Melanoma

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

I recently met Jane, a 53-year-old woman with metastatic breast cancer. She was referred to me by the breast oncology team, which routinely refers all metastatic patients to our palliative care clinic.

Clocking in at under 20 minutes, my consultation with Jane might have been one of my shortest on record. Not only had the breast oncology team already addressed Jane’s symptoms, which mainly consisted of hot flashes and joint pain attributable to treatment with an aromatase inhibitor, but they had already started planning ahead for the future of her illness. Jane had completed an advance directive and had a realistic and hopeful perspective on how her illness would progress. She understood the goal of her treatment was to “keep the cancer asleep,” as she put it, and she was very clear about her own goals: to live long enough to see her granddaughter graduate from high school in 2 years and to take a long-awaited trip to Australia later in 2023.

There wasn’t much for me to do. In fact, I daresay that Jane really did not need to see a palliative care specialist because the primary palliative care she was receiving from the breast oncology team was superb. Jane was receiving excellent symptom management from a nurse practitioner and oncologist, plus a social worker provided her with coping strategies. She was already having conversations with her primary medical team and her family about what to expect in the future and how to plan ahead for all possible outcomes.
 

When should a patient be referred to palliative care?

Integrating palliative care into routine oncologic care need not always require the time and skill of a palliative care team for every patient. Oncology providers can provide basic palliative care services without consulting a palliative care specialist.

For example, if a primary care doctor tried to refer every patient with hypertension to cardiology, the cardiologist would probably say that primary care should be able to handle basic hypertension management. In my experience from working in an oncology clinic for the past 9 years, I’ve found that oncology providers don’t need to refer every advanced cancer patient to our palliative care program. Most oncologists have good communication skills and are more than capable of managing symptoms for patients.

But don’t get me wrong. I’m not discouraging referrals to palliative care, instead I’m suggesting the careful triage of patients.
 

Palliative care for all?

In 2010, Jennifer S. Temel MD, published a landmark study in the New England Journal of Medicine that demonstrated significant improvements in quality of life and mood in patients with metastatic lung cancer who received concurrent palliative care. After the study was published many voices inside oncology and palliative care began to advocate for a “palliative care for all” approach to patients with metastatic disease. But this is often interpreted as “specialty palliative care for all,” rather than its original intended meaning that all patients with metastatic disease receive the essential elements of palliative care (biopsychosocial symptom support and conversations about goals of care) either through their primary oncology teams or, if needed, specialty palliative care teams.

The fact is that most specialty palliative care clinics do not have the manpower to meet the needs of all patients with advanced cancers, much less all patients living with serious illness. A main goal of integrating palliative care into routine outpatient health care has always been (and in my opinion, should continue to be) to enhance the primary palliative care skills of specialists, such as oncologists and cardiologists, who care for some of our sickest patients.

This could take many forms. For one, it can be helpful to screen patients for palliative care needs. The American College of Surgeons Commission on Cancer mandates distress screening for all patients as a condition of accreditation. Distress screening using a validated tool such as the National Comprehensive Cancer Network Distress Thermometer can differentiate patients who have minimal distress and may not need much additional support beyond what is provided by their oncology team from those whose distress feels unmanageable and overwhelming.

In terms of primary palliative care symptom management, most oncology teams I work with are comfortable prescribing basic medications for pain, nausea, constipation, and anxiety. They’re also comfortable referring oncology patients for nutrition needs while undergoing chemotherapy as well as to social work and spiritual care for emotional support and counseling.

Oncology teams should continually work on communications skills. They should use “Ask, Tell, Ask” to elicit prognostic awareness, convey critical information, and assess for recall and understanding at pivotal points in the cancer journey, such as when the disease progresses or the patient’s clinical condition changes. They should practice a normalizing script they can use to introduce advance care planning to their patients in the first few visits. When I meet with a patient for the first time, I usually begin by asking if they have prepared an advanced directive. If not, I ask if they’ve thought about who will make medical decisions for them should the need arise. If the patient has documented in writing their preference for care in an emergency situation, I ask for a copy for their chart.
 

When should patients be referred to a specialty palliative care program?

I tell our oncology teams to involve me after they have tried to intervene, but unsuccessfully because of the patient having intractable symptoms, such as pain, or the disease is not responding to treatments. Or, because there are significant communication or health literacy barriers. Or, because there are challenging family dynamics that are impeding progress in establishing goals of care.

A physician should refer to specialty palliative care when there are multiple comorbid conditions that impact a patient’s prognosis and ability to tolerate treatments. These patients will need detailed symptom management and nuanced conversations about the delicate balance of maintaining quality of life and trying to address their malignancy while also avoiding treatments that may do more harm than good.

At the end of the day, all patients with serious illnesses deserve a palliative care approach to their care from all of their clinicians, not just from the palliative care team. By continuously honing and implementing primary palliative care skills, oncology teams can feel empowered to meet the needs of their patients themselves, strengthening their bond with their patients making truly patient-centered care much more likely.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I recently met Jane, a 53-year-old woman with metastatic breast cancer. She was referred to me by the breast oncology team, which routinely refers all metastatic patients to our palliative care clinic.

Clocking in at under 20 minutes, my consultation with Jane might have been one of my shortest on record. Not only had the breast oncology team already addressed Jane’s symptoms, which mainly consisted of hot flashes and joint pain attributable to treatment with an aromatase inhibitor, but they had already started planning ahead for the future of her illness. Jane had completed an advance directive and had a realistic and hopeful perspective on how her illness would progress. She understood the goal of her treatment was to “keep the cancer asleep,” as she put it, and she was very clear about her own goals: to live long enough to see her granddaughter graduate from high school in 2 years and to take a long-awaited trip to Australia later in 2023.

There wasn’t much for me to do. In fact, I daresay that Jane really did not need to see a palliative care specialist because the primary palliative care she was receiving from the breast oncology team was superb. Jane was receiving excellent symptom management from a nurse practitioner and oncologist, plus a social worker provided her with coping strategies. She was already having conversations with her primary medical team and her family about what to expect in the future and how to plan ahead for all possible outcomes.
 

When should a patient be referred to palliative care?

Integrating palliative care into routine oncologic care need not always require the time and skill of a palliative care team for every patient. Oncology providers can provide basic palliative care services without consulting a palliative care specialist.

For example, if a primary care doctor tried to refer every patient with hypertension to cardiology, the cardiologist would probably say that primary care should be able to handle basic hypertension management. In my experience from working in an oncology clinic for the past 9 years, I’ve found that oncology providers don’t need to refer every advanced cancer patient to our palliative care program. Most oncologists have good communication skills and are more than capable of managing symptoms for patients.

But don’t get me wrong. I’m not discouraging referrals to palliative care, instead I’m suggesting the careful triage of patients.
 

Palliative care for all?

In 2010, Jennifer S. Temel MD, published a landmark study in the New England Journal of Medicine that demonstrated significant improvements in quality of life and mood in patients with metastatic lung cancer who received concurrent palliative care. After the study was published many voices inside oncology and palliative care began to advocate for a “palliative care for all” approach to patients with metastatic disease. But this is often interpreted as “specialty palliative care for all,” rather than its original intended meaning that all patients with metastatic disease receive the essential elements of palliative care (biopsychosocial symptom support and conversations about goals of care) either through their primary oncology teams or, if needed, specialty palliative care teams.

The fact is that most specialty palliative care clinics do not have the manpower to meet the needs of all patients with advanced cancers, much less all patients living with serious illness. A main goal of integrating palliative care into routine outpatient health care has always been (and in my opinion, should continue to be) to enhance the primary palliative care skills of specialists, such as oncologists and cardiologists, who care for some of our sickest patients.

This could take many forms. For one, it can be helpful to screen patients for palliative care needs. The American College of Surgeons Commission on Cancer mandates distress screening for all patients as a condition of accreditation. Distress screening using a validated tool such as the National Comprehensive Cancer Network Distress Thermometer can differentiate patients who have minimal distress and may not need much additional support beyond what is provided by their oncology team from those whose distress feels unmanageable and overwhelming.

In terms of primary palliative care symptom management, most oncology teams I work with are comfortable prescribing basic medications for pain, nausea, constipation, and anxiety. They’re also comfortable referring oncology patients for nutrition needs while undergoing chemotherapy as well as to social work and spiritual care for emotional support and counseling.

Oncology teams should continually work on communications skills. They should use “Ask, Tell, Ask” to elicit prognostic awareness, convey critical information, and assess for recall and understanding at pivotal points in the cancer journey, such as when the disease progresses or the patient’s clinical condition changes. They should practice a normalizing script they can use to introduce advance care planning to their patients in the first few visits. When I meet with a patient for the first time, I usually begin by asking if they have prepared an advanced directive. If not, I ask if they’ve thought about who will make medical decisions for them should the need arise. If the patient has documented in writing their preference for care in an emergency situation, I ask for a copy for their chart.
 

When should patients be referred to a specialty palliative care program?

I tell our oncology teams to involve me after they have tried to intervene, but unsuccessfully because of the patient having intractable symptoms, such as pain, or the disease is not responding to treatments. Or, because there are significant communication or health literacy barriers. Or, because there are challenging family dynamics that are impeding progress in establishing goals of care.

A physician should refer to specialty palliative care when there are multiple comorbid conditions that impact a patient’s prognosis and ability to tolerate treatments. These patients will need detailed symptom management and nuanced conversations about the delicate balance of maintaining quality of life and trying to address their malignancy while also avoiding treatments that may do more harm than good.

At the end of the day, all patients with serious illnesses deserve a palliative care approach to their care from all of their clinicians, not just from the palliative care team. By continuously honing and implementing primary palliative care skills, oncology teams can feel empowered to meet the needs of their patients themselves, strengthening their bond with their patients making truly patient-centered care much more likely.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I recently met Jane, a 53-year-old woman with metastatic breast cancer. She was referred to me by the breast oncology team, which routinely refers all metastatic patients to our palliative care clinic.

Clocking in at under 20 minutes, my consultation with Jane might have been one of my shortest on record. Not only had the breast oncology team already addressed Jane’s symptoms, which mainly consisted of hot flashes and joint pain attributable to treatment with an aromatase inhibitor, but they had already started planning ahead for the future of her illness. Jane had completed an advance directive and had a realistic and hopeful perspective on how her illness would progress. She understood the goal of her treatment was to “keep the cancer asleep,” as she put it, and she was very clear about her own goals: to live long enough to see her granddaughter graduate from high school in 2 years and to take a long-awaited trip to Australia later in 2023.

There wasn’t much for me to do. In fact, I daresay that Jane really did not need to see a palliative care specialist because the primary palliative care she was receiving from the breast oncology team was superb. Jane was receiving excellent symptom management from a nurse practitioner and oncologist, plus a social worker provided her with coping strategies. She was already having conversations with her primary medical team and her family about what to expect in the future and how to plan ahead for all possible outcomes.
 

When should a patient be referred to palliative care?

Integrating palliative care into routine oncologic care need not always require the time and skill of a palliative care team for every patient. Oncology providers can provide basic palliative care services without consulting a palliative care specialist.

For example, if a primary care doctor tried to refer every patient with hypertension to cardiology, the cardiologist would probably say that primary care should be able to handle basic hypertension management. In my experience from working in an oncology clinic for the past 9 years, I’ve found that oncology providers don’t need to refer every advanced cancer patient to our palliative care program. Most oncologists have good communication skills and are more than capable of managing symptoms for patients.

But don’t get me wrong. I’m not discouraging referrals to palliative care, instead I’m suggesting the careful triage of patients.
 

Palliative care for all?

In 2010, Jennifer S. Temel MD, published a landmark study in the New England Journal of Medicine that demonstrated significant improvements in quality of life and mood in patients with metastatic lung cancer who received concurrent palliative care. After the study was published many voices inside oncology and palliative care began to advocate for a “palliative care for all” approach to patients with metastatic disease. But this is often interpreted as “specialty palliative care for all,” rather than its original intended meaning that all patients with metastatic disease receive the essential elements of palliative care (biopsychosocial symptom support and conversations about goals of care) either through their primary oncology teams or, if needed, specialty palliative care teams.

The fact is that most specialty palliative care clinics do not have the manpower to meet the needs of all patients with advanced cancers, much less all patients living with serious illness. A main goal of integrating palliative care into routine outpatient health care has always been (and in my opinion, should continue to be) to enhance the primary palliative care skills of specialists, such as oncologists and cardiologists, who care for some of our sickest patients.

This could take many forms. For one, it can be helpful to screen patients for palliative care needs. The American College of Surgeons Commission on Cancer mandates distress screening for all patients as a condition of accreditation. Distress screening using a validated tool such as the National Comprehensive Cancer Network Distress Thermometer can differentiate patients who have minimal distress and may not need much additional support beyond what is provided by their oncology team from those whose distress feels unmanageable and overwhelming.

In terms of primary palliative care symptom management, most oncology teams I work with are comfortable prescribing basic medications for pain, nausea, constipation, and anxiety. They’re also comfortable referring oncology patients for nutrition needs while undergoing chemotherapy as well as to social work and spiritual care for emotional support and counseling.

Oncology teams should continually work on communications skills. They should use “Ask, Tell, Ask” to elicit prognostic awareness, convey critical information, and assess for recall and understanding at pivotal points in the cancer journey, such as when the disease progresses or the patient’s clinical condition changes. They should practice a normalizing script they can use to introduce advance care planning to their patients in the first few visits. When I meet with a patient for the first time, I usually begin by asking if they have prepared an advanced directive. If not, I ask if they’ve thought about who will make medical decisions for them should the need arise. If the patient has documented in writing their preference for care in an emergency situation, I ask for a copy for their chart.
 

When should patients be referred to a specialty palliative care program?

I tell our oncology teams to involve me after they have tried to intervene, but unsuccessfully because of the patient having intractable symptoms, such as pain, or the disease is not responding to treatments. Or, because there are significant communication or health literacy barriers. Or, because there are challenging family dynamics that are impeding progress in establishing goals of care.

A physician should refer to specialty palliative care when there are multiple comorbid conditions that impact a patient’s prognosis and ability to tolerate treatments. These patients will need detailed symptom management and nuanced conversations about the delicate balance of maintaining quality of life and trying to address their malignancy while also avoiding treatments that may do more harm than good.

At the end of the day, all patients with serious illnesses deserve a palliative care approach to their care from all of their clinicians, not just from the palliative care team. By continuously honing and implementing primary palliative care skills, oncology teams can feel empowered to meet the needs of their patients themselves, strengthening their bond with their patients making truly patient-centered care much more likely.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

Individuals who regularly take vitamin D supplements are significantly less likely to have a history of malignant melanoma or any type of skin cancers than are nonusers, say Finnish investigators. They also found a trend for benefit with occasional use.

The study, published in Melanoma Research, involved almost 500 individuals attending a dermatology clinic who reported on their use of vitamin D supplements.

Zbynek Pospisil/Getty Images

Regular users had a significant 55% reduction in the odds of having a past or present melanoma diagnosis, while occasional use was associated with a nonsignificant 46% reduction. The reduction was similar for all skin cancer types.

However, senior author Ilkka T. Harvima, MD, PhD, department of dermatology, University of Eastern Finland and Kuopio (Finland) University Hospital, warned there are limitations to the study.

Despite adjustment for several possible confounding factors, “it is still possible that some other, yet unidentified or untested, factors can still confound the present result,” he said.

Consequently, “the causal link between vitamin D and melanoma cannot be confirmed by the present results,” Dr. Harvima said in a statement.

Even if the link were to be proven, “the question about the optimal dose of oral vitamin D in order to for it to have beneficial effects remains to be answered,” he said.

“Until we know more, national intake recommendations should be followed.”

The incidence of cutaneous malignant melanoma and other skin cancers has been increasing steadily in Western populations, particularly in immunosuppressed individuals, the authors pointed out, and they attributed the rise to an increased exposure to ultraviolet radiation.

While ultraviolet radiation exposure is a well-known risk factor, “the other side of the coin is that public sun protection campaigns have led to alerts that insufficient sun exposure is a significant public health problem, resulting in insufficient vitamin D status.”

For their study, the team reviewed the records of 498 patients aged 21-79 years at a  dermatology outpatient clinic who were deemed by an experienced dermatologist to be at risk of any type of skin cancer.

Among these patients, 295 individuals had a history of past or present cutaneous malignancy, with 100 diagnosed with melanoma, 213 with basal cell carcinoma, and 41 with squamous cell carcinoma. A further 70 subjects had cancer elsewhere, including breast, prostate, kidney, bladder, intestine, and blood cancers.

A subgroup of 96 patients were immunocompromised and were considered separately.

The 402 remaining patients were categorized, based on their self-reported use of oral vitamin D preparations, as nonusers (n = 99), occasional users (n = 126), and regular users (n = 177).

Regular use of vitamin D was associated with being more educated (P = .032), less frequent outdoor working (P = .003), lower tobacco pack years (P = .001), and more frequent solarium exposure (P = .002).

There was no significant association between vitamin D use and photoaging, actinic keratoses, nevi, basal or squamous cell carcinoma, body mass index, or self-estimated lifetime exposure to sunlight or sunburns.

However, there were significant associations between regular use of vitamin D and a lower incidence of melanoma and other cancer types.

There were significantly fewer individuals in the regular vitamin D use group with a past or present history of melanoma when compared with the nonuse group, at 18.1% vs. 32.3% (P = .021), or any type of skin cancer, at 62.1% vs. 74.7% (P = .027).

Multivariate logistic regression analysis revealed that regular vitamin D use was significantly associated with a reduced melanoma risk, at an odds ratio vs. nonuse of 0.447 (P = .016).

Occasional use was associated with a reduced, albeit nonsignificant, risk, with an odds ratio versus nonuse of 0.540 (P = .08).

For any type of skin cancers, regular vitamin D use was associated with an odds ratio vs. nonuse of 0.478 (P = .032), while that for occasional vitamin D use was 0.543 (P = .061).

“Somewhat similar” results were obtained when the investigators looked at the subgroup of immunocompromised individuals, although they note that “the number of subjects was low.”

The study was supported by the Cancer Center of Eastern Finland of the University of Eastern Finland, the Finnish Cancer Research Foundation, and the VTR-funding of Kuopio University Hospital. The authors report no relevant financial relationships.

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

Individuals who regularly take vitamin D supplements are significantly less likely to have a history of malignant melanoma or any type of skin cancers than are nonusers, say Finnish investigators. They also found a trend for benefit with occasional use.

The study, published in Melanoma Research, involved almost 500 individuals attending a dermatology clinic who reported on their use of vitamin D supplements.

Zbynek Pospisil/Getty Images

Regular users had a significant 55% reduction in the odds of having a past or present melanoma diagnosis, while occasional use was associated with a nonsignificant 46% reduction. The reduction was similar for all skin cancer types.

However, senior author Ilkka T. Harvima, MD, PhD, department of dermatology, University of Eastern Finland and Kuopio (Finland) University Hospital, warned there are limitations to the study.

Despite adjustment for several possible confounding factors, “it is still possible that some other, yet unidentified or untested, factors can still confound the present result,” he said.

Consequently, “the causal link between vitamin D and melanoma cannot be confirmed by the present results,” Dr. Harvima said in a statement.

Even if the link were to be proven, “the question about the optimal dose of oral vitamin D in order to for it to have beneficial effects remains to be answered,” he said.

“Until we know more, national intake recommendations should be followed.”

The incidence of cutaneous malignant melanoma and other skin cancers has been increasing steadily in Western populations, particularly in immunosuppressed individuals, the authors pointed out, and they attributed the rise to an increased exposure to ultraviolet radiation.

While ultraviolet radiation exposure is a well-known risk factor, “the other side of the coin is that public sun protection campaigns have led to alerts that insufficient sun exposure is a significant public health problem, resulting in insufficient vitamin D status.”

For their study, the team reviewed the records of 498 patients aged 21-79 years at a  dermatology outpatient clinic who were deemed by an experienced dermatologist to be at risk of any type of skin cancer.

Among these patients, 295 individuals had a history of past or present cutaneous malignancy, with 100 diagnosed with melanoma, 213 with basal cell carcinoma, and 41 with squamous cell carcinoma. A further 70 subjects had cancer elsewhere, including breast, prostate, kidney, bladder, intestine, and blood cancers.

A subgroup of 96 patients were immunocompromised and were considered separately.

The 402 remaining patients were categorized, based on their self-reported use of oral vitamin D preparations, as nonusers (n = 99), occasional users (n = 126), and regular users (n = 177).

Regular use of vitamin D was associated with being more educated (P = .032), less frequent outdoor working (P = .003), lower tobacco pack years (P = .001), and more frequent solarium exposure (P = .002).

There was no significant association between vitamin D use and photoaging, actinic keratoses, nevi, basal or squamous cell carcinoma, body mass index, or self-estimated lifetime exposure to sunlight or sunburns.

However, there were significant associations between regular use of vitamin D and a lower incidence of melanoma and other cancer types.

There were significantly fewer individuals in the regular vitamin D use group with a past or present history of melanoma when compared with the nonuse group, at 18.1% vs. 32.3% (P = .021), or any type of skin cancer, at 62.1% vs. 74.7% (P = .027).

Multivariate logistic regression analysis revealed that regular vitamin D use was significantly associated with a reduced melanoma risk, at an odds ratio vs. nonuse of 0.447 (P = .016).

Occasional use was associated with a reduced, albeit nonsignificant, risk, with an odds ratio versus nonuse of 0.540 (P = .08).

For any type of skin cancers, regular vitamin D use was associated with an odds ratio vs. nonuse of 0.478 (P = .032), while that for occasional vitamin D use was 0.543 (P = .061).

“Somewhat similar” results were obtained when the investigators looked at the subgroup of immunocompromised individuals, although they note that “the number of subjects was low.”

The study was supported by the Cancer Center of Eastern Finland of the University of Eastern Finland, the Finnish Cancer Research Foundation, and the VTR-funding of Kuopio University Hospital. The authors report no relevant financial relationships.

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

Individuals who regularly take vitamin D supplements are significantly less likely to have a history of malignant melanoma or any type of skin cancers than are nonusers, say Finnish investigators. They also found a trend for benefit with occasional use.

The study, published in Melanoma Research, involved almost 500 individuals attending a dermatology clinic who reported on their use of vitamin D supplements.

Zbynek Pospisil/Getty Images

Regular users had a significant 55% reduction in the odds of having a past or present melanoma diagnosis, while occasional use was associated with a nonsignificant 46% reduction. The reduction was similar for all skin cancer types.

However, senior author Ilkka T. Harvima, MD, PhD, department of dermatology, University of Eastern Finland and Kuopio (Finland) University Hospital, warned there are limitations to the study.

Despite adjustment for several possible confounding factors, “it is still possible that some other, yet unidentified or untested, factors can still confound the present result,” he said.

Consequently, “the causal link between vitamin D and melanoma cannot be confirmed by the present results,” Dr. Harvima said in a statement.

Even if the link were to be proven, “the question about the optimal dose of oral vitamin D in order to for it to have beneficial effects remains to be answered,” he said.

“Until we know more, national intake recommendations should be followed.”

The incidence of cutaneous malignant melanoma and other skin cancers has been increasing steadily in Western populations, particularly in immunosuppressed individuals, the authors pointed out, and they attributed the rise to an increased exposure to ultraviolet radiation.

While ultraviolet radiation exposure is a well-known risk factor, “the other side of the coin is that public sun protection campaigns have led to alerts that insufficient sun exposure is a significant public health problem, resulting in insufficient vitamin D status.”

For their study, the team reviewed the records of 498 patients aged 21-79 years at a  dermatology outpatient clinic who were deemed by an experienced dermatologist to be at risk of any type of skin cancer.

Among these patients, 295 individuals had a history of past or present cutaneous malignancy, with 100 diagnosed with melanoma, 213 with basal cell carcinoma, and 41 with squamous cell carcinoma. A further 70 subjects had cancer elsewhere, including breast, prostate, kidney, bladder, intestine, and blood cancers.

A subgroup of 96 patients were immunocompromised and were considered separately.

The 402 remaining patients were categorized, based on their self-reported use of oral vitamin D preparations, as nonusers (n = 99), occasional users (n = 126), and regular users (n = 177).

Regular use of vitamin D was associated with being more educated (P = .032), less frequent outdoor working (P = .003), lower tobacco pack years (P = .001), and more frequent solarium exposure (P = .002).

There was no significant association between vitamin D use and photoaging, actinic keratoses, nevi, basal or squamous cell carcinoma, body mass index, or self-estimated lifetime exposure to sunlight or sunburns.

However, there were significant associations between regular use of vitamin D and a lower incidence of melanoma and other cancer types.

There were significantly fewer individuals in the regular vitamin D use group with a past or present history of melanoma when compared with the nonuse group, at 18.1% vs. 32.3% (P = .021), or any type of skin cancer, at 62.1% vs. 74.7% (P = .027).

Multivariate logistic regression analysis revealed that regular vitamin D use was significantly associated with a reduced melanoma risk, at an odds ratio vs. nonuse of 0.447 (P = .016).

Occasional use was associated with a reduced, albeit nonsignificant, risk, with an odds ratio versus nonuse of 0.540 (P = .08).

For any type of skin cancers, regular vitamin D use was associated with an odds ratio vs. nonuse of 0.478 (P = .032), while that for occasional vitamin D use was 0.543 (P = .061).

“Somewhat similar” results were obtained when the investigators looked at the subgroup of immunocompromised individuals, although they note that “the number of subjects was low.”

The study was supported by the Cancer Center of Eastern Finland of the University of Eastern Finland, the Finnish Cancer Research Foundation, and the VTR-funding of Kuopio University Hospital. The authors report no relevant financial relationships.

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

Among children and adolescents with melanomas, primary tumor ulceration, head/neck location, and a Breslow thickness of > 4 mm predicted worse survival, results from a retrospective study demonstrated.

“Cutaneous melanomas are rare in children and much less common in adolescents than in later life,” researchers led by Mary-Ann El Sharouni, PhD, wrote in the study, which was published online in the Journal of the American Academy of Dermatology. “Management of these young patients currently follows guidelines developed for adults. Better understanding of melanoma occurring in the first 2 decades of life is, therefore, warranted.”

copyright Dlumen/Thinkstock

Drawing from two datasets – one from the Netherlands and the other from Melanoma Institute Australia (MIA) at the University of Sydney – Dr. El Sharouni of the MIA and of the department of dermatology at University Medical Center Utrecht in the Netherlands, and colleagues, evaluated all patients younger than 20 years of age who were diagnosed with invasive melanoma between January 2000 and December 2014. The pooled cohort included 397 Dutch and 117 Australian individuals. Of these, 62 were children and 452 were adolescents. To determine melanoma subtypes, the researchers reevaluated pathology reports and used multivariate Cox models to calculate recurrence-free survival (RFS) and overall survival (OS).

The median Breslow thickness was 2.7 mm in children and 1.0 mm in adolescents. Most patients (83%) had conventional melanoma, which consisted of superficial spreading, nodular, desmoplastic, and acral lentiginous forms, while 78 had spitzoid melanoma and 8 had melanoma associated with a congenital nevus. The 10-year RFS was 91.5% in children and 86.4% in adolescents (P =.32), while the 10-year OS was 100% in children and 92.7% in adolescents (P = .09).

On multivariable analysis, which was possible only for the adolescent cohort because of the small number of children, ulceration status and anatomic site were associated with RFS and OS, whereas age, sex, mitotic index, sentinel node status, and melanoma subtype were not. Breslow thickness > 4 mm was associated with worse RFS. As for affected anatomic site, those with melanomas located on the upper and lower limbs had a better overall RFS and OS compared with those who had head or neck melanomas.

The authors acknowledged certain limitation of the analysis, including its retrospective design and the small number of children. “Our data suggest that adolescent melanomas are often similar to adult-type melanomas, whilst those which occur in young children frequently occur via different molecular mechanisms,” they concluded. “In the future it is likely that further understanding of these molecular mechanisms and ability to classify melanomas based on their molecular characteristics will assist in further refining prognostic estimates and possible guiding treatment for young patients with melanoma.”

Rebecca M. Thiede, MD, assistant program director of the division of dermatology at the University of Arizona, Tucson, who was asked to comment on the study, said that the analysis “greatly contributes to dermatology, as we are still learning the differences between melanoma in children and adolescents versus adults.

This study found that adolescents with melanoma had worse survival if mitosis were present and/or located on head/neck, which could aid in aggressiveness of treatment.”

Among children and adolescents with melanomas, primary tumor ulceration, head/neck location, and a Breslow thickness of > 4 mm predicted worse survival, results from a retrospective study demonstrated.

“Cutaneous melanomas are rare in children and much less common in adolescents than in later life,” researchers led by Mary-Ann El Sharouni, PhD, wrote in the study, which was published online in the Journal of the American Academy of Dermatology. “Management of these young patients currently follows guidelines developed for adults. Better understanding of melanoma occurring in the first 2 decades of life is, therefore, warranted.”

copyright Dlumen/Thinkstock

Drawing from two datasets – one from the Netherlands and the other from Melanoma Institute Australia (MIA) at the University of Sydney – Dr. El Sharouni of the MIA and of the department of dermatology at University Medical Center Utrecht in the Netherlands, and colleagues, evaluated all patients younger than 20 years of age who were diagnosed with invasive melanoma between January 2000 and December 2014. The pooled cohort included 397 Dutch and 117 Australian individuals. Of these, 62 were children and 452 were adolescents. To determine melanoma subtypes, the researchers reevaluated pathology reports and used multivariate Cox models to calculate recurrence-free survival (RFS) and overall survival (OS).

The median Breslow thickness was 2.7 mm in children and 1.0 mm in adolescents. Most patients (83%) had conventional melanoma, which consisted of superficial spreading, nodular, desmoplastic, and acral lentiginous forms, while 78 had spitzoid melanoma and 8 had melanoma associated with a congenital nevus. The 10-year RFS was 91.5% in children and 86.4% in adolescents (P =.32), while the 10-year OS was 100% in children and 92.7% in adolescents (P = .09).

On multivariable analysis, which was possible only for the adolescent cohort because of the small number of children, ulceration status and anatomic site were associated with RFS and OS, whereas age, sex, mitotic index, sentinel node status, and melanoma subtype were not. Breslow thickness > 4 mm was associated with worse RFS. As for affected anatomic site, those with melanomas located on the upper and lower limbs had a better overall RFS and OS compared with those who had head or neck melanomas.

The authors acknowledged certain limitation of the analysis, including its retrospective design and the small number of children. “Our data suggest that adolescent melanomas are often similar to adult-type melanomas, whilst those which occur in young children frequently occur via different molecular mechanisms,” they concluded. “In the future it is likely that further understanding of these molecular mechanisms and ability to classify melanomas based on their molecular characteristics will assist in further refining prognostic estimates and possible guiding treatment for young patients with melanoma.”

Rebecca M. Thiede, MD, assistant program director of the division of dermatology at the University of Arizona, Tucson, who was asked to comment on the study, said that the analysis “greatly contributes to dermatology, as we are still learning the differences between melanoma in children and adolescents versus adults.

This study found that adolescents with melanoma had worse survival if mitosis were present and/or located on head/neck, which could aid in aggressiveness of treatment.”

Among children and adolescents with melanomas, primary tumor ulceration, head/neck location, and a Breslow thickness of > 4 mm predicted worse survival, results from a retrospective study demonstrated.

“Cutaneous melanomas are rare in children and much less common in adolescents than in later life,” researchers led by Mary-Ann El Sharouni, PhD, wrote in the study, which was published online in the Journal of the American Academy of Dermatology. “Management of these young patients currently follows guidelines developed for adults. Better understanding of melanoma occurring in the first 2 decades of life is, therefore, warranted.”

copyright Dlumen/Thinkstock

Drawing from two datasets – one from the Netherlands and the other from Melanoma Institute Australia (MIA) at the University of Sydney – Dr. El Sharouni of the MIA and of the department of dermatology at University Medical Center Utrecht in the Netherlands, and colleagues, evaluated all patients younger than 20 years of age who were diagnosed with invasive melanoma between January 2000 and December 2014. The pooled cohort included 397 Dutch and 117 Australian individuals. Of these, 62 were children and 452 were adolescents. To determine melanoma subtypes, the researchers reevaluated pathology reports and used multivariate Cox models to calculate recurrence-free survival (RFS) and overall survival (OS).

The median Breslow thickness was 2.7 mm in children and 1.0 mm in adolescents. Most patients (83%) had conventional melanoma, which consisted of superficial spreading, nodular, desmoplastic, and acral lentiginous forms, while 78 had spitzoid melanoma and 8 had melanoma associated with a congenital nevus. The 10-year RFS was 91.5% in children and 86.4% in adolescents (P =.32), while the 10-year OS was 100% in children and 92.7% in adolescents (P = .09).

On multivariable analysis, which was possible only for the adolescent cohort because of the small number of children, ulceration status and anatomic site were associated with RFS and OS, whereas age, sex, mitotic index, sentinel node status, and melanoma subtype were not. Breslow thickness > 4 mm was associated with worse RFS. As for affected anatomic site, those with melanomas located on the upper and lower limbs had a better overall RFS and OS compared with those who had head or neck melanomas.

The authors acknowledged certain limitation of the analysis, including its retrospective design and the small number of children. “Our data suggest that adolescent melanomas are often similar to adult-type melanomas, whilst those which occur in young children frequently occur via different molecular mechanisms,” they concluded. “In the future it is likely that further understanding of these molecular mechanisms and ability to classify melanomas based on their molecular characteristics will assist in further refining prognostic estimates and possible guiding treatment for young patients with melanoma.”

Rebecca M. Thiede, MD, assistant program director of the division of dermatology at the University of Arizona, Tucson, who was asked to comment on the study, said that the analysis “greatly contributes to dermatology, as we are still learning the differences between melanoma in children and adolescents versus adults.

This study found that adolescents with melanoma had worse survival if mitosis were present and/or located on head/neck, which could aid in aggressiveness of treatment.”

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, and cutaneous melanoma is projected to be the fifth most common form of cancer in 2022, with increasing incidence and high potential for mortality.^1-3 Estimates indicate that 35% to 45% of all cancers in White patients are cutaneous, with 4% to 5% occurring in Hispanic patients, 2% to 4% in Asian patients, and 1% to 2% in Black patients.⁴ Of the keratinocyte carcinomas, basal cell carcinoma (BCC) is the most prevalent, projected to affect approximately 33% to 39% of White males and 23% to 28% of White females in the United States during their lifetimes. Squamous cell carcinoma (SCC) is the second most common skin malignancy, with a lifetime risk of 9% to 14% for White males and 4% to 9% for White females in the United States.⁵ The incidence of melanoma continues to increase, with approximately 99,780 new cases expected in the United States in 2022.¹

UV-induced DNA damage plays a key role in the pathogenesis and development of various skin malignancies.⁶ UV radiation from sunlight or tanning devices causes photocarcinogenesis due to molecular and cellular effects, including the generation of reactive oxygen species, DNA damage due to the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone, melanogenesis, apoptosis, and the increased expression of harmful genes and proteins.⁶ The summation of this damage can result in skin malignancies, including NMSC and melanoma.^6,7 Dietary antioxidants theoretically help prevent oxidative reactions from occurring within the body, and it has been suggested that intake of dietary antioxidants may decrease DNA damage and prevent tumorigenesis secondary to UV radiation.⁸ Antioxidants exist naturally in the body but can be acquired exogenously. Investigators have studied dietary antioxidants in preventing skin cancer formation with promising results in the laboratory setting.^8-11 Recently, more robust human studies have been initiated to further delineate this relationship. We present clinical evidence of several frequently utilized antioxidant vitamins and their effects on melanoma and NMSC.

Antioxidants

Vitamin A—Vitamin A is a fat-soluble vitamin found in animal sources, including fish, liver, and eggs. Carotenoids, such as beta carotene, are provitamin A plant derivatives found in fruits and vegetables that are converted into biologically active retinol and retinoic acid.¹² Retinols play a key role in cellular growth and differentiation and are thought to be protective against skin cancer via the inactivation of free radicals and immunologic enhancement due to their antiproliferative, antioxidative, and antiapoptotic effects.^13-16 Animal studies have demonstrated this protective effect and the ability of retinoids to suppress carcinogenesis; however, human studies reveal conflicting results.^17,18

Greenberg et al¹⁹ investigated the use of beta carotene in preventing the formation of NMSC. Patients (N=1805) were randomized to receive 50 mg of beta carotene daily or placebo. Over a 5-year period, there was no significant reduction in the occurrence of NMSC (relative risk [RR], 1.05; 95% CI, 0.91-1.22).¹⁹ Frieling et al²⁰ conducted a similar randomized, double-blind, placebo-controlled trial investigating beta carotene for primary prevention of NMSC in 22,071 healthy male physicians. The study group received 50 mg of beta carotene every other day for 12 years’ duration, and there was no significant effect on the incidence of first NMSC development (RR, 0.98; 95% CI, 0.92-1.05).²⁰

A case-control study by Naldi et al²¹ found an inverse association between vitamin A intake and development of melanoma. Study participants were stratified into quartiles based on level of dietary intake and found an odds ratio (OR) of 0.71 for beta carotene (95% CI, 0.50-1.02), 0.57 for retinol (95% CI, 0.39-0.83), and 0.51 for total vitamin A (95% CI, 0.35-0.75) when comparing the upper quartile of vitamin A intake to the lower quartile. Upper-quartile cutoff values of vitamin A intake were 214 µg/d for beta carotene, 149 µg/d for retinol, and 359 µg/d for total vitamin A.²¹ More recently, a meta-analysis by Zhang et al²² pooled data from 8 case-control studies and 2 prospective studies. Intake of retinol but not total vitamin A or beta carotene was associated with a reduced risk for development of melanoma (retinol: OR, 0.80; 95% CI, 0.69-0.92; total vitamin A: OR, 0.86; 95% CI, 0.59-1.25; beta carotene: OR, 0.87; 95% CI, 0.62-1.20).²² Feskanich et al²³ demonstrated similar findings with use of food-frequency questionnaires in White women, suggesting that retinol intake from food combined with supplements may be protective for women who were otherwise at a low risk for melanoma based on nondietary factors. These factors included painful or blistering sunburns during childhood, history of more than 6 sunburns, more than 3 moles on the left arm, having red or blonde hair, and having a parent or sibling with melanoma (P=.01). However, this relationship did not hold true when looking at women at an intermediate or high risk for melanoma (P=.16 and P=.46).²³

When looking at high-risk patients, such as transplant patients, oral retinoids have been beneficial in preventing NMSC.^24-27 Bavinck et al²⁴ investigated 44 renal transplant patients with a history of more than 10 NMSCs treated with 30 mg of acitretin daily vs placebo. Patients receiving oral retinoid supplementation developed fewer NMSCs over a 6-month treatment period (P=.01).²⁴ Similarly, George et al²⁵ investigated acitretin in renal transplant patients and found a statistically significant decrease in number of SCCs in patients on supplementation (P=.002). Solomon-Cohen et al²⁶ performed a retrospective case-crossover study in solid organ transplant recipients and found that those treated with 10 mg of acitretin daily for 2 years had a significant reduction in the number of new keratinocyte carcinomas (P=.002). Other investigators have demonstrated similar results, and in 2006, Otley et al²⁷ proposed standardized dosing of acitretin for chemoprevention in high-risk patients, including patients developing 5 to 10 NMSCs per year, solid organ transplant recipients, and those with syndromes associated with the development of NMSC.^28,29 Overall, in the general population, vitamin A and related compounds have not demonstrated a significant association with decreased development of NMSC; however, oral retinoids have proven useful for high-risk patients. Furthermore, several studies have suggested a negative association between vitamin A levels and the incidence of melanoma, specifically in the retinol formulation. 

Vitamin B₃—Nicotinamide (also known as niacinamide) is a water-soluble form of vitamin B₃ and is obtained from animal-based and plant-based foods, such as meat, fish, and legumes.³⁰ Nicotinamide plays a key role in cellular metabolism, cellular signaling, and DNA repair, including protection from UV damage within keratinocytes.^31,32 Early mouse models demonstrated decreased formation of skin tumors in mice treated with topical or oral nicotinamide.^32,33 A number of human studies have revealed similar results.^34-36

Chen et al³⁴ conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).³⁴ Drago et al³⁵ specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.³⁵

Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.^34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.^31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.^31,37

Vitamin B₉—Folate, the natural form of vitamin B₉, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.^38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.³⁸ Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.^38,40 Donnenfeld et al⁴¹ conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.⁴¹ Similar effects were observed by Fung et al,⁴² who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).⁴² Fung et al⁴³ also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al⁴⁰ conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.⁴⁰ In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.

Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.^44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.⁴⁴ Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.^46-48 Despite these findings, minimal photoprotective effects have been found in the human population.

Kune et al⁴⁹ performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).⁴⁹ In addition, Vural et al⁵⁰ analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).⁵¹ More recently, Heinen et al⁵² performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).⁵² Similarly, Fung et al⁴² performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).

The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.⁵³ Feskanich et al²³ examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.

Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.⁵⁴ Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.⁵⁴ Vitamin D receptors are expressed on keratinocytes and melanocytes.⁵⁵ Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.⁵⁶ In a mouse model, Ellison et al⁵⁶ found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.

Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.^57-60 Eide et al⁵⁷ studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).⁵⁷ An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.⁵⁸ This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).⁵⁸ Furthermore, Park et al⁶⁰ looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.^59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al⁶³ performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.

Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.⁶⁴ It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.^65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.^64,65

Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.^67,68 Human studies have not consistently shown these effects. Vural et al⁵⁰ investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,⁴² which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted. 

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, and cutaneous melanoma is projected to be the fifth most common form of cancer in 2022, with increasing incidence and high potential for mortality.^1-3 Estimates indicate that 35% to 45% of all cancers in White patients are cutaneous, with 4% to 5% occurring in Hispanic patients, 2% to 4% in Asian patients, and 1% to 2% in Black patients.⁴ Of the keratinocyte carcinomas, basal cell carcinoma (BCC) is the most prevalent, projected to affect approximately 33% to 39% of White males and 23% to 28% of White females in the United States during their lifetimes. Squamous cell carcinoma (SCC) is the second most common skin malignancy, with a lifetime risk of 9% to 14% for White males and 4% to 9% for White females in the United States.⁵ The incidence of melanoma continues to increase, with approximately 99,780 new cases expected in the United States in 2022.¹

UV-induced DNA damage plays a key role in the pathogenesis and development of various skin malignancies.⁶ UV radiation from sunlight or tanning devices causes photocarcinogenesis due to molecular and cellular effects, including the generation of reactive oxygen species, DNA damage due to the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone, melanogenesis, apoptosis, and the increased expression of harmful genes and proteins.⁶ The summation of this damage can result in skin malignancies, including NMSC and melanoma.^6,7 Dietary antioxidants theoretically help prevent oxidative reactions from occurring within the body, and it has been suggested that intake of dietary antioxidants may decrease DNA damage and prevent tumorigenesis secondary to UV radiation.⁸ Antioxidants exist naturally in the body but can be acquired exogenously. Investigators have studied dietary antioxidants in preventing skin cancer formation with promising results in the laboratory setting.^8-11 Recently, more robust human studies have been initiated to further delineate this relationship. We present clinical evidence of several frequently utilized antioxidant vitamins and their effects on melanoma and NMSC.

Antioxidants

Vitamin A—Vitamin A is a fat-soluble vitamin found in animal sources, including fish, liver, and eggs. Carotenoids, such as beta carotene, are provitamin A plant derivatives found in fruits and vegetables that are converted into biologically active retinol and retinoic acid.¹² Retinols play a key role in cellular growth and differentiation and are thought to be protective against skin cancer via the inactivation of free radicals and immunologic enhancement due to their antiproliferative, antioxidative, and antiapoptotic effects.^13-16 Animal studies have demonstrated this protective effect and the ability of retinoids to suppress carcinogenesis; however, human studies reveal conflicting results.^17,18

Greenberg et al¹⁹ investigated the use of beta carotene in preventing the formation of NMSC. Patients (N=1805) were randomized to receive 50 mg of beta carotene daily or placebo. Over a 5-year period, there was no significant reduction in the occurrence of NMSC (relative risk [RR], 1.05; 95% CI, 0.91-1.22).¹⁹ Frieling et al²⁰ conducted a similar randomized, double-blind, placebo-controlled trial investigating beta carotene for primary prevention of NMSC in 22,071 healthy male physicians. The study group received 50 mg of beta carotene every other day for 12 years’ duration, and there was no significant effect on the incidence of first NMSC development (RR, 0.98; 95% CI, 0.92-1.05).²⁰

A case-control study by Naldi et al²¹ found an inverse association between vitamin A intake and development of melanoma. Study participants were stratified into quartiles based on level of dietary intake and found an odds ratio (OR) of 0.71 for beta carotene (95% CI, 0.50-1.02), 0.57 for retinol (95% CI, 0.39-0.83), and 0.51 for total vitamin A (95% CI, 0.35-0.75) when comparing the upper quartile of vitamin A intake to the lower quartile. Upper-quartile cutoff values of vitamin A intake were 214 µg/d for beta carotene, 149 µg/d for retinol, and 359 µg/d for total vitamin A.²¹ More recently, a meta-analysis by Zhang et al²² pooled data from 8 case-control studies and 2 prospective studies. Intake of retinol but not total vitamin A or beta carotene was associated with a reduced risk for development of melanoma (retinol: OR, 0.80; 95% CI, 0.69-0.92; total vitamin A: OR, 0.86; 95% CI, 0.59-1.25; beta carotene: OR, 0.87; 95% CI, 0.62-1.20).²² Feskanich et al²³ demonstrated similar findings with use of food-frequency questionnaires in White women, suggesting that retinol intake from food combined with supplements may be protective for women who were otherwise at a low risk for melanoma based on nondietary factors. These factors included painful or blistering sunburns during childhood, history of more than 6 sunburns, more than 3 moles on the left arm, having red or blonde hair, and having a parent or sibling with melanoma (P=.01). However, this relationship did not hold true when looking at women at an intermediate or high risk for melanoma (P=.16 and P=.46).²³

When looking at high-risk patients, such as transplant patients, oral retinoids have been beneficial in preventing NMSC.^24-27 Bavinck et al²⁴ investigated 44 renal transplant patients with a history of more than 10 NMSCs treated with 30 mg of acitretin daily vs placebo. Patients receiving oral retinoid supplementation developed fewer NMSCs over a 6-month treatment period (P=.01).²⁴ Similarly, George et al²⁵ investigated acitretin in renal transplant patients and found a statistically significant decrease in number of SCCs in patients on supplementation (P=.002). Solomon-Cohen et al²⁶ performed a retrospective case-crossover study in solid organ transplant recipients and found that those treated with 10 mg of acitretin daily for 2 years had a significant reduction in the number of new keratinocyte carcinomas (P=.002). Other investigators have demonstrated similar results, and in 2006, Otley et al²⁷ proposed standardized dosing of acitretin for chemoprevention in high-risk patients, including patients developing 5 to 10 NMSCs per year, solid organ transplant recipients, and those with syndromes associated with the development of NMSC.^28,29 Overall, in the general population, vitamin A and related compounds have not demonstrated a significant association with decreased development of NMSC; however, oral retinoids have proven useful for high-risk patients. Furthermore, several studies have suggested a negative association between vitamin A levels and the incidence of melanoma, specifically in the retinol formulation. 

Vitamin B₃—Nicotinamide (also known as niacinamide) is a water-soluble form of vitamin B₃ and is obtained from animal-based and plant-based foods, such as meat, fish, and legumes.³⁰ Nicotinamide plays a key role in cellular metabolism, cellular signaling, and DNA repair, including protection from UV damage within keratinocytes.^31,32 Early mouse models demonstrated decreased formation of skin tumors in mice treated with topical or oral nicotinamide.^32,33 A number of human studies have revealed similar results.^34-36

Chen et al³⁴ conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).³⁴ Drago et al³⁵ specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.³⁵

Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.^34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.^31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.^31,37

Vitamin B₉—Folate, the natural form of vitamin B₉, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.^38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.³⁸ Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.^38,40 Donnenfeld et al⁴¹ conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.⁴¹ Similar effects were observed by Fung et al,⁴² who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).⁴² Fung et al⁴³ also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al⁴⁰ conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.⁴⁰ In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.

Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.^44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.⁴⁴ Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.^46-48 Despite these findings, minimal photoprotective effects have been found in the human population.

Kune et al⁴⁹ performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).⁴⁹ In addition, Vural et al⁵⁰ analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).⁵¹ More recently, Heinen et al⁵² performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).⁵² Similarly, Fung et al⁴² performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).

The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.⁵³ Feskanich et al²³ examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.

Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.⁵⁴ Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.⁵⁴ Vitamin D receptors are expressed on keratinocytes and melanocytes.⁵⁵ Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.⁵⁶ In a mouse model, Ellison et al⁵⁶ found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.

Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.^57-60 Eide et al⁵⁷ studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).⁵⁷ An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.⁵⁸ This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).⁵⁸ Furthermore, Park et al⁶⁰ looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.^59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al⁶³ performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.

Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.⁶⁴ It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.^65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.^64,65

Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.^67,68 Human studies have not consistently shown these effects. Vural et al⁵⁰ investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,⁴² which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted. 

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, and cutaneous melanoma is projected to be the fifth most common form of cancer in 2022, with increasing incidence and high potential for mortality.^1-3 Estimates indicate that 35% to 45% of all cancers in White patients are cutaneous, with 4% to 5% occurring in Hispanic patients, 2% to 4% in Asian patients, and 1% to 2% in Black patients.⁴ Of the keratinocyte carcinomas, basal cell carcinoma (BCC) is the most prevalent, projected to affect approximately 33% to 39% of White males and 23% to 28% of White females in the United States during their lifetimes. Squamous cell carcinoma (SCC) is the second most common skin malignancy, with a lifetime risk of 9% to 14% for White males and 4% to 9% for White females in the United States.⁵ The incidence of melanoma continues to increase, with approximately 99,780 new cases expected in the United States in 2022.¹

UV-induced DNA damage plays a key role in the pathogenesis and development of various skin malignancies.⁶ UV radiation from sunlight or tanning devices causes photocarcinogenesis due to molecular and cellular effects, including the generation of reactive oxygen species, DNA damage due to the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone, melanogenesis, apoptosis, and the increased expression of harmful genes and proteins.⁶ The summation of this damage can result in skin malignancies, including NMSC and melanoma.^6,7 Dietary antioxidants theoretically help prevent oxidative reactions from occurring within the body, and it has been suggested that intake of dietary antioxidants may decrease DNA damage and prevent tumorigenesis secondary to UV radiation.⁸ Antioxidants exist naturally in the body but can be acquired exogenously. Investigators have studied dietary antioxidants in preventing skin cancer formation with promising results in the laboratory setting.^8-11 Recently, more robust human studies have been initiated to further delineate this relationship. We present clinical evidence of several frequently utilized antioxidant vitamins and their effects on melanoma and NMSC.

Antioxidants

Vitamin A—Vitamin A is a fat-soluble vitamin found in animal sources, including fish, liver, and eggs. Carotenoids, such as beta carotene, are provitamin A plant derivatives found in fruits and vegetables that are converted into biologically active retinol and retinoic acid.¹² Retinols play a key role in cellular growth and differentiation and are thought to be protective against skin cancer via the inactivation of free radicals and immunologic enhancement due to their antiproliferative, antioxidative, and antiapoptotic effects.^13-16 Animal studies have demonstrated this protective effect and the ability of retinoids to suppress carcinogenesis; however, human studies reveal conflicting results.^17,18

Greenberg et al¹⁹ investigated the use of beta carotene in preventing the formation of NMSC. Patients (N=1805) were randomized to receive 50 mg of beta carotene daily or placebo. Over a 5-year period, there was no significant reduction in the occurrence of NMSC (relative risk [RR], 1.05; 95% CI, 0.91-1.22).¹⁹ Frieling et al²⁰ conducted a similar randomized, double-blind, placebo-controlled trial investigating beta carotene for primary prevention of NMSC in 22,071 healthy male physicians. The study group received 50 mg of beta carotene every other day for 12 years’ duration, and there was no significant effect on the incidence of first NMSC development (RR, 0.98; 95% CI, 0.92-1.05).²⁰

A case-control study by Naldi et al²¹ found an inverse association between vitamin A intake and development of melanoma. Study participants were stratified into quartiles based on level of dietary intake and found an odds ratio (OR) of 0.71 for beta carotene (95% CI, 0.50-1.02), 0.57 for retinol (95% CI, 0.39-0.83), and 0.51 for total vitamin A (95% CI, 0.35-0.75) when comparing the upper quartile of vitamin A intake to the lower quartile. Upper-quartile cutoff values of vitamin A intake were 214 µg/d for beta carotene, 149 µg/d for retinol, and 359 µg/d for total vitamin A.²¹ More recently, a meta-analysis by Zhang et al²² pooled data from 8 case-control studies and 2 prospective studies. Intake of retinol but not total vitamin A or beta carotene was associated with a reduced risk for development of melanoma (retinol: OR, 0.80; 95% CI, 0.69-0.92; total vitamin A: OR, 0.86; 95% CI, 0.59-1.25; beta carotene: OR, 0.87; 95% CI, 0.62-1.20).²² Feskanich et al²³ demonstrated similar findings with use of food-frequency questionnaires in White women, suggesting that retinol intake from food combined with supplements may be protective for women who were otherwise at a low risk for melanoma based on nondietary factors. These factors included painful or blistering sunburns during childhood, history of more than 6 sunburns, more than 3 moles on the left arm, having red or blonde hair, and having a parent or sibling with melanoma (P=.01). However, this relationship did not hold true when looking at women at an intermediate or high risk for melanoma (P=.16 and P=.46).²³

When looking at high-risk patients, such as transplant patients, oral retinoids have been beneficial in preventing NMSC.^24-27 Bavinck et al²⁴ investigated 44 renal transplant patients with a history of more than 10 NMSCs treated with 30 mg of acitretin daily vs placebo. Patients receiving oral retinoid supplementation developed fewer NMSCs over a 6-month treatment period (P=.01).²⁴ Similarly, George et al²⁵ investigated acitretin in renal transplant patients and found a statistically significant decrease in number of SCCs in patients on supplementation (P=.002). Solomon-Cohen et al²⁶ performed a retrospective case-crossover study in solid organ transplant recipients and found that those treated with 10 mg of acitretin daily for 2 years had a significant reduction in the number of new keratinocyte carcinomas (P=.002). Other investigators have demonstrated similar results, and in 2006, Otley et al²⁷ proposed standardized dosing of acitretin for chemoprevention in high-risk patients, including patients developing 5 to 10 NMSCs per year, solid organ transplant recipients, and those with syndromes associated with the development of NMSC.^28,29 Overall, in the general population, vitamin A and related compounds have not demonstrated a significant association with decreased development of NMSC; however, oral retinoids have proven useful for high-risk patients. Furthermore, several studies have suggested a negative association between vitamin A levels and the incidence of melanoma, specifically in the retinol formulation. 

Vitamin B₃—Nicotinamide (also known as niacinamide) is a water-soluble form of vitamin B₃ and is obtained from animal-based and plant-based foods, such as meat, fish, and legumes.³⁰ Nicotinamide plays a key role in cellular metabolism, cellular signaling, and DNA repair, including protection from UV damage within keratinocytes.^31,32 Early mouse models demonstrated decreased formation of skin tumors in mice treated with topical or oral nicotinamide.^32,33 A number of human studies have revealed similar results.^34-36

Chen et al³⁴ conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).³⁴ Drago et al³⁵ specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.³⁵

Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.^34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.^31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.^31,37

Vitamin B₉—Folate, the natural form of vitamin B₉, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.^38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.³⁸ Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.^38,40 Donnenfeld et al⁴¹ conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.⁴¹ Similar effects were observed by Fung et al,⁴² who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).⁴² Fung et al⁴³ also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al⁴⁰ conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.⁴⁰ In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.

Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.^44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.⁴⁴ Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.^46-48 Despite these findings, minimal photoprotective effects have been found in the human population.

Kune et al⁴⁹ performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).⁴⁹ In addition, Vural et al⁵⁰ analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).⁵¹ More recently, Heinen et al⁵² performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).⁵² Similarly, Fung et al⁴² performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).

The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.⁵³ Feskanich et al²³ examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.

Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.⁵⁴ Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.⁵⁴ Vitamin D receptors are expressed on keratinocytes and melanocytes.⁵⁵ Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.⁵⁶ In a mouse model, Ellison et al⁵⁶ found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.

Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.^57-60 Eide et al⁵⁷ studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).⁵⁷ An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.⁵⁸ This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).⁵⁸ Furthermore, Park et al⁶⁰ looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.^59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al⁶³ performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.

Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.⁶⁴ It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.^65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.^64,65

Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.^67,68 Human studies have not consistently shown these effects. Vural et al⁵⁰ investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,⁴² which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted. 

Among patients with metastatic melanoma who undergo treatment with single or combination immune checkpoint inhibitors (ICIs) and who experience immune adverse events, overall survival is significantly longer, regardless of the need for hospitalization. Survival is further improved if the immunotherapy is continued after the adverse event develops, a new study confirms.

“In the largest clinical cohort to date, our data support a positive association with overall survival for patients who develop clinically significant immune-related adverse events while receiving combination immune checkpoint blockade, in keeping with other reported series,” the authors wrote.

The study was published online in JAMA Network Open.

Immune-related adverse events are common with these drugs. Severe events of grade 3 or higher occur in 59% of trial patients who receive combination ICI therapy.

The adverse events have increasingly been positively associated with survival. However, the effects for patients with metastatic melanoma, in particular, are less clear. There is little research on the effects in relation to combination therapy with ipilimumab and nivolumab, which is the standard of care for many patients with metastatic melanoma.

To investigate, Alexander S. Watson, MD, and colleagues evaluated data on 492 patients with metastatic melanoma who had been treated with one or more doses of an anti–programmed death 1 agent as single or combination immune checkpoint blockade in the multicenter Alberta Immunotherapy Database from August 2013 to May 2020.

Of these 492 patients, 198 patients (40%) developed immune-related adverse events. The mean age of the patients who developed adverse events was 61.8 years; of those who did not develop adverse events, the mean age was 65.5 years. Men made up 69.2% and 62.2%, respectively.

A total of 288 patients received pembrolizumab as their first ICI therapy, 80 received nivolumab, and 124 received combination blockade with ipilimumab-nivolumab.

Overall, with a median follow-up of 36.6 months, among patients who experienced clinically significant immune-related adverse events, defined as requiring systemic corticosteroids and/or a treatment delay, median overall survival was significantly improved, at 56.3 months, compared with 18.5 months among those who did not experience immune-related adverse events (P < .001).

In addition, among those who received combination ICI treatment, the median overall survival was 56.2 months for those who experienced adverse events versus 19.0 months for those who did not (P < .001).

There were no significant differences in overall survival between those who were and those who were not hospitalized for their immune-related adverse events (P = .53).

For patients who resumed their ICI therapy following the adverse events, overall survival was longer, compared with those who did not resume the therapy (median, 56.3 months vs. 31.5 months; P = .009).

The improvements in overall survival seen with immune-related adverse events remained consistent after adjustment in a multivariable analysis (hazard ratio for death, 0.382; P < .001).

There were no significant differences in the median number of cycles of ICIs between those with and those without the adverse events.

The risk of recurrence of immune-related adverse events following the reintroduction of therapy after initial events was a concern, so the improved overall survival among those patients is encouraging, although further investigation is needed, commented lead author Dr. Watson, from the department of oncology, University of Calgary (Alta.).

“It may be, for certain patients with immune-related adverse events, that continued immune-priming is safe and optimizes anticancer response,” he told this news organization. “However, in a retrospective analysis such as ours, selection bias can have an impact.”

“Confirming this finding and better identifying patients who may benefit from resumption will be an area for future investigation,” he said.  

Patients who developed immune-related adverse events were more likely to be younger than 50 years (21.8% vs. 13.9%), have normal albumin levels (86.4% vs. 74.8%), and have a more robust Eastern Cooperative Oncology Group status, which is consistent with other studies that have shown survival benefits among those who experience adverse events.

“We, and others, speculate this could be due to such groups having immune systems more ready to respond strongly to immunotherapy,” Dr. Watson explained.

After controlling for age and performance status in the multivariable analysis, however, “immune-related adverse events remained strongly associated with survival, potentially [indicating] that robust responses to immunotherapy lead to both cancer control and immune-related adverse events,” he said.

Overall, “we feel these findings will help clinicians in discussions with patients and in clinical decision-making after adverse events develop,” Dr. Watson said.

Dr. Watson has received personal fees from Apobiologix Canada.

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

Among patients with metastatic melanoma who undergo treatment with single or combination immune checkpoint inhibitors (ICIs) and who experience immune adverse events, overall survival is significantly longer, regardless of the need for hospitalization. Survival is further improved if the immunotherapy is continued after the adverse event develops, a new study confirms.

“In the largest clinical cohort to date, our data support a positive association with overall survival for patients who develop clinically significant immune-related adverse events while receiving combination immune checkpoint blockade, in keeping with other reported series,” the authors wrote.

The study was published online in JAMA Network Open.

Immune-related adverse events are common with these drugs. Severe events of grade 3 or higher occur in 59% of trial patients who receive combination ICI therapy.

The adverse events have increasingly been positively associated with survival. However, the effects for patients with metastatic melanoma, in particular, are less clear. There is little research on the effects in relation to combination therapy with ipilimumab and nivolumab, which is the standard of care for many patients with metastatic melanoma.

To investigate, Alexander S. Watson, MD, and colleagues evaluated data on 492 patients with metastatic melanoma who had been treated with one or more doses of an anti–programmed death 1 agent as single or combination immune checkpoint blockade in the multicenter Alberta Immunotherapy Database from August 2013 to May 2020.

Of these 492 patients, 198 patients (40%) developed immune-related adverse events. The mean age of the patients who developed adverse events was 61.8 years; of those who did not develop adverse events, the mean age was 65.5 years. Men made up 69.2% and 62.2%, respectively.

A total of 288 patients received pembrolizumab as their first ICI therapy, 80 received nivolumab, and 124 received combination blockade with ipilimumab-nivolumab.

Overall, with a median follow-up of 36.6 months, among patients who experienced clinically significant immune-related adverse events, defined as requiring systemic corticosteroids and/or a treatment delay, median overall survival was significantly improved, at 56.3 months, compared with 18.5 months among those who did not experience immune-related adverse events (P < .001).

In addition, among those who received combination ICI treatment, the median overall survival was 56.2 months for those who experienced adverse events versus 19.0 months for those who did not (P < .001).

There were no significant differences in overall survival between those who were and those who were not hospitalized for their immune-related adverse events (P = .53).

For patients who resumed their ICI therapy following the adverse events, overall survival was longer, compared with those who did not resume the therapy (median, 56.3 months vs. 31.5 months; P = .009).

The improvements in overall survival seen with immune-related adverse events remained consistent after adjustment in a multivariable analysis (hazard ratio for death, 0.382; P < .001).

There were no significant differences in the median number of cycles of ICIs between those with and those without the adverse events.

The risk of recurrence of immune-related adverse events following the reintroduction of therapy after initial events was a concern, so the improved overall survival among those patients is encouraging, although further investigation is needed, commented lead author Dr. Watson, from the department of oncology, University of Calgary (Alta.).

“It may be, for certain patients with immune-related adverse events, that continued immune-priming is safe and optimizes anticancer response,” he told this news organization. “However, in a retrospective analysis such as ours, selection bias can have an impact.”

“Confirming this finding and better identifying patients who may benefit from resumption will be an area for future investigation,” he said.  

Patients who developed immune-related adverse events were more likely to be younger than 50 years (21.8% vs. 13.9%), have normal albumin levels (86.4% vs. 74.8%), and have a more robust Eastern Cooperative Oncology Group status, which is consistent with other studies that have shown survival benefits among those who experience adverse events.

“We, and others, speculate this could be due to such groups having immune systems more ready to respond strongly to immunotherapy,” Dr. Watson explained.

After controlling for age and performance status in the multivariable analysis, however, “immune-related adverse events remained strongly associated with survival, potentially [indicating] that robust responses to immunotherapy lead to both cancer control and immune-related adverse events,” he said.

Overall, “we feel these findings will help clinicians in discussions with patients and in clinical decision-making after adverse events develop,” Dr. Watson said.

Dr. Watson has received personal fees from Apobiologix Canada.

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

Among patients with metastatic melanoma who undergo treatment with single or combination immune checkpoint inhibitors (ICIs) and who experience immune adverse events, overall survival is significantly longer, regardless of the need for hospitalization. Survival is further improved if the immunotherapy is continued after the adverse event develops, a new study confirms.

“In the largest clinical cohort to date, our data support a positive association with overall survival for patients who develop clinically significant immune-related adverse events while receiving combination immune checkpoint blockade, in keeping with other reported series,” the authors wrote.

The study was published online in JAMA Network Open.

Immune-related adverse events are common with these drugs. Severe events of grade 3 or higher occur in 59% of trial patients who receive combination ICI therapy.

The adverse events have increasingly been positively associated with survival. However, the effects for patients with metastatic melanoma, in particular, are less clear. There is little research on the effects in relation to combination therapy with ipilimumab and nivolumab, which is the standard of care for many patients with metastatic melanoma.

To investigate, Alexander S. Watson, MD, and colleagues evaluated data on 492 patients with metastatic melanoma who had been treated with one or more doses of an anti–programmed death 1 agent as single or combination immune checkpoint blockade in the multicenter Alberta Immunotherapy Database from August 2013 to May 2020.

Of these 492 patients, 198 patients (40%) developed immune-related adverse events. The mean age of the patients who developed adverse events was 61.8 years; of those who did not develop adverse events, the mean age was 65.5 years. Men made up 69.2% and 62.2%, respectively.

A total of 288 patients received pembrolizumab as their first ICI therapy, 80 received nivolumab, and 124 received combination blockade with ipilimumab-nivolumab.

Overall, with a median follow-up of 36.6 months, among patients who experienced clinically significant immune-related adverse events, defined as requiring systemic corticosteroids and/or a treatment delay, median overall survival was significantly improved, at 56.3 months, compared with 18.5 months among those who did not experience immune-related adverse events (P < .001).

In addition, among those who received combination ICI treatment, the median overall survival was 56.2 months for those who experienced adverse events versus 19.0 months for those who did not (P < .001).

There were no significant differences in overall survival between those who were and those who were not hospitalized for their immune-related adverse events (P = .53).

For patients who resumed their ICI therapy following the adverse events, overall survival was longer, compared with those who did not resume the therapy (median, 56.3 months vs. 31.5 months; P = .009).

The improvements in overall survival seen with immune-related adverse events remained consistent after adjustment in a multivariable analysis (hazard ratio for death, 0.382; P < .001).

There were no significant differences in the median number of cycles of ICIs between those with and those without the adverse events.

The risk of recurrence of immune-related adverse events following the reintroduction of therapy after initial events was a concern, so the improved overall survival among those patients is encouraging, although further investigation is needed, commented lead author Dr. Watson, from the department of oncology, University of Calgary (Alta.).

“It may be, for certain patients with immune-related adverse events, that continued immune-priming is safe and optimizes anticancer response,” he told this news organization. “However, in a retrospective analysis such as ours, selection bias can have an impact.”

“Confirming this finding and better identifying patients who may benefit from resumption will be an area for future investigation,” he said.  

Patients who developed immune-related adverse events were more likely to be younger than 50 years (21.8% vs. 13.9%), have normal albumin levels (86.4% vs. 74.8%), and have a more robust Eastern Cooperative Oncology Group status, which is consistent with other studies that have shown survival benefits among those who experience adverse events.

“We, and others, speculate this could be due to such groups having immune systems more ready to respond strongly to immunotherapy,” Dr. Watson explained.

After controlling for age and performance status in the multivariable analysis, however, “immune-related adverse events remained strongly associated with survival, potentially [indicating] that robust responses to immunotherapy lead to both cancer control and immune-related adverse events,” he said.

Overall, “we feel these findings will help clinicians in discussions with patients and in clinical decision-making after adverse events develop,” Dr. Watson said.

Dr. Watson has received personal fees from Apobiologix Canada.

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

A new generation of treatments appears to have caused U.S. melanoma mortality rates to plunge between 2013 and 2017 for the first time in 4 decades, a new study finds, although the dip appeared to stabilize over the next 2 years.

“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”

The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”

New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.

The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.

Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.

“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”

But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”

In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”

A new generation of treatments appears to have caused U.S. melanoma mortality rates to plunge between 2013 and 2017 for the first time in 4 decades, a new study finds, although the dip appeared to stabilize over the next 2 years.

“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”

The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”

New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.

The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.

Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.

“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”

But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”

In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”

A new generation of treatments appears to have caused U.S. melanoma mortality rates to plunge between 2013 and 2017 for the first time in 4 decades, a new study finds, although the dip appeared to stabilize over the next 2 years.

“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”

The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”

New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.

The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.

Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.

“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”

But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”

In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”

Although melanoma is the most serious skin cancer, most patients do have high chances of survival. New research has now identified a subset of patients with early disease who have a very low risk of dying from the disease.

In a cohort of almost 11,600 patients, the overall 7-year rate of death from melanoma was 2.5%, but the risk in a subset of 25% of patients was below 1%. Conversely, the study authors were also able to identify a small subset of high‐risk patients with a greater than 20% risk for death.

Though more data are needed and the findings verified in other studies, the use of a different term such as “melanocytic neoplasm of low malignant potential” may be more appropriate and may help to begin to address the problem of overdiagnosis, they note.

“While the topic of very low-risk melanomas has been presented at national and international meetings, there have been no formal discussions to define the classification of ‘melanocytic neoplasms of low malignant potential’ at this time,” first author Megan M. Eguchi, MPH, of the department of medicine, University of California, Los Angeles, said in an interview. “Criteria would need to be established using study designs beyond those available using SEER data.”

She emphasized that currently, they do not propose any change to treatment of these lesions, just a change to the terminology. “A diagnosis of ‘MNLMP’ rather than ‘melanoma’ may potentially alleviate people’s concerns related to prognosis and begin to address the problem of overdiagnosis,” said Ms. Eguchi. The study was recently published online in Cancer.

Even though melanoma is considered to be the most common potentially lethal tumor of the skin, prognosis is often very good for those with T1 tumors, the lowest risk category. Prognostic modeling has been used to predict survival in patients with melanoma and identify prognostic variables, the authors note, with the most prominent attributes being Breslow thickness and ulceration of the primary tumor, which form the basis of the current American Joint Committee on Cancer (AJCC) staging system.

There is evidence that the increasing incidence of melanoma is partly due to overdiagnosis, meaning the diagnosis of lesions that will not lead to symptoms or death. The authors write that they were interested in identifying lesions that are currently diagnosed as melanoma but might lack the capacity for metastasis, cases that could potentially be part of the phenomenon of overdiagnosis.

Subsets with low and high risk for death

In the study, Ms. Eguchi and colleagues analyzed information from the United States Surveillance, Epidemiology, and End Results (SEER) database and identified 11,594 patients who were diagnosed in 2010 and 2011 with stage 1 melanoma that was less than or equal to 1.0 mm in thickness and had not spread to the lymph nodes. Prognostic models for risk for death from melanoma in patients with low-risk melanomas were developed, then the ability of the models to identify very‐low risk subsets of patients with melanoma‐specific survival surpassing that of T1 overall was evaluated.

The median age of the patients was 58 years, the median Breslow thickness was 0.45 mm (interquartile range, 0.30-0.65 mm), and 71% were assigned stage IA. Ulceration was present in 4% of cases, 27% were mitogenic, and 45% were Clark level II, and within this cohort, 292 (2.5%) patients died of melanoma within 7 years. In the training data set, 177 of 7,652 (2.3%) patients died of melanoma within 7 years, and numbers were similar in the testing set (115 of 3,942; 2.9%).

Overall, the investigators identified three large subsets of patients who were in the AJCC seventh edition classification for stage I (“thin”) melanoma, who had a risk for death of approximately less than 1%. This was a marked improvement from the rate of the overall sample. In the simplest model (Model 1A), patients who were younger than 70 years at diagnosis with Clark level II invasion were deemed as very low risk.

In Model 1B, the same initial classification was used, but it was further refined and limited to patients who were either age 43 years or younger or 44-69 years with Breslow thickness less than 0.40 mm. At 10 years postdiagnosis, this subset also showed a less than 1% risk for death from melanoma. The logistic regression model (Model 2) was similar, as it identified about 25% of patients with a predicted risk for death of less than 0.5%, incorporating patient age, sex, mitogenicity, Clark level, and ulceration. Model 2 was also able to further identify a small subset of patients with no deaths.

The logistic regression model was also able to identify a very small subset (0.7% and 0.8%) of patients who had a risk for death that exceeded 20%, which was markedly higher, compared with most patients with T1b tumors.

This study was supported by the National Cancer Institute. Ms. Eguchi had no disclosures to report.

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

Although melanoma is the most serious skin cancer, most patients do have high chances of survival. New research has now identified a subset of patients with early disease who have a very low risk of dying from the disease.

In a cohort of almost 11,600 patients, the overall 7-year rate of death from melanoma was 2.5%, but the risk in a subset of 25% of patients was below 1%. Conversely, the study authors were also able to identify a small subset of high‐risk patients with a greater than 20% risk for death.

Though more data are needed and the findings verified in other studies, the use of a different term such as “melanocytic neoplasm of low malignant potential” may be more appropriate and may help to begin to address the problem of overdiagnosis, they note.

“While the topic of very low-risk melanomas has been presented at national and international meetings, there have been no formal discussions to define the classification of ‘melanocytic neoplasms of low malignant potential’ at this time,” first author Megan M. Eguchi, MPH, of the department of medicine, University of California, Los Angeles, said in an interview. “Criteria would need to be established using study designs beyond those available using SEER data.”

She emphasized that currently, they do not propose any change to treatment of these lesions, just a change to the terminology. “A diagnosis of ‘MNLMP’ rather than ‘melanoma’ may potentially alleviate people’s concerns related to prognosis and begin to address the problem of overdiagnosis,” said Ms. Eguchi. The study was recently published online in Cancer.

Even though melanoma is considered to be the most common potentially lethal tumor of the skin, prognosis is often very good for those with T1 tumors, the lowest risk category. Prognostic modeling has been used to predict survival in patients with melanoma and identify prognostic variables, the authors note, with the most prominent attributes being Breslow thickness and ulceration of the primary tumor, which form the basis of the current American Joint Committee on Cancer (AJCC) staging system.

There is evidence that the increasing incidence of melanoma is partly due to overdiagnosis, meaning the diagnosis of lesions that will not lead to symptoms or death. The authors write that they were interested in identifying lesions that are currently diagnosed as melanoma but might lack the capacity for metastasis, cases that could potentially be part of the phenomenon of overdiagnosis.

Subsets with low and high risk for death

In the study, Ms. Eguchi and colleagues analyzed information from the United States Surveillance, Epidemiology, and End Results (SEER) database and identified 11,594 patients who were diagnosed in 2010 and 2011 with stage 1 melanoma that was less than or equal to 1.0 mm in thickness and had not spread to the lymph nodes. Prognostic models for risk for death from melanoma in patients with low-risk melanomas were developed, then the ability of the models to identify very‐low risk subsets of patients with melanoma‐specific survival surpassing that of T1 overall was evaluated.

The median age of the patients was 58 years, the median Breslow thickness was 0.45 mm (interquartile range, 0.30-0.65 mm), and 71% were assigned stage IA. Ulceration was present in 4% of cases, 27% were mitogenic, and 45% were Clark level II, and within this cohort, 292 (2.5%) patients died of melanoma within 7 years. In the training data set, 177 of 7,652 (2.3%) patients died of melanoma within 7 years, and numbers were similar in the testing set (115 of 3,942; 2.9%).

Overall, the investigators identified three large subsets of patients who were in the AJCC seventh edition classification for stage I (“thin”) melanoma, who had a risk for death of approximately less than 1%. This was a marked improvement from the rate of the overall sample. In the simplest model (Model 1A), patients who were younger than 70 years at diagnosis with Clark level II invasion were deemed as very low risk.

In Model 1B, the same initial classification was used, but it was further refined and limited to patients who were either age 43 years or younger or 44-69 years with Breslow thickness less than 0.40 mm. At 10 years postdiagnosis, this subset also showed a less than 1% risk for death from melanoma. The logistic regression model (Model 2) was similar, as it identified about 25% of patients with a predicted risk for death of less than 0.5%, incorporating patient age, sex, mitogenicity, Clark level, and ulceration. Model 2 was also able to further identify a small subset of patients with no deaths.

The logistic regression model was also able to identify a very small subset (0.7% and 0.8%) of patients who had a risk for death that exceeded 20%, which was markedly higher, compared with most patients with T1b tumors.

This study was supported by the National Cancer Institute. Ms. Eguchi had no disclosures to report.

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

Although melanoma is the most serious skin cancer, most patients do have high chances of survival. New research has now identified a subset of patients with early disease who have a very low risk of dying from the disease.

In a cohort of almost 11,600 patients, the overall 7-year rate of death from melanoma was 2.5%, but the risk in a subset of 25% of patients was below 1%. Conversely, the study authors were also able to identify a small subset of high‐risk patients with a greater than 20% risk for death.

Though more data are needed and the findings verified in other studies, the use of a different term such as “melanocytic neoplasm of low malignant potential” may be more appropriate and may help to begin to address the problem of overdiagnosis, they note.

“While the topic of very low-risk melanomas has been presented at national and international meetings, there have been no formal discussions to define the classification of ‘melanocytic neoplasms of low malignant potential’ at this time,” first author Megan M. Eguchi, MPH, of the department of medicine, University of California, Los Angeles, said in an interview. “Criteria would need to be established using study designs beyond those available using SEER data.”

She emphasized that currently, they do not propose any change to treatment of these lesions, just a change to the terminology. “A diagnosis of ‘MNLMP’ rather than ‘melanoma’ may potentially alleviate people’s concerns related to prognosis and begin to address the problem of overdiagnosis,” said Ms. Eguchi. The study was recently published online in Cancer.

Even though melanoma is considered to be the most common potentially lethal tumor of the skin, prognosis is often very good for those with T1 tumors, the lowest risk category. Prognostic modeling has been used to predict survival in patients with melanoma and identify prognostic variables, the authors note, with the most prominent attributes being Breslow thickness and ulceration of the primary tumor, which form the basis of the current American Joint Committee on Cancer (AJCC) staging system.

There is evidence that the increasing incidence of melanoma is partly due to overdiagnosis, meaning the diagnosis of lesions that will not lead to symptoms or death. The authors write that they were interested in identifying lesions that are currently diagnosed as melanoma but might lack the capacity for metastasis, cases that could potentially be part of the phenomenon of overdiagnosis.

Subsets with low and high risk for death

In the study, Ms. Eguchi and colleagues analyzed information from the United States Surveillance, Epidemiology, and End Results (SEER) database and identified 11,594 patients who were diagnosed in 2010 and 2011 with stage 1 melanoma that was less than or equal to 1.0 mm in thickness and had not spread to the lymph nodes. Prognostic models for risk for death from melanoma in patients with low-risk melanomas were developed, then the ability of the models to identify very‐low risk subsets of patients with melanoma‐specific survival surpassing that of T1 overall was evaluated.

The median age of the patients was 58 years, the median Breslow thickness was 0.45 mm (interquartile range, 0.30-0.65 mm), and 71% were assigned stage IA. Ulceration was present in 4% of cases, 27% were mitogenic, and 45% were Clark level II, and within this cohort, 292 (2.5%) patients died of melanoma within 7 years. In the training data set, 177 of 7,652 (2.3%) patients died of melanoma within 7 years, and numbers were similar in the testing set (115 of 3,942; 2.9%).

Overall, the investigators identified three large subsets of patients who were in the AJCC seventh edition classification for stage I (“thin”) melanoma, who had a risk for death of approximately less than 1%. This was a marked improvement from the rate of the overall sample. In the simplest model (Model 1A), patients who were younger than 70 years at diagnosis with Clark level II invasion were deemed as very low risk.

In Model 1B, the same initial classification was used, but it was further refined and limited to patients who were either age 43 years or younger or 44-69 years with Breslow thickness less than 0.40 mm. At 10 years postdiagnosis, this subset also showed a less than 1% risk for death from melanoma. The logistic regression model (Model 2) was similar, as it identified about 25% of patients with a predicted risk for death of less than 0.5%, incorporating patient age, sex, mitogenicity, Clark level, and ulceration. Model 2 was also able to further identify a small subset of patients with no deaths.

The logistic regression model was also able to identify a very small subset (0.7% and 0.8%) of patients who had a risk for death that exceeded 20%, which was markedly higher, compared with most patients with T1b tumors.

This study was supported by the National Cancer Institute. Ms. Eguchi had no disclosures to report.

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

Sunscreens marketed to individuals with skin of color are generally more expensive than products broadly marketed to consumers, and more than 40% contain a UV blocker that may create a white cast.

Ridofranz / iStock / Getty Images

Those are among the findings from a study by Michelle Xiong, a medical student at Brown University, Providence, R.I., and Erin M. Warshaw, MD, of the department of dermatology at Park Nicollet/Health Partners Health Services, Minneapolis, which was published online in the Journal of the American Academy of Dermatology.

“There is increasing awareness of the negative effects of ultraviolet (UV) light in individuals with skin of color (SOC), especially in regards to pigmentation disorders induced and/or exacerbated by UV exposure,” the authors wrote. “As a result, there has been a surge in sunscreens marketed to this population. We aimed to characterize cost, marketing claims, and potential allergenic ingredients in sunscreens marketed to individuals with SOC.”

Between December 2021 and October 2022, the researchers used the following search terms on Google: “sunscreen” plus “skin of 36 color,” “dark skin,” “brown skin,” “LatinX skin,” and/or “Black skin.” They extracted price, marketing claims, and ingredients from manufacturers’ websites and used 90 allergens contained in the American Contact Dermatitis Society 2020 Core series to identify potential allergens. Next, they combined cross-reactors/synonyms into allergen categories based on ACDS Contact Allergen Management Plan (CAMP) cross-reactor classification. If multiple ingredients in a sunscreen were represented by a single allergen category, it was counted only once. A similar approach was utilized for marketing categories.

A total of 12 sunscreens were included in the analysis: Absolute Joi, Black Girl Sunscreen, Black Girl Sunscreen Make It Matte, Bolden SPF Brightening Moisturizer, Eleven on the Defense Unrivaled Sun Serum, Kinlo Golden Rays Sunscreen, Live Tinted Hueguard 3-in-1 Mineral Sunscreen, Mele Dew The Most Sheer Moisturizer SPF30 Broad Spectrum Sunscreen, Mele No Shade Sunscreen Oil, Specific Beauty Active Radiance Day Moi, Unsun Mineral Sunscreen, and Urban Skin Rx Complexion Protection. Their average cost was $19.30 per ounce (range, $6.33-$50.00) and common marketing claims for these products were “no white cast” (91.7%), being free of an ingredient (83.3%), and “moisturizing” (75%).

Of the 12 sunscreens, 7 (58.3%) contained a chemical sunscreen agent, 5 (41.7%) contained a physical UV blocker, and all contained at least one allergen. The average number of allergens per product was 4.7, most commonly fragrance/botanicals (83.3%), tocopherol (83.3%), sodium benzoates/derivatives (58.3%), and sorbitan sesquiolate/derivatives (58.3%).

“Average cost of sunscreens marketed to individuals with SOC was $19.30/oz, much higher than the median price of $3.32/oz reported in a separate study of 65 popular sunscreens,” the study authors wrote. “As many of the sunscreens in our study were sold by smaller businesses, higher prices may be due to higher production costs or a perceived smaller market.”

The authors expressed surprise that five sunscreens marketed to individuals with SOC contained a physical UV blocker which may create a white cast. They contacted the manufacturers of these five sunscreens and confirmed that three used micronized formulations. “While ingested/inhaled nanoparticles of titanium dioxide may cause tissue effects, most studies of topical products show excellent safety,” they wrote.

They also noted that the average of 4.7 allergens per product observed in the analysis was similar to the average of 4.9 seen in a separate study of 52 popular sunscreens. “However, that study only included 34 allergens while this study evaluated 90 allergens,” the authors wrote. “Consumers and providers should be aware sunscreens marketed to individuals with SOC may cause allergic contact dermatitis,” they commented.

“It is interesting to see how costly these products are now compared to store bought and general commercially available sunscreens several years ago,” said Lawrence J. Green, clinical professor of dermatology at George Washington University, Washington, who was asked to comment on the study. “However, to me that is not surprising as products marketed and targeted to specific populations are often priced at a premium. It wasn’t clear to me how many of these specialized online SOC sunscreens are tinted. I wish the authors had compared the cost of tinted sunscreens in general to nontinted sunscreens because tinted ones are more useful for SOC, because when rubbed in, they can readily match SOC and can also offer protection in the visible light spectrum.”

The authors reported having no financial disclosures; the study had no funding source. Dr. Green disclosed that he is a speaker, consultant, or investigator for many pharmaceutical companies.

Sunscreens marketed to individuals with skin of color are generally more expensive than products broadly marketed to consumers, and more than 40% contain a UV blocker that may create a white cast.

Ridofranz / iStock / Getty Images

Those are among the findings from a study by Michelle Xiong, a medical student at Brown University, Providence, R.I., and Erin M. Warshaw, MD, of the department of dermatology at Park Nicollet/Health Partners Health Services, Minneapolis, which was published online in the Journal of the American Academy of Dermatology.

“There is increasing awareness of the negative effects of ultraviolet (UV) light in individuals with skin of color (SOC), especially in regards to pigmentation disorders induced and/or exacerbated by UV exposure,” the authors wrote. “As a result, there has been a surge in sunscreens marketed to this population. We aimed to characterize cost, marketing claims, and potential allergenic ingredients in sunscreens marketed to individuals with SOC.”

Between December 2021 and October 2022, the researchers used the following search terms on Google: “sunscreen” plus “skin of 36 color,” “dark skin,” “brown skin,” “LatinX skin,” and/or “Black skin.” They extracted price, marketing claims, and ingredients from manufacturers’ websites and used 90 allergens contained in the American Contact Dermatitis Society 2020 Core series to identify potential allergens. Next, they combined cross-reactors/synonyms into allergen categories based on ACDS Contact Allergen Management Plan (CAMP) cross-reactor classification. If multiple ingredients in a sunscreen were represented by a single allergen category, it was counted only once. A similar approach was utilized for marketing categories.

A total of 12 sunscreens were included in the analysis: Absolute Joi, Black Girl Sunscreen, Black Girl Sunscreen Make It Matte, Bolden SPF Brightening Moisturizer, Eleven on the Defense Unrivaled Sun Serum, Kinlo Golden Rays Sunscreen, Live Tinted Hueguard 3-in-1 Mineral Sunscreen, Mele Dew The Most Sheer Moisturizer SPF30 Broad Spectrum Sunscreen, Mele No Shade Sunscreen Oil, Specific Beauty Active Radiance Day Moi, Unsun Mineral Sunscreen, and Urban Skin Rx Complexion Protection. Their average cost was $19.30 per ounce (range, $6.33-$50.00) and common marketing claims for these products were “no white cast” (91.7%), being free of an ingredient (83.3%), and “moisturizing” (75%).

Of the 12 sunscreens, 7 (58.3%) contained a chemical sunscreen agent, 5 (41.7%) contained a physical UV blocker, and all contained at least one allergen. The average number of allergens per product was 4.7, most commonly fragrance/botanicals (83.3%), tocopherol (83.3%), sodium benzoates/derivatives (58.3%), and sorbitan sesquiolate/derivatives (58.3%).

“Average cost of sunscreens marketed to individuals with SOC was $19.30/oz, much higher than the median price of $3.32/oz reported in a separate study of 65 popular sunscreens,” the study authors wrote. “As many of the sunscreens in our study were sold by smaller businesses, higher prices may be due to higher production costs or a perceived smaller market.”

The authors expressed surprise that five sunscreens marketed to individuals with SOC contained a physical UV blocker which may create a white cast. They contacted the manufacturers of these five sunscreens and confirmed that three used micronized formulations. “While ingested/inhaled nanoparticles of titanium dioxide may cause tissue effects, most studies of topical products show excellent safety,” they wrote.

They also noted that the average of 4.7 allergens per product observed in the analysis was similar to the average of 4.9 seen in a separate study of 52 popular sunscreens. “However, that study only included 34 allergens while this study evaluated 90 allergens,” the authors wrote. “Consumers and providers should be aware sunscreens marketed to individuals with SOC may cause allergic contact dermatitis,” they commented.

“It is interesting to see how costly these products are now compared to store bought and general commercially available sunscreens several years ago,” said Lawrence J. Green, clinical professor of dermatology at George Washington University, Washington, who was asked to comment on the study. “However, to me that is not surprising as products marketed and targeted to specific populations are often priced at a premium. It wasn’t clear to me how many of these specialized online SOC sunscreens are tinted. I wish the authors had compared the cost of tinted sunscreens in general to nontinted sunscreens because tinted ones are more useful for SOC, because when rubbed in, they can readily match SOC and can also offer protection in the visible light spectrum.”

The authors reported having no financial disclosures; the study had no funding source. Dr. Green disclosed that he is a speaker, consultant, or investigator for many pharmaceutical companies.

Sunscreens marketed to individuals with skin of color are generally more expensive than products broadly marketed to consumers, and more than 40% contain a UV blocker that may create a white cast.

Ridofranz / iStock / Getty Images

Those are among the findings from a study by Michelle Xiong, a medical student at Brown University, Providence, R.I., and Erin M. Warshaw, MD, of the department of dermatology at Park Nicollet/Health Partners Health Services, Minneapolis, which was published online in the Journal of the American Academy of Dermatology.

“There is increasing awareness of the negative effects of ultraviolet (UV) light in individuals with skin of color (SOC), especially in regards to pigmentation disorders induced and/or exacerbated by UV exposure,” the authors wrote. “As a result, there has been a surge in sunscreens marketed to this population. We aimed to characterize cost, marketing claims, and potential allergenic ingredients in sunscreens marketed to individuals with SOC.”

Between December 2021 and October 2022, the researchers used the following search terms on Google: “sunscreen” plus “skin of 36 color,” “dark skin,” “brown skin,” “LatinX skin,” and/or “Black skin.” They extracted price, marketing claims, and ingredients from manufacturers’ websites and used 90 allergens contained in the American Contact Dermatitis Society 2020 Core series to identify potential allergens. Next, they combined cross-reactors/synonyms into allergen categories based on ACDS Contact Allergen Management Plan (CAMP) cross-reactor classification. If multiple ingredients in a sunscreen were represented by a single allergen category, it was counted only once. A similar approach was utilized for marketing categories.

A total of 12 sunscreens were included in the analysis: Absolute Joi, Black Girl Sunscreen, Black Girl Sunscreen Make It Matte, Bolden SPF Brightening Moisturizer, Eleven on the Defense Unrivaled Sun Serum, Kinlo Golden Rays Sunscreen, Live Tinted Hueguard 3-in-1 Mineral Sunscreen, Mele Dew The Most Sheer Moisturizer SPF30 Broad Spectrum Sunscreen, Mele No Shade Sunscreen Oil, Specific Beauty Active Radiance Day Moi, Unsun Mineral Sunscreen, and Urban Skin Rx Complexion Protection. Their average cost was $19.30 per ounce (range, $6.33-$50.00) and common marketing claims for these products were “no white cast” (91.7%), being free of an ingredient (83.3%), and “moisturizing” (75%).

Of the 12 sunscreens, 7 (58.3%) contained a chemical sunscreen agent, 5 (41.7%) contained a physical UV blocker, and all contained at least one allergen. The average number of allergens per product was 4.7, most commonly fragrance/botanicals (83.3%), tocopherol (83.3%), sodium benzoates/derivatives (58.3%), and sorbitan sesquiolate/derivatives (58.3%).

“Average cost of sunscreens marketed to individuals with SOC was $19.30/oz, much higher than the median price of $3.32/oz reported in a separate study of 65 popular sunscreens,” the study authors wrote. “As many of the sunscreens in our study were sold by smaller businesses, higher prices may be due to higher production costs or a perceived smaller market.”

The authors expressed surprise that five sunscreens marketed to individuals with SOC contained a physical UV blocker which may create a white cast. They contacted the manufacturers of these five sunscreens and confirmed that three used micronized formulations. “While ingested/inhaled nanoparticles of titanium dioxide may cause tissue effects, most studies of topical products show excellent safety,” they wrote.

They also noted that the average of 4.7 allergens per product observed in the analysis was similar to the average of 4.9 seen in a separate study of 52 popular sunscreens. “However, that study only included 34 allergens while this study evaluated 90 allergens,” the authors wrote. “Consumers and providers should be aware sunscreens marketed to individuals with SOC may cause allergic contact dermatitis,” they commented.

“It is interesting to see how costly these products are now compared to store bought and general commercially available sunscreens several years ago,” said Lawrence J. Green, clinical professor of dermatology at George Washington University, Washington, who was asked to comment on the study. “However, to me that is not surprising as products marketed and targeted to specific populations are often priced at a premium. It wasn’t clear to me how many of these specialized online SOC sunscreens are tinted. I wish the authors had compared the cost of tinted sunscreens in general to nontinted sunscreens because tinted ones are more useful for SOC, because when rubbed in, they can readily match SOC and can also offer protection in the visible light spectrum.”

The authors reported having no financial disclosures; the study had no funding source. Dr. Green disclosed that he is a speaker, consultant, or investigator for many pharmaceutical companies.