Melanoma

Acral lentiginous melanoma (ALM) is a rare subtype of melanoma that occurs on the palms, soles, and nail apparatus. Unlike more common types of melanoma, ALM occurs on sun-protected areas of the skin and has distinct clinical, histologic, and genetic features. Acral lentiginous melanoma accounts for a larger proportion of melanomas in individuals with skin of color and has a worse prognosis and recurrence rate than other forms of melanoma.

Population Trends in Skin of Color

Much of the literature on malignant melanoma historically has involved non-Hispanic white patients, but the incidence in lighter-skinned populations has been increasing steadily over the last few decades.¹ Although ALM can occur in any race, it disproportionately affects skin of color populations; ALM accounts for only 0.8% to 1% of all melanomas in white populations, but it constitutes 4% to 58% of melanomas in ethnic populations and is the most common melanoma subtype among black Americans.^2-5 Acral lentiginous melanoma also is associated with a worse prognosis compared to other subtypes, which may indicate a more aggressive biological nature⁶ but also may point toward socioeconomic and cultural barriers (eg, low income or education levels, lack of insurance, lower health literacy), leading to disparities in access to care and diagnosis at advanced stages.⁵

Similarly, the distribution of acral melanocytic nevi appears to demonstrate an association with ethnicity and skin pigmentation. Although skin of color patients have fewer nevi than non-Hispanic whites, the proportion of acral melanocytic nevi tends to be greater.^6,7 Given its grim prognosis, accurately differentiating ALM from acral nevi is of utmost importance.

Diagnostic Challenges of Acral Lesions

Due to the unique nature of the surfaces of acral sites, melanocytic lesions on the palms, soles, and nail apparatus present many diagnostic challenges. It can be difficult to distinguish acral melanoma from benign lesions using the naked eye alone. Volar surfaces are characterized by the presence of dermatoglyphics, and pigment deposition along ridges and furrows create particular dermoscopic patterns exclusive to these sites.⁸ Thus, dermoscopy can be useful on acral surfaces, but the dermoscopic features are different from those on the rest of the body and must be learned separately.

In addition, nearly half of patients are unaware of their acral lesions.⁶ Acral surfaces may not always be examined by clinicians during total-body skin examinations, leading to further possibility of overlooking a lesion. Obtaining biopsies on glabrous skin or nails also is challenging because they can be more painful and hemostasis can be more difficult, especially in the nail. Acral melanomas also may be amelanotic, including those at subungual sites. Although the overall incidence of amelanotic ALM is low, approximately 20% to 28% of amelanotic melanomas in Asian patients are located on acral sites.⁹ Due to these challenges, acral lesions may be overlooked or misdiagnosed as warts,¹⁰ tinea pedis,¹¹ or traumatic ulcers.¹²

Dermoscopic Patterns of Acral Volar Skin

Dermoscopy is a useful noninvasive tool for distinguishing between benign and malignant acral melanocytic lesions, and its efficacy in improving diagnostic accuracy and decreasing unnecessary biopsies is well-established in the literature.^13,14 Acral dermoscopy allows for visualization of pigment along the dermatoglyphics that constitute the characteristic dermoscopic patterns.

Acral Lentiginous Melanoma
The hallmark dermoscopic pattern and most important finding of ALM is the parallel ridge pattern, characterized by parallel linear pigmentation along the ridges of dermatoglyphics. In the early phases of malignancy, the pattern appears light brown and involves most of the lesion; as the tumor develops, increasing melanin production results in focal areas of the parallel ridge pattern with darker bands.^15,16 The sensitivity and specificity of a parallel ridge pattern for diagnosing early ALM has been shown to be 86% and 99%, respectively.^15,16

A pattern of irregular diffuse pigmentation also can be observed in more advanced ALM. Dermoscopy may reveal a structureless pattern (ie, lack of identifiable structures or patterns) in a background of tan-black coloration due to more exuberant melanocyte proliferation along the epidermis.¹⁵ Sensitivity and specificity of this dermoscopic finding for invasive lesions is high at 94% and 97%, respectively.^16,17 Interestingly, once ALM lesions have advanced even further, conventional melanoma-associated structures (ie, blue-white veil, polymorphous blood vessels, ulceration, irregular dots/globules or streaks) or atypical forms of typically benign acral dermoscopic patterns may be observed.¹⁵

Per a 3-step diagnostic algorithm created by Koga and Saida,¹⁸ a suspected acral lesion should first be evaluated for a parallel ridge pattern to determine the need for biopsy, as it is seen in approximately two-thirds of ALMs.¹⁹ If no parallel ridge pattern is observed, the lesion should then be checked for any of the typical dermoscopic patterns seen in benign acral nevi (eg, parallel furrow, latticelike, or fibrillar patterns).¹⁸ The maximum diameter should be measured only if the lesion does not exhibit any of the typical dermoscopic patterns. If the lesion’s diameter is greater than 7 mm in diameter, it should be biopsied; if the diameter is less than 7 mm, it should have regular clinical and dermoscopic follow-up.¹⁸

In 2015, Lallas et al²⁰ developed the BRAAFF checklist, a scoring system of 6 variables: blotches, ridge pattern, asymmetry of structures, asymmetry of colors, parallel furrow pattern, and fibrillar pattern. The checklist also was shown to substantially improve diagnostic accuracy of dermoscopy for ALM, with sensitivity and specificity at 93.1% and 86.7%, respectively.²⁰

Acquired Acral Nevi
Three classic dermoscopic patterns are associated with acquired acral nevi: parallel furrow pattern, latticelike pattern, and fibrillar pattern.^15,21 Approximately three-quarters of all acquired acral nevi exhibit one of these patterns, roughly half exhibiting parallel furrow with tan-brown bandlike pigmentation along dermatoglyphic grooves.^16,17

Latticelike patterns also are characterized by brown parallel lines along the sulci of dermatoglyphics but additionally have multiple intersecting lines. Thus, this pattern can be considered a variant of the parallel furrow pattern.¹⁵ The crisscross markings can be predominantly found in the plantar arch.²² This dermoscopic pattern comprises 15% to 25% of all acral nevi.²¹

Fibrillar pattern accounts for 10% to 20% of all acral melanocytic nevi.²¹ Dermoscopically, these lesions demonstrate parallel filamentous streaks that cross dermatoglyphics obliquely. The fibrillar pattern is predominantly found on weight-bearing areas of the sole,²² which likely is explained by pressure causing slanting of melanin columns in the horny layer.²³ The fibrillar pattern has been shown to be the benign acral dermoscopic pattern that is most commonly misdiagnosed, with higher reported rates of biopsy.²⁴

Acral Congenital Melanocytic Nevi
Congenital melanocytic nevi (CMN) present at birth or appear during the first few weeks of life. Congenital melanocytic nevi can vary widely in size, shape, and color, and they are occasionally biopsied in cases of larger diameter or dermoscopic atypia to differentiate from melanoma.²⁵ Congenital melanocytic nevi also can occur on acral volar surfaces. Possible dermoscopic patterns include parallel furrow or fibrillar patterns as well as a crista dotted pattern, defined as evenly spaced dots/globules on the ridges near the openings of eccrine ducts.²⁶ A more commonly observed dermoscopic pattern in acral CMN is a combination of the crista dotted and parallel furrow patterns, known as the peas-in-a-pod pattern. Changes in the clinical appearance and dermoscopic features of an acral CMN are possible over time; some lesions also may fade with age.²⁶

Final Thoughts

Acral lentiginous melanoma is a rare but potentially aggressive melanoma subtype that accounts for a larger proportion of melanomas in patients with skin of color than in white patients. Dermoscopy of acral volar skin provides invaluable diagnostic information and allows for better management of acral melanocytic lesions. Dermoscopic patterns such as the parallel ridge, parallel furrow, latticelike, fibrillar, and peas-in-a-pod patterns are unique to acral sites and can be used to differentiate between ALMs, acquired nevi, or CMNs.

Acral lentiginous melanoma (ALM) is a rare subtype of melanoma that occurs on the palms, soles, and nail apparatus. Unlike more common types of melanoma, ALM occurs on sun-protected areas of the skin and has distinct clinical, histologic, and genetic features. Acral lentiginous melanoma accounts for a larger proportion of melanomas in individuals with skin of color and has a worse prognosis and recurrence rate than other forms of melanoma.

Population Trends in Skin of Color

Much of the literature on malignant melanoma historically has involved non-Hispanic white patients, but the incidence in lighter-skinned populations has been increasing steadily over the last few decades.¹ Although ALM can occur in any race, it disproportionately affects skin of color populations; ALM accounts for only 0.8% to 1% of all melanomas in white populations, but it constitutes 4% to 58% of melanomas in ethnic populations and is the most common melanoma subtype among black Americans.^2-5 Acral lentiginous melanoma also is associated with a worse prognosis compared to other subtypes, which may indicate a more aggressive biological nature⁶ but also may point toward socioeconomic and cultural barriers (eg, low income or education levels, lack of insurance, lower health literacy), leading to disparities in access to care and diagnosis at advanced stages.⁵

Similarly, the distribution of acral melanocytic nevi appears to demonstrate an association with ethnicity and skin pigmentation. Although skin of color patients have fewer nevi than non-Hispanic whites, the proportion of acral melanocytic nevi tends to be greater.^6,7 Given its grim prognosis, accurately differentiating ALM from acral nevi is of utmost importance.

Diagnostic Challenges of Acral Lesions

Due to the unique nature of the surfaces of acral sites, melanocytic lesions on the palms, soles, and nail apparatus present many diagnostic challenges. It can be difficult to distinguish acral melanoma from benign lesions using the naked eye alone. Volar surfaces are characterized by the presence of dermatoglyphics, and pigment deposition along ridges and furrows create particular dermoscopic patterns exclusive to these sites.⁸ Thus, dermoscopy can be useful on acral surfaces, but the dermoscopic features are different from those on the rest of the body and must be learned separately.

In addition, nearly half of patients are unaware of their acral lesions.⁶ Acral surfaces may not always be examined by clinicians during total-body skin examinations, leading to further possibility of overlooking a lesion. Obtaining biopsies on glabrous skin or nails also is challenging because they can be more painful and hemostasis can be more difficult, especially in the nail. Acral melanomas also may be amelanotic, including those at subungual sites. Although the overall incidence of amelanotic ALM is low, approximately 20% to 28% of amelanotic melanomas in Asian patients are located on acral sites.⁹ Due to these challenges, acral lesions may be overlooked or misdiagnosed as warts,¹⁰ tinea pedis,¹¹ or traumatic ulcers.¹²

Dermoscopic Patterns of Acral Volar Skin

Dermoscopy is a useful noninvasive tool for distinguishing between benign and malignant acral melanocytic lesions, and its efficacy in improving diagnostic accuracy and decreasing unnecessary biopsies is well-established in the literature.^13,14 Acral dermoscopy allows for visualization of pigment along the dermatoglyphics that constitute the characteristic dermoscopic patterns.

Acral Lentiginous Melanoma
The hallmark dermoscopic pattern and most important finding of ALM is the parallel ridge pattern, characterized by parallel linear pigmentation along the ridges of dermatoglyphics. In the early phases of malignancy, the pattern appears light brown and involves most of the lesion; as the tumor develops, increasing melanin production results in focal areas of the parallel ridge pattern with darker bands.^15,16 The sensitivity and specificity of a parallel ridge pattern for diagnosing early ALM has been shown to be 86% and 99%, respectively.^15,16

A pattern of irregular diffuse pigmentation also can be observed in more advanced ALM. Dermoscopy may reveal a structureless pattern (ie, lack of identifiable structures or patterns) in a background of tan-black coloration due to more exuberant melanocyte proliferation along the epidermis.¹⁵ Sensitivity and specificity of this dermoscopic finding for invasive lesions is high at 94% and 97%, respectively.^16,17 Interestingly, once ALM lesions have advanced even further, conventional melanoma-associated structures (ie, blue-white veil, polymorphous blood vessels, ulceration, irregular dots/globules or streaks) or atypical forms of typically benign acral dermoscopic patterns may be observed.¹⁵

Per a 3-step diagnostic algorithm created by Koga and Saida,¹⁸ a suspected acral lesion should first be evaluated for a parallel ridge pattern to determine the need for biopsy, as it is seen in approximately two-thirds of ALMs.¹⁹ If no parallel ridge pattern is observed, the lesion should then be checked for any of the typical dermoscopic patterns seen in benign acral nevi (eg, parallel furrow, latticelike, or fibrillar patterns).¹⁸ The maximum diameter should be measured only if the lesion does not exhibit any of the typical dermoscopic patterns. If the lesion’s diameter is greater than 7 mm in diameter, it should be biopsied; if the diameter is less than 7 mm, it should have regular clinical and dermoscopic follow-up.¹⁸

In 2015, Lallas et al²⁰ developed the BRAAFF checklist, a scoring system of 6 variables: blotches, ridge pattern, asymmetry of structures, asymmetry of colors, parallel furrow pattern, and fibrillar pattern. The checklist also was shown to substantially improve diagnostic accuracy of dermoscopy for ALM, with sensitivity and specificity at 93.1% and 86.7%, respectively.²⁰

Acquired Acral Nevi
Three classic dermoscopic patterns are associated with acquired acral nevi: parallel furrow pattern, latticelike pattern, and fibrillar pattern.^15,21 Approximately three-quarters of all acquired acral nevi exhibit one of these patterns, roughly half exhibiting parallel furrow with tan-brown bandlike pigmentation along dermatoglyphic grooves.^16,17

Latticelike patterns also are characterized by brown parallel lines along the sulci of dermatoglyphics but additionally have multiple intersecting lines. Thus, this pattern can be considered a variant of the parallel furrow pattern.¹⁵ The crisscross markings can be predominantly found in the plantar arch.²² This dermoscopic pattern comprises 15% to 25% of all acral nevi.²¹

Fibrillar pattern accounts for 10% to 20% of all acral melanocytic nevi.²¹ Dermoscopically, these lesions demonstrate parallel filamentous streaks that cross dermatoglyphics obliquely. The fibrillar pattern is predominantly found on weight-bearing areas of the sole,²² which likely is explained by pressure causing slanting of melanin columns in the horny layer.²³ The fibrillar pattern has been shown to be the benign acral dermoscopic pattern that is most commonly misdiagnosed, with higher reported rates of biopsy.²⁴

Acral Congenital Melanocytic Nevi
Congenital melanocytic nevi (CMN) present at birth or appear during the first few weeks of life. Congenital melanocytic nevi can vary widely in size, shape, and color, and they are occasionally biopsied in cases of larger diameter or dermoscopic atypia to differentiate from melanoma.²⁵ Congenital melanocytic nevi also can occur on acral volar surfaces. Possible dermoscopic patterns include parallel furrow or fibrillar patterns as well as a crista dotted pattern, defined as evenly spaced dots/globules on the ridges near the openings of eccrine ducts.²⁶ A more commonly observed dermoscopic pattern in acral CMN is a combination of the crista dotted and parallel furrow patterns, known as the peas-in-a-pod pattern. Changes in the clinical appearance and dermoscopic features of an acral CMN are possible over time; some lesions also may fade with age.²⁶

Final Thoughts

Acral lentiginous melanoma is a rare but potentially aggressive melanoma subtype that accounts for a larger proportion of melanomas in patients with skin of color than in white patients. Dermoscopy of acral volar skin provides invaluable diagnostic information and allows for better management of acral melanocytic lesions. Dermoscopic patterns such as the parallel ridge, parallel furrow, latticelike, fibrillar, and peas-in-a-pod patterns are unique to acral sites and can be used to differentiate between ALMs, acquired nevi, or CMNs.

Acral lentiginous melanoma (ALM) is a rare subtype of melanoma that occurs on the palms, soles, and nail apparatus. Unlike more common types of melanoma, ALM occurs on sun-protected areas of the skin and has distinct clinical, histologic, and genetic features. Acral lentiginous melanoma accounts for a larger proportion of melanomas in individuals with skin of color and has a worse prognosis and recurrence rate than other forms of melanoma.

Population Trends in Skin of Color

Much of the literature on malignant melanoma historically has involved non-Hispanic white patients, but the incidence in lighter-skinned populations has been increasing steadily over the last few decades.¹ Although ALM can occur in any race, it disproportionately affects skin of color populations; ALM accounts for only 0.8% to 1% of all melanomas in white populations, but it constitutes 4% to 58% of melanomas in ethnic populations and is the most common melanoma subtype among black Americans.^2-5 Acral lentiginous melanoma also is associated with a worse prognosis compared to other subtypes, which may indicate a more aggressive biological nature⁶ but also may point toward socioeconomic and cultural barriers (eg, low income or education levels, lack of insurance, lower health literacy), leading to disparities in access to care and diagnosis at advanced stages.⁵

Similarly, the distribution of acral melanocytic nevi appears to demonstrate an association with ethnicity and skin pigmentation. Although skin of color patients have fewer nevi than non-Hispanic whites, the proportion of acral melanocytic nevi tends to be greater.^6,7 Given its grim prognosis, accurately differentiating ALM from acral nevi is of utmost importance.

Diagnostic Challenges of Acral Lesions

Due to the unique nature of the surfaces of acral sites, melanocytic lesions on the palms, soles, and nail apparatus present many diagnostic challenges. It can be difficult to distinguish acral melanoma from benign lesions using the naked eye alone. Volar surfaces are characterized by the presence of dermatoglyphics, and pigment deposition along ridges and furrows create particular dermoscopic patterns exclusive to these sites.⁸ Thus, dermoscopy can be useful on acral surfaces, but the dermoscopic features are different from those on the rest of the body and must be learned separately.

In addition, nearly half of patients are unaware of their acral lesions.⁶ Acral surfaces may not always be examined by clinicians during total-body skin examinations, leading to further possibility of overlooking a lesion. Obtaining biopsies on glabrous skin or nails also is challenging because they can be more painful and hemostasis can be more difficult, especially in the nail. Acral melanomas also may be amelanotic, including those at subungual sites. Although the overall incidence of amelanotic ALM is low, approximately 20% to 28% of amelanotic melanomas in Asian patients are located on acral sites.⁹ Due to these challenges, acral lesions may be overlooked or misdiagnosed as warts,¹⁰ tinea pedis,¹¹ or traumatic ulcers.¹²

Dermoscopic Patterns of Acral Volar Skin

Dermoscopy is a useful noninvasive tool for distinguishing between benign and malignant acral melanocytic lesions, and its efficacy in improving diagnostic accuracy and decreasing unnecessary biopsies is well-established in the literature.^13,14 Acral dermoscopy allows for visualization of pigment along the dermatoglyphics that constitute the characteristic dermoscopic patterns.

Acral Lentiginous Melanoma
The hallmark dermoscopic pattern and most important finding of ALM is the parallel ridge pattern, characterized by parallel linear pigmentation along the ridges of dermatoglyphics. In the early phases of malignancy, the pattern appears light brown and involves most of the lesion; as the tumor develops, increasing melanin production results in focal areas of the parallel ridge pattern with darker bands.^15,16 The sensitivity and specificity of a parallel ridge pattern for diagnosing early ALM has been shown to be 86% and 99%, respectively.^15,16

A pattern of irregular diffuse pigmentation also can be observed in more advanced ALM. Dermoscopy may reveal a structureless pattern (ie, lack of identifiable structures or patterns) in a background of tan-black coloration due to more exuberant melanocyte proliferation along the epidermis.¹⁵ Sensitivity and specificity of this dermoscopic finding for invasive lesions is high at 94% and 97%, respectively.^16,17 Interestingly, once ALM lesions have advanced even further, conventional melanoma-associated structures (ie, blue-white veil, polymorphous blood vessels, ulceration, irregular dots/globules or streaks) or atypical forms of typically benign acral dermoscopic patterns may be observed.¹⁵

Per a 3-step diagnostic algorithm created by Koga and Saida,¹⁸ a suspected acral lesion should first be evaluated for a parallel ridge pattern to determine the need for biopsy, as it is seen in approximately two-thirds of ALMs.¹⁹ If no parallel ridge pattern is observed, the lesion should then be checked for any of the typical dermoscopic patterns seen in benign acral nevi (eg, parallel furrow, latticelike, or fibrillar patterns).¹⁸ The maximum diameter should be measured only if the lesion does not exhibit any of the typical dermoscopic patterns. If the lesion’s diameter is greater than 7 mm in diameter, it should be biopsied; if the diameter is less than 7 mm, it should have regular clinical and dermoscopic follow-up.¹⁸

In 2015, Lallas et al²⁰ developed the BRAAFF checklist, a scoring system of 6 variables: blotches, ridge pattern, asymmetry of structures, asymmetry of colors, parallel furrow pattern, and fibrillar pattern. The checklist also was shown to substantially improve diagnostic accuracy of dermoscopy for ALM, with sensitivity and specificity at 93.1% and 86.7%, respectively.²⁰

Acquired Acral Nevi
Three classic dermoscopic patterns are associated with acquired acral nevi: parallel furrow pattern, latticelike pattern, and fibrillar pattern.^15,21 Approximately three-quarters of all acquired acral nevi exhibit one of these patterns, roughly half exhibiting parallel furrow with tan-brown bandlike pigmentation along dermatoglyphic grooves.^16,17

Latticelike patterns also are characterized by brown parallel lines along the sulci of dermatoglyphics but additionally have multiple intersecting lines. Thus, this pattern can be considered a variant of the parallel furrow pattern.¹⁵ The crisscross markings can be predominantly found in the plantar arch.²² This dermoscopic pattern comprises 15% to 25% of all acral nevi.²¹

Fibrillar pattern accounts for 10% to 20% of all acral melanocytic nevi.²¹ Dermoscopically, these lesions demonstrate parallel filamentous streaks that cross dermatoglyphics obliquely. The fibrillar pattern is predominantly found on weight-bearing areas of the sole,²² which likely is explained by pressure causing slanting of melanin columns in the horny layer.²³ The fibrillar pattern has been shown to be the benign acral dermoscopic pattern that is most commonly misdiagnosed, with higher reported rates of biopsy.²⁴

Acral Congenital Melanocytic Nevi
Congenital melanocytic nevi (CMN) present at birth or appear during the first few weeks of life. Congenital melanocytic nevi can vary widely in size, shape, and color, and they are occasionally biopsied in cases of larger diameter or dermoscopic atypia to differentiate from melanoma.²⁵ Congenital melanocytic nevi also can occur on acral volar surfaces. Possible dermoscopic patterns include parallel furrow or fibrillar patterns as well as a crista dotted pattern, defined as evenly spaced dots/globules on the ridges near the openings of eccrine ducts.²⁶ A more commonly observed dermoscopic pattern in acral CMN is a combination of the crista dotted and parallel furrow patterns, known as the peas-in-a-pod pattern. Changes in the clinical appearance and dermoscopic features of an acral CMN are possible over time; some lesions also may fade with age.²⁶

Final Thoughts

Acral lentiginous melanoma is a rare but potentially aggressive melanoma subtype that accounts for a larger proportion of melanomas in patients with skin of color than in white patients. Dermoscopy of acral volar skin provides invaluable diagnostic information and allows for better management of acral melanocytic lesions. Dermoscopic patterns such as the parallel ridge, parallel furrow, latticelike, fibrillar, and peas-in-a-pod patterns are unique to acral sites and can be used to differentiate between ALMs, acquired nevi, or CMNs.

In February 2019, Dayanara Torres announced that she had been diagnosed with metastatic melanoma. Ms. Torres, a Puerto Rican–born former Miss Universe who has more than 1 million followers on Instagram (@dayanarapr), seemed an unlikely candidate for skin cancer, which often is associated with fair-skinned and light-eyed individuals. She shared the news of her diagnosis in an Instagram video that has now received more than 850,000 views. In the video, Ms. Torres described a new mole with uneven surface that had developed on her leg and noted that she had ignored it, even though it had been growing for years. Ultimately, she was diagnosed with melanoma that had already metastasized to regional lymph nodes in her leg. Ms. Torres concluded the video by urging fans and viewers to be mindful of new or changing skin lesions and to be aware of the seriousness of skin cancer. In March 2019, Ms. Torres posted a follow-up educational video on Instagram highlighting the features of melanoma that has now received more than 300,000 views.

Since her announcement, we have noticed that more Hispanic patients with concerns about skin cancer are presenting to our dermatology clinic, which is located in a highly diverse city (New Brunswick, New Jersey) with approximately 50% of residents identifying as Hispanic.¹ Most Hispanic patients typically present to our dermatology clinic for non–skin cancer–related concerns, such as acne, rash, and dyschromia; however, following Ms. Torres’ announcement, many have cited her diagnosis of metastatic melanoma as a cause for concern and a motivating factor in having their skin examined. The diagnosis in a prominent celebrity and Hispanic woman has given a new face to metastatic melanoma.

Although melanoma most commonly occurs in white patients, Hispanic patients experience disproportionately greater morbidity and mortality when diagnosed with melanoma.² Poor prognosis in patients with skin of color is multifactorial and may be due to poor use of sun protection, misconceptions about melanoma risk, atypical clinical presentation, impaired access to care, and delay in diagnosis. The Hispanic community encompasses a wide variety of individuals with varying levels of skin pigmentation and sun sensitivity.³ However, Hispanics report low levels of sun-protective behaviors. They also may have misconceptions that sunscreen is ineffective in preventing skin cancer and that little can be done to decrease the risk for developing skin cancer.^4,5 Additionally, Hispanic patients often have lower perceptions of their personal risk for melanoma and report low rates of clinical and self-examinations compared to non-Hispanic white patients.^6-8 Many Hispanic patients have reported that they were not instructed to perform self-examinations of their skin regularly by dermatologists or other providers and did not know the signs of skin cancer.⁷ Furthermore, a language barrier also may impede communication and education regarding melanoma risk.⁹

Similar to white patients, superficial spreading melanoma is the most common histologic subtype in Hispanic patients, followed by acral lentiginous melanoma, which is the most common subtype in black and Asian patients.^2,4 Compared to non-Hispanic white patients, who most commonly present with truncal melanomas, Hispanic patients (particularly those from Puerto Rico, such as Ms. Torres) are more likely to present with melanoma on the lower extremities.^4,10 Additionally, Hispanic patients have high rates of head, neck, and mucosal melanomas compared to all other racial and ethnic groups.²

Hispanic patients diagnosed with melanoma are more likely to present with thicker primary tumors, later stages of disease, and distant metastases compared to non-Hispanic white patients, all of which are associated with poor prognosis.^2,4,11 Five-year survival rates for melanoma are lower in Hispanic patients compared to non-Hispanic white patients.¹² Although the Hispanic community is diverse in socioeconomic and immigration status as well as occupation, lack of insurance also may contribute to decreased access to care, delayed diagnosis, and ultimately worse survival.

These disparities have spurred suggestions for increased education about skin cancer and the signs and symptoms of melanoma, encouragement of self-examinations, and routine clinical skin examinations for Hispanic patients by dermatologists and other providers.⁸ There is evidence that knowledge-based interventions, especially when presented in Spanish, produce statistically significant improvements in knowledge of skin cancer risk and sun-protective behavior among Hispanic patients.¹² Similarly, we have observed that the videos shared by Ms. Torres regarding her melanoma diagnosis and the features of melanoma, in which she spoke in Spanish, have compelled many Hispanic patients to examine their own skin and have led to increased concern for skin cancer in this patient population. In our practice, we refer to the increase in spot checks and skin examinations requested by Hispanic patients as “The Dayanara Effect,” and we hypothesize that this same effect may be taking place throughout the dermatology community.

In February 2019, Dayanara Torres announced that she had been diagnosed with metastatic melanoma. Ms. Torres, a Puerto Rican–born former Miss Universe who has more than 1 million followers on Instagram (@dayanarapr), seemed an unlikely candidate for skin cancer, which often is associated with fair-skinned and light-eyed individuals. She shared the news of her diagnosis in an Instagram video that has now received more than 850,000 views. In the video, Ms. Torres described a new mole with uneven surface that had developed on her leg and noted that she had ignored it, even though it had been growing for years. Ultimately, she was diagnosed with melanoma that had already metastasized to regional lymph nodes in her leg. Ms. Torres concluded the video by urging fans and viewers to be mindful of new or changing skin lesions and to be aware of the seriousness of skin cancer. In March 2019, Ms. Torres posted a follow-up educational video on Instagram highlighting the features of melanoma that has now received more than 300,000 views.

Since her announcement, we have noticed that more Hispanic patients with concerns about skin cancer are presenting to our dermatology clinic, which is located in a highly diverse city (New Brunswick, New Jersey) with approximately 50% of residents identifying as Hispanic.¹ Most Hispanic patients typically present to our dermatology clinic for non–skin cancer–related concerns, such as acne, rash, and dyschromia; however, following Ms. Torres’ announcement, many have cited her diagnosis of metastatic melanoma as a cause for concern and a motivating factor in having their skin examined. The diagnosis in a prominent celebrity and Hispanic woman has given a new face to metastatic melanoma.

Although melanoma most commonly occurs in white patients, Hispanic patients experience disproportionately greater morbidity and mortality when diagnosed with melanoma.² Poor prognosis in patients with skin of color is multifactorial and may be due to poor use of sun protection, misconceptions about melanoma risk, atypical clinical presentation, impaired access to care, and delay in diagnosis. The Hispanic community encompasses a wide variety of individuals with varying levels of skin pigmentation and sun sensitivity.³ However, Hispanics report low levels of sun-protective behaviors. They also may have misconceptions that sunscreen is ineffective in preventing skin cancer and that little can be done to decrease the risk for developing skin cancer.^4,5 Additionally, Hispanic patients often have lower perceptions of their personal risk for melanoma and report low rates of clinical and self-examinations compared to non-Hispanic white patients.^6-8 Many Hispanic patients have reported that they were not instructed to perform self-examinations of their skin regularly by dermatologists or other providers and did not know the signs of skin cancer.⁷ Furthermore, a language barrier also may impede communication and education regarding melanoma risk.⁹

Similar to white patients, superficial spreading melanoma is the most common histologic subtype in Hispanic patients, followed by acral lentiginous melanoma, which is the most common subtype in black and Asian patients.^2,4 Compared to non-Hispanic white patients, who most commonly present with truncal melanomas, Hispanic patients (particularly those from Puerto Rico, such as Ms. Torres) are more likely to present with melanoma on the lower extremities.^4,10 Additionally, Hispanic patients have high rates of head, neck, and mucosal melanomas compared to all other racial and ethnic groups.²

Hispanic patients diagnosed with melanoma are more likely to present with thicker primary tumors, later stages of disease, and distant metastases compared to non-Hispanic white patients, all of which are associated with poor prognosis.^2,4,11 Five-year survival rates for melanoma are lower in Hispanic patients compared to non-Hispanic white patients.¹² Although the Hispanic community is diverse in socioeconomic and immigration status as well as occupation, lack of insurance also may contribute to decreased access to care, delayed diagnosis, and ultimately worse survival.

These disparities have spurred suggestions for increased education about skin cancer and the signs and symptoms of melanoma, encouragement of self-examinations, and routine clinical skin examinations for Hispanic patients by dermatologists and other providers.⁸ There is evidence that knowledge-based interventions, especially when presented in Spanish, produce statistically significant improvements in knowledge of skin cancer risk and sun-protective behavior among Hispanic patients.¹² Similarly, we have observed that the videos shared by Ms. Torres regarding her melanoma diagnosis and the features of melanoma, in which she spoke in Spanish, have compelled many Hispanic patients to examine their own skin and have led to increased concern for skin cancer in this patient population. In our practice, we refer to the increase in spot checks and skin examinations requested by Hispanic patients as “The Dayanara Effect,” and we hypothesize that this same effect may be taking place throughout the dermatology community.

In February 2019, Dayanara Torres announced that she had been diagnosed with metastatic melanoma. Ms. Torres, a Puerto Rican–born former Miss Universe who has more than 1 million followers on Instagram (@dayanarapr), seemed an unlikely candidate for skin cancer, which often is associated with fair-skinned and light-eyed individuals. She shared the news of her diagnosis in an Instagram video that has now received more than 850,000 views. In the video, Ms. Torres described a new mole with uneven surface that had developed on her leg and noted that she had ignored it, even though it had been growing for years. Ultimately, she was diagnosed with melanoma that had already metastasized to regional lymph nodes in her leg. Ms. Torres concluded the video by urging fans and viewers to be mindful of new or changing skin lesions and to be aware of the seriousness of skin cancer. In March 2019, Ms. Torres posted a follow-up educational video on Instagram highlighting the features of melanoma that has now received more than 300,000 views.

Since her announcement, we have noticed that more Hispanic patients with concerns about skin cancer are presenting to our dermatology clinic, which is located in a highly diverse city (New Brunswick, New Jersey) with approximately 50% of residents identifying as Hispanic.¹ Most Hispanic patients typically present to our dermatology clinic for non–skin cancer–related concerns, such as acne, rash, and dyschromia; however, following Ms. Torres’ announcement, many have cited her diagnosis of metastatic melanoma as a cause for concern and a motivating factor in having their skin examined. The diagnosis in a prominent celebrity and Hispanic woman has given a new face to metastatic melanoma.

Although melanoma most commonly occurs in white patients, Hispanic patients experience disproportionately greater morbidity and mortality when diagnosed with melanoma.² Poor prognosis in patients with skin of color is multifactorial and may be due to poor use of sun protection, misconceptions about melanoma risk, atypical clinical presentation, impaired access to care, and delay in diagnosis. The Hispanic community encompasses a wide variety of individuals with varying levels of skin pigmentation and sun sensitivity.³ However, Hispanics report low levels of sun-protective behaviors. They also may have misconceptions that sunscreen is ineffective in preventing skin cancer and that little can be done to decrease the risk for developing skin cancer.^4,5 Additionally, Hispanic patients often have lower perceptions of their personal risk for melanoma and report low rates of clinical and self-examinations compared to non-Hispanic white patients.^6-8 Many Hispanic patients have reported that they were not instructed to perform self-examinations of their skin regularly by dermatologists or other providers and did not know the signs of skin cancer.⁷ Furthermore, a language barrier also may impede communication and education regarding melanoma risk.⁹

Similar to white patients, superficial spreading melanoma is the most common histologic subtype in Hispanic patients, followed by acral lentiginous melanoma, which is the most common subtype in black and Asian patients.^2,4 Compared to non-Hispanic white patients, who most commonly present with truncal melanomas, Hispanic patients (particularly those from Puerto Rico, such as Ms. Torres) are more likely to present with melanoma on the lower extremities.^4,10 Additionally, Hispanic patients have high rates of head, neck, and mucosal melanomas compared to all other racial and ethnic groups.²

Hispanic patients diagnosed with melanoma are more likely to present with thicker primary tumors, later stages of disease, and distant metastases compared to non-Hispanic white patients, all of which are associated with poor prognosis.^2,4,11 Five-year survival rates for melanoma are lower in Hispanic patients compared to non-Hispanic white patients.¹² Although the Hispanic community is diverse in socioeconomic and immigration status as well as occupation, lack of insurance also may contribute to decreased access to care, delayed diagnosis, and ultimately worse survival.

These disparities have spurred suggestions for increased education about skin cancer and the signs and symptoms of melanoma, encouragement of self-examinations, and routine clinical skin examinations for Hispanic patients by dermatologists and other providers.⁸ There is evidence that knowledge-based interventions, especially when presented in Spanish, produce statistically significant improvements in knowledge of skin cancer risk and sun-protective behavior among Hispanic patients.¹² Similarly, we have observed that the videos shared by Ms. Torres regarding her melanoma diagnosis and the features of melanoma, in which she spoke in Spanish, have compelled many Hispanic patients to examine their own skin and have led to increased concern for skin cancer in this patient population. In our practice, we refer to the increase in spot checks and skin examinations requested by Hispanic patients as “The Dayanara Effect,” and we hypothesize that this same effect may be taking place throughout the dermatology community.

As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.

Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.

The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.

“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).

They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.

Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm², thickness, ulceration, and primary tumor location on the head or neck.

Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.

“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”

The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.

“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”

To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.

“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.

The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.

“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).

The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.

The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).

Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).

“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”

Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.

As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.

Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.

The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.

“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).

They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.

Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm², thickness, ulceration, and primary tumor location on the head or neck.

Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.

“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”

The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.

“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”

To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.

“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.

The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.

“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).

The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.

The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).

Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).

“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”

Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.

As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.

Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.

The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.

“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).

They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.

Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm², thickness, ulceration, and primary tumor location on the head or neck.

Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.

“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”

The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.

“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”

To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.

“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.

The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.

“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).

The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.

The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).

Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).

“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”

Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

[email protected]

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

[email protected]

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

[email protected]

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

If by now you have not had a patient ask, “Doctor, what sunscreen should I use NOW?” you will soon.

The US Food and Drug Administration (FDA) recently published a press release detailing a proposed rule on how manufacturers will be required to test and label sunscreens in the United States.^1,2 Although the press release was complicated and contained much information, the media specifically latched onto the FDA’s consideration of only 2 active sunscreen ingredients—zinc oxide and titanium dioxide—as generally recognized as safe and effective (GRASE). In response, some patients may assume that most sunscreens on the market are dangerous.

How did this new proposed rule come about? To understand the process, it takes some explanation of the history of the FDA’s regulation of sunscreens.

How are sunscreens regulated by the FDA?

The regulatory process for sunscreens in the United States is complicated. The FDA regulates sunscreens as over-the-counter (OTC) drugs rather than as cosmetics, which is how they are regulated in most of the rest of the world.

The US sunscreen regulation process began in 1978 with an advance notice of proposed rulemaking from the FDA that included recommendations from an advisory review panel on the safe and effective use of OTC sunscreen products.³ At that time, 21 active sunscreen ingredients and their maximum use concentrations were listed and determined to be safe, or GRASE. It also gave manufacturers guidance on how to test for efficacy with the methodology for determining the sun protection factor (SPF) as well as various labeling requirements. Over the years, the FDA has issued a number of other sunscreen guidelines, such as removing padimate A and adding avobenzone and zinc oxide to the list of GRASE ingredients in the 1990s.^4,5

In 1999, the FDA issued a final rule that listed 16 active sunscreen ingredients and concentrations as GRASE.⁶ There were some restrictions as to certain combinations of ingredients that could not be used in a finished product. Labeling requirements, including a maximum SPF of 30, also were put in place. This final rule established a final sunscreen monograph that was supposed to have been effective by 2002; however, in 2001 the agency delayed the effective date indefinitely because they had not yet established broad-spectrum (UVA) protection testing and labeling.⁷

The FDA published a proposed rule in 2007 as well as a final rule in 2011 that again listed the same 16 ingredients as GRASE and specified labeling and testing methods for establishing SPF, broad-spectrum protection, and water-resistance claims.^8,9 The final rule limited product labels to a maximum SPF of 50+; provided directions for use with regard to other labeling elements (eg, warnings); and identified specific claims that would not be allowed on product labels, such as “waterproof” and “all-day protection.”⁹

Nevertheless, an effective final OTC monograph for sunscreen products has not yet been published.

What is the Sunscreen Innovation Act?

In 2014, the US Congress enacted the Sunscreen Innovation Act¹⁰ primarily to mandate that the FDA develop a more efficient way to determine the safety and efficacy of new active sunscreen ingredients that were commonly used in Europe and other parts of the world at the time. Many of these agents were thought to be more protective in the UVA and/or UVB spectrum, and if added to the list of GRASE ingredients available to US manufacturers, they would lead to the development of products that would improve the protection offered by sunscreens marketed to US consumers. The time and extent application (TEA) was established, a method that allowed manufacturers to apply for FDA approval of specific agents. The TEA also suggested allowing data generated in other countries where these agents were already in use for years to be considered in the FDA’s evaluation of the agents as GRASE. In addition, Congress mandated that a final monograph on OTC sunscreens be published by the end of 2019. A number of manufacturers have submitted TEAs for new active sunscreen ingredients, and so far, all have been rejected.

Why is the FDA interested in more safety data?

Since then, the FDA has become concerned not only with the safety and efficacy of newly proposed agents through the TEA but also with the original 16 active sunscreen ingredients listed as GRASE in the 2011 final rule. In the 1970s and 1980s, sunscreen use was limited to beach vacations or outdoor sporting events, but sun-protective behaviors have changed dramatically since that time, with health care providers now becoming cognizant of the growing threats of skin cancer and melanoma as well as the cosmetic concerns of photoaging, thereby recommending daily sunscreen use to their patients. In addition, the science behind sunscreens with higher concentrations of active ingredients intended to achieve higher and higher SPFs and their respective penetration of the skin has evolved, leading to new concerns about systemic toxicity. Early limited research frequently touted by the lay media has suggested that some of these agents might lead to hormonal changes, reproductive toxicity, and carcinogenicity.

In November 2016, the FDA issued a guidance for manufacturers that outlined the safety data that would be required to establish an OTC sunscreen active ingredient as GRASE.¹¹ It also provided detailed information about both clinical and nonclinical safety testing, including human irritation and sensitization studies as well as human photosafety studies. In vitro dermal and systemic carcinogenicity studies and animal developmental and reproductive toxicity studies also were required as well studies regarding safety in children.

Many of these recommendations were already being utilized by manufacturers; however, one important change was the requirement for human absorption studies by a maximal usage trial, which more accurately addresses the absorption of sunscreen agents according to actual use. Such studies will be required at the highest allowable concentration of an agent in multiple vehicles and over large body surface areas for considerable exposure times.

This guidance to sunscreen manufacturers was announced to the public in a press release in May 2018.¹²

What are the new regulations?

All of this has culminated in the recent proposed rule, which includes several important proposals²:

• Of the 16 currently marketed active sunscreen ingredients, only 2—zinc oxide and titanium dioxide—are considered GRASE. Two ingredients—trolamine salicylate and para-aminobenzoic acid—are considered non-GRASE, but there is not enough information at this time to determine if the remaining 12 ingredients are GRASE. The FDA is working with manufacturers to obtain sufficient information to make this determination.

• Approved dosage formulations include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. Further information is needed regarding powders before they can be considered.

• The maximum SPF will be increased from 50+ to 60+.

• Sunscreens with an SPF of 15 or higher are required to provide broad-spectrum protection commensurate with the SPF, expanding on critical wavelength testing.

• There are new labeling changes, including a requirement that active ingredients be listed on the front of the packaging.
• Sunscreen products that contain insect repellents are considered non-GRASE.

What’s next?

The process for the proposed final rule has now entered a 90-day public comment period that will end on May 27, 2019; however, it is unlikely that a final monograph as mandated by Congress will be produced by the end of this year.

Sunscreen manufacturers currently are coordinating a response to the proposed rule through the Personal Care Products Council and the Consumer Healthcare Products Association Sunscreen Task Force. It is likely that the new required testing will be costly, with estimates exceeding tens or even hundreds of millions of dollars. In all likelihood, the number of active ingredients that the industry will agree to support with costly testing will be fewer than the 12 that are now on the list. It also is likely that this process will lead to fewer sunscreen products for consumers to choose from and almost certainly at a higher cost.

What do we tell patients in the meantime?

According to the FDA’s rules, it was necessary that this process was made public, but it will almost certainly concern our patients as to the safety of the sunscreen products they have been using. We should be concerned that some of our patients may limit their use of sunscreens because of safety concerns.

There is no question that, as physicians, we want to “first, do no harm,” so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data. The good news is that when this process is completed, a large number of agents will likely be found to be GRASE. When the FDA finally gives its imprimatur to sunscreens, it will hopefully help to silence those naysayers who report that sunscreens are dangerous for consumers; however, it has been suggested by some in industry that the new testing required may take at least 5 years.

What should dermatologists do when we are asked, “What sunscreen should I use NOW?” For most patients, I would explain the regulatory process and assure them that the risk-benefit ratio at this point suggests they should continue using the same sunscreens that they are currently using. For special situations such as pregnant women and children, it may be best to suggest products that contain only the 2 GRASE inorganic agents.

If by now you have not had a patient ask, “Doctor, what sunscreen should I use NOW?” you will soon.

The US Food and Drug Administration (FDA) recently published a press release detailing a proposed rule on how manufacturers will be required to test and label sunscreens in the United States.^1,2 Although the press release was complicated and contained much information, the media specifically latched onto the FDA’s consideration of only 2 active sunscreen ingredients—zinc oxide and titanium dioxide—as generally recognized as safe and effective (GRASE). In response, some patients may assume that most sunscreens on the market are dangerous.

How did this new proposed rule come about? To understand the process, it takes some explanation of the history of the FDA’s regulation of sunscreens.

How are sunscreens regulated by the FDA?

The regulatory process for sunscreens in the United States is complicated. The FDA regulates sunscreens as over-the-counter (OTC) drugs rather than as cosmetics, which is how they are regulated in most of the rest of the world.

The US sunscreen regulation process began in 1978 with an advance notice of proposed rulemaking from the FDA that included recommendations from an advisory review panel on the safe and effective use of OTC sunscreen products.³ At that time, 21 active sunscreen ingredients and their maximum use concentrations were listed and determined to be safe, or GRASE. It also gave manufacturers guidance on how to test for efficacy with the methodology for determining the sun protection factor (SPF) as well as various labeling requirements. Over the years, the FDA has issued a number of other sunscreen guidelines, such as removing padimate A and adding avobenzone and zinc oxide to the list of GRASE ingredients in the 1990s.^4,5

In 1999, the FDA issued a final rule that listed 16 active sunscreen ingredients and concentrations as GRASE.⁶ There were some restrictions as to certain combinations of ingredients that could not be used in a finished product. Labeling requirements, including a maximum SPF of 30, also were put in place. This final rule established a final sunscreen monograph that was supposed to have been effective by 2002; however, in 2001 the agency delayed the effective date indefinitely because they had not yet established broad-spectrum (UVA) protection testing and labeling.⁷

The FDA published a proposed rule in 2007 as well as a final rule in 2011 that again listed the same 16 ingredients as GRASE and specified labeling and testing methods for establishing SPF, broad-spectrum protection, and water-resistance claims.^8,9 The final rule limited product labels to a maximum SPF of 50+; provided directions for use with regard to other labeling elements (eg, warnings); and identified specific claims that would not be allowed on product labels, such as “waterproof” and “all-day protection.”⁹

Nevertheless, an effective final OTC monograph for sunscreen products has not yet been published.

What is the Sunscreen Innovation Act?

In 2014, the US Congress enacted the Sunscreen Innovation Act¹⁰ primarily to mandate that the FDA develop a more efficient way to determine the safety and efficacy of new active sunscreen ingredients that were commonly used in Europe and other parts of the world at the time. Many of these agents were thought to be more protective in the UVA and/or UVB spectrum, and if added to the list of GRASE ingredients available to US manufacturers, they would lead to the development of products that would improve the protection offered by sunscreens marketed to US consumers. The time and extent application (TEA) was established, a method that allowed manufacturers to apply for FDA approval of specific agents. The TEA also suggested allowing data generated in other countries where these agents were already in use for years to be considered in the FDA’s evaluation of the agents as GRASE. In addition, Congress mandated that a final monograph on OTC sunscreens be published by the end of 2019. A number of manufacturers have submitted TEAs for new active sunscreen ingredients, and so far, all have been rejected.

Why is the FDA interested in more safety data?

Since then, the FDA has become concerned not only with the safety and efficacy of newly proposed agents through the TEA but also with the original 16 active sunscreen ingredients listed as GRASE in the 2011 final rule. In the 1970s and 1980s, sunscreen use was limited to beach vacations or outdoor sporting events, but sun-protective behaviors have changed dramatically since that time, with health care providers now becoming cognizant of the growing threats of skin cancer and melanoma as well as the cosmetic concerns of photoaging, thereby recommending daily sunscreen use to their patients. In addition, the science behind sunscreens with higher concentrations of active ingredients intended to achieve higher and higher SPFs and their respective penetration of the skin has evolved, leading to new concerns about systemic toxicity. Early limited research frequently touted by the lay media has suggested that some of these agents might lead to hormonal changes, reproductive toxicity, and carcinogenicity.

In November 2016, the FDA issued a guidance for manufacturers that outlined the safety data that would be required to establish an OTC sunscreen active ingredient as GRASE.¹¹ It also provided detailed information about both clinical and nonclinical safety testing, including human irritation and sensitization studies as well as human photosafety studies. In vitro dermal and systemic carcinogenicity studies and animal developmental and reproductive toxicity studies also were required as well studies regarding safety in children.

Many of these recommendations were already being utilized by manufacturers; however, one important change was the requirement for human absorption studies by a maximal usage trial, which more accurately addresses the absorption of sunscreen agents according to actual use. Such studies will be required at the highest allowable concentration of an agent in multiple vehicles and over large body surface areas for considerable exposure times.

This guidance to sunscreen manufacturers was announced to the public in a press release in May 2018.¹²

What are the new regulations?

All of this has culminated in the recent proposed rule, which includes several important proposals²:

• Of the 16 currently marketed active sunscreen ingredients, only 2—zinc oxide and titanium dioxide—are considered GRASE. Two ingredients—trolamine salicylate and para-aminobenzoic acid—are considered non-GRASE, but there is not enough information at this time to determine if the remaining 12 ingredients are GRASE. The FDA is working with manufacturers to obtain sufficient information to make this determination.

• Approved dosage formulations include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. Further information is needed regarding powders before they can be considered.

• The maximum SPF will be increased from 50+ to 60+.

• Sunscreens with an SPF of 15 or higher are required to provide broad-spectrum protection commensurate with the SPF, expanding on critical wavelength testing.

• There are new labeling changes, including a requirement that active ingredients be listed on the front of the packaging.
• Sunscreen products that contain insect repellents are considered non-GRASE.

What’s next?

The process for the proposed final rule has now entered a 90-day public comment period that will end on May 27, 2019; however, it is unlikely that a final monograph as mandated by Congress will be produced by the end of this year.

Sunscreen manufacturers currently are coordinating a response to the proposed rule through the Personal Care Products Council and the Consumer Healthcare Products Association Sunscreen Task Force. It is likely that the new required testing will be costly, with estimates exceeding tens or even hundreds of millions of dollars. In all likelihood, the number of active ingredients that the industry will agree to support with costly testing will be fewer than the 12 that are now on the list. It also is likely that this process will lead to fewer sunscreen products for consumers to choose from and almost certainly at a higher cost.

What do we tell patients in the meantime?

According to the FDA’s rules, it was necessary that this process was made public, but it will almost certainly concern our patients as to the safety of the sunscreen products they have been using. We should be concerned that some of our patients may limit their use of sunscreens because of safety concerns.

There is no question that, as physicians, we want to “first, do no harm,” so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data. The good news is that when this process is completed, a large number of agents will likely be found to be GRASE. When the FDA finally gives its imprimatur to sunscreens, it will hopefully help to silence those naysayers who report that sunscreens are dangerous for consumers; however, it has been suggested by some in industry that the new testing required may take at least 5 years.

What should dermatologists do when we are asked, “What sunscreen should I use NOW?” For most patients, I would explain the regulatory process and assure them that the risk-benefit ratio at this point suggests they should continue using the same sunscreens that they are currently using. For special situations such as pregnant women and children, it may be best to suggest products that contain only the 2 GRASE inorganic agents.

If by now you have not had a patient ask, “Doctor, what sunscreen should I use NOW?” you will soon.

The US Food and Drug Administration (FDA) recently published a press release detailing a proposed rule on how manufacturers will be required to test and label sunscreens in the United States.^1,2 Although the press release was complicated and contained much information, the media specifically latched onto the FDA’s consideration of only 2 active sunscreen ingredients—zinc oxide and titanium dioxide—as generally recognized as safe and effective (GRASE). In response, some patients may assume that most sunscreens on the market are dangerous.

How did this new proposed rule come about? To understand the process, it takes some explanation of the history of the FDA’s regulation of sunscreens.

How are sunscreens regulated by the FDA?

The regulatory process for sunscreens in the United States is complicated. The FDA regulates sunscreens as over-the-counter (OTC) drugs rather than as cosmetics, which is how they are regulated in most of the rest of the world.

The US sunscreen regulation process began in 1978 with an advance notice of proposed rulemaking from the FDA that included recommendations from an advisory review panel on the safe and effective use of OTC sunscreen products.³ At that time, 21 active sunscreen ingredients and their maximum use concentrations were listed and determined to be safe, or GRASE. It also gave manufacturers guidance on how to test for efficacy with the methodology for determining the sun protection factor (SPF) as well as various labeling requirements. Over the years, the FDA has issued a number of other sunscreen guidelines, such as removing padimate A and adding avobenzone and zinc oxide to the list of GRASE ingredients in the 1990s.^4,5

In 1999, the FDA issued a final rule that listed 16 active sunscreen ingredients and concentrations as GRASE.⁶ There were some restrictions as to certain combinations of ingredients that could not be used in a finished product. Labeling requirements, including a maximum SPF of 30, also were put in place. This final rule established a final sunscreen monograph that was supposed to have been effective by 2002; however, in 2001 the agency delayed the effective date indefinitely because they had not yet established broad-spectrum (UVA) protection testing and labeling.⁷

The FDA published a proposed rule in 2007 as well as a final rule in 2011 that again listed the same 16 ingredients as GRASE and specified labeling and testing methods for establishing SPF, broad-spectrum protection, and water-resistance claims.^8,9 The final rule limited product labels to a maximum SPF of 50+; provided directions for use with regard to other labeling elements (eg, warnings); and identified specific claims that would not be allowed on product labels, such as “waterproof” and “all-day protection.”⁹

Nevertheless, an effective final OTC monograph for sunscreen products has not yet been published.

What is the Sunscreen Innovation Act?

In 2014, the US Congress enacted the Sunscreen Innovation Act¹⁰ primarily to mandate that the FDA develop a more efficient way to determine the safety and efficacy of new active sunscreen ingredients that were commonly used in Europe and other parts of the world at the time. Many of these agents were thought to be more protective in the UVA and/or UVB spectrum, and if added to the list of GRASE ingredients available to US manufacturers, they would lead to the development of products that would improve the protection offered by sunscreens marketed to US consumers. The time and extent application (TEA) was established, a method that allowed manufacturers to apply for FDA approval of specific agents. The TEA also suggested allowing data generated in other countries where these agents were already in use for years to be considered in the FDA’s evaluation of the agents as GRASE. In addition, Congress mandated that a final monograph on OTC sunscreens be published by the end of 2019. A number of manufacturers have submitted TEAs for new active sunscreen ingredients, and so far, all have been rejected.

Why is the FDA interested in more safety data?

Since then, the FDA has become concerned not only with the safety and efficacy of newly proposed agents through the TEA but also with the original 16 active sunscreen ingredients listed as GRASE in the 2011 final rule. In the 1970s and 1980s, sunscreen use was limited to beach vacations or outdoor sporting events, but sun-protective behaviors have changed dramatically since that time, with health care providers now becoming cognizant of the growing threats of skin cancer and melanoma as well as the cosmetic concerns of photoaging, thereby recommending daily sunscreen use to their patients. In addition, the science behind sunscreens with higher concentrations of active ingredients intended to achieve higher and higher SPFs and their respective penetration of the skin has evolved, leading to new concerns about systemic toxicity. Early limited research frequently touted by the lay media has suggested that some of these agents might lead to hormonal changes, reproductive toxicity, and carcinogenicity.

In November 2016, the FDA issued a guidance for manufacturers that outlined the safety data that would be required to establish an OTC sunscreen active ingredient as GRASE.¹¹ It also provided detailed information about both clinical and nonclinical safety testing, including human irritation and sensitization studies as well as human photosafety studies. In vitro dermal and systemic carcinogenicity studies and animal developmental and reproductive toxicity studies also were required as well studies regarding safety in children.

Many of these recommendations were already being utilized by manufacturers; however, one important change was the requirement for human absorption studies by a maximal usage trial, which more accurately addresses the absorption of sunscreen agents according to actual use. Such studies will be required at the highest allowable concentration of an agent in multiple vehicles and over large body surface areas for considerable exposure times.

This guidance to sunscreen manufacturers was announced to the public in a press release in May 2018.¹²

What are the new regulations?

All of this has culminated in the recent proposed rule, which includes several important proposals²:

• Of the 16 currently marketed active sunscreen ingredients, only 2—zinc oxide and titanium dioxide—are considered GRASE. Two ingredients—trolamine salicylate and para-aminobenzoic acid—are considered non-GRASE, but there is not enough information at this time to determine if the remaining 12 ingredients are GRASE. The FDA is working with manufacturers to obtain sufficient information to make this determination.

• Approved dosage formulations include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. Further information is needed regarding powders before they can be considered.

• The maximum SPF will be increased from 50+ to 60+.

• Sunscreens with an SPF of 15 or higher are required to provide broad-spectrum protection commensurate with the SPF, expanding on critical wavelength testing.

• There are new labeling changes, including a requirement that active ingredients be listed on the front of the packaging.
• Sunscreen products that contain insect repellents are considered non-GRASE.

What’s next?

The process for the proposed final rule has now entered a 90-day public comment period that will end on May 27, 2019; however, it is unlikely that a final monograph as mandated by Congress will be produced by the end of this year.

Sunscreen manufacturers currently are coordinating a response to the proposed rule through the Personal Care Products Council and the Consumer Healthcare Products Association Sunscreen Task Force. It is likely that the new required testing will be costly, with estimates exceeding tens or even hundreds of millions of dollars. In all likelihood, the number of active ingredients that the industry will agree to support with costly testing will be fewer than the 12 that are now on the list. It also is likely that this process will lead to fewer sunscreen products for consumers to choose from and almost certainly at a higher cost.

What do we tell patients in the meantime?

According to the FDA’s rules, it was necessary that this process was made public, but it will almost certainly concern our patients as to the safety of the sunscreen products they have been using. We should be concerned that some of our patients may limit their use of sunscreens because of safety concerns.

There is no question that, as physicians, we want to “first, do no harm,” so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data. The good news is that when this process is completed, a large number of agents will likely be found to be GRASE. When the FDA finally gives its imprimatur to sunscreens, it will hopefully help to silence those naysayers who report that sunscreens are dangerous for consumers; however, it has been suggested by some in industry that the new testing required may take at least 5 years.

What should dermatologists do when we are asked, “What sunscreen should I use NOW?” For most patients, I would explain the regulatory process and assure them that the risk-benefit ratio at this point suggests they should continue using the same sunscreens that they are currently using. For special situations such as pregnant women and children, it may be best to suggest products that contain only the 2 GRASE inorganic agents.

WAIKOLOA, HAWAII – The widely utilized 5-mm surgical margins for excision of melanoma in situ are inadequate in many cases, Christopher B. Zachary, MD, said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

“You probably should be considering more like 9- or 10-mm margins for melanoma in situ,” advised Dr. Zachary, professor and chair of the department of dermatology at the University of California, Irvine.

This has been a controversial matter. The recommendation for the long-standard 5-mm margins for excision of melanoma in situ (MIS) date back to a 1992 consensus opinion. Since then, however, persuasive data have emerged showing that 5-mm margins are often inadequate for clearance, and the latest American Academy of Dermatology guidelines for the management of primary cutaneous melanoma recommend margins of 5-10 mm (J Am Acad Dermatol. 2019 Jan;80[1]:208-50).


Dr. Zachary’s advice to go on the high side of that 5- to 10-mm zone is based in large part on studies led by John A Zitelli, MD, of the University of Pittsburgh. More than 20 years ago, Dr. Zitelli and his coinvestigators published a provocative prospective series of 535 patients whose melanomas – in situ or invasive – were excised via Mohs micrographic surgery with frozen section examination of the margins. A 9-mm margin successfully removed 95% of the melanomas, a 12-mm margin removed 97%, and a 6-mm margin successfully excised only 83% of the lesions (J Am Acad Dermatol. 1997 Sep;37(3 Pt 1):422-9).

In a follow-up study, Dr. Zitelli and his colleagues reported on a prospective series of 1,072 patients with 1,120 MIS, all excised by Mohs micrographic surgery with frozen sections (J Am Acad Dermatol. 2012 Mar;66[3]:438-44). They determined that 86% of the MIS were completely cleared using a 6-mm margin, compared with 98.9% excised with a 9 mm margin, a statistically significant difference (P less than .001).

Support for Dr. Zitelli’s stance that 5-mm margins for MIS are inadequate was provided by dermatologic surgeons at the Mayo Clinic in Scottsdale, Ariz. Of 46 patients who underwent Mohs micrographic surgery with immunostaining for excision of MIS, margins of 6 mm achieved clearance in only half of them. Surgical excision margins of 15 mm were required to successfully clear 96% of the MIS (Dermatol Surg. 2000 Aug;26[8]:771-84).

Quite a few hands shot up when Dr. Zachary asked how many members of his audience utilize 5-mm margins for surgical excision of MIS.

“That had been my practice as well until quite recently,” he said.

Dr. Zachary reported having no financial conflicts of interest regarding his presentation.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – The widely utilized 5-mm surgical margins for excision of melanoma in situ are inadequate in many cases, Christopher B. Zachary, MD, said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

“You probably should be considering more like 9- or 10-mm margins for melanoma in situ,” advised Dr. Zachary, professor and chair of the department of dermatology at the University of California, Irvine.

This has been a controversial matter. The recommendation for the long-standard 5-mm margins for excision of melanoma in situ (MIS) date back to a 1992 consensus opinion. Since then, however, persuasive data have emerged showing that 5-mm margins are often inadequate for clearance, and the latest American Academy of Dermatology guidelines for the management of primary cutaneous melanoma recommend margins of 5-10 mm (J Am Acad Dermatol. 2019 Jan;80[1]:208-50).


Dr. Zachary’s advice to go on the high side of that 5- to 10-mm zone is based in large part on studies led by John A Zitelli, MD, of the University of Pittsburgh. More than 20 years ago, Dr. Zitelli and his coinvestigators published a provocative prospective series of 535 patients whose melanomas – in situ or invasive – were excised via Mohs micrographic surgery with frozen section examination of the margins. A 9-mm margin successfully removed 95% of the melanomas, a 12-mm margin removed 97%, and a 6-mm margin successfully excised only 83% of the lesions (J Am Acad Dermatol. 1997 Sep;37(3 Pt 1):422-9).

In a follow-up study, Dr. Zitelli and his colleagues reported on a prospective series of 1,072 patients with 1,120 MIS, all excised by Mohs micrographic surgery with frozen sections (J Am Acad Dermatol. 2012 Mar;66[3]:438-44). They determined that 86% of the MIS were completely cleared using a 6-mm margin, compared with 98.9% excised with a 9 mm margin, a statistically significant difference (P less than .001).

Support for Dr. Zitelli’s stance that 5-mm margins for MIS are inadequate was provided by dermatologic surgeons at the Mayo Clinic in Scottsdale, Ariz. Of 46 patients who underwent Mohs micrographic surgery with immunostaining for excision of MIS, margins of 6 mm achieved clearance in only half of them. Surgical excision margins of 15 mm were required to successfully clear 96% of the MIS (Dermatol Surg. 2000 Aug;26[8]:771-84).

Quite a few hands shot up when Dr. Zachary asked how many members of his audience utilize 5-mm margins for surgical excision of MIS.

“That had been my practice as well until quite recently,” he said.

Dr. Zachary reported having no financial conflicts of interest regarding his presentation.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – The widely utilized 5-mm surgical margins for excision of melanoma in situ are inadequate in many cases, Christopher B. Zachary, MD, said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

“You probably should be considering more like 9- or 10-mm margins for melanoma in situ,” advised Dr. Zachary, professor and chair of the department of dermatology at the University of California, Irvine.

This has been a controversial matter. The recommendation for the long-standard 5-mm margins for excision of melanoma in situ (MIS) date back to a 1992 consensus opinion. Since then, however, persuasive data have emerged showing that 5-mm margins are often inadequate for clearance, and the latest American Academy of Dermatology guidelines for the management of primary cutaneous melanoma recommend margins of 5-10 mm (J Am Acad Dermatol. 2019 Jan;80[1]:208-50).


Dr. Zachary’s advice to go on the high side of that 5- to 10-mm zone is based in large part on studies led by John A Zitelli, MD, of the University of Pittsburgh. More than 20 years ago, Dr. Zitelli and his coinvestigators published a provocative prospective series of 535 patients whose melanomas – in situ or invasive – were excised via Mohs micrographic surgery with frozen section examination of the margins. A 9-mm margin successfully removed 95% of the melanomas, a 12-mm margin removed 97%, and a 6-mm margin successfully excised only 83% of the lesions (J Am Acad Dermatol. 1997 Sep;37(3 Pt 1):422-9).

In a follow-up study, Dr. Zitelli and his colleagues reported on a prospective series of 1,072 patients with 1,120 MIS, all excised by Mohs micrographic surgery with frozen sections (J Am Acad Dermatol. 2012 Mar;66[3]:438-44). They determined that 86% of the MIS were completely cleared using a 6-mm margin, compared with 98.9% excised with a 9 mm margin, a statistically significant difference (P less than .001).

Support for Dr. Zitelli’s stance that 5-mm margins for MIS are inadequate was provided by dermatologic surgeons at the Mayo Clinic in Scottsdale, Ariz. Of 46 patients who underwent Mohs micrographic surgery with immunostaining for excision of MIS, margins of 6 mm achieved clearance in only half of them. Surgical excision margins of 15 mm were required to successfully clear 96% of the MIS (Dermatol Surg. 2000 Aug;26[8]:771-84).

Quite a few hands shot up when Dr. Zachary asked how many members of his audience utilize 5-mm margins for surgical excision of MIS.

“That had been my practice as well until quite recently,” he said.

Dr. Zachary reported having no financial conflicts of interest regarding his presentation.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

WASHINGTON – Psoriasis induced by tumor necrosis factor (TNF) therapy is among the treatment-associated effects that involve the skin in patients with inflammatory bowel disease (IBD), Sophia Delano, MD, said during a session on the cutaneous effects of IBD at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

This is a paradoxical reaction, which can happen “weeks to years after starting a TNF blocker,” with about 70% of cases occurring during the first year of therapy, said Dr. Delano, an attending physician in the dermatology program at Boston Children’s Hospital.

Those receiving infliximab are more likely to develop TNF inhibitor–induced psoriasis, compared with those on adalimumab or etanercept. TNF inhibitor–induced psoriasis may not track with gastrointestinal activity, and some patients whose gastrointestinal disease is responding to treatment can begin to develop psoriasis, she noted.

The clinical presentation of TNF inhibitor–induced psoriasis can also vary. In one study of 216 cases, 26.9% of patients had a mixed morphology, with the most common presentations including plaque psoriasis (44.8%) and palmoplantar pustular psoriasis (36.3%). Other presentations were psoriasiform dermatitis (19.9%), scalp involvement with alopecia (7.5%), and generalized pustular psoriasis (10.9%). Locations affected were the soles of the feet (45.8%), extremities (45.4%), palms (44.9%), scalp (36.1%), and trunk (32.4%), Dr. Delano said.


TNF inhibitor–induced psoriasis is likely a class effect, she said, noting that, in the same review, symptoms resolved in 47.7% of patients who discontinued TNF inhibitors, in 36.7% of patients who switched to another TNF inhibitor, and in 32.9% of patients who continued their original therapy (J Am Acad Dermatol. 2017 Feb;76[2]:334-41). In the study, Crohn’s disease and RA were the most common diseases, in 40.7% and 37.0% of the patients, respectively.

There have been case reports of TNF antagonist–induced lupus-like syndrome (TAILS), which is more common in patients with RA and ulcerative colitis. TAILS occurs more often in women than in men; can present similarly to systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus; and resolves by stopping TNF inhibitor treatment, Dr. Delano said.

Skin cancer risk, infections, and injection site reactions

Both adult and pediatric patients treated with TNF inhibitors for IBD may be at increased risk for lymphoma, visceral tumors, melanoma, and nonmelanoma skin cancers. Dr. Delano referred to a study published in 2014, which identified 972 reports of melanoma in the Food and Drug Administration’s Adverse Event Reporting System database associated with TNF inhibitor use; of these, 69 cases involved patients using more than one TNF inhibitor. Infliximab, golimumab, etanercept, and adalimumab were associated with a safety signal for melanoma, but not certolizumab (Br J Dermatol. 2014 May;170[5]:1170-2).

Dr. Delano observed that thiopurines such as azathioprine are also associated with an increased cancer risk, as noted in one retrospective study that found that the risk of nonmelanoma skin cancer was 2.1 times higher in a mostly white male cohort with ulcerative colitis during treatment with thiopurines, compared with patients not treated with thiopurines (Am J Gastroenterol. 2014 Nov;109[11]:1781-93). A greater duration of treatment (more than 6 months) and higher doses were associated with higher risks.

Adalimumab, golimumab, and certolizumab can also cause injection site reactions, typically within 1- 2 days of injection, said Dr. Delano. In these cases, symptoms of erythema, warmth, burning, or pruritus are worse at the beginning of treatment and can be relieved by rotating the injection site as well as providing cool compresses, topical steroids, antihistamines, and supportive care.

“If you have a patient with a worsening reaction, consider it may represent the type 1 IgE-related hypersensitivity requiring desensitization to continue that systemic,” she noted.

Cutaneous bacterial, fungal, and viral infections such as molluscum contagiosum, verruca vulgaris, herpes simplex, and varicella zoster can occur as a result of TNF inhibition as well, and can be difficult to clear because of immunosuppression, she added.

Dr. Delano reported no relevant conflicts of interest.

WASHINGTON – Psoriasis induced by tumor necrosis factor (TNF) therapy is among the treatment-associated effects that involve the skin in patients with inflammatory bowel disease (IBD), Sophia Delano, MD, said during a session on the cutaneous effects of IBD at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

This is a paradoxical reaction, which can happen “weeks to years after starting a TNF blocker,” with about 70% of cases occurring during the first year of therapy, said Dr. Delano, an attending physician in the dermatology program at Boston Children’s Hospital.

Those receiving infliximab are more likely to develop TNF inhibitor–induced psoriasis, compared with those on adalimumab or etanercept. TNF inhibitor–induced psoriasis may not track with gastrointestinal activity, and some patients whose gastrointestinal disease is responding to treatment can begin to develop psoriasis, she noted.

The clinical presentation of TNF inhibitor–induced psoriasis can also vary. In one study of 216 cases, 26.9% of patients had a mixed morphology, with the most common presentations including plaque psoriasis (44.8%) and palmoplantar pustular psoriasis (36.3%). Other presentations were psoriasiform dermatitis (19.9%), scalp involvement with alopecia (7.5%), and generalized pustular psoriasis (10.9%). Locations affected were the soles of the feet (45.8%), extremities (45.4%), palms (44.9%), scalp (36.1%), and trunk (32.4%), Dr. Delano said.


TNF inhibitor–induced psoriasis is likely a class effect, she said, noting that, in the same review, symptoms resolved in 47.7% of patients who discontinued TNF inhibitors, in 36.7% of patients who switched to another TNF inhibitor, and in 32.9% of patients who continued their original therapy (J Am Acad Dermatol. 2017 Feb;76[2]:334-41). In the study, Crohn’s disease and RA were the most common diseases, in 40.7% and 37.0% of the patients, respectively.

There have been case reports of TNF antagonist–induced lupus-like syndrome (TAILS), which is more common in patients with RA and ulcerative colitis. TAILS occurs more often in women than in men; can present similarly to systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus; and resolves by stopping TNF inhibitor treatment, Dr. Delano said.

Skin cancer risk, infections, and injection site reactions

Both adult and pediatric patients treated with TNF inhibitors for IBD may be at increased risk for lymphoma, visceral tumors, melanoma, and nonmelanoma skin cancers. Dr. Delano referred to a study published in 2014, which identified 972 reports of melanoma in the Food and Drug Administration’s Adverse Event Reporting System database associated with TNF inhibitor use; of these, 69 cases involved patients using more than one TNF inhibitor. Infliximab, golimumab, etanercept, and adalimumab were associated with a safety signal for melanoma, but not certolizumab (Br J Dermatol. 2014 May;170[5]:1170-2).

Dr. Delano observed that thiopurines such as azathioprine are also associated with an increased cancer risk, as noted in one retrospective study that found that the risk of nonmelanoma skin cancer was 2.1 times higher in a mostly white male cohort with ulcerative colitis during treatment with thiopurines, compared with patients not treated with thiopurines (Am J Gastroenterol. 2014 Nov;109[11]:1781-93). A greater duration of treatment (more than 6 months) and higher doses were associated with higher risks.

Adalimumab, golimumab, and certolizumab can also cause injection site reactions, typically within 1- 2 days of injection, said Dr. Delano. In these cases, symptoms of erythema, warmth, burning, or pruritus are worse at the beginning of treatment and can be relieved by rotating the injection site as well as providing cool compresses, topical steroids, antihistamines, and supportive care.

“If you have a patient with a worsening reaction, consider it may represent the type 1 IgE-related hypersensitivity requiring desensitization to continue that systemic,” she noted.

Cutaneous bacterial, fungal, and viral infections such as molluscum contagiosum, verruca vulgaris, herpes simplex, and varicella zoster can occur as a result of TNF inhibition as well, and can be difficult to clear because of immunosuppression, she added.

Dr. Delano reported no relevant conflicts of interest.

WASHINGTON – Psoriasis induced by tumor necrosis factor (TNF) therapy is among the treatment-associated effects that involve the skin in patients with inflammatory bowel disease (IBD), Sophia Delano, MD, said during a session on the cutaneous effects of IBD at the annual meeting of the American Academy of Dermatology.

Jeff Craven/MDedge News

This is a paradoxical reaction, which can happen “weeks to years after starting a TNF blocker,” with about 70% of cases occurring during the first year of therapy, said Dr. Delano, an attending physician in the dermatology program at Boston Children’s Hospital.

Those receiving infliximab are more likely to develop TNF inhibitor–induced psoriasis, compared with those on adalimumab or etanercept. TNF inhibitor–induced psoriasis may not track with gastrointestinal activity, and some patients whose gastrointestinal disease is responding to treatment can begin to develop psoriasis, she noted.

The clinical presentation of TNF inhibitor–induced psoriasis can also vary. In one study of 216 cases, 26.9% of patients had a mixed morphology, with the most common presentations including plaque psoriasis (44.8%) and palmoplantar pustular psoriasis (36.3%). Other presentations were psoriasiform dermatitis (19.9%), scalp involvement with alopecia (7.5%), and generalized pustular psoriasis (10.9%). Locations affected were the soles of the feet (45.8%), extremities (45.4%), palms (44.9%), scalp (36.1%), and trunk (32.4%), Dr. Delano said.


TNF inhibitor–induced psoriasis is likely a class effect, she said, noting that, in the same review, symptoms resolved in 47.7% of patients who discontinued TNF inhibitors, in 36.7% of patients who switched to another TNF inhibitor, and in 32.9% of patients who continued their original therapy (J Am Acad Dermatol. 2017 Feb;76[2]:334-41). In the study, Crohn’s disease and RA were the most common diseases, in 40.7% and 37.0% of the patients, respectively.

There have been case reports of TNF antagonist–induced lupus-like syndrome (TAILS), which is more common in patients with RA and ulcerative colitis. TAILS occurs more often in women than in men; can present similarly to systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus; and resolves by stopping TNF inhibitor treatment, Dr. Delano said.

Skin cancer risk, infections, and injection site reactions

Both adult and pediatric patients treated with TNF inhibitors for IBD may be at increased risk for lymphoma, visceral tumors, melanoma, and nonmelanoma skin cancers. Dr. Delano referred to a study published in 2014, which identified 972 reports of melanoma in the Food and Drug Administration’s Adverse Event Reporting System database associated with TNF inhibitor use; of these, 69 cases involved patients using more than one TNF inhibitor. Infliximab, golimumab, etanercept, and adalimumab were associated with a safety signal for melanoma, but not certolizumab (Br J Dermatol. 2014 May;170[5]:1170-2).

Dr. Delano observed that thiopurines such as azathioprine are also associated with an increased cancer risk, as noted in one retrospective study that found that the risk of nonmelanoma skin cancer was 2.1 times higher in a mostly white male cohort with ulcerative colitis during treatment with thiopurines, compared with patients not treated with thiopurines (Am J Gastroenterol. 2014 Nov;109[11]:1781-93). A greater duration of treatment (more than 6 months) and higher doses were associated with higher risks.

Adalimumab, golimumab, and certolizumab can also cause injection site reactions, typically within 1- 2 days of injection, said Dr. Delano. In these cases, symptoms of erythema, warmth, burning, or pruritus are worse at the beginning of treatment and can be relieved by rotating the injection site as well as providing cool compresses, topical steroids, antihistamines, and supportive care.

“If you have a patient with a worsening reaction, consider it may represent the type 1 IgE-related hypersensitivity requiring desensitization to continue that systemic,” she noted.

Cutaneous bacterial, fungal, and viral infections such as molluscum contagiosum, verruca vulgaris, herpes simplex, and varicella zoster can occur as a result of TNF inhibition as well, and can be difficult to clear because of immunosuppression, she added.

Dr. Delano reported no relevant conflicts of interest.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – Antibiotic exposure in the month before cancer immunotherapy starts may hamper the efficacy of immune checkpoint inhibitors, investigators caution.

Neil Osterweil/MDedge News

A prospective study of 196 patients treated with immune checkpoint inhibitors for various cancers showed that the 29 patients who received antibiotics within 30 days of starting immunotherapy had significantly worse overall survival than patients without antibiotic exposure; this effect was seen across cancer types, reported David James Pinato, MD, PhD, from Imperial College London.

In contrast, concurrent antibiotic and checkpoint inhibitor use was not significantly associated with overall survival differences, he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

“I think these data are quite interesting in showing an independent detrimental effect, both on response and survival, in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” Dr. Pinato said.

The data also suggest “the timing of antibiotic exposure is crucial,” he added. Antibiotic treatment concurrent with immunotherapy did not appear to affect prognosis. Alternatively, prior antibiotic therapy appeared to have “a sort of a priming effect towards the immune system.”

Broad-spectrum antibiotics can affect the diversity of the gut microbiome, which influences mucosal immunity, dendritic cell function, and antigen presentation. Alternatively, enrichment of the microbiome with several bacterial species can enhance the potency of checkpoint inhibitors by facilitating the process of tumor rejection, Dr. Pinato explained.

To see whether antibiotic disruption, or “dysbiosis” of the gut microbiome, could hinder responsiveness to checkpoint inhibitors regardless of the tumor site and whether there were time-dependent effects of antibiotic exposure on response to checkpoint inhibitors, the investigators conducted a prospective, observational study in 196 patients treated with checkpoint inhibitors for non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, head and neck cancer, transitional cell carcinoma of the bladder, and other cancers.

The researchers defined prior antibiotic exposure as more than 30 days before the start of checkpoint inhibitor therapy and concurrent exposure as antibiotics begun on the first day of the first cycle of checkpoint inhibitor dosing.

Of the 196 patients, 29 had previously received antibiotics, and 68 received them concurrently. The most frequently prescribed antibiotics were beta-lactam agents given in a single, short course. Other classes of drugs, used in eight or fewer patients each, included quinolones, macrolides, sulfonamides, tetracyclines, aminoglycosides, and nitroimidazole.

Median overall survival for the entire cohort, one of two primary outcomes, was 2 months for patients who had received prior antibiotics and 26 months for patients with no prior exposure. This difference was similar for patients with NSCLC (2.5 vs. 26 months), melanoma (3.9 vs. 14 months), and other cancers combined (1.1 vs. 11.0 months; log-rank P less than .01 for all comparisons).

In multivariate analysis, only response to checkpoints inhibitors (complete vs. partial response, stable disease, or progression) and prior antibiotic exposure were significantly associated with survival. The hazard ratio for survival for patients who had not previously received antibiotics was 3.5 (P less than .001).

In contrast, concurrent antibiotic and checkpoint inhibitor use did not have a significant effect on survival.

An analysis of radiologic responses also showed that patients with prior antibiotic exposure had a significantly higher probability of primary disease progression than those without (81% vs. 44%; P less than .001). There were no associations, however, between specific classes of antibiotics or corticosteroid use.

The findings indicate that “certainly, mechanistic studies are required here, not just to investigate the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity,” Dr. Pinato concluded.

The study was internally supported. Dr. Pinato reported receiving grant funding from Merck and Bristol-Myers Squibb unrelated to the study, as well as honoraria from ViiV Healthcare.

SOURCE: Pinato DJ et al. ASCO-SITC, Abstract 147.

SAN FRANCISCO – Antibiotic exposure in the month before cancer immunotherapy starts may hamper the efficacy of immune checkpoint inhibitors, investigators caution.

Neil Osterweil/MDedge News

A prospective study of 196 patients treated with immune checkpoint inhibitors for various cancers showed that the 29 patients who received antibiotics within 30 days of starting immunotherapy had significantly worse overall survival than patients without antibiotic exposure; this effect was seen across cancer types, reported David James Pinato, MD, PhD, from Imperial College London.

In contrast, concurrent antibiotic and checkpoint inhibitor use was not significantly associated with overall survival differences, he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

“I think these data are quite interesting in showing an independent detrimental effect, both on response and survival, in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” Dr. Pinato said.

The data also suggest “the timing of antibiotic exposure is crucial,” he added. Antibiotic treatment concurrent with immunotherapy did not appear to affect prognosis. Alternatively, prior antibiotic therapy appeared to have “a sort of a priming effect towards the immune system.”

Broad-spectrum antibiotics can affect the diversity of the gut microbiome, which influences mucosal immunity, dendritic cell function, and antigen presentation. Alternatively, enrichment of the microbiome with several bacterial species can enhance the potency of checkpoint inhibitors by facilitating the process of tumor rejection, Dr. Pinato explained.

To see whether antibiotic disruption, or “dysbiosis” of the gut microbiome, could hinder responsiveness to checkpoint inhibitors regardless of the tumor site and whether there were time-dependent effects of antibiotic exposure on response to checkpoint inhibitors, the investigators conducted a prospective, observational study in 196 patients treated with checkpoint inhibitors for non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, head and neck cancer, transitional cell carcinoma of the bladder, and other cancers.

The researchers defined prior antibiotic exposure as more than 30 days before the start of checkpoint inhibitor therapy and concurrent exposure as antibiotics begun on the first day of the first cycle of checkpoint inhibitor dosing.

Of the 196 patients, 29 had previously received antibiotics, and 68 received them concurrently. The most frequently prescribed antibiotics were beta-lactam agents given in a single, short course. Other classes of drugs, used in eight or fewer patients each, included quinolones, macrolides, sulfonamides, tetracyclines, aminoglycosides, and nitroimidazole.

Median overall survival for the entire cohort, one of two primary outcomes, was 2 months for patients who had received prior antibiotics and 26 months for patients with no prior exposure. This difference was similar for patients with NSCLC (2.5 vs. 26 months), melanoma (3.9 vs. 14 months), and other cancers combined (1.1 vs. 11.0 months; log-rank P less than .01 for all comparisons).

In multivariate analysis, only response to checkpoints inhibitors (complete vs. partial response, stable disease, or progression) and prior antibiotic exposure were significantly associated with survival. The hazard ratio for survival for patients who had not previously received antibiotics was 3.5 (P less than .001).

In contrast, concurrent antibiotic and checkpoint inhibitor use did not have a significant effect on survival.

An analysis of radiologic responses also showed that patients with prior antibiotic exposure had a significantly higher probability of primary disease progression than those without (81% vs. 44%; P less than .001). There were no associations, however, between specific classes of antibiotics or corticosteroid use.

The findings indicate that “certainly, mechanistic studies are required here, not just to investigate the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity,” Dr. Pinato concluded.

The study was internally supported. Dr. Pinato reported receiving grant funding from Merck and Bristol-Myers Squibb unrelated to the study, as well as honoraria from ViiV Healthcare.

SOURCE: Pinato DJ et al. ASCO-SITC, Abstract 147.

SAN FRANCISCO – Antibiotic exposure in the month before cancer immunotherapy starts may hamper the efficacy of immune checkpoint inhibitors, investigators caution.

Neil Osterweil/MDedge News

A prospective study of 196 patients treated with immune checkpoint inhibitors for various cancers showed that the 29 patients who received antibiotics within 30 days of starting immunotherapy had significantly worse overall survival than patients without antibiotic exposure; this effect was seen across cancer types, reported David James Pinato, MD, PhD, from Imperial College London.

In contrast, concurrent antibiotic and checkpoint inhibitor use was not significantly associated with overall survival differences, he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

“I think these data are quite interesting in showing an independent detrimental effect, both on response and survival, in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” Dr. Pinato said.

The data also suggest “the timing of antibiotic exposure is crucial,” he added. Antibiotic treatment concurrent with immunotherapy did not appear to affect prognosis. Alternatively, prior antibiotic therapy appeared to have “a sort of a priming effect towards the immune system.”

Broad-spectrum antibiotics can affect the diversity of the gut microbiome, which influences mucosal immunity, dendritic cell function, and antigen presentation. Alternatively, enrichment of the microbiome with several bacterial species can enhance the potency of checkpoint inhibitors by facilitating the process of tumor rejection, Dr. Pinato explained.

To see whether antibiotic disruption, or “dysbiosis” of the gut microbiome, could hinder responsiveness to checkpoint inhibitors regardless of the tumor site and whether there were time-dependent effects of antibiotic exposure on response to checkpoint inhibitors, the investigators conducted a prospective, observational study in 196 patients treated with checkpoint inhibitors for non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, head and neck cancer, transitional cell carcinoma of the bladder, and other cancers.

The researchers defined prior antibiotic exposure as more than 30 days before the start of checkpoint inhibitor therapy and concurrent exposure as antibiotics begun on the first day of the first cycle of checkpoint inhibitor dosing.

Of the 196 patients, 29 had previously received antibiotics, and 68 received them concurrently. The most frequently prescribed antibiotics were beta-lactam agents given in a single, short course. Other classes of drugs, used in eight or fewer patients each, included quinolones, macrolides, sulfonamides, tetracyclines, aminoglycosides, and nitroimidazole.

Median overall survival for the entire cohort, one of two primary outcomes, was 2 months for patients who had received prior antibiotics and 26 months for patients with no prior exposure. This difference was similar for patients with NSCLC (2.5 vs. 26 months), melanoma (3.9 vs. 14 months), and other cancers combined (1.1 vs. 11.0 months; log-rank P less than .01 for all comparisons).

In multivariate analysis, only response to checkpoints inhibitors (complete vs. partial response, stable disease, or progression) and prior antibiotic exposure were significantly associated with survival. The hazard ratio for survival for patients who had not previously received antibiotics was 3.5 (P less than .001).

In contrast, concurrent antibiotic and checkpoint inhibitor use did not have a significant effect on survival.

An analysis of radiologic responses also showed that patients with prior antibiotic exposure had a significantly higher probability of primary disease progression than those without (81% vs. 44%; P less than .001). There were no associations, however, between specific classes of antibiotics or corticosteroid use.

The findings indicate that “certainly, mechanistic studies are required here, not just to investigate the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity,” Dr. Pinato concluded.

The study was internally supported. Dr. Pinato reported receiving grant funding from Merck and Bristol-Myers Squibb unrelated to the study, as well as honoraria from ViiV Healthcare.

SOURCE: Pinato DJ et al. ASCO-SITC, Abstract 147.

WASHINGTON – The 31-gene expression profile test has met the highest level of evidence under the Strength of Recommendation Taxonomy (SORT) method as a prognostic marker for accurately predicting recurrence-free survival and distant metastasis-free survival and melanoma-specific survival, according to results presented by Bradley N. Greenhaw, MD, at a late-breaking research session at the annual meeting of the American Academy of Dermatology.

Dr. Greenhaw, a dermatologist affiliated with the North Mississippi Medical Center-Tupelo, and his colleagues pooled together 1,268 patients from the following studies that analyzed results from melanoma patients who had their disease classified with the 31-gene expression profile (31-GEP) test.

• A single-center study, conducted by Dr. Greenhaw and his associates (Greenhaw BN et al. Dermatol Surg. 2018 Dec. doi: 10.1097/DSS.0000000000001588.
• A multicenter prospective study (J Hematol Oncol. 2017 Aug. doi: 10.1186/s13045-017-0520-1.
• A retrospective archival study (J Am Acad Dermatol. 2019 Jan. doi: 10.1016/j.jaad.2018.07.028.

The 31-GEP test stratifies an individual’s likelihood of developing metastasis within 5 years as low and high risk. In the three studies, the test was used to identify tumors with low-risk (class 1A, class 1B), higher-risk (class 2A), and highest-risk (class 2B) melanoma based on tumor gene expression. In these individual studies, class 2B melanoma independently predicted recurrence-free survival (RFS), distant metastasis–free, and melanoma-specific survival.

Dr. Greenhaw and colleagues performed a meta-analysis of 1,268 patients with stage I through stage III melanoma from those three studies, using fixed and random effects weighting to account for study differences and heterogeneity, respectively. For class 2B tumors, they found a 2.96 increased risk for recurrent metastases and a 2.88 increased risk for distant metastases. The researchers also found no heterogeneity across the studies.

Melanoma-specific survival was not included in the meta-analysis because one paper did not contain any mortality events in class 1A melanoma patients.

“The meta-analysis demonstrated that the GEP test was able to accurately identify those melanoma patients who were at higher risk of metastasis, and we saw a consistent effect across multiple studies,” Dr. Greenhaw said.

Since publication of the 2019 JAAD paper, there were an additional 211 patients who met inclusion criteria and were included in an additional meta-analysis to determine whether inclusion of these patients affected the results. Dr. Greenhaw and colleagues found a 91.4% recurrence-free survival rate and a 94.1% distant metastasis–free survival rate for class 1A melanomas, compared with 45.7% and 55.5% , respectively, for class 2B tumors.

“You can see a big divergence,” Dr. Greenhaw said at the meeting. “Just by using this one test, it’s able to separate out melanomas that otherwise may be grouped in together under current AJCC [American Joint Committee on Cancer] staging,” he added. “The class 2B designation really did confirm a higher risk for recurrence in distant metastasis.”

The researchers used the SORT method to rate the quality of the data across all three studies. Level 1 evidence under the SORT method represents a systematic review or meta-analysis of good-quality studies and/or a prospective study with good follow-up, while an A-level recommendation represents good, quality evidence. Based on the meta-analysis results, the 31-GEP test meets level 1A evidence under the SORT method, Dr. Greenhaw said.

As a prognostic tool, 31-GEP has the potential to change how dermatologists manage their patients with regard to follow-up and adjuvant therapy. “It is being used not just as this novel test that gives us more information, it’s being used clinically,” said Dr. Greenhaw, who noted he regularly uses the 31-GEP test in his practice.

This is the first time that a meta-analysis has been performed for this test, he noted.

Dr. Greenhaw reports a pending relationship with Castle Biosciences.

SOURCE: Greenhaw BN et al. AAD 19. Session F055, Abstract 11370.

WASHINGTON – The 31-gene expression profile test has met the highest level of evidence under the Strength of Recommendation Taxonomy (SORT) method as a prognostic marker for accurately predicting recurrence-free survival and distant metastasis-free survival and melanoma-specific survival, according to results presented by Bradley N. Greenhaw, MD, at a late-breaking research session at the annual meeting of the American Academy of Dermatology.

Dr. Greenhaw, a dermatologist affiliated with the North Mississippi Medical Center-Tupelo, and his colleagues pooled together 1,268 patients from the following studies that analyzed results from melanoma patients who had their disease classified with the 31-gene expression profile (31-GEP) test.

• A single-center study, conducted by Dr. Greenhaw and his associates (Greenhaw BN et al. Dermatol Surg. 2018 Dec. doi: 10.1097/DSS.0000000000001588.
• A multicenter prospective study (J Hematol Oncol. 2017 Aug. doi: 10.1186/s13045-017-0520-1.
• A retrospective archival study (J Am Acad Dermatol. 2019 Jan. doi: 10.1016/j.jaad.2018.07.028.

The 31-GEP test stratifies an individual’s likelihood of developing metastasis within 5 years as low and high risk. In the three studies, the test was used to identify tumors with low-risk (class 1A, class 1B), higher-risk (class 2A), and highest-risk (class 2B) melanoma based on tumor gene expression. In these individual studies, class 2B melanoma independently predicted recurrence-free survival (RFS), distant metastasis–free, and melanoma-specific survival.

Dr. Greenhaw and colleagues performed a meta-analysis of 1,268 patients with stage I through stage III melanoma from those three studies, using fixed and random effects weighting to account for study differences and heterogeneity, respectively. For class 2B tumors, they found a 2.96 increased risk for recurrent metastases and a 2.88 increased risk for distant metastases. The researchers also found no heterogeneity across the studies.

Melanoma-specific survival was not included in the meta-analysis because one paper did not contain any mortality events in class 1A melanoma patients.

“The meta-analysis demonstrated that the GEP test was able to accurately identify those melanoma patients who were at higher risk of metastasis, and we saw a consistent effect across multiple studies,” Dr. Greenhaw said.

Since publication of the 2019 JAAD paper, there were an additional 211 patients who met inclusion criteria and were included in an additional meta-analysis to determine whether inclusion of these patients affected the results. Dr. Greenhaw and colleagues found a 91.4% recurrence-free survival rate and a 94.1% distant metastasis–free survival rate for class 1A melanomas, compared with 45.7% and 55.5% , respectively, for class 2B tumors.

“You can see a big divergence,” Dr. Greenhaw said at the meeting. “Just by using this one test, it’s able to separate out melanomas that otherwise may be grouped in together under current AJCC [American Joint Committee on Cancer] staging,” he added. “The class 2B designation really did confirm a higher risk for recurrence in distant metastasis.”

The researchers used the SORT method to rate the quality of the data across all three studies. Level 1 evidence under the SORT method represents a systematic review or meta-analysis of good-quality studies and/or a prospective study with good follow-up, while an A-level recommendation represents good, quality evidence. Based on the meta-analysis results, the 31-GEP test meets level 1A evidence under the SORT method, Dr. Greenhaw said.

As a prognostic tool, 31-GEP has the potential to change how dermatologists manage their patients with regard to follow-up and adjuvant therapy. “It is being used not just as this novel test that gives us more information, it’s being used clinically,” said Dr. Greenhaw, who noted he regularly uses the 31-GEP test in his practice.

This is the first time that a meta-analysis has been performed for this test, he noted.

Dr. Greenhaw reports a pending relationship with Castle Biosciences.

SOURCE: Greenhaw BN et al. AAD 19. Session F055, Abstract 11370.

WASHINGTON – The 31-gene expression profile test has met the highest level of evidence under the Strength of Recommendation Taxonomy (SORT) method as a prognostic marker for accurately predicting recurrence-free survival and distant metastasis-free survival and melanoma-specific survival, according to results presented by Bradley N. Greenhaw, MD, at a late-breaking research session at the annual meeting of the American Academy of Dermatology.

Dr. Greenhaw, a dermatologist affiliated with the North Mississippi Medical Center-Tupelo, and his colleagues pooled together 1,268 patients from the following studies that analyzed results from melanoma patients who had their disease classified with the 31-gene expression profile (31-GEP) test.

• A single-center study, conducted by Dr. Greenhaw and his associates (Greenhaw BN et al. Dermatol Surg. 2018 Dec. doi: 10.1097/DSS.0000000000001588.
• A multicenter prospective study (J Hematol Oncol. 2017 Aug. doi: 10.1186/s13045-017-0520-1.
• A retrospective archival study (J Am Acad Dermatol. 2019 Jan. doi: 10.1016/j.jaad.2018.07.028.

The 31-GEP test stratifies an individual’s likelihood of developing metastasis within 5 years as low and high risk. In the three studies, the test was used to identify tumors with low-risk (class 1A, class 1B), higher-risk (class 2A), and highest-risk (class 2B) melanoma based on tumor gene expression. In these individual studies, class 2B melanoma independently predicted recurrence-free survival (RFS), distant metastasis–free, and melanoma-specific survival.

Dr. Greenhaw and colleagues performed a meta-analysis of 1,268 patients with stage I through stage III melanoma from those three studies, using fixed and random effects weighting to account for study differences and heterogeneity, respectively. For class 2B tumors, they found a 2.96 increased risk for recurrent metastases and a 2.88 increased risk for distant metastases. The researchers also found no heterogeneity across the studies.

Melanoma-specific survival was not included in the meta-analysis because one paper did not contain any mortality events in class 1A melanoma patients.

“The meta-analysis demonstrated that the GEP test was able to accurately identify those melanoma patients who were at higher risk of metastasis, and we saw a consistent effect across multiple studies,” Dr. Greenhaw said.

Since publication of the 2019 JAAD paper, there were an additional 211 patients who met inclusion criteria and were included in an additional meta-analysis to determine whether inclusion of these patients affected the results. Dr. Greenhaw and colleagues found a 91.4% recurrence-free survival rate and a 94.1% distant metastasis–free survival rate for class 1A melanomas, compared with 45.7% and 55.5% , respectively, for class 2B tumors.

“You can see a big divergence,” Dr. Greenhaw said at the meeting. “Just by using this one test, it’s able to separate out melanomas that otherwise may be grouped in together under current AJCC [American Joint Committee on Cancer] staging,” he added. “The class 2B designation really did confirm a higher risk for recurrence in distant metastasis.”

The researchers used the SORT method to rate the quality of the data across all three studies. Level 1 evidence under the SORT method represents a systematic review or meta-analysis of good-quality studies and/or a prospective study with good follow-up, while an A-level recommendation represents good, quality evidence. Based on the meta-analysis results, the 31-GEP test meets level 1A evidence under the SORT method, Dr. Greenhaw said.

As a prognostic tool, 31-GEP has the potential to change how dermatologists manage their patients with regard to follow-up and adjuvant therapy. “It is being used not just as this novel test that gives us more information, it’s being used clinically,” said Dr. Greenhaw, who noted he regularly uses the 31-GEP test in his practice.

This is the first time that a meta-analysis has been performed for this test, he noted.

Dr. Greenhaw reports a pending relationship with Castle Biosciences.

SOURCE: Greenhaw BN et al. AAD 19. Session F055, Abstract 11370.