre of Evidence Based Dermatology, University of Nottingham (England).

“The one thing you mustn’t do in a situation where early diagnosis can make a difference between life and death is you mustn’t miss the melanoma,” he said in an interview.

“These apps were missing melanomas, and that’s very worrisome,” he commented.

The review included nine studies of skin cancer smartphone apps, including two apps, SkinScan and SkinVision, that have been given Conformit Europenne (CE) marks, allowing them to be marketed across Europe. These apps are also available in Australia and New Zealand, but not in the United States.

The review found that SkinScan was not able to identify any melanomas in the one study that assessed this app, while SkinVision had a relatively low sensitivity and specificity, with 12% of cancerous or precancerous lesions missed and 21% of benign lesions wrongly identified as cancerous.

This means that among 1,000 people with a melanoma prevalence of 3%, 4 of 30 melanomas would be missed, and 200 people would be incorrectly told that a mole was of high concern, the authors estimated.

The research was published by The BMJ on Feb. 10.

“Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps,” Dr. Williams commented in a statement.

Coauthor Jac Dinnes, PhD, from the Institute of Applied Health Research at the University of Birmingham (England), added it is “really disappointing that there is not better quality evidence available to judge the efficacy of these apps.”

“It is vital that health care professionals are aware of the current limitations both in the technologies and in their evaluations,” she added.

The results also highlight the limitations of the regulatory system governing smartphone apps in that they are currently not subject to assessment by bodies such as the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), the authors commented.

“Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create,” said co-lead author Jonathan J. Deeks, PhD, also at the Institute of Applied Health Research.

“We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Speaking in an interview, Williams lamented the poor quality of the research that had been conducted. “These studies were not good enough,” he said, adding that “there’s no excuse for really poor study design and poor reporting.”

He would like to see the regulations tightened around AI apps purporting to inform decision making for the general public and suggests that these devices should be assessed by the MHRA. “I really do think a CE mark is not enough,” he said.

The team noted that the skin cancer apps “all include disclaimers that the results should only be used as a guide and cannot replace health care advice,” through which the manufacturers “attempt to evade any responsibility for negative outcomes experienced by users.”

Nevertheless, the “poor and variable performance” of the apps revealed by their review indicates that they “have not yet shown sufficient promise to recommend their use,” they concluded.

The “official approval” implied by a CE mark “will give consumers the impression that the apps have been assessed as effective and safe,” wrote Ben Goldacre, DataLab director, Nuffield Department of Primary Care, University of Oxford (England), and colleagues in an accompanying editorial.

“The implicit assumption is that apps are similarly low-risk technology” to devices such as sticking plasters and reading glasses, they comment.

“But shortcomings in diagnostic apps can have serious implications,” they warn. The “risks include psychological harm from health anxiety or ‘cyberchondria,’ and physical harm from misdiagnosis or overdiagnosis; for clinicians there is a risk of increased workload, and changes to ethical or legal responsibilities around triage, referral, diagnosis, and treatment.” There is also potential for “inappropriate resource use, and even loss of credibility for digital technology in general.”

Details of the review

For their review, the authors searched the Cochrane Central Register on Controlled Trials, the MEDLNE, Embase, Cumulative Index to Nursing and Allied Health Literature, Conference Proceedings Citation index, Zetoc, and Science Citation Index databases, and online trial registers for studies published between August 2016 and April 2019.

From 80 studies identified, 9 met the eligibility criteria.

Of those, six studies, evaluating a total of 725 skin lesions, determined the accuracy of smartphone apps in risk stratifying suspicious skin lesions by comparing them against a histopathological reference standard diagnosis or expert follow-up.

Five of these studies aimed to detect only melanoma, while one sought to differentiate between malignant or premalignant lesions (including melanoma, basal cell carcinoma, and squamous cell carcinoma) and benign lesions.

The three remaining studies, which evaluated 407 lesions in all, compared smartphone app recommendations against a reference standard of expert recommendations for further investigation or intervention.

The researchers found the studies had a string of potential biases and limitations.

For example, only four studies recruited a consecutive sample of study participants and lesions, and only two included lesions selected by study participants, whereas five studies used lesions that had been selected by a clinician.

Three studies reported that it took 5-10 attempts to obtain an adequate image. In seven studies, it was the researchers and not the patients who used the app to photograph the lesions, and two studies used images obtained from dermatology databases.

This “raised concerns that the results of the studies were unlikely to be representative of real life use,” the authors comment.

In addition, the exclusion of unevaluable images “might have systematically inflated the diagnostic performance of the tested apps,” they add.

The independent research was supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham and is an update of one of a collection of reviews funded by the NIHR through its Cochrane Systematic Review Programme Grant.
 

This article first appeared on Medscape.com.

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

Patients with stage III melanoma who have circulating tumor cells (CTCs) at baseline may benefit from adjuvant therapy, according to investigators.

A prospective study showed that patients with at least one CTC upon first presentation had increased risks of both short-term and long-term recurrence, reported lead author Anthony Lucci, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

While previous studies have suggested that CTCs hold prognostic value for melanoma patients, no trials had evaluated the CellSearch CTC Test – a standardized technique approved by the Food and Drug Administration – in patients with stage III disease, the investigators wrote. Their report is in Clinical Cancer Research.

In the present study, the investigators tested the CellSearch system in 243 patients with stage III cutaneous melanoma who were treated at MD Anderson Cancer Center. Patients with uveal or mucosal melanoma, or distant metastatic disease, were excluded.

Baseline blood samples were drawn within 3 months of regional lymph node metastasis, determined by either lymphadenectomy or sentinel lymph node biopsy. CTC assay positivity required that at least one CTC was detected within a single 7.5 mL tube of blood.

Out of 243 patients, 90 (37%) had a positive test. Of these 90 patients, almost one-quarter (23%) relapsed within 6 months, compared with 8% of patients who had a negative CTC assay. Within the full follow-up period, which was as long as 64 months, 48% of patients with CTCs at baseline relapsed, compared with 37% of patients without CTCs.

Multivariable regression analysis, which was adjusted for age, sex, pathological nodal stage, Breslow thickness, ulceration, and lymphovascular invasion, showed that baseline CTC positivity was an independent risk factor for melanoma recurrence, both in the short term and the long term. Compared with patients who lacked CTCs, those who tested positive were three times as likely to have disease recurrence within 6 months (hazard ratio, 3.13; P = .018). For relapse-free survival within 54 months, this hazard ratio decreased to 2.25 (P = .006).

Although a Cochran-Armitage test suggested that recurrence risks increased with CTC count, the investigators noted that a minority of patients (17%) had two or more CTCs, and just 5% had three or more CTCs.

According to the investigators, CTCs at baseline could become the first reliable blood-based biomarker for this patient population.

“[CTCs] clearly identified a group of stage III patients at high risk for relapse,” the investigators wrote. “This would be clinically very significant as an independent risk factor to help identify the stage III patients who would benefit most from adjuvant systemic therapy.”

This study was funded by the Kiefer family, Sheila Prenowitz, the Simon and Linda Eyles Foundation, the Sam and Janna Moore family, and the Wintermann Foundation. The investigators reported no conflicts of interest.

SOURCE: Lucci et al. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-2670.

Patients with stage III melanoma who have circulating tumor cells (CTCs) at baseline may benefit from adjuvant therapy, according to investigators.

A prospective study showed that patients with at least one CTC upon first presentation had increased risks of both short-term and long-term recurrence, reported lead author Anthony Lucci, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

While previous studies have suggested that CTCs hold prognostic value for melanoma patients, no trials had evaluated the CellSearch CTC Test – a standardized technique approved by the Food and Drug Administration – in patients with stage III disease, the investigators wrote. Their report is in Clinical Cancer Research.

In the present study, the investigators tested the CellSearch system in 243 patients with stage III cutaneous melanoma who were treated at MD Anderson Cancer Center. Patients with uveal or mucosal melanoma, or distant metastatic disease, were excluded.

Baseline blood samples were drawn within 3 months of regional lymph node metastasis, determined by either lymphadenectomy or sentinel lymph node biopsy. CTC assay positivity required that at least one CTC was detected within a single 7.5 mL tube of blood.

Out of 243 patients, 90 (37%) had a positive test. Of these 90 patients, almost one-quarter (23%) relapsed within 6 months, compared with 8% of patients who had a negative CTC assay. Within the full follow-up period, which was as long as 64 months, 48% of patients with CTCs at baseline relapsed, compared with 37% of patients without CTCs.

Multivariable regression analysis, which was adjusted for age, sex, pathological nodal stage, Breslow thickness, ulceration, and lymphovascular invasion, showed that baseline CTC positivity was an independent risk factor for melanoma recurrence, both in the short term and the long term. Compared with patients who lacked CTCs, those who tested positive were three times as likely to have disease recurrence within 6 months (hazard ratio, 3.13; P = .018). For relapse-free survival within 54 months, this hazard ratio decreased to 2.25 (P = .006).

Although a Cochran-Armitage test suggested that recurrence risks increased with CTC count, the investigators noted that a minority of patients (17%) had two or more CTCs, and just 5% had three or more CTCs.

According to the investigators, CTCs at baseline could become the first reliable blood-based biomarker for this patient population.

“[CTCs] clearly identified a group of stage III patients at high risk for relapse,” the investigators wrote. “This would be clinically very significant as an independent risk factor to help identify the stage III patients who would benefit most from adjuvant systemic therapy.”

This study was funded by the Kiefer family, Sheila Prenowitz, the Simon and Linda Eyles Foundation, the Sam and Janna Moore family, and the Wintermann Foundation. The investigators reported no conflicts of interest.

SOURCE: Lucci et al. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-2670.

Patients with stage III melanoma who have circulating tumor cells (CTCs) at baseline may benefit from adjuvant therapy, according to investigators.

A prospective study showed that patients with at least one CTC upon first presentation had increased risks of both short-term and long-term recurrence, reported lead author Anthony Lucci, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

While previous studies have suggested that CTCs hold prognostic value for melanoma patients, no trials had evaluated the CellSearch CTC Test – a standardized technique approved by the Food and Drug Administration – in patients with stage III disease, the investigators wrote. Their report is in Clinical Cancer Research.

In the present study, the investigators tested the CellSearch system in 243 patients with stage III cutaneous melanoma who were treated at MD Anderson Cancer Center. Patients with uveal or mucosal melanoma, or distant metastatic disease, were excluded.

Baseline blood samples were drawn within 3 months of regional lymph node metastasis, determined by either lymphadenectomy or sentinel lymph node biopsy. CTC assay positivity required that at least one CTC was detected within a single 7.5 mL tube of blood.

Out of 243 patients, 90 (37%) had a positive test. Of these 90 patients, almost one-quarter (23%) relapsed within 6 months, compared with 8% of patients who had a negative CTC assay. Within the full follow-up period, which was as long as 64 months, 48% of patients with CTCs at baseline relapsed, compared with 37% of patients without CTCs.

Multivariable regression analysis, which was adjusted for age, sex, pathological nodal stage, Breslow thickness, ulceration, and lymphovascular invasion, showed that baseline CTC positivity was an independent risk factor for melanoma recurrence, both in the short term and the long term. Compared with patients who lacked CTCs, those who tested positive were three times as likely to have disease recurrence within 6 months (hazard ratio, 3.13; P = .018). For relapse-free survival within 54 months, this hazard ratio decreased to 2.25 (P = .006).

Although a Cochran-Armitage test suggested that recurrence risks increased with CTC count, the investigators noted that a minority of patients (17%) had two or more CTCs, and just 5% had three or more CTCs.

According to the investigators, CTCs at baseline could become the first reliable blood-based biomarker for this patient population.

“[CTCs] clearly identified a group of stage III patients at high risk for relapse,” the investigators wrote. “This would be clinically very significant as an independent risk factor to help identify the stage III patients who would benefit most from adjuvant systemic therapy.”

This study was funded by the Kiefer family, Sheila Prenowitz, the Simon and Linda Eyles Foundation, the Sam and Janna Moore family, and the Wintermann Foundation. The investigators reported no conflicts of interest.

SOURCE: Lucci et al. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-2670.

To the Editor:

Pembrolizumab is an anti–programmed death receptor 1 humanized monoclonal antibody used for treating advanced or metastatic melanoma.¹ It is associated with several immune-related adverse events because it blocks a T-cell receptor checkpoint.² The most common dermatologic immune-related adverse event seen with anti–programmed death receptor 1 medications is a nonspecific morbilliform rash, usually seen after the second treatment cycle; however, pruritus, vitiligo, bullous disorders, and lichenoid reactions also have been reported.³ We report a case of pembrolizumab-induced, self-limited lobular panniculitis in a patient with metastatic melanoma.

A 37-year-old woman with malignant melanoma presented with tender, erythematous, subcutaneous nodules on the hips and legs of 2 weeks’ duration (Figure 1). Twelve years prior to the current presentation, she was diagnosed with metastases to the cecum, lung, and brain. A review of systems was otherwise negative. She had been receiving pembrolizumab infusions (2 mg/kg every 3 weeks) for the last 2.7 years as second-line therapy after previously undergoing chemotherapy, radiation, and resection. She was not taking oral contraceptives or other hormone-based medications and did not report any new medications.

Chest computed tomography was normal in our patient, and she reported no systemic symptoms. Additional laboratory studies to evaluate for sarcoidosis were not obtained. Furthermore, the lesions quickly resolved despite continued use of pembrolizumab. We report this case to highlight that pembrolizumab may induce an isolated, self-limited lobular panniculitis years after medication initiation.

To the Editor:

Pembrolizumab is an anti–programmed death receptor 1 humanized monoclonal antibody used for treating advanced or metastatic melanoma.¹ It is associated with several immune-related adverse events because it blocks a T-cell receptor checkpoint.² The most common dermatologic immune-related adverse event seen with anti–programmed death receptor 1 medications is a nonspecific morbilliform rash, usually seen after the second treatment cycle; however, pruritus, vitiligo, bullous disorders, and lichenoid reactions also have been reported.³ We report a case of pembrolizumab-induced, self-limited lobular panniculitis in a patient with metastatic melanoma.

A 37-year-old woman with malignant melanoma presented with tender, erythematous, subcutaneous nodules on the hips and legs of 2 weeks’ duration (Figure 1). Twelve years prior to the current presentation, she was diagnosed with metastases to the cecum, lung, and brain. A review of systems was otherwise negative. She had been receiving pembrolizumab infusions (2 mg/kg every 3 weeks) for the last 2.7 years as second-line therapy after previously undergoing chemotherapy, radiation, and resection. She was not taking oral contraceptives or other hormone-based medications and did not report any new medications.

Chest computed tomography was normal in our patient, and she reported no systemic symptoms. Additional laboratory studies to evaluate for sarcoidosis were not obtained. Furthermore, the lesions quickly resolved despite continued use of pembrolizumab. We report this case to highlight that pembrolizumab may induce an isolated, self-limited lobular panniculitis years after medication initiation.

To the Editor:

Pembrolizumab is an anti–programmed death receptor 1 humanized monoclonal antibody used for treating advanced or metastatic melanoma.¹ It is associated with several immune-related adverse events because it blocks a T-cell receptor checkpoint.² The most common dermatologic immune-related adverse event seen with anti–programmed death receptor 1 medications is a nonspecific morbilliform rash, usually seen after the second treatment cycle; however, pruritus, vitiligo, bullous disorders, and lichenoid reactions also have been reported.³ We report a case of pembrolizumab-induced, self-limited lobular panniculitis in a patient with metastatic melanoma.

A 37-year-old woman with malignant melanoma presented with tender, erythematous, subcutaneous nodules on the hips and legs of 2 weeks’ duration (Figure 1). Twelve years prior to the current presentation, she was diagnosed with metastases to the cecum, lung, and brain. A review of systems was otherwise negative. She had been receiving pembrolizumab infusions (2 mg/kg every 3 weeks) for the last 2.7 years as second-line therapy after previously undergoing chemotherapy, radiation, and resection. She was not taking oral contraceptives or other hormone-based medications and did not report any new medications.

Chest computed tomography was normal in our patient, and she reported no systemic symptoms. Additional laboratory studies to evaluate for sarcoidosis were not obtained. Furthermore, the lesions quickly resolved despite continued use of pembrolizumab. We report this case to highlight that pembrolizumab may induce an isolated, self-limited lobular panniculitis years after medication initiation.

To the Editor:

Melanoma is the third most common skin cancer. It is estimated that 18% of melanoma patients will develop skin metastases, with skin being the first site of involvement in 56% of cases.¹ Of all cancers, it is estimated that 5% will develop skin metastases. It is the presenting sign in nearly 1% of visceral cancers.² Melanoma and nonmelanoma metastases can have sundry presentations. We present a case of metastatic melanoma with multiple keratoacanthoma (KA)–like skin lesions in a patient with a known history of nonmelanoma skin cancer (NMSC) as well as melanoma.

A 76-year-old man with a history of pT2aNXMX melanoma on the left upper back presented for a routine 3-month follow-up and reported several new asymptomatic bumps on the chest, back, and right upper extremity within the last 2 weeks. The melanoma was removed via wide local excision 2 years prior at an outside facility with a Breslow depth of 1.05 mm and a negative sentinel lymph node biopsy. The mitotic rate or ulceration status was unknown. He also had a history of several NMSCs, as well as a medical history of coronary artery disease, myocardial infarction, and ventricular tachycardia with cardiac defibrillator placement. Physical examination revealed 5 pink, volcano-shaped nodules with central keratotic plugs on the upper back (Figure 1), chest, and right upper extremity, in addition to 1 pink pearly nodule on the right side of the chest. The history and appearance of the lesions were suspicious for eruptive KAs. There was no evidence of cancer recurrence at the prior melanoma and NMSC sites.

Although melanoma is well known to metastasize years and even decades later, KA-like lesions have not been reported as manifestations of metastatic melanoma.^4,5 Our patient likely had a primary amelanotic melanoma, as the medical records from the outside facility stated that basal cell carcinoma was ruled out via biopsy. The amelanotic nature of the primary melanoma may have influenced the amelanotic appearance of the metastases. Our patient had no signs of immunosuppression that could have contributed to the sudden skin metastases.

Depending on the subtype of cutaneous metastases (eg, satellitosis, in-transit disease, distant cutaneous metastases), the location prevalence of the primary melanoma varies. In a study of 4865 melanoma patients who were diagnosed and followed prospectively over a 30-year period, skin metastases were mostly locoregional and presentation on the leg and foot were disproportionate.¹ In contrast, the trunk was overrepresented for distant metastases. Distant metastases also were more associated with concurrent metastases to the viscera.¹ Accordingly, a patient’s prognosis and management will differ depending on the subtype of cutaneous metastases.

Eruptive or multiple KAs classically have been associated with the Grzybowski variant, the Ferguson-Smith familial variant, and Muir-Torre syndrome. It was reported as a paraneoplastic syndrome associated with colon cancer, ovarian cancer, and once with myelodysplastic syndrome.³ Keratoacanthomas are being classified as well-differentiated squamous cell carcinomas and have metastatic potential. A biopsy is recommended to diagnose KAs as opposed to historically being monitored for resolution. A skin biopsy is the standard of care in management of KAs.

In addition to being associated with Muir-Torre syndrome and classified as a paraneoplastic syndrome,³ eruptive KAs can occur following skin resurfacing for actinic damage, fractional photothermolysis, cryotherapy, Jessner peels, and trichloroacetic acid peels.⁶ A couple other uncommon settings include a case report of an arc welder with job-associated radiation and multiple reports of tattoo-induced KAs.^7,8 There is the new increasingly common association of squamous cell carcinomas with BRAF inhibitors, such as vemurafenib, for metastatic melanoma.⁹

In a 2012 review article on cutaneous metastases, Riahi and Cohen¹⁰ found 8 cases of cutaneous metastases presenting as KA-like lesions; none were metastatic melanoma. All were solitary lesions, not multiple lesions, as in our patient. The sources were lung (3 cases), breast, esophagus, chondrosarcoma, bronchial, and mesothelioma. The most common location was the upper lip. Additionally, similar to our patient, they behaved clinically as KAs with rapid growth and keratotic plugs and were asymptomatic.¹⁰

Metastatic melanoma may mimic many other cutaneous processes that may make the diagnosis more difficult. Our case indicates that cutaneous metastases may mimic KAs. Although multiple KA-like lesions can spontaneously occur, a paraneoplastic syndrome and other underlying etiologies should be considered.

To the Editor:

Melanoma is the third most common skin cancer. It is estimated that 18% of melanoma patients will develop skin metastases, with skin being the first site of involvement in 56% of cases.¹ Of all cancers, it is estimated that 5% will develop skin metastases. It is the presenting sign in nearly 1% of visceral cancers.² Melanoma and nonmelanoma metastases can have sundry presentations. We present a case of metastatic melanoma with multiple keratoacanthoma (KA)–like skin lesions in a patient with a known history of nonmelanoma skin cancer (NMSC) as well as melanoma.

A 76-year-old man with a history of pT2aNXMX melanoma on the left upper back presented for a routine 3-month follow-up and reported several new asymptomatic bumps on the chest, back, and right upper extremity within the last 2 weeks. The melanoma was removed via wide local excision 2 years prior at an outside facility with a Breslow depth of 1.05 mm and a negative sentinel lymph node biopsy. The mitotic rate or ulceration status was unknown. He also had a history of several NMSCs, as well as a medical history of coronary artery disease, myocardial infarction, and ventricular tachycardia with cardiac defibrillator placement. Physical examination revealed 5 pink, volcano-shaped nodules with central keratotic plugs on the upper back (Figure 1), chest, and right upper extremity, in addition to 1 pink pearly nodule on the right side of the chest. The history and appearance of the lesions were suspicious for eruptive KAs. There was no evidence of cancer recurrence at the prior melanoma and NMSC sites.

Although melanoma is well known to metastasize years and even decades later, KA-like lesions have not been reported as manifestations of metastatic melanoma.^4,5 Our patient likely had a primary amelanotic melanoma, as the medical records from the outside facility stated that basal cell carcinoma was ruled out via biopsy. The amelanotic nature of the primary melanoma may have influenced the amelanotic appearance of the metastases. Our patient had no signs of immunosuppression that could have contributed to the sudden skin metastases.

Depending on the subtype of cutaneous metastases (eg, satellitosis, in-transit disease, distant cutaneous metastases), the location prevalence of the primary melanoma varies. In a study of 4865 melanoma patients who were diagnosed and followed prospectively over a 30-year period, skin metastases were mostly locoregional and presentation on the leg and foot were disproportionate.¹ In contrast, the trunk was overrepresented for distant metastases. Distant metastases also were more associated with concurrent metastases to the viscera.¹ Accordingly, a patient’s prognosis and management will differ depending on the subtype of cutaneous metastases.

Eruptive or multiple KAs classically have been associated with the Grzybowski variant, the Ferguson-Smith familial variant, and Muir-Torre syndrome. It was reported as a paraneoplastic syndrome associated with colon cancer, ovarian cancer, and once with myelodysplastic syndrome.³ Keratoacanthomas are being classified as well-differentiated squamous cell carcinomas and have metastatic potential. A biopsy is recommended to diagnose KAs as opposed to historically being monitored for resolution. A skin biopsy is the standard of care in management of KAs.

In addition to being associated with Muir-Torre syndrome and classified as a paraneoplastic syndrome,³ eruptive KAs can occur following skin resurfacing for actinic damage, fractional photothermolysis, cryotherapy, Jessner peels, and trichloroacetic acid peels.⁶ A couple other uncommon settings include a case report of an arc welder with job-associated radiation and multiple reports of tattoo-induced KAs.^7,8 There is the new increasingly common association of squamous cell carcinomas with BRAF inhibitors, such as vemurafenib, for metastatic melanoma.⁹

In a 2012 review article on cutaneous metastases, Riahi and Cohen¹⁰ found 8 cases of cutaneous metastases presenting as KA-like lesions; none were metastatic melanoma. All were solitary lesions, not multiple lesions, as in our patient. The sources were lung (3 cases), breast, esophagus, chondrosarcoma, bronchial, and mesothelioma. The most common location was the upper lip. Additionally, similar to our patient, they behaved clinically as KAs with rapid growth and keratotic plugs and were asymptomatic.¹⁰

Metastatic melanoma may mimic many other cutaneous processes that may make the diagnosis more difficult. Our case indicates that cutaneous metastases may mimic KAs. Although multiple KA-like lesions can spontaneously occur, a paraneoplastic syndrome and other underlying etiologies should be considered.

To the Editor:

Melanoma is the third most common skin cancer. It is estimated that 18% of melanoma patients will develop skin metastases, with skin being the first site of involvement in 56% of cases.¹ Of all cancers, it is estimated that 5% will develop skin metastases. It is the presenting sign in nearly 1% of visceral cancers.² Melanoma and nonmelanoma metastases can have sundry presentations. We present a case of metastatic melanoma with multiple keratoacanthoma (KA)–like skin lesions in a patient with a known history of nonmelanoma skin cancer (NMSC) as well as melanoma.

A 76-year-old man with a history of pT2aNXMX melanoma on the left upper back presented for a routine 3-month follow-up and reported several new asymptomatic bumps on the chest, back, and right upper extremity within the last 2 weeks. The melanoma was removed via wide local excision 2 years prior at an outside facility with a Breslow depth of 1.05 mm and a negative sentinel lymph node biopsy. The mitotic rate or ulceration status was unknown. He also had a history of several NMSCs, as well as a medical history of coronary artery disease, myocardial infarction, and ventricular tachycardia with cardiac defibrillator placement. Physical examination revealed 5 pink, volcano-shaped nodules with central keratotic plugs on the upper back (Figure 1), chest, and right upper extremity, in addition to 1 pink pearly nodule on the right side of the chest. The history and appearance of the lesions were suspicious for eruptive KAs. There was no evidence of cancer recurrence at the prior melanoma and NMSC sites.

Although melanoma is well known to metastasize years and even decades later, KA-like lesions have not been reported as manifestations of metastatic melanoma.^4,5 Our patient likely had a primary amelanotic melanoma, as the medical records from the outside facility stated that basal cell carcinoma was ruled out via biopsy. The amelanotic nature of the primary melanoma may have influenced the amelanotic appearance of the metastases. Our patient had no signs of immunosuppression that could have contributed to the sudden skin metastases.

Depending on the subtype of cutaneous metastases (eg, satellitosis, in-transit disease, distant cutaneous metastases), the location prevalence of the primary melanoma varies. In a study of 4865 melanoma patients who were diagnosed and followed prospectively over a 30-year period, skin metastases were mostly locoregional and presentation on the leg and foot were disproportionate.¹ In contrast, the trunk was overrepresented for distant metastases. Distant metastases also were more associated with concurrent metastases to the viscera.¹ Accordingly, a patient’s prognosis and management will differ depending on the subtype of cutaneous metastases.

Eruptive or multiple KAs classically have been associated with the Grzybowski variant, the Ferguson-Smith familial variant, and Muir-Torre syndrome. It was reported as a paraneoplastic syndrome associated with colon cancer, ovarian cancer, and once with myelodysplastic syndrome.³ Keratoacanthomas are being classified as well-differentiated squamous cell carcinomas and have metastatic potential. A biopsy is recommended to diagnose KAs as opposed to historically being monitored for resolution. A skin biopsy is the standard of care in management of KAs.

In addition to being associated with Muir-Torre syndrome and classified as a paraneoplastic syndrome,³ eruptive KAs can occur following skin resurfacing for actinic damage, fractional photothermolysis, cryotherapy, Jessner peels, and trichloroacetic acid peels.⁶ A couple other uncommon settings include a case report of an arc welder with job-associated radiation and multiple reports of tattoo-induced KAs.^7,8 There is the new increasingly common association of squamous cell carcinomas with BRAF inhibitors, such as vemurafenib, for metastatic melanoma.⁹

In a 2012 review article on cutaneous metastases, Riahi and Cohen¹⁰ found 8 cases of cutaneous metastases presenting as KA-like lesions; none were metastatic melanoma. All were solitary lesions, not multiple lesions, as in our patient. The sources were lung (3 cases), breast, esophagus, chondrosarcoma, bronchial, and mesothelioma. The most common location was the upper lip. Additionally, similar to our patient, they behaved clinically as KAs with rapid growth and keratotic plugs and were asymptomatic.¹⁰

Metastatic melanoma may mimic many other cutaneous processes that may make the diagnosis more difficult. Our case indicates that cutaneous metastases may mimic KAs. Although multiple KA-like lesions can spontaneously occur, a paraneoplastic syndrome and other underlying etiologies should be considered.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

This infographic is available in the PDF above.

This infographic is available in the PDF above.

This infographic is available in the PDF above.

Declines in death rates for lung cancer and melanoma have gained momentum in recent years, fueling a record drop in cancer mortality, the American Cancer Society says.

Lung cancer death rates, which were falling by 3% in men and 2% in women annually in 2008 through 2013, dropped by 5% in men and nearly 4% per year in women annually from 2013 to 2017, according to the society’s 2020 statistical report.

Those accelerating reductions in death rates helped fuel the biggest-ever single year decline in overall cancer mortality, of 2.2%, from 2016 to 2017, their report shows.

According to the investigators, the decline in melanoma death rates escalated to 6.9% per year among 20- to 49-year-olds over 2013-2017, compared with a decline of just 2.9% per year during 2006-2010. Likewise, the melanoma death rate decline was 7.2% annually for the more recent time period, compared with just 1.3% annually in the earlier time period. The finding was even more remarkable for those 65 years of age and older, according to investigators, since the declines in melanoma death rates reached 6.2% annually, compared with a 0.9% annual increase in the years before immunotherapy.

Smoking cessation has been the main driver of progress in cutting lung cancer death rates, according to the report, while in melanoma, death rates have dropped after the introduction of immune checkpoint inhibitors and targeted therapies.

By contrast, reductions in death rates have slowed for colorectal cancers and female breast cancers, and have stabilized for prostate cancer, Ms. Siegel and coauthors stated, adding that racial and geographic disparities persist in preventable cancers, including those of the lung and cervix.

“Increased investment in both the equitable application of existing cancer control interventions and basic and clinical research to further advance treatment options would undoubtedly accelerate progress against cancer,” said the investigators. The report appears in CA: A Cancer Journal for Clinicians.

While the decline in lung cancer death rates is good news, the disease remains a major killer, responsible for more deaths than breast, colorectal, and ovarian cancer combined, said Jacques P. Fontaine, MD, a thoracic surgeon at Moffitt Cancer Center in Tampa, Fla.

“Five-year survival rates are still around the 18%-20% range, which is much lower than breast and prostate cancer,” Dr. Fontaine said in an interview. “Nonetheless, we’ve made a little dent in that, and we’re improving.”

Two other factors that have helped spur that improvement, according to Dr. Fontaine, are the reduced incidence of squamous cell carcinomas, which are linked to smoking, and the increased use of lung cancer screening with low-dose computed tomography.

Squamous cell carcinomas tend to be a central rather than peripheral, which makes the tumors harder to resect: “Surgery is sometimes not an option, and even to this day in 2020, the single most effective treatment for lung cancer remains surgical resection,” said Dr. Fontaine.

Likewise, centrally located tumors may preclude giving high-dose radiation and may result in more “collateral damage” to healthy tissue, he added.

Landmark studies show that low-dose CT scans reduce lung cancer deaths by 20% or more; however, screening can have false-positive results that lead to unnecessary biopsies and other harms, suggesting that the procedures should be done in centers of excellence that provide high-quality, responsible screening for early lung cancer, Dr. Fontaine said.

While the drop in melanoma death rates is encouraging and, not surprising in light of new cutting-edge therapies, an ongoing unmet treatment need still exists, according to Vishal Anil Patel, MD, director of cutaneous oncology at the George Washington Cancer Center in Washington.

“We still have a lot to learn, and a way to go, because we’ve really just made the first breakthrough,” Dr. Patel said in an interview.

SOURCE: Siegel RL et al. CA Cancer J Clin. 2020;70(1):7-30. doi: 10.3322/caac.21590.

Declines in death rates for lung cancer and melanoma have gained momentum in recent years, fueling a record drop in cancer mortality, the American Cancer Society says.

Lung cancer death rates, which were falling by 3% in men and 2% in women annually in 2008 through 2013, dropped by 5% in men and nearly 4% per year in women annually from 2013 to 2017, according to the society’s 2020 statistical report.

Those accelerating reductions in death rates helped fuel the biggest-ever single year decline in overall cancer mortality, of 2.2%, from 2016 to 2017, their report shows.

According to the investigators, the decline in melanoma death rates escalated to 6.9% per year among 20- to 49-year-olds over 2013-2017, compared with a decline of just 2.9% per year during 2006-2010. Likewise, the melanoma death rate decline was 7.2% annually for the more recent time period, compared with just 1.3% annually in the earlier time period. The finding was even more remarkable for those 65 years of age and older, according to investigators, since the declines in melanoma death rates reached 6.2% annually, compared with a 0.9% annual increase in the years before immunotherapy.

Smoking cessation has been the main driver of progress in cutting lung cancer death rates, according to the report, while in melanoma, death rates have dropped after the introduction of immune checkpoint inhibitors and targeted therapies.

By contrast, reductions in death rates have slowed for colorectal cancers and female breast cancers, and have stabilized for prostate cancer, Ms. Siegel and coauthors stated, adding that racial and geographic disparities persist in preventable cancers, including those of the lung and cervix.

“Increased investment in both the equitable application of existing cancer control interventions and basic and clinical research to further advance treatment options would undoubtedly accelerate progress against cancer,” said the investigators. The report appears in CA: A Cancer Journal for Clinicians.

While the decline in lung cancer death rates is good news, the disease remains a major killer, responsible for more deaths than breast, colorectal, and ovarian cancer combined, said Jacques P. Fontaine, MD, a thoracic surgeon at Moffitt Cancer Center in Tampa, Fla.

“Five-year survival rates are still around the 18%-20% range, which is much lower than breast and prostate cancer,” Dr. Fontaine said in an interview. “Nonetheless, we’ve made a little dent in that, and we’re improving.”

Two other factors that have helped spur that improvement, according to Dr. Fontaine, are the reduced incidence of squamous cell carcinomas, which are linked to smoking, and the increased use of lung cancer screening with low-dose computed tomography.

Squamous cell carcinomas tend to be a central rather than peripheral, which makes the tumors harder to resect: “Surgery is sometimes not an option, and even to this day in 2020, the single most effective treatment for lung cancer remains surgical resection,” said Dr. Fontaine.

Likewise, centrally located tumors may preclude giving high-dose radiation and may result in more “collateral damage” to healthy tissue, he added.

Landmark studies show that low-dose CT scans reduce lung cancer deaths by 20% or more; however, screening can have false-positive results that lead to unnecessary biopsies and other harms, suggesting that the procedures should be done in centers of excellence that provide high-quality, responsible screening for early lung cancer, Dr. Fontaine said.

While the drop in melanoma death rates is encouraging and, not surprising in light of new cutting-edge therapies, an ongoing unmet treatment need still exists, according to Vishal Anil Patel, MD, director of cutaneous oncology at the George Washington Cancer Center in Washington.

“We still have a lot to learn, and a way to go, because we’ve really just made the first breakthrough,” Dr. Patel said in an interview.

SOURCE: Siegel RL et al. CA Cancer J Clin. 2020;70(1):7-30. doi: 10.3322/caac.21590.

Declines in death rates for lung cancer and melanoma have gained momentum in recent years, fueling a record drop in cancer mortality, the American Cancer Society says.

Lung cancer death rates, which were falling by 3% in men and 2% in women annually in 2008 through 2013, dropped by 5% in men and nearly 4% per year in women annually from 2013 to 2017, according to the society’s 2020 statistical report.

Those accelerating reductions in death rates helped fuel the biggest-ever single year decline in overall cancer mortality, of 2.2%, from 2016 to 2017, their report shows.

According to the investigators, the decline in melanoma death rates escalated to 6.9% per year among 20- to 49-year-olds over 2013-2017, compared with a decline of just 2.9% per year during 2006-2010. Likewise, the melanoma death rate decline was 7.2% annually for the more recent time period, compared with just 1.3% annually in the earlier time period. The finding was even more remarkable for those 65 years of age and older, according to investigators, since the declines in melanoma death rates reached 6.2% annually, compared with a 0.9% annual increase in the years before immunotherapy.

Smoking cessation has been the main driver of progress in cutting lung cancer death rates, according to the report, while in melanoma, death rates have dropped after the introduction of immune checkpoint inhibitors and targeted therapies.

By contrast, reductions in death rates have slowed for colorectal cancers and female breast cancers, and have stabilized for prostate cancer, Ms. Siegel and coauthors stated, adding that racial and geographic disparities persist in preventable cancers, including those of the lung and cervix.

“Increased investment in both the equitable application of existing cancer control interventions and basic and clinical research to further advance treatment options would undoubtedly accelerate progress against cancer,” said the investigators. The report appears in CA: A Cancer Journal for Clinicians.

While the decline in lung cancer death rates is good news, the disease remains a major killer, responsible for more deaths than breast, colorectal, and ovarian cancer combined, said Jacques P. Fontaine, MD, a thoracic surgeon at Moffitt Cancer Center in Tampa, Fla.

“Five-year survival rates are still around the 18%-20% range, which is much lower than breast and prostate cancer,” Dr. Fontaine said in an interview. “Nonetheless, we’ve made a little dent in that, and we’re improving.”

Two other factors that have helped spur that improvement, according to Dr. Fontaine, are the reduced incidence of squamous cell carcinomas, which are linked to smoking, and the increased use of lung cancer screening with low-dose computed tomography.

Squamous cell carcinomas tend to be a central rather than peripheral, which makes the tumors harder to resect: “Surgery is sometimes not an option, and even to this day in 2020, the single most effective treatment for lung cancer remains surgical resection,” said Dr. Fontaine.

Likewise, centrally located tumors may preclude giving high-dose radiation and may result in more “collateral damage” to healthy tissue, he added.

Landmark studies show that low-dose CT scans reduce lung cancer deaths by 20% or more; however, screening can have false-positive results that lead to unnecessary biopsies and other harms, suggesting that the procedures should be done in centers of excellence that provide high-quality, responsible screening for early lung cancer, Dr. Fontaine said.

While the drop in melanoma death rates is encouraging and, not surprising in light of new cutting-edge therapies, an ongoing unmet treatment need still exists, according to Vishal Anil Patel, MD, director of cutaneous oncology at the George Washington Cancer Center in Washington.

“We still have a lot to learn, and a way to go, because we’ve really just made the first breakthrough,” Dr. Patel said in an interview.

SOURCE: Siegel RL et al. CA Cancer J Clin. 2020;70(1):7-30. doi: 10.3322/caac.21590.

A new tool specifically designed to evaluate immune checkpoint inhibitor–related toxicity, developed based on direct patient involvement, picks up on cutaneous and other side effects that would be missed using traditional quality of life questionnaires, investigators say.

The 25-item list represents the first-ever health-related quality of life (HRQOL) toxicity subscale developed for patients receiving checkpoint inhibitors, according to the investigators, led by Aaron R. Hansen, MBBS, of the division of medical oncology and hematology in the department of medicine at the University of Toronto.

The toxicity subscale is combined with the Functional Assessment of Cancer Therapy–General (FACT-G), which measures physical, emotional, family and social, and functional domains, to form the Functional Assessment of Cancer Therapy–Immune Checkpoint Modulator (FACT-ICM), Dr. Hansen stated in a recent report that describes initial development and early validation efforts.

The FACT-ICM could become an important tool for measuring HRQOL in patients receiving checkpoint inhibitors, depending on results of further investigations including more patients, the authors wrote in that report.

“Currently, we would recommend that our toxicity subscale be validated first before use in clinical care, or in trials with QOL as a primary or secondary endpoint,” wrote Dr. Hansen and colleagues in the report, which appears in Cancer.

The toxicity subscale asks patients to rate items such as “I am bothered by dry skin,” “I feel pain, soreness or aches in some of my muscles,” and “My fatigue keeps me from doing the things I want do” on a scale of 0 (not at all) to 4 (very much).

Development of the toxicity subscale was based on focus groups and interviews with 37 patients with a variety of cancer types who were being treated with a PD-1, PD-L1, and CTLA-4 immune checkpoint inhibitors. Sixteen physicians were surveyed to evaluate the patient input, while 11 of them also participated in follow-up interviews.

“At every step in this process, the patients were central,” the investigators wrote in their report.

According to the investigators, that approach is in line with guidance from the Food and Drug Administration, which has said that meaningful patient input should be used in the upfront development of patient-reported outcome (PRO) measures, rather than obtaining patient endorsement after the fact.

By contrast, an electronic PRO immune-oncology module recently developed, based on 19 immune-related adverse events from drug labels and clinical trial reports, had “no evaluation” of effects on HRQOL, according to Dr. Hansen and coauthors, who added that the tool “did not adhere” to the FDA call for meaningful patient input.

Some previous studies of quality of life in immune checkpoint inhibitor–treated patients have used tumor-specific PROs and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 Items (EORTC-QLQ-C30).

The new, immune checkpoint inhibitor–specific toxicity subscale has “broader coverage” of side effects that reportedly affect HRQOL in patients treated with these agents, including taste disturbance, cough, and fever or chills, according to the investigators.

Moreover, the EORTC-QLQ-C30 and the EORTC head and neck cancer–specific-35 module (EORTC QLQ-H&N35), do not include items related to cutaneous adverse events such as itch, rash, and dry skin that have been seen in some checkpoint inhibitor clinical trials, they noted.

“This represents a clear limitation of such preexisting PRO instruments, which should be addressed with our immune checkpoint moduator–specific tool,” they wrote.

The study was supported by a grant from the University of Toronto. Authors of the study provided disclosures related to Merck, Bristol-Myers Squibb, Karyopharm, Boston Biomedical, Novartis, Genentech, Hoffmann La Roche, GlaxoSmithKline, and others.

SOURCE: Hansen AR et al. Cancer. 2020 Jan 8. doi: 10.1002/cncr.32692.

A new tool specifically designed to evaluate immune checkpoint inhibitor–related toxicity, developed based on direct patient involvement, picks up on cutaneous and other side effects that would be missed using traditional quality of life questionnaires, investigators say.

The 25-item list represents the first-ever health-related quality of life (HRQOL) toxicity subscale developed for patients receiving checkpoint inhibitors, according to the investigators, led by Aaron R. Hansen, MBBS, of the division of medical oncology and hematology in the department of medicine at the University of Toronto.

The toxicity subscale is combined with the Functional Assessment of Cancer Therapy–General (FACT-G), which measures physical, emotional, family and social, and functional domains, to form the Functional Assessment of Cancer Therapy–Immune Checkpoint Modulator (FACT-ICM), Dr. Hansen stated in a recent report that describes initial development and early validation efforts.

The FACT-ICM could become an important tool for measuring HRQOL in patients receiving checkpoint inhibitors, depending on results of further investigations including more patients, the authors wrote in that report.

“Currently, we would recommend that our toxicity subscale be validated first before use in clinical care, or in trials with QOL as a primary or secondary endpoint,” wrote Dr. Hansen and colleagues in the report, which appears in Cancer.

The toxicity subscale asks patients to rate items such as “I am bothered by dry skin,” “I feel pain, soreness or aches in some of my muscles,” and “My fatigue keeps me from doing the things I want do” on a scale of 0 (not at all) to 4 (very much).

Development of the toxicity subscale was based on focus groups and interviews with 37 patients with a variety of cancer types who were being treated with a PD-1, PD-L1, and CTLA-4 immune checkpoint inhibitors. Sixteen physicians were surveyed to evaluate the patient input, while 11 of them also participated in follow-up interviews.

“At every step in this process, the patients were central,” the investigators wrote in their report.

According to the investigators, that approach is in line with guidance from the Food and Drug Administration, which has said that meaningful patient input should be used in the upfront development of patient-reported outcome (PRO) measures, rather than obtaining patient endorsement after the fact.

By contrast, an electronic PRO immune-oncology module recently developed, based on 19 immune-related adverse events from drug labels and clinical trial reports, had “no evaluation” of effects on HRQOL, according to Dr. Hansen and coauthors, who added that the tool “did not adhere” to the FDA call for meaningful patient input.

Some previous studies of quality of life in immune checkpoint inhibitor–treated patients have used tumor-specific PROs and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 Items (EORTC-QLQ-C30).

The new, immune checkpoint inhibitor–specific toxicity subscale has “broader coverage” of side effects that reportedly affect HRQOL in patients treated with these agents, including taste disturbance, cough, and fever or chills, according to the investigators.

Moreover, the EORTC-QLQ-C30 and the EORTC head and neck cancer–specific-35 module (EORTC QLQ-H&N35), do not include items related to cutaneous adverse events such as itch, rash, and dry skin that have been seen in some checkpoint inhibitor clinical trials, they noted.

“This represents a clear limitation of such preexisting PRO instruments, which should be addressed with our immune checkpoint moduator–specific tool,” they wrote.

The study was supported by a grant from the University of Toronto. Authors of the study provided disclosures related to Merck, Bristol-Myers Squibb, Karyopharm, Boston Biomedical, Novartis, Genentech, Hoffmann La Roche, GlaxoSmithKline, and others.

SOURCE: Hansen AR et al. Cancer. 2020 Jan 8. doi: 10.1002/cncr.32692.

A new tool specifically designed to evaluate immune checkpoint inhibitor–related toxicity, developed based on direct patient involvement, picks up on cutaneous and other side effects that would be missed using traditional quality of life questionnaires, investigators say.

The 25-item list represents the first-ever health-related quality of life (HRQOL) toxicity subscale developed for patients receiving checkpoint inhibitors, according to the investigators, led by Aaron R. Hansen, MBBS, of the division of medical oncology and hematology in the department of medicine at the University of Toronto.

The toxicity subscale is combined with the Functional Assessment of Cancer Therapy–General (FACT-G), which measures physical, emotional, family and social, and functional domains, to form the Functional Assessment of Cancer Therapy–Immune Checkpoint Modulator (FACT-ICM), Dr. Hansen stated in a recent report that describes initial development and early validation efforts.

The FACT-ICM could become an important tool for measuring HRQOL in patients receiving checkpoint inhibitors, depending on results of further investigations including more patients, the authors wrote in that report.

“Currently, we would recommend that our toxicity subscale be validated first before use in clinical care, or in trials with QOL as a primary or secondary endpoint,” wrote Dr. Hansen and colleagues in the report, which appears in Cancer.

The toxicity subscale asks patients to rate items such as “I am bothered by dry skin,” “I feel pain, soreness or aches in some of my muscles,” and “My fatigue keeps me from doing the things I want do” on a scale of 0 (not at all) to 4 (very much).

Development of the toxicity subscale was based on focus groups and interviews with 37 patients with a variety of cancer types who were being treated with a PD-1, PD-L1, and CTLA-4 immune checkpoint inhibitors. Sixteen physicians were surveyed to evaluate the patient input, while 11 of them also participated in follow-up interviews.

“At every step in this process, the patients were central,” the investigators wrote in their report.

According to the investigators, that approach is in line with guidance from the Food and Drug Administration, which has said that meaningful patient input should be used in the upfront development of patient-reported outcome (PRO) measures, rather than obtaining patient endorsement after the fact.

By contrast, an electronic PRO immune-oncology module recently developed, based on 19 immune-related adverse events from drug labels and clinical trial reports, had “no evaluation” of effects on HRQOL, according to Dr. Hansen and coauthors, who added that the tool “did not adhere” to the FDA call for meaningful patient input.

Some previous studies of quality of life in immune checkpoint inhibitor–treated patients have used tumor-specific PROs and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 Items (EORTC-QLQ-C30).

The new, immune checkpoint inhibitor–specific toxicity subscale has “broader coverage” of side effects that reportedly affect HRQOL in patients treated with these agents, including taste disturbance, cough, and fever or chills, according to the investigators.

Moreover, the EORTC-QLQ-C30 and the EORTC head and neck cancer–specific-35 module (EORTC QLQ-H&N35), do not include items related to cutaneous adverse events such as itch, rash, and dry skin that have been seen in some checkpoint inhibitor clinical trials, they noted.

“This represents a clear limitation of such preexisting PRO instruments, which should be addressed with our immune checkpoint moduator–specific tool,” they wrote.

The study was supported by a grant from the University of Toronto. Authors of the study provided disclosures related to Merck, Bristol-Myers Squibb, Karyopharm, Boston Biomedical, Novartis, Genentech, Hoffmann La Roche, GlaxoSmithKline, and others.

SOURCE: Hansen AR et al. Cancer. 2020 Jan 8. doi: 10.1002/cncr.32692.