Melanoma

Military dermatologists are charged with caring for a diverse population of active-duty members, civilian dependents, and military retirees. Although certain risk factors for cutaneous malignancies are common in all of these groups, the active-duty population experiences unique exposures to be considered when determining their risk for skin cancer. One subset that may be at a higher risk is military pilots who fly at high altitudes on irregular schedules in austere environments. Through the unparalleled comradeship inherent in many military units, pilots “hear” from their fellow pilots that they are at increased risk for skin cancer. Do their occupational exposures translate into increased risk for cutaneous malignancy? This article will survey the literature pertaining to pilots and skin cancer so that all dermatologists may better care for this unique population.

Epidemiology

Anecdotally, we have observed basal cell carcinoma in pilots in their 20s and early 30s, earlier than would be expected in an otherwise healthy prescreened military population.¹ Woolley and Hughes² published a case report of skin cancer in a young military aviator. The patient was a 32-year-old male helicopter pilot with Fitzpatrick skin type II and no personal or family history of skin cancer who was diagnosed with a periocular nodular basal cell carcinoma. He deployed to locations with high UV radiation (UVR) indices, and his vacation time also was spent in such areas.² UV radiation exposure and Fitzpatrick skin type are known risk factors across occupations, but are there special exposures that come with military aviation service?

To better understand the risk for malignancy in this special population, the US Air Force examined the rates of all cancer types among a cohort of flying versus nonflying officers.³ Aviation personnel showed increased incidence of testicular, bladder, and all-site cancers combined. Noticeably absent was a statistically significant increased risk for malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). Other epidemiological studies examined the incidence rates of MM in the US Armed Forces compared with age- and race-matched civilian populations and showed mixed results: 2 studies showed increased risk,^4,5 while a third showed decreased risk.⁶ Despite finding opposite results of MM rates in military members versus the civilian population, 2 of these studies showed US Air Force members to have higher rates of MM than those in the US Army or Navy.^4,6 Interestingly, the air force has the highest number of pilots among all the services, with 4000 more pilots than the army and navy.⁷ Further studies are needed to determine if the higher air force MM rates occur in pilots.

Although there are mixed and limited data pertaining to military flight crews, there is more robust literature concerning civilian flight personnel. One meta-analysis pooled studies related to cancer risk in cabin crews and civil and military pilots.⁸ In military pilots, they found a standardized incidence ratio (SIR) of 1.43 (95% confidence interval [CI], 1.09-1.87) for MM and 1.80 (95% CI, 1.25-2.80) for NMSC. The SIRs were higher for male cabin attendants (3.42 and 7.46, respectively) and civil pilots (2.18 and 1.88, respectively). They also found the most common cause of mortality in civilian cabin crews was AIDS, possibly explaining the higher SIRs for all types of malignancy in that population.⁸ In the United States, many civilian pilots previously were military pilots⁹ who likely served in the military for at least 10 years.¹⁰ A 2015 meta-analysis of 19 studies of more than 266,000 civil pilots and aircrew members found an SIR for MM of 2.22 (95% CI, 1.67-2.93) for civil pilots and 2.09 (95% CI, 1.67-2.62) for aircrews, stating the risk for MM is at least twice that of the general population.¹¹

Risk Factors

UV Radiation
These studies suggest flight duties increase the risk for cutaneous malignancy. UV radiation is a known risk factor for skin cancer.¹² The main body of the aircraft may protect the cabin’s crew and passengers from UVR, but pilots are exposed to more UVR, especially in aircraft with larger windshields. A government study in 2007 examined the transmittance of UVR through windscreens of 8 aircraft: 3 commercial jets, 2 commercial propeller planes, 1 private jet, and 2 small propeller planes.¹³ UVB was attenuated by all the windscreens (<1% transmittance), but 43% to 54% of UVA was transmitted, with plastic windshields attenuating more than glass. Sanlorenzo et al¹⁴ measured UVA irradiance at the pilot’s seat of a turboprop aircraft at 30,000-ft altitude. They compared this exposure to a UVA tanning bed and estimated that 57 minutes of flight at 30,000-ft altitude was equivalent to 20 minutes inside a UVA tanning booth, a startling finding.¹⁴

Cosmic Radiation
Cosmic radiation consists of neutrons and gamma rays that originate outside Earth’s atmosphere. Pilots are exposed to higher doses of cosmic radiation than nonpilots, but the health effects are difficult to study. Boice et al¹⁵ described how factors such as altitude, latitude, and flight time determine pilots’ cumulative exposure. With longer flight times at higher altitudes, a pilot’s exposure to cosmic radiation is increasing over the years.¹⁵ A 2012 review found that aircrews have low-level cosmic radiation exposure. Despite increases in MM and NMSC in pilots and increased rates of breast cancer in female aircrew, overall cancer-related mortality was lower in flying versus nonflying controls.¹⁶ Thus, cosmic radiation may not be as onerous of an occupational hazard for pilots as has been postulated.

Altered Circadian Rhythms
Aviation duties, especially in the military, require irregular work schedules that repeatedly interfere with normal sleep-wake cycles, disrupt circadian rhythms, and lead to reduced melatonin levels.⁸ Evidence suggests that low levels of melatonin could increase the risk for breast and prostate cancer—both cancers that occur more frequently in female aircrew and male pilots, respectively—by reducing melatonin’s natural protective role in such malignancies.^17,18 A World Health Organization working group categorized shift work as “probably carcinogenic” and cited alterations of melatonin levels, changes in other circadian rhythm–related gene pathways, and relative immunosuppression as likely causative factors.¹⁹ In a 2011 study, exposing mice to UVR during times when nucleotide excision repair mechanisms were at their lowest activity caused an increased rate of skin cancers.²⁰ A 2014 review discussed how epidemiological studies of shift workers such as nurses, firefighters, pilots, and flight crews found contradictory data, but molecular studies show that circadian rhythm–linked repair and tumorigenesis mechanisms are altered by aberrations in the normal sleep-wake cycle.²¹

Cockpit Instrumentation
Electromagnetic energy from the flight instruments in the cockpit also could influence malignancy risk. Nicholas et al²² found magnetic field measurements within the cockpit to be 2 to 10 times that experienced within the home or office. However, no studies examining the health effects of cockpit flight instruments and magnetic fields were found.

Final Thoughts

It is important to counsel pilots on the generally recognized, nonaviation-specific risk factors of family history, skin type, and UVR exposure in the development of skin cancer. Additionally, it is important to explain the possible role of exposure to UVR at higher altitudes, cosmic radiation, and electromagnetic energy from cockpit instruments, as well as altered sleep-wake cycles. A pilot’s risk for MM may be twice that of matched controls, and the risk for NMSC could be higher.^8,11 Although the literature lacks specific recommendations for pilots, it is reasonable to screen pilots once per year to better assess their individual risk and encourage diligent use of sunscreen and sun-protective measures when flying. It also may be important to advocate for the development of engineering controls that decrease UVR transmittance through windscreens, particularly for aircraft flying at higher altitudes for longer flights. More research is needed to determine if changes in circadian rhythm and decreases in melatonin increase skin cancer risk, which could impact how pilots’ schedules are managed. Together, we can ensure adequate surveillance, diagnosis, and treatment in this at-risk population.

Military dermatologists are charged with caring for a diverse population of active-duty members, civilian dependents, and military retirees. Although certain risk factors for cutaneous malignancies are common in all of these groups, the active-duty population experiences unique exposures to be considered when determining their risk for skin cancer. One subset that may be at a higher risk is military pilots who fly at high altitudes on irregular schedules in austere environments. Through the unparalleled comradeship inherent in many military units, pilots “hear” from their fellow pilots that they are at increased risk for skin cancer. Do their occupational exposures translate into increased risk for cutaneous malignancy? This article will survey the literature pertaining to pilots and skin cancer so that all dermatologists may better care for this unique population.

Epidemiology

Anecdotally, we have observed basal cell carcinoma in pilots in their 20s and early 30s, earlier than would be expected in an otherwise healthy prescreened military population.¹ Woolley and Hughes² published a case report of skin cancer in a young military aviator. The patient was a 32-year-old male helicopter pilot with Fitzpatrick skin type II and no personal or family history of skin cancer who was diagnosed with a periocular nodular basal cell carcinoma. He deployed to locations with high UV radiation (UVR) indices, and his vacation time also was spent in such areas.² UV radiation exposure and Fitzpatrick skin type are known risk factors across occupations, but are there special exposures that come with military aviation service?

To better understand the risk for malignancy in this special population, the US Air Force examined the rates of all cancer types among a cohort of flying versus nonflying officers.³ Aviation personnel showed increased incidence of testicular, bladder, and all-site cancers combined. Noticeably absent was a statistically significant increased risk for malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). Other epidemiological studies examined the incidence rates of MM in the US Armed Forces compared with age- and race-matched civilian populations and showed mixed results: 2 studies showed increased risk,^4,5 while a third showed decreased risk.⁶ Despite finding opposite results of MM rates in military members versus the civilian population, 2 of these studies showed US Air Force members to have higher rates of MM than those in the US Army or Navy.^4,6 Interestingly, the air force has the highest number of pilots among all the services, with 4000 more pilots than the army and navy.⁷ Further studies are needed to determine if the higher air force MM rates occur in pilots.

Although there are mixed and limited data pertaining to military flight crews, there is more robust literature concerning civilian flight personnel. One meta-analysis pooled studies related to cancer risk in cabin crews and civil and military pilots.⁸ In military pilots, they found a standardized incidence ratio (SIR) of 1.43 (95% confidence interval [CI], 1.09-1.87) for MM and 1.80 (95% CI, 1.25-2.80) for NMSC. The SIRs were higher for male cabin attendants (3.42 and 7.46, respectively) and civil pilots (2.18 and 1.88, respectively). They also found the most common cause of mortality in civilian cabin crews was AIDS, possibly explaining the higher SIRs for all types of malignancy in that population.⁸ In the United States, many civilian pilots previously were military pilots⁹ who likely served in the military for at least 10 years.¹⁰ A 2015 meta-analysis of 19 studies of more than 266,000 civil pilots and aircrew members found an SIR for MM of 2.22 (95% CI, 1.67-2.93) for civil pilots and 2.09 (95% CI, 1.67-2.62) for aircrews, stating the risk for MM is at least twice that of the general population.¹¹

Risk Factors

UV Radiation
These studies suggest flight duties increase the risk for cutaneous malignancy. UV radiation is a known risk factor for skin cancer.¹² The main body of the aircraft may protect the cabin’s crew and passengers from UVR, but pilots are exposed to more UVR, especially in aircraft with larger windshields. A government study in 2007 examined the transmittance of UVR through windscreens of 8 aircraft: 3 commercial jets, 2 commercial propeller planes, 1 private jet, and 2 small propeller planes.¹³ UVB was attenuated by all the windscreens (<1% transmittance), but 43% to 54% of UVA was transmitted, with plastic windshields attenuating more than glass. Sanlorenzo et al¹⁴ measured UVA irradiance at the pilot’s seat of a turboprop aircraft at 30,000-ft altitude. They compared this exposure to a UVA tanning bed and estimated that 57 minutes of flight at 30,000-ft altitude was equivalent to 20 minutes inside a UVA tanning booth, a startling finding.¹⁴

Cosmic Radiation
Cosmic radiation consists of neutrons and gamma rays that originate outside Earth’s atmosphere. Pilots are exposed to higher doses of cosmic radiation than nonpilots, but the health effects are difficult to study. Boice et al¹⁵ described how factors such as altitude, latitude, and flight time determine pilots’ cumulative exposure. With longer flight times at higher altitudes, a pilot’s exposure to cosmic radiation is increasing over the years.¹⁵ A 2012 review found that aircrews have low-level cosmic radiation exposure. Despite increases in MM and NMSC in pilots and increased rates of breast cancer in female aircrew, overall cancer-related mortality was lower in flying versus nonflying controls.¹⁶ Thus, cosmic radiation may not be as onerous of an occupational hazard for pilots as has been postulated.

Altered Circadian Rhythms
Aviation duties, especially in the military, require irregular work schedules that repeatedly interfere with normal sleep-wake cycles, disrupt circadian rhythms, and lead to reduced melatonin levels.⁸ Evidence suggests that low levels of melatonin could increase the risk for breast and prostate cancer—both cancers that occur more frequently in female aircrew and male pilots, respectively—by reducing melatonin’s natural protective role in such malignancies.^17,18 A World Health Organization working group categorized shift work as “probably carcinogenic” and cited alterations of melatonin levels, changes in other circadian rhythm–related gene pathways, and relative immunosuppression as likely causative factors.¹⁹ In a 2011 study, exposing mice to UVR during times when nucleotide excision repair mechanisms were at their lowest activity caused an increased rate of skin cancers.²⁰ A 2014 review discussed how epidemiological studies of shift workers such as nurses, firefighters, pilots, and flight crews found contradictory data, but molecular studies show that circadian rhythm–linked repair and tumorigenesis mechanisms are altered by aberrations in the normal sleep-wake cycle.²¹

Cockpit Instrumentation
Electromagnetic energy from the flight instruments in the cockpit also could influence malignancy risk. Nicholas et al²² found magnetic field measurements within the cockpit to be 2 to 10 times that experienced within the home or office. However, no studies examining the health effects of cockpit flight instruments and magnetic fields were found.

Final Thoughts

It is important to counsel pilots on the generally recognized, nonaviation-specific risk factors of family history, skin type, and UVR exposure in the development of skin cancer. Additionally, it is important to explain the possible role of exposure to UVR at higher altitudes, cosmic radiation, and electromagnetic energy from cockpit instruments, as well as altered sleep-wake cycles. A pilot’s risk for MM may be twice that of matched controls, and the risk for NMSC could be higher.^8,11 Although the literature lacks specific recommendations for pilots, it is reasonable to screen pilots once per year to better assess their individual risk and encourage diligent use of sunscreen and sun-protective measures when flying. It also may be important to advocate for the development of engineering controls that decrease UVR transmittance through windscreens, particularly for aircraft flying at higher altitudes for longer flights. More research is needed to determine if changes in circadian rhythm and decreases in melatonin increase skin cancer risk, which could impact how pilots’ schedules are managed. Together, we can ensure adequate surveillance, diagnosis, and treatment in this at-risk population.

Military dermatologists are charged with caring for a diverse population of active-duty members, civilian dependents, and military retirees. Although certain risk factors for cutaneous malignancies are common in all of these groups, the active-duty population experiences unique exposures to be considered when determining their risk for skin cancer. One subset that may be at a higher risk is military pilots who fly at high altitudes on irregular schedules in austere environments. Through the unparalleled comradeship inherent in many military units, pilots “hear” from their fellow pilots that they are at increased risk for skin cancer. Do their occupational exposures translate into increased risk for cutaneous malignancy? This article will survey the literature pertaining to pilots and skin cancer so that all dermatologists may better care for this unique population.

Epidemiology

Anecdotally, we have observed basal cell carcinoma in pilots in their 20s and early 30s, earlier than would be expected in an otherwise healthy prescreened military population.¹ Woolley and Hughes² published a case report of skin cancer in a young military aviator. The patient was a 32-year-old male helicopter pilot with Fitzpatrick skin type II and no personal or family history of skin cancer who was diagnosed with a periocular nodular basal cell carcinoma. He deployed to locations with high UV radiation (UVR) indices, and his vacation time also was spent in such areas.² UV radiation exposure and Fitzpatrick skin type are known risk factors across occupations, but are there special exposures that come with military aviation service?

To better understand the risk for malignancy in this special population, the US Air Force examined the rates of all cancer types among a cohort of flying versus nonflying officers.³ Aviation personnel showed increased incidence of testicular, bladder, and all-site cancers combined. Noticeably absent was a statistically significant increased risk for malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). Other epidemiological studies examined the incidence rates of MM in the US Armed Forces compared with age- and race-matched civilian populations and showed mixed results: 2 studies showed increased risk,^4,5 while a third showed decreased risk.⁶ Despite finding opposite results of MM rates in military members versus the civilian population, 2 of these studies showed US Air Force members to have higher rates of MM than those in the US Army or Navy.^4,6 Interestingly, the air force has the highest number of pilots among all the services, with 4000 more pilots than the army and navy.⁷ Further studies are needed to determine if the higher air force MM rates occur in pilots.

Although there are mixed and limited data pertaining to military flight crews, there is more robust literature concerning civilian flight personnel. One meta-analysis pooled studies related to cancer risk in cabin crews and civil and military pilots.⁸ In military pilots, they found a standardized incidence ratio (SIR) of 1.43 (95% confidence interval [CI], 1.09-1.87) for MM and 1.80 (95% CI, 1.25-2.80) for NMSC. The SIRs were higher for male cabin attendants (3.42 and 7.46, respectively) and civil pilots (2.18 and 1.88, respectively). They also found the most common cause of mortality in civilian cabin crews was AIDS, possibly explaining the higher SIRs for all types of malignancy in that population.⁸ In the United States, many civilian pilots previously were military pilots⁹ who likely served in the military for at least 10 years.¹⁰ A 2015 meta-analysis of 19 studies of more than 266,000 civil pilots and aircrew members found an SIR for MM of 2.22 (95% CI, 1.67-2.93) for civil pilots and 2.09 (95% CI, 1.67-2.62) for aircrews, stating the risk for MM is at least twice that of the general population.¹¹

Risk Factors

UV Radiation
These studies suggest flight duties increase the risk for cutaneous malignancy. UV radiation is a known risk factor for skin cancer.¹² The main body of the aircraft may protect the cabin’s crew and passengers from UVR, but pilots are exposed to more UVR, especially in aircraft with larger windshields. A government study in 2007 examined the transmittance of UVR through windscreens of 8 aircraft: 3 commercial jets, 2 commercial propeller planes, 1 private jet, and 2 small propeller planes.¹³ UVB was attenuated by all the windscreens (<1% transmittance), but 43% to 54% of UVA was transmitted, with plastic windshields attenuating more than glass. Sanlorenzo et al¹⁴ measured UVA irradiance at the pilot’s seat of a turboprop aircraft at 30,000-ft altitude. They compared this exposure to a UVA tanning bed and estimated that 57 minutes of flight at 30,000-ft altitude was equivalent to 20 minutes inside a UVA tanning booth, a startling finding.¹⁴

Cosmic Radiation
Cosmic radiation consists of neutrons and gamma rays that originate outside Earth’s atmosphere. Pilots are exposed to higher doses of cosmic radiation than nonpilots, but the health effects are difficult to study. Boice et al¹⁵ described how factors such as altitude, latitude, and flight time determine pilots’ cumulative exposure. With longer flight times at higher altitudes, a pilot’s exposure to cosmic radiation is increasing over the years.¹⁵ A 2012 review found that aircrews have low-level cosmic radiation exposure. Despite increases in MM and NMSC in pilots and increased rates of breast cancer in female aircrew, overall cancer-related mortality was lower in flying versus nonflying controls.¹⁶ Thus, cosmic radiation may not be as onerous of an occupational hazard for pilots as has been postulated.

Altered Circadian Rhythms
Aviation duties, especially in the military, require irregular work schedules that repeatedly interfere with normal sleep-wake cycles, disrupt circadian rhythms, and lead to reduced melatonin levels.⁸ Evidence suggests that low levels of melatonin could increase the risk for breast and prostate cancer—both cancers that occur more frequently in female aircrew and male pilots, respectively—by reducing melatonin’s natural protective role in such malignancies.^17,18 A World Health Organization working group categorized shift work as “probably carcinogenic” and cited alterations of melatonin levels, changes in other circadian rhythm–related gene pathways, and relative immunosuppression as likely causative factors.¹⁹ In a 2011 study, exposing mice to UVR during times when nucleotide excision repair mechanisms were at their lowest activity caused an increased rate of skin cancers.²⁰ A 2014 review discussed how epidemiological studies of shift workers such as nurses, firefighters, pilots, and flight crews found contradictory data, but molecular studies show that circadian rhythm–linked repair and tumorigenesis mechanisms are altered by aberrations in the normal sleep-wake cycle.²¹

Cockpit Instrumentation
Electromagnetic energy from the flight instruments in the cockpit also could influence malignancy risk. Nicholas et al²² found magnetic field measurements within the cockpit to be 2 to 10 times that experienced within the home or office. However, no studies examining the health effects of cockpit flight instruments and magnetic fields were found.

Final Thoughts

It is important to counsel pilots on the generally recognized, nonaviation-specific risk factors of family history, skin type, and UVR exposure in the development of skin cancer. Additionally, it is important to explain the possible role of exposure to UVR at higher altitudes, cosmic radiation, and electromagnetic energy from cockpit instruments, as well as altered sleep-wake cycles. A pilot’s risk for MM may be twice that of matched controls, and the risk for NMSC could be higher.^8,11 Although the literature lacks specific recommendations for pilots, it is reasonable to screen pilots once per year to better assess their individual risk and encourage diligent use of sunscreen and sun-protective measures when flying. It also may be important to advocate for the development of engineering controls that decrease UVR transmittance through windscreens, particularly for aircraft flying at higher altitudes for longer flights. More research is needed to determine if changes in circadian rhythm and decreases in melatonin increase skin cancer risk, which could impact how pilots’ schedules are managed. Together, we can ensure adequate surveillance, diagnosis, and treatment in this at-risk population.

The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.

Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).

Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.

“Our current results may be clinically exploitable. ... Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD, a hematology-oncology fellow at the university.

In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the ... results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”

The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.

For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing (Guardant360) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.

The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.

Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.

Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.

“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.

The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.

aotto@frontlinemedcom.com

The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.

Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).

Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.

“Our current results may be clinically exploitable. ... Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD, a hematology-oncology fellow at the university.

In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the ... results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”

The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.

For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing (Guardant360) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.

The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.

Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.

Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.

“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.

The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.

aotto@frontlinemedcom.com

The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.

Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).

Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.

“Our current results may be clinically exploitable. ... Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD, a hematology-oncology fellow at the university.

In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the ... results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”

The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.

For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing (Guardant360) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.

The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.

Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.

Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.

“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.

The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.

aotto@frontlinemedcom.com

Adults with a history of lithium exposure had a 32% lower risk of melanoma than did those who were not exposed in an unadjusted analysis of data from more than 2 million patients.

Microarray gene profiling techniques suggest that Wnt genes, which “encode a family of secreted glycoproteins that activate cellular signaling pathways to control cell differentiation, proliferation, and motility,” may be involved in melanoma development, wrote Maryam M. Asgari, MD, of the department of dermatology at Massachusetts General Hospital and the department of population medicine at Harvard University, both in Boston, and her colleagues. In particular, “transcriptional profiling of melanoma cell lines has suggested that Wnt/beta-catenin signaling regulates a transcriptional signature predictive of less aggressive melanoma,” they wrote.

The psychiatric medication lithium activates the Wnt/beta-catenin signaling pathway and has shown an ability to inhibit the proliferation of melanoma cells in a mouse model, but “to our knowledge, no published epidemiologic studies have examined the association of melanoma risk with lithium exposure,” they wrote.

The researchers reviewed data from the Kaiser Permanente Northern California database of 2,213,848 adult white patients who were members during 1997-2012, which included 11,317 with lithium exposure. They evaluated the association between lithium exposure and both incident melanoma risk and melanoma-associated mortality (J Invest Dermatol. 2017 Oct;137[10]:2087-91.).

Individuals exposed to lithium had a 32% reduced risk of melanoma in an unadjusted analysis; in an adjusted analysis, the reduced risk was 23% and was not significant.

However, there was a significant difference in melanoma incidence per 100,000 person-years in lithium-exposed individuals, compared with unexposed individuals (67.4 vs. 92.5, respectively; P = .027).

Among patients with melanoma, those with exposure to lithium had a lower mortality rate than those not exposed (4.68 vs. 7.21 per 1,000 person-years, respectively), but the sample size for this subgroup was too small to determine statistical significance. In addition, lithium exposure was associated with reduced likelihood of developing skin tumors greater than 4 mm and of presenting with extensive disease. Among those exposed to lithium, none presented with a thick tumor (Breslow depth greater than 4 mm), and none had regional or distant disease when they were diagnosed, compared with 2.8% and 6.3%, respectively, of those not exposed to lithium.

The findings were limited by several factors, including reliance on prescription information to determine lithium exposure, a homogeneous study population, and confounding variables, such as sun exposure behaviors, the researchers noted. However, the large study population adds strength to the results, and “our conclusions provide evidence that lithium, a relatively inexpensive and readily available drug, warrants further study in melanoma,” they said.

Lead author Dr. Asgari and one of the other four authors disclosed serving as investigators for studies funded by Valeant Pharmaceuticals and Pfizer. This study was supported by the National Cancer Institute. Dr. Asgari is principal investigator in the Patient-Oriented Research in the Epidemiology of Skin Diseases lab at Massachusetts General Hospital, Boston.

Adults with a history of lithium exposure had a 32% lower risk of melanoma than did those who were not exposed in an unadjusted analysis of data from more than 2 million patients.

Microarray gene profiling techniques suggest that Wnt genes, which “encode a family of secreted glycoproteins that activate cellular signaling pathways to control cell differentiation, proliferation, and motility,” may be involved in melanoma development, wrote Maryam M. Asgari, MD, of the department of dermatology at Massachusetts General Hospital and the department of population medicine at Harvard University, both in Boston, and her colleagues. In particular, “transcriptional profiling of melanoma cell lines has suggested that Wnt/beta-catenin signaling regulates a transcriptional signature predictive of less aggressive melanoma,” they wrote.

The psychiatric medication lithium activates the Wnt/beta-catenin signaling pathway and has shown an ability to inhibit the proliferation of melanoma cells in a mouse model, but “to our knowledge, no published epidemiologic studies have examined the association of melanoma risk with lithium exposure,” they wrote.

The researchers reviewed data from the Kaiser Permanente Northern California database of 2,213,848 adult white patients who were members during 1997-2012, which included 11,317 with lithium exposure. They evaluated the association between lithium exposure and both incident melanoma risk and melanoma-associated mortality (J Invest Dermatol. 2017 Oct;137[10]:2087-91.).

Individuals exposed to lithium had a 32% reduced risk of melanoma in an unadjusted analysis; in an adjusted analysis, the reduced risk was 23% and was not significant.

However, there was a significant difference in melanoma incidence per 100,000 person-years in lithium-exposed individuals, compared with unexposed individuals (67.4 vs. 92.5, respectively; P = .027).

Among patients with melanoma, those with exposure to lithium had a lower mortality rate than those not exposed (4.68 vs. 7.21 per 1,000 person-years, respectively), but the sample size for this subgroup was too small to determine statistical significance. In addition, lithium exposure was associated with reduced likelihood of developing skin tumors greater than 4 mm and of presenting with extensive disease. Among those exposed to lithium, none presented with a thick tumor (Breslow depth greater than 4 mm), and none had regional or distant disease when they were diagnosed, compared with 2.8% and 6.3%, respectively, of those not exposed to lithium.

The findings were limited by several factors, including reliance on prescription information to determine lithium exposure, a homogeneous study population, and confounding variables, such as sun exposure behaviors, the researchers noted. However, the large study population adds strength to the results, and “our conclusions provide evidence that lithium, a relatively inexpensive and readily available drug, warrants further study in melanoma,” they said.

Lead author Dr. Asgari and one of the other four authors disclosed serving as investigators for studies funded by Valeant Pharmaceuticals and Pfizer. This study was supported by the National Cancer Institute. Dr. Asgari is principal investigator in the Patient-Oriented Research in the Epidemiology of Skin Diseases lab at Massachusetts General Hospital, Boston.

Adults with a history of lithium exposure had a 32% lower risk of melanoma than did those who were not exposed in an unadjusted analysis of data from more than 2 million patients.

Microarray gene profiling techniques suggest that Wnt genes, which “encode a family of secreted glycoproteins that activate cellular signaling pathways to control cell differentiation, proliferation, and motility,” may be involved in melanoma development, wrote Maryam M. Asgari, MD, of the department of dermatology at Massachusetts General Hospital and the department of population medicine at Harvard University, both in Boston, and her colleagues. In particular, “transcriptional profiling of melanoma cell lines has suggested that Wnt/beta-catenin signaling regulates a transcriptional signature predictive of less aggressive melanoma,” they wrote.

The psychiatric medication lithium activates the Wnt/beta-catenin signaling pathway and has shown an ability to inhibit the proliferation of melanoma cells in a mouse model, but “to our knowledge, no published epidemiologic studies have examined the association of melanoma risk with lithium exposure,” they wrote.

The researchers reviewed data from the Kaiser Permanente Northern California database of 2,213,848 adult white patients who were members during 1997-2012, which included 11,317 with lithium exposure. They evaluated the association between lithium exposure and both incident melanoma risk and melanoma-associated mortality (J Invest Dermatol. 2017 Oct;137[10]:2087-91.).

Individuals exposed to lithium had a 32% reduced risk of melanoma in an unadjusted analysis; in an adjusted analysis, the reduced risk was 23% and was not significant.

However, there was a significant difference in melanoma incidence per 100,000 person-years in lithium-exposed individuals, compared with unexposed individuals (67.4 vs. 92.5, respectively; P = .027).

Among patients with melanoma, those with exposure to lithium had a lower mortality rate than those not exposed (4.68 vs. 7.21 per 1,000 person-years, respectively), but the sample size for this subgroup was too small to determine statistical significance. In addition, lithium exposure was associated with reduced likelihood of developing skin tumors greater than 4 mm and of presenting with extensive disease. Among those exposed to lithium, none presented with a thick tumor (Breslow depth greater than 4 mm), and none had regional or distant disease when they were diagnosed, compared with 2.8% and 6.3%, respectively, of those not exposed to lithium.

The findings were limited by several factors, including reliance on prescription information to determine lithium exposure, a homogeneous study population, and confounding variables, such as sun exposure behaviors, the researchers noted. However, the large study population adds strength to the results, and “our conclusions provide evidence that lithium, a relatively inexpensive and readily available drug, warrants further study in melanoma,” they said.

Lead author Dr. Asgari and one of the other four authors disclosed serving as investigators for studies funded by Valeant Pharmaceuticals and Pfizer. This study was supported by the National Cancer Institute. Dr. Asgari is principal investigator in the Patient-Oriented Research in the Epidemiology of Skin Diseases lab at Massachusetts General Hospital, Boston.

SAN FRANCISCO – Mitotic rate was not found to be a good indicator for the outcome of sentinel lymph node (SLN) biopsy in thin tumors, in an analysis of melanoma cases.

The finding supports the 2017 revision in the American Joint Committee on Cancer guideline, which dropped mitotic rate from its criteria for upstaging thin melanomas.

An earlier version of the guideline, published in 2010, had called for upgrading thin (less than 1 mm), nonulcerated melanomas with a mitotic rate (MR) of at least 1/mm² to T1B, which could then trigger an SLN biopsy.

SLN biopsy is controversial in thin melanomas, because there is no evidence that it has a survival benefit in these populations, though it is useful as a prognostic measure. However, the procedure carries a risk of complications.

“This makes judicious selection of patients for the procedures even more important,” Heidi Wat, MD, of the division of dermatology at the University of Alberta, Edmonton, said during her presentation of the research at the annual meeting of the Pacific Dermatologic Association.

The researchers set out to determine the predictive value of mitotic rate (the number of cells undergoing cell division) on SLN status, particularly when stratified by tumor thickness. They analyzed 990 SLN biopsy procedures performed in Alberta from January 2007 through December 2013, which were pulled from the Cancer Surgery Alberta tumor database and provincial pathology records. The mean age of the patients was 57 years (range, 15-93 years), and 55% were male; 171 records involved thin melanomas.

Overall, 25.4% of SLN biopsies came back positive, including 8.8% of thin melanomas. Among all cases, there was a statistically significant association between a mitotic rate of 1 or higher and a positive SLN biopsy.

However, when the researchers stratified the results by thickness, they found a statistically significant association only between mitotic rate and SLN biopsy positivity in thicker tumors (1-2 mm, P = .01).

Further analysis of factors including age, ulceration, and tumor location showed that MR and thickness measures were not independent, and the potential for MR to predict SLN biopsy positivity declined at lower thickness values.

“Performing sentinel lymph node biopsy in thin melanomas upstaged purely because of the finding of a single mitotic (event) has questionable clinical value,” said Dr. Wat.

The 2010 AJCC guidelines called for upgrading thin tumors with an MR of 1 or higher, or ulceration, to T1b. The new AJCC guidelines restrict the definition of T1b to tumors 0.8-1.0 mm in size with or without ulceration, or tumors 0.8 mm or smaller with ulceration.

“The results really confirm the latest recommendations,” said Nina Botto, MD, of the department of dermatology at the University of California, San Francisco, who chaired the session in which the research was presented.

SLN status remains a useful prognostic indicator, Dr. Wat said, and MR may still be useful for intermediate and thick melanomas.

Dr. Wat and Dr. Botto reported no relevant financial disclosures.

SAN FRANCISCO – Mitotic rate was not found to be a good indicator for the outcome of sentinel lymph node (SLN) biopsy in thin tumors, in an analysis of melanoma cases.

The finding supports the 2017 revision in the American Joint Committee on Cancer guideline, which dropped mitotic rate from its criteria for upstaging thin melanomas.

An earlier version of the guideline, published in 2010, had called for upgrading thin (less than 1 mm), nonulcerated melanomas with a mitotic rate (MR) of at least 1/mm² to T1B, which could then trigger an SLN biopsy.

SLN biopsy is controversial in thin melanomas, because there is no evidence that it has a survival benefit in these populations, though it is useful as a prognostic measure. However, the procedure carries a risk of complications.

“This makes judicious selection of patients for the procedures even more important,” Heidi Wat, MD, of the division of dermatology at the University of Alberta, Edmonton, said during her presentation of the research at the annual meeting of the Pacific Dermatologic Association.

The researchers set out to determine the predictive value of mitotic rate (the number of cells undergoing cell division) on SLN status, particularly when stratified by tumor thickness. They analyzed 990 SLN biopsy procedures performed in Alberta from January 2007 through December 2013, which were pulled from the Cancer Surgery Alberta tumor database and provincial pathology records. The mean age of the patients was 57 years (range, 15-93 years), and 55% were male; 171 records involved thin melanomas.

Overall, 25.4% of SLN biopsies came back positive, including 8.8% of thin melanomas. Among all cases, there was a statistically significant association between a mitotic rate of 1 or higher and a positive SLN biopsy.

However, when the researchers stratified the results by thickness, they found a statistically significant association only between mitotic rate and SLN biopsy positivity in thicker tumors (1-2 mm, P = .01).

Further analysis of factors including age, ulceration, and tumor location showed that MR and thickness measures were not independent, and the potential for MR to predict SLN biopsy positivity declined at lower thickness values.

“Performing sentinel lymph node biopsy in thin melanomas upstaged purely because of the finding of a single mitotic (event) has questionable clinical value,” said Dr. Wat.

The 2010 AJCC guidelines called for upgrading thin tumors with an MR of 1 or higher, or ulceration, to T1b. The new AJCC guidelines restrict the definition of T1b to tumors 0.8-1.0 mm in size with or without ulceration, or tumors 0.8 mm or smaller with ulceration.

“The results really confirm the latest recommendations,” said Nina Botto, MD, of the department of dermatology at the University of California, San Francisco, who chaired the session in which the research was presented.

SLN status remains a useful prognostic indicator, Dr. Wat said, and MR may still be useful for intermediate and thick melanomas.

Dr. Wat and Dr. Botto reported no relevant financial disclosures.

SAN FRANCISCO – Mitotic rate was not found to be a good indicator for the outcome of sentinel lymph node (SLN) biopsy in thin tumors, in an analysis of melanoma cases.

The finding supports the 2017 revision in the American Joint Committee on Cancer guideline, which dropped mitotic rate from its criteria for upstaging thin melanomas.

An earlier version of the guideline, published in 2010, had called for upgrading thin (less than 1 mm), nonulcerated melanomas with a mitotic rate (MR) of at least 1/mm² to T1B, which could then trigger an SLN biopsy.

SLN biopsy is controversial in thin melanomas, because there is no evidence that it has a survival benefit in these populations, though it is useful as a prognostic measure. However, the procedure carries a risk of complications.

“This makes judicious selection of patients for the procedures even more important,” Heidi Wat, MD, of the division of dermatology at the University of Alberta, Edmonton, said during her presentation of the research at the annual meeting of the Pacific Dermatologic Association.

The researchers set out to determine the predictive value of mitotic rate (the number of cells undergoing cell division) on SLN status, particularly when stratified by tumor thickness. They analyzed 990 SLN biopsy procedures performed in Alberta from January 2007 through December 2013, which were pulled from the Cancer Surgery Alberta tumor database and provincial pathology records. The mean age of the patients was 57 years (range, 15-93 years), and 55% were male; 171 records involved thin melanomas.

Overall, 25.4% of SLN biopsies came back positive, including 8.8% of thin melanomas. Among all cases, there was a statistically significant association between a mitotic rate of 1 or higher and a positive SLN biopsy.

However, when the researchers stratified the results by thickness, they found a statistically significant association only between mitotic rate and SLN biopsy positivity in thicker tumors (1-2 mm, P = .01).

Further analysis of factors including age, ulceration, and tumor location showed that MR and thickness measures were not independent, and the potential for MR to predict SLN biopsy positivity declined at lower thickness values.

“Performing sentinel lymph node biopsy in thin melanomas upstaged purely because of the finding of a single mitotic (event) has questionable clinical value,” said Dr. Wat.

The 2010 AJCC guidelines called for upgrading thin tumors with an MR of 1 or higher, or ulceration, to T1b. The new AJCC guidelines restrict the definition of T1b to tumors 0.8-1.0 mm in size with or without ulceration, or tumors 0.8 mm or smaller with ulceration.

“The results really confirm the latest recommendations,” said Nina Botto, MD, of the department of dermatology at the University of California, San Francisco, who chaired the session in which the research was presented.

SLN status remains a useful prognostic indicator, Dr. Wat said, and MR may still be useful for intermediate and thick melanomas.

Dr. Wat and Dr. Botto reported no relevant financial disclosures.

Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.

A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027).

Courtesy UCLA Jonsson Comprehensive Cancer Center

Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.

A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027).

Courtesy UCLA Jonsson Comprehensive Cancer Center

Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.

A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027).

Courtesy UCLA Jonsson Comprehensive Cancer Center

MADRID – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.

Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial, the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).

MADRID – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.

Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial, the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).

MADRID – A combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) delivered in the adjuvant setting was associated with a halving of the risk for relapse compared with placebo among patients with advanced melanoma with BRAF V600 mutations, late-breaking results from a phase 3 trial show.

Among 438 patients with stage III BRAF V600-mutated melanoma randomly assigned after complete surgical resection to dabrafenib/trametinib in the COMBI-AD trial, the estimated rate of 3-year relapse-free survival (RFS) was 58%, compared with 39% for 432 patients assigned to double placebos. This difference translated into a hazard ratio for relapse with the dabrafenib/trametinib combination of 0.47 (P less than .001).

MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.

Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.

MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.

Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.

MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.

Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.