Melanoma

To the Editor:

A 53-year-old woman was referred by her oncologist to our dermatology office with lesions on the face and body that presented 8 days after starting vemurafenib 960 mg twice daily for metastatic melanoma. The patient denied any symptoms from the lesions but was concerned they would spread to cover her entire face and body.

The patient's medical history included a diagnosis of metastatic melanoma 6 years prior to presentation. She stated that the primary cutaneous melanoma site was unknown. The patient had endured numerous surgeries to excise lymph node tumors, with some lesions up to 3 cm. The patient recently started vemurafenib, a treatment for BRAF V600E mutation-positive metastatic melanoma. The patient's personal history was notable for hepatitis A, B, and C, and her family history revealed her mother had metastatic lung cancer.

Physical examination revealed numerous 2- to 3-mm, round-oval, flesh-colored to light-brown papules on the cheeks, chest, abdomen (Figure 1), back, and both arms and legs. Some papules were inflamed and some had a stuck-on appearance. Lesions on the chest between the breasts and inframammary region were slightly inflamed. Two skin biopsies were performed. Biopsy of the lesion on the right lateral back revealed solar lentigo, early macular seborrheic keratosis, and a focus of inflamed mild solar keratosis. The dermis showed a mild superficial perivascular and interstitial inflammatory infiltrate composed mostly of lymphocytes, histiocytes, and eosinophils. There were occasional melanophages present (Figure 2). Biopsy of the lesion between the breasts revealed inflamed verrucous seborrheic keratosis (Figure 3).

We treated the lesion on the right lateral back with cycles of cryotherapy and explained to the patient that the lesion between the breasts was benign. We also reiterated to the patient the importance of wearing sun-protective clothing and UVA/UVB sunblock with a sun protection factor of 30 or higher.

Our patient was diagnosed with pneumonia and subsequently had to discontinue vemurafenib. During the period of nontreatment, the keratotic lesions cleared with postinflammatory hyperpigmentation and no epidermal changes, which showed a possible inference of a direct relationship between the vemurafenib and the appearance of the nonmalignant cutaneous lesions. Although this report only represents 1 patient, other patients possibly can benefit from a modified dose of vemurafenib, which either would resolve or lessen the quantity of these lesions.

Vemurafenib is the first US Food and Drug Administration-approved treatment for nonresectable metastatic melanoma with the BRAF V600E mutation as detected by a US Food and Drug Administration-approved test.^1,2 Mutated BRAF is present in approximately 60% of cutaneous melanomas.³ Vemurafenib targets the oncogenic BRAF V600E making the protein inactive, thus inhibiting cell proliferation and leading to apoptosis and shrinkage of the metastatic tumors.^3-5 Vemurafenib has a response rate of more than 50% and is associated with rapid improvement in quality of life.³

Cutaneous side effects include increased incidence of squamous cell carcinoma and keratoacanthomas, appearing approximately 7 to 8 weeks after starting vemurafenib.⁴ The incidence of these lesions increases in patients 65 years and older and in patients with prior skin cancer and chronic sun exposure. The paradoxical activation of the mitogen-activated protein kinase pathway by mutant BRAF-selective inhibitors provides an explanation of the induction of squamous cell carcinomas.⁴ Prior to the initiation of vemurafenib, all patients should receive a total-body skin examination and every 2 months thereafter while on treatment. After discontinuation of the medicine, the patient should continue to receive total-body skin evaluations every 6 months indefinitely.

Patients should be aware of the potential for mild to severe photosensitivity reactions. They should be advised to limit their sun exposure time and to wear sun-protective clothing when outdoors. The use of broad-spectrum UVA/UVB sunscreen and lip protectant with a sun protection factor of 30 or higher also should be stressed.^6,7 Patients should be aware that UVA rays penetrate glass; therefore, UV-protective clothing should be worn throughout the day and during all seasons.⁷

In clinical trials of vemurafenib, Stevens-Johnson syndrome and toxic epidermal necrolysis was reported in 2 patients.^8,9 Clinical trials also reported patients developing new primary malignant melanoma lesions.¹⁰ These findings further emphasize the need for patients to undergo total-body skin examinations during and after treatment.

Other possible dermatologic reactions include a generalized rash, erythema, alopecia, and pruritus.^2,3 The development of benign growths associated with patients on vemurafenib include follicular plugging seen in keratosis pilaris, palmar and plantar hyperkeratosis, seborrheic dermatitis-like rashes, verrucous keratosis, and acantholytic dyskeratosis.^8,11,12

We report a case of nonmalignant growths occurring 8 days after starting vemurafenib. This case illustrates potential cutaneous adverse reactions that were benign yet still of great concern to our patient. Many of these nonmalignant cutaneous findings are associated with abnormal follicular keratinization thought to be secondary to abnormal signaling of the mitogen-activated protein kinase pathway that occurs with the use of BRAF inhibitors.⁸ Although in this case malignant lesions were not discovered, the need for total-body skin examinations exists during all stages of treatment. Supportive care and reassurance should be given to patients along with local treatments including topical therapies (steroids, retinoids), cryotherapy, and biopsies or excisions when necessary.^13,14

To the Editor:

A 53-year-old woman was referred by her oncologist to our dermatology office with lesions on the face and body that presented 8 days after starting vemurafenib 960 mg twice daily for metastatic melanoma. The patient denied any symptoms from the lesions but was concerned they would spread to cover her entire face and body.

The patient's medical history included a diagnosis of metastatic melanoma 6 years prior to presentation. She stated that the primary cutaneous melanoma site was unknown. The patient had endured numerous surgeries to excise lymph node tumors, with some lesions up to 3 cm. The patient recently started vemurafenib, a treatment for BRAF V600E mutation-positive metastatic melanoma. The patient's personal history was notable for hepatitis A, B, and C, and her family history revealed her mother had metastatic lung cancer.

Physical examination revealed numerous 2- to 3-mm, round-oval, flesh-colored to light-brown papules on the cheeks, chest, abdomen (Figure 1), back, and both arms and legs. Some papules were inflamed and some had a stuck-on appearance. Lesions on the chest between the breasts and inframammary region were slightly inflamed. Two skin biopsies were performed. Biopsy of the lesion on the right lateral back revealed solar lentigo, early macular seborrheic keratosis, and a focus of inflamed mild solar keratosis. The dermis showed a mild superficial perivascular and interstitial inflammatory infiltrate composed mostly of lymphocytes, histiocytes, and eosinophils. There were occasional melanophages present (Figure 2). Biopsy of the lesion between the breasts revealed inflamed verrucous seborrheic keratosis (Figure 3).

We treated the lesion on the right lateral back with cycles of cryotherapy and explained to the patient that the lesion between the breasts was benign. We also reiterated to the patient the importance of wearing sun-protective clothing and UVA/UVB sunblock with a sun protection factor of 30 or higher.

Our patient was diagnosed with pneumonia and subsequently had to discontinue vemurafenib. During the period of nontreatment, the keratotic lesions cleared with postinflammatory hyperpigmentation and no epidermal changes, which showed a possible inference of a direct relationship between the vemurafenib and the appearance of the nonmalignant cutaneous lesions. Although this report only represents 1 patient, other patients possibly can benefit from a modified dose of vemurafenib, which either would resolve or lessen the quantity of these lesions.

Vemurafenib is the first US Food and Drug Administration-approved treatment for nonresectable metastatic melanoma with the BRAF V600E mutation as detected by a US Food and Drug Administration-approved test.^1,2 Mutated BRAF is present in approximately 60% of cutaneous melanomas.³ Vemurafenib targets the oncogenic BRAF V600E making the protein inactive, thus inhibiting cell proliferation and leading to apoptosis and shrinkage of the metastatic tumors.^3-5 Vemurafenib has a response rate of more than 50% and is associated with rapid improvement in quality of life.³

Cutaneous side effects include increased incidence of squamous cell carcinoma and keratoacanthomas, appearing approximately 7 to 8 weeks after starting vemurafenib.⁴ The incidence of these lesions increases in patients 65 years and older and in patients with prior skin cancer and chronic sun exposure. The paradoxical activation of the mitogen-activated protein kinase pathway by mutant BRAF-selective inhibitors provides an explanation of the induction of squamous cell carcinomas.⁴ Prior to the initiation of vemurafenib, all patients should receive a total-body skin examination and every 2 months thereafter while on treatment. After discontinuation of the medicine, the patient should continue to receive total-body skin evaluations every 6 months indefinitely.

Patients should be aware of the potential for mild to severe photosensitivity reactions. They should be advised to limit their sun exposure time and to wear sun-protective clothing when outdoors. The use of broad-spectrum UVA/UVB sunscreen and lip protectant with a sun protection factor of 30 or higher also should be stressed.^6,7 Patients should be aware that UVA rays penetrate glass; therefore, UV-protective clothing should be worn throughout the day and during all seasons.⁷

In clinical trials of vemurafenib, Stevens-Johnson syndrome and toxic epidermal necrolysis was reported in 2 patients.^8,9 Clinical trials also reported patients developing new primary malignant melanoma lesions.¹⁰ These findings further emphasize the need for patients to undergo total-body skin examinations during and after treatment.

Other possible dermatologic reactions include a generalized rash, erythema, alopecia, and pruritus.^2,3 The development of benign growths associated with patients on vemurafenib include follicular plugging seen in keratosis pilaris, palmar and plantar hyperkeratosis, seborrheic dermatitis-like rashes, verrucous keratosis, and acantholytic dyskeratosis.^8,11,12

We report a case of nonmalignant growths occurring 8 days after starting vemurafenib. This case illustrates potential cutaneous adverse reactions that were benign yet still of great concern to our patient. Many of these nonmalignant cutaneous findings are associated with abnormal follicular keratinization thought to be secondary to abnormal signaling of the mitogen-activated protein kinase pathway that occurs with the use of BRAF inhibitors.⁸ Although in this case malignant lesions were not discovered, the need for total-body skin examinations exists during all stages of treatment. Supportive care and reassurance should be given to patients along with local treatments including topical therapies (steroids, retinoids), cryotherapy, and biopsies or excisions when necessary.^13,14

To the Editor:

A 53-year-old woman was referred by her oncologist to our dermatology office with lesions on the face and body that presented 8 days after starting vemurafenib 960 mg twice daily for metastatic melanoma. The patient denied any symptoms from the lesions but was concerned they would spread to cover her entire face and body.

The patient's medical history included a diagnosis of metastatic melanoma 6 years prior to presentation. She stated that the primary cutaneous melanoma site was unknown. The patient had endured numerous surgeries to excise lymph node tumors, with some lesions up to 3 cm. The patient recently started vemurafenib, a treatment for BRAF V600E mutation-positive metastatic melanoma. The patient's personal history was notable for hepatitis A, B, and C, and her family history revealed her mother had metastatic lung cancer.

Physical examination revealed numerous 2- to 3-mm, round-oval, flesh-colored to light-brown papules on the cheeks, chest, abdomen (Figure 1), back, and both arms and legs. Some papules were inflamed and some had a stuck-on appearance. Lesions on the chest between the breasts and inframammary region were slightly inflamed. Two skin biopsies were performed. Biopsy of the lesion on the right lateral back revealed solar lentigo, early macular seborrheic keratosis, and a focus of inflamed mild solar keratosis. The dermis showed a mild superficial perivascular and interstitial inflammatory infiltrate composed mostly of lymphocytes, histiocytes, and eosinophils. There were occasional melanophages present (Figure 2). Biopsy of the lesion between the breasts revealed inflamed verrucous seborrheic keratosis (Figure 3).

We treated the lesion on the right lateral back with cycles of cryotherapy and explained to the patient that the lesion between the breasts was benign. We also reiterated to the patient the importance of wearing sun-protective clothing and UVA/UVB sunblock with a sun protection factor of 30 or higher.

Our patient was diagnosed with pneumonia and subsequently had to discontinue vemurafenib. During the period of nontreatment, the keratotic lesions cleared with postinflammatory hyperpigmentation and no epidermal changes, which showed a possible inference of a direct relationship between the vemurafenib and the appearance of the nonmalignant cutaneous lesions. Although this report only represents 1 patient, other patients possibly can benefit from a modified dose of vemurafenib, which either would resolve or lessen the quantity of these lesions.

Vemurafenib is the first US Food and Drug Administration-approved treatment for nonresectable metastatic melanoma with the BRAF V600E mutation as detected by a US Food and Drug Administration-approved test.^1,2 Mutated BRAF is present in approximately 60% of cutaneous melanomas.³ Vemurafenib targets the oncogenic BRAF V600E making the protein inactive, thus inhibiting cell proliferation and leading to apoptosis and shrinkage of the metastatic tumors.^3-5 Vemurafenib has a response rate of more than 50% and is associated with rapid improvement in quality of life.³

Cutaneous side effects include increased incidence of squamous cell carcinoma and keratoacanthomas, appearing approximately 7 to 8 weeks after starting vemurafenib.⁴ The incidence of these lesions increases in patients 65 years and older and in patients with prior skin cancer and chronic sun exposure. The paradoxical activation of the mitogen-activated protein kinase pathway by mutant BRAF-selective inhibitors provides an explanation of the induction of squamous cell carcinomas.⁴ Prior to the initiation of vemurafenib, all patients should receive a total-body skin examination and every 2 months thereafter while on treatment. After discontinuation of the medicine, the patient should continue to receive total-body skin evaluations every 6 months indefinitely.

Patients should be aware of the potential for mild to severe photosensitivity reactions. They should be advised to limit their sun exposure time and to wear sun-protective clothing when outdoors. The use of broad-spectrum UVA/UVB sunscreen and lip protectant with a sun protection factor of 30 or higher also should be stressed.^6,7 Patients should be aware that UVA rays penetrate glass; therefore, UV-protective clothing should be worn throughout the day and during all seasons.⁷

In clinical trials of vemurafenib, Stevens-Johnson syndrome and toxic epidermal necrolysis was reported in 2 patients.^8,9 Clinical trials also reported patients developing new primary malignant melanoma lesions.¹⁰ These findings further emphasize the need for patients to undergo total-body skin examinations during and after treatment.

Other possible dermatologic reactions include a generalized rash, erythema, alopecia, and pruritus.^2,3 The development of benign growths associated with patients on vemurafenib include follicular plugging seen in keratosis pilaris, palmar and plantar hyperkeratosis, seborrheic dermatitis-like rashes, verrucous keratosis, and acantholytic dyskeratosis.^8,11,12

We report a case of nonmalignant growths occurring 8 days after starting vemurafenib. This case illustrates potential cutaneous adverse reactions that were benign yet still of great concern to our patient. Many of these nonmalignant cutaneous findings are associated with abnormal follicular keratinization thought to be secondary to abnormal signaling of the mitogen-activated protein kinase pathway that occurs with the use of BRAF inhibitors.⁸ Although in this case malignant lesions were not discovered, the need for total-body skin examinations exists during all stages of treatment. Supportive care and reassurance should be given to patients along with local treatments including topical therapies (steroids, retinoids), cryotherapy, and biopsies or excisions when necessary.^13,14

The incidence of melanoma is increasing at a rate greater than any other cancer,¹ possibly due to the increasing use of indoor tanning devices. These devices emit unnaturally high levels of UVA and low levels of UVA and UVB rays.² The risks of using these devices include increased incidence of melanoma (3438 cases attributed to indoor tanning in 2008) and keratinocytes cancer (increased risk of squamous cell carcinoma by 67% and basal cell carcinoma by 29%), severe sunburns (61.1% of female users and 44.6% of male users have reported sunburns), and aggravation of underlying disorders such as systemic lupus erythematosus.^3-5

The literature varies in its explanation of how indoor tanning increases the risk of developing melanoma. Some authors suggest it is due to increased frequency of use, duration of sessions, and years of using tanning devices.^1,6 Others suggest the increased cancer risk is the result of starting to tan at an earlier age.^2,3,6-10 There is conflicting literature on the level of increased risk of melanoma in those who tan indoors at a young age (<35 years). Although the estimated rate of increased skin cancer risk varies, with rates up to 75% compared to nonusers, nearly all sources support an increased rate.⁶ Despite the growing body of knowledge that indoor tanning is dangerous, as well as the academic publication of these risks (eg, carcinogenesis, short-term and long-term eye injury, burns, UV sensitivity when combined with certain medications), teenagers in the United States and affluent countries appear to disregard the risks of tanning.¹¹

Tanning companies have promoted the misconception that only UVB rays cause cell damage and UVA rays, which the devices emit, result in “damage-free” or “safe” tans.^2,3 Until 2013, indoor tanning devices were classified by the US Food and Drug Administration (FDA) as class I, indicating that they are safe in terms of electrical shock. Many indoor tanning facilities have promoted the FDA “safe” label without clarifying that the safety indications only referred to electrical-shock potential. Nonetheless, it is known now that these devices, which emit high UVA and low UVB rays, promote melanoma, nonmelanoma skin cancers, and severe sunburns, as well as aggravate existing conditions (eg, systemic lupus erythematosus).⁴ As a result of an unacceptably high incidence of these disease complications, a 2014 FDA regulation categorized tanning beds as class II, requiring that tanning bed users be informed of the risk of skin cancer in an effort to reverse the growing trend of indoor tanning.¹² Despite these regulatory interventions, it is not clear if this knowledge of cancer risk deters patients from indoor tanning.

The purpose of this study was to investigate the patients’ perspective on indoor tanning behaviors as associated with the severity of their melanoma and the time frame in which they were diagnosed as well as their perceived views on the safety of indoor tanning and the frequency in which they continue to tan indoors. This information is highly relevant in helping to determine if requiring a warning of the risk of skin cancer will deter patients from this unhealthy habit, especially given recent reclassification of sunbeds as class II by the FDA. Additional insights from these data may clarify if indoor tanning decreases the time frame in which melanoma is diagnosed or increases the severity of the resulting melanoma. Moreover, it will help elucidate whether or not the age at which indoor tanning is initiated affects the time frame to melanoma onset and corresponding severity.

Methods

An original unvalidated online survey was conducted worldwide via a link distributed to the following supporting institutions: Advanced Dermatology & Cosmetic Surgery, Ameriderm Research, Melanoma Research Foundation (a melanoma patient advocacy group), Florida State University Department of Dermatology, Moffitt Cancer Center Cutaneous Oncology Program, Cleveland Clinic, Ohio State University Division of Medical Oncology, Harvard Medical School Department of Dermatology, The University of Texas MD Anderson Cancer Center Department of Dermatology, University of Colorado Department of Dermatology, and Northwestern University Department of Dermatology. However, there was not confirmation that all of these institutions promoted the survey. Additionally, respondents were recruited through patient advocacy groups and social media sites including Facebook, Twitter, LinkedIn, Tumblr, and Instagram. The patient advocacy groups and social media sites invited participation through recruitment announcements, including DermNetNZ (a global dermatology patient information site), with additional help from the International Federation of Dermatology Clinical Trial Network.

The survey was restricted to those who were self-identified as 18 years or older and who self-reported a diagnosis of melanoma following the use of indoor tanning devices. The survey was hosted by SurveyMonkey, which allowed consent to be obtained and responses to remain anonymous. Access to the survey was sponsored by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. The University of Central Florida (Orlando, Florida) institutional review board reviewed and approved this study as exempt human research.

Survey responses collected from January 2014 to June 2015 were analyzed herein. The survey contained 58 questions and was divided into different topics including indoor tanning background (eg, states/countries in which participants tanned indoors, age when they first tanned, frequency of tanning), consenting process (eg, length, did someone review the consent with participants, what was contained in the consent), indoor tanning and melanoma (eg, how long after tanning did melanoma develop, age at development, location of melanoma), indoor tanning postmelanoma (eg, did participants tan after diagnosis and why), and other risk factors (eg, did participants smoke or drink pre- or postmelanoma).

Statistical Analysis
The data consist of both categorical and continuous variables. The categorical variables included age (<35 years or ≥35 years), frequency of indoor tanning (≤1 time weekly or >1 time weekly), and onset of melanoma diagnosis (within or after 5 years of indoor tanning). The continuous variables consisted of current age, age at start of indoor tanning, age at melanoma diagnosis, Breslow depth, and Clark level. Frequency of indoor tanning and warning of the risk of skin cancer were converted to be used as both categorical and continuous variables. For frequency of indoor tanning, the variables less than or equal to once weekly and more than once weekly were used as categorical variables, whereas less than monthly, 1 time monthly, 4 times monthly, 2 times weekly, and more than 2 times weekly were used as continuous variables. For warning of the risk of skin cancer, no and yes were converted to 0 and 1 for use in the Spearman correlations, which allowed for greater analyses among other variables. Spearman correlation was used to determine if a significant relationship existed among the age at melanoma diagnosis, age at start of indoor tanning, Breslow depth, Clark level, frequency of indoor and outdoor tanning, and knowledge and warning of the risk of skin cancer. All data were analyzed by use of IBM SPSS Statistics (version 21.0).

Difference in proportions among groups, age, frequency of tanning, onset of melanoma diagnosis within or after 5 years of starting indoor tanning, and knowledge of cancer risks was tested for significance using the χ² test. Reported P values were 2-tailed, corresponding with a significance level of P<.05. All data were analyzed using SPSS (version 21.0). All statistical analyses were conducted independent of the participants’ sex.

Results

Of the 454 participants who accessed the survey, 448 were analyzed in this study; 6 participants did not complete the questionnaire. Both males and females were analyzed: 289 females, 12 males, and 153 who did not report gender. The age range of participants was 18 to 69 years. The age at start of indoor tanning ranged from 8 to 54 years, with a mean of 22 years. Additional participant characteristics are described in Table 1. The mean frequency of indoor tanning was reported as 2 times weekly. When participants were asked if they were warned of the risk of skin cancer, 21.5% reported yes while 78.4% reported not being told of the risk. This knowledge was compared to their frequency of indoor tanning. Having the knowledge of the risk of skin cancer had no influence on their frequency of indoor tanning (Table 2).

Among responders, those who perceived indoor tanning as safer than outdoor tanning tanned indoors more frequently than those who do not (Spearman r=−0.224; P<.05)(Table 3). The frequency of indoor tanning was divided into those who tanned indoors more than once weekly and those who tanned indoors once a week or less. This study showed that the frequency of indoor tanning had no effect on the latency time between the commencement of indoor tanning and diagnosis of melanoma (Table 4). The time frame from the onset of melanoma diagnosis also was compared to the age at which the participants started to tan indoors. Age was divided into those younger than 35 years and those 35 years and older. There was no correlation between the age when indoor tanning began and the time frame in which the melanoma was diagnosed (eTable).

Comment

Thirty million Americans utilize indoor tanning devices at least once a year.¹³ UVA light comprises the majority of the spectrum used by indoor tanning devices, with a fraction (<5%) being UVB light. Until recently, UVB light was the only solar spectrum considered carcinogenic. In 2009, the International Agency for Research on Cancer classified the whole spectrum as carcinogenic to humans.^5,11 Despite this evidence, indoor tanning facilities have promoted indoor tanning as damage free.³ The goal of this study was to collect the patient perspective on the safety of indoor tanning, indoor tanning behaviors, time frame of onset of melanoma, and the severity (ie, Breslow depth) of those melanomas.

Melanoma is the most prevalent cancer in females aged 25 to 29 years.³ The median age of diagnosis of melanoma (with and without the use of indoor tanning devices) is approximately 60 years¹⁴ versus our study, which found the average age at diagnosis was 37.6 years. Our findings are consistent with other literature in that those who start indoor tanning earlier (<35 years of age) develop melanoma at an earlier age.^14,15 Cust et al¹⁴ also promoted the idea that patients develop melanoma earlier because younger individuals are more biologically susceptible to the carcinogenic effects of artificial UV light. However, our study found that those who started indoor tanning at an older age reported being diagnosed with a melanoma of greater Breslow depth, seemingly incongruent with the aforementioned hypothesis. One limitation is the age range for this research sample (18–69 years). The young age range may be attributable to the recruitment through social media, which is geared toward a younger population. Additionally, indoor tanning is a relatively new phenomenon practiced since the 1980s,² which may contribute to the younger sample size. However, 2.7 billion individuals use social media worldwide with 40% of those older than 65 years on social media.¹⁶

Prior research has shown that those who start indoor tanning before the age of 35 years have a 75% increased risk of developing melanoma.¹⁴ Another study also has suggested that UVA-rich sunlamps may shorten the latency period for induction of melanoma and nonmelanoma skin cancers.³ Our study used similar age cutoffs in concluding that there was no earlier onset of melanoma diagnosis between those who started indoor tanning before the age of 35 years and those who started at the age of 35 years or older. Limitations include that our study is cross-sectional, and therefore time course cannot be established. Also, survey responses were self-reported, allowing the possibility of recall bias.

A plethora of research has been conducted to determine if there is a connection between the use of indoor tanning devices and developing melanoma. Cust et al¹⁴ suggested the risk of melanoma was 41% higher for those who had ever used a sunbed in comparison to those who had not. Other studies describe the difficulty in making the connection between indoor tanning and melanoma, as those who more frequently tan indoors also more frequently tan outdoors,¹¹ as suggested by this study. However, there is a paucity of literature on the patients’ perspectives on the safety of indoor tanning. This study determined that those who more frequently tan indoors believed that indoor tanning is safer than outdoor tanning. With this altered perception promoted by the indoor tanning industry, the FDA has added a warning label to all indoor tanning devices about the risk of skin cancer. Our study revealed that having the knowledge of the risk of skin cancer had no influence on the frequency of indoor tanning. This concerning finding highlights a pressing need for an alternative approach to increase awareness of the harmful consequences that accompany indoor tanning. Further studies may elaborate on potential effective methods and messages to relate to an indoor tanning population comprised mostly of young females.

Acknowledgments
Supported and funded by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. This research project was completed as part of the FIRE Module at the University of Central Florida, College of Medicine. We thank the FIRE Module faculty and staff for their assistance with this project.

The incidence of melanoma is increasing at a rate greater than any other cancer,¹ possibly due to the increasing use of indoor tanning devices. These devices emit unnaturally high levels of UVA and low levels of UVA and UVB rays.² The risks of using these devices include increased incidence of melanoma (3438 cases attributed to indoor tanning in 2008) and keratinocytes cancer (increased risk of squamous cell carcinoma by 67% and basal cell carcinoma by 29%), severe sunburns (61.1% of female users and 44.6% of male users have reported sunburns), and aggravation of underlying disorders such as systemic lupus erythematosus.^3-5

The literature varies in its explanation of how indoor tanning increases the risk of developing melanoma. Some authors suggest it is due to increased frequency of use, duration of sessions, and years of using tanning devices.^1,6 Others suggest the increased cancer risk is the result of starting to tan at an earlier age.^2,3,6-10 There is conflicting literature on the level of increased risk of melanoma in those who tan indoors at a young age (<35 years). Although the estimated rate of increased skin cancer risk varies, with rates up to 75% compared to nonusers, nearly all sources support an increased rate.⁶ Despite the growing body of knowledge that indoor tanning is dangerous, as well as the academic publication of these risks (eg, carcinogenesis, short-term and long-term eye injury, burns, UV sensitivity when combined with certain medications), teenagers in the United States and affluent countries appear to disregard the risks of tanning.¹¹

Tanning companies have promoted the misconception that only UVB rays cause cell damage and UVA rays, which the devices emit, result in “damage-free” or “safe” tans.^2,3 Until 2013, indoor tanning devices were classified by the US Food and Drug Administration (FDA) as class I, indicating that they are safe in terms of electrical shock. Many indoor tanning facilities have promoted the FDA “safe” label without clarifying that the safety indications only referred to electrical-shock potential. Nonetheless, it is known now that these devices, which emit high UVA and low UVB rays, promote melanoma, nonmelanoma skin cancers, and severe sunburns, as well as aggravate existing conditions (eg, systemic lupus erythematosus).⁴ As a result of an unacceptably high incidence of these disease complications, a 2014 FDA regulation categorized tanning beds as class II, requiring that tanning bed users be informed of the risk of skin cancer in an effort to reverse the growing trend of indoor tanning.¹² Despite these regulatory interventions, it is not clear if this knowledge of cancer risk deters patients from indoor tanning.

The purpose of this study was to investigate the patients’ perspective on indoor tanning behaviors as associated with the severity of their melanoma and the time frame in which they were diagnosed as well as their perceived views on the safety of indoor tanning and the frequency in which they continue to tan indoors. This information is highly relevant in helping to determine if requiring a warning of the risk of skin cancer will deter patients from this unhealthy habit, especially given recent reclassification of sunbeds as class II by the FDA. Additional insights from these data may clarify if indoor tanning decreases the time frame in which melanoma is diagnosed or increases the severity of the resulting melanoma. Moreover, it will help elucidate whether or not the age at which indoor tanning is initiated affects the time frame to melanoma onset and corresponding severity.

Methods

An original unvalidated online survey was conducted worldwide via a link distributed to the following supporting institutions: Advanced Dermatology & Cosmetic Surgery, Ameriderm Research, Melanoma Research Foundation (a melanoma patient advocacy group), Florida State University Department of Dermatology, Moffitt Cancer Center Cutaneous Oncology Program, Cleveland Clinic, Ohio State University Division of Medical Oncology, Harvard Medical School Department of Dermatology, The University of Texas MD Anderson Cancer Center Department of Dermatology, University of Colorado Department of Dermatology, and Northwestern University Department of Dermatology. However, there was not confirmation that all of these institutions promoted the survey. Additionally, respondents were recruited through patient advocacy groups and social media sites including Facebook, Twitter, LinkedIn, Tumblr, and Instagram. The patient advocacy groups and social media sites invited participation through recruitment announcements, including DermNetNZ (a global dermatology patient information site), with additional help from the International Federation of Dermatology Clinical Trial Network.

The survey was restricted to those who were self-identified as 18 years or older and who self-reported a diagnosis of melanoma following the use of indoor tanning devices. The survey was hosted by SurveyMonkey, which allowed consent to be obtained and responses to remain anonymous. Access to the survey was sponsored by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. The University of Central Florida (Orlando, Florida) institutional review board reviewed and approved this study as exempt human research.

Survey responses collected from January 2014 to June 2015 were analyzed herein. The survey contained 58 questions and was divided into different topics including indoor tanning background (eg, states/countries in which participants tanned indoors, age when they first tanned, frequency of tanning), consenting process (eg, length, did someone review the consent with participants, what was contained in the consent), indoor tanning and melanoma (eg, how long after tanning did melanoma develop, age at development, location of melanoma), indoor tanning postmelanoma (eg, did participants tan after diagnosis and why), and other risk factors (eg, did participants smoke or drink pre- or postmelanoma).

Statistical Analysis
The data consist of both categorical and continuous variables. The categorical variables included age (<35 years or ≥35 years), frequency of indoor tanning (≤1 time weekly or >1 time weekly), and onset of melanoma diagnosis (within or after 5 years of indoor tanning). The continuous variables consisted of current age, age at start of indoor tanning, age at melanoma diagnosis, Breslow depth, and Clark level. Frequency of indoor tanning and warning of the risk of skin cancer were converted to be used as both categorical and continuous variables. For frequency of indoor tanning, the variables less than or equal to once weekly and more than once weekly were used as categorical variables, whereas less than monthly, 1 time monthly, 4 times monthly, 2 times weekly, and more than 2 times weekly were used as continuous variables. For warning of the risk of skin cancer, no and yes were converted to 0 and 1 for use in the Spearman correlations, which allowed for greater analyses among other variables. Spearman correlation was used to determine if a significant relationship existed among the age at melanoma diagnosis, age at start of indoor tanning, Breslow depth, Clark level, frequency of indoor and outdoor tanning, and knowledge and warning of the risk of skin cancer. All data were analyzed by use of IBM SPSS Statistics (version 21.0).

Difference in proportions among groups, age, frequency of tanning, onset of melanoma diagnosis within or after 5 years of starting indoor tanning, and knowledge of cancer risks was tested for significance using the χ² test. Reported P values were 2-tailed, corresponding with a significance level of P<.05. All data were analyzed using SPSS (version 21.0). All statistical analyses were conducted independent of the participants’ sex.

Results

Of the 454 participants who accessed the survey, 448 were analyzed in this study; 6 participants did not complete the questionnaire. Both males and females were analyzed: 289 females, 12 males, and 153 who did not report gender. The age range of participants was 18 to 69 years. The age at start of indoor tanning ranged from 8 to 54 years, with a mean of 22 years. Additional participant characteristics are described in Table 1. The mean frequency of indoor tanning was reported as 2 times weekly. When participants were asked if they were warned of the risk of skin cancer, 21.5% reported yes while 78.4% reported not being told of the risk. This knowledge was compared to their frequency of indoor tanning. Having the knowledge of the risk of skin cancer had no influence on their frequency of indoor tanning (Table 2).

Among responders, those who perceived indoor tanning as safer than outdoor tanning tanned indoors more frequently than those who do not (Spearman r=−0.224; P<.05)(Table 3). The frequency of indoor tanning was divided into those who tanned indoors more than once weekly and those who tanned indoors once a week or less. This study showed that the frequency of indoor tanning had no effect on the latency time between the commencement of indoor tanning and diagnosis of melanoma (Table 4). The time frame from the onset of melanoma diagnosis also was compared to the age at which the participants started to tan indoors. Age was divided into those younger than 35 years and those 35 years and older. There was no correlation between the age when indoor tanning began and the time frame in which the melanoma was diagnosed (eTable).

Comment

Thirty million Americans utilize indoor tanning devices at least once a year.¹³ UVA light comprises the majority of the spectrum used by indoor tanning devices, with a fraction (<5%) being UVB light. Until recently, UVB light was the only solar spectrum considered carcinogenic. In 2009, the International Agency for Research on Cancer classified the whole spectrum as carcinogenic to humans.^5,11 Despite this evidence, indoor tanning facilities have promoted indoor tanning as damage free.³ The goal of this study was to collect the patient perspective on the safety of indoor tanning, indoor tanning behaviors, time frame of onset of melanoma, and the severity (ie, Breslow depth) of those melanomas.

Melanoma is the most prevalent cancer in females aged 25 to 29 years.³ The median age of diagnosis of melanoma (with and without the use of indoor tanning devices) is approximately 60 years¹⁴ versus our study, which found the average age at diagnosis was 37.6 years. Our findings are consistent with other literature in that those who start indoor tanning earlier (<35 years of age) develop melanoma at an earlier age.^14,15 Cust et al¹⁴ also promoted the idea that patients develop melanoma earlier because younger individuals are more biologically susceptible to the carcinogenic effects of artificial UV light. However, our study found that those who started indoor tanning at an older age reported being diagnosed with a melanoma of greater Breslow depth, seemingly incongruent with the aforementioned hypothesis. One limitation is the age range for this research sample (18–69 years). The young age range may be attributable to the recruitment through social media, which is geared toward a younger population. Additionally, indoor tanning is a relatively new phenomenon practiced since the 1980s,² which may contribute to the younger sample size. However, 2.7 billion individuals use social media worldwide with 40% of those older than 65 years on social media.¹⁶

Prior research has shown that those who start indoor tanning before the age of 35 years have a 75% increased risk of developing melanoma.¹⁴ Another study also has suggested that UVA-rich sunlamps may shorten the latency period for induction of melanoma and nonmelanoma skin cancers.³ Our study used similar age cutoffs in concluding that there was no earlier onset of melanoma diagnosis between those who started indoor tanning before the age of 35 years and those who started at the age of 35 years or older. Limitations include that our study is cross-sectional, and therefore time course cannot be established. Also, survey responses were self-reported, allowing the possibility of recall bias.

A plethora of research has been conducted to determine if there is a connection between the use of indoor tanning devices and developing melanoma. Cust et al¹⁴ suggested the risk of melanoma was 41% higher for those who had ever used a sunbed in comparison to those who had not. Other studies describe the difficulty in making the connection between indoor tanning and melanoma, as those who more frequently tan indoors also more frequently tan outdoors,¹¹ as suggested by this study. However, there is a paucity of literature on the patients’ perspectives on the safety of indoor tanning. This study determined that those who more frequently tan indoors believed that indoor tanning is safer than outdoor tanning. With this altered perception promoted by the indoor tanning industry, the FDA has added a warning label to all indoor tanning devices about the risk of skin cancer. Our study revealed that having the knowledge of the risk of skin cancer had no influence on the frequency of indoor tanning. This concerning finding highlights a pressing need for an alternative approach to increase awareness of the harmful consequences that accompany indoor tanning. Further studies may elaborate on potential effective methods and messages to relate to an indoor tanning population comprised mostly of young females.

Acknowledgments
Supported and funded by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. This research project was completed as part of the FIRE Module at the University of Central Florida, College of Medicine. We thank the FIRE Module faculty and staff for their assistance with this project.

The incidence of melanoma is increasing at a rate greater than any other cancer,¹ possibly due to the increasing use of indoor tanning devices. These devices emit unnaturally high levels of UVA and low levels of UVA and UVB rays.² The risks of using these devices include increased incidence of melanoma (3438 cases attributed to indoor tanning in 2008) and keratinocytes cancer (increased risk of squamous cell carcinoma by 67% and basal cell carcinoma by 29%), severe sunburns (61.1% of female users and 44.6% of male users have reported sunburns), and aggravation of underlying disorders such as systemic lupus erythematosus.^3-5

The literature varies in its explanation of how indoor tanning increases the risk of developing melanoma. Some authors suggest it is due to increased frequency of use, duration of sessions, and years of using tanning devices.^1,6 Others suggest the increased cancer risk is the result of starting to tan at an earlier age.^2,3,6-10 There is conflicting literature on the level of increased risk of melanoma in those who tan indoors at a young age (<35 years). Although the estimated rate of increased skin cancer risk varies, with rates up to 75% compared to nonusers, nearly all sources support an increased rate.⁶ Despite the growing body of knowledge that indoor tanning is dangerous, as well as the academic publication of these risks (eg, carcinogenesis, short-term and long-term eye injury, burns, UV sensitivity when combined with certain medications), teenagers in the United States and affluent countries appear to disregard the risks of tanning.¹¹

Tanning companies have promoted the misconception that only UVB rays cause cell damage and UVA rays, which the devices emit, result in “damage-free” or “safe” tans.^2,3 Until 2013, indoor tanning devices were classified by the US Food and Drug Administration (FDA) as class I, indicating that they are safe in terms of electrical shock. Many indoor tanning facilities have promoted the FDA “safe” label without clarifying that the safety indications only referred to electrical-shock potential. Nonetheless, it is known now that these devices, which emit high UVA and low UVB rays, promote melanoma, nonmelanoma skin cancers, and severe sunburns, as well as aggravate existing conditions (eg, systemic lupus erythematosus).⁴ As a result of an unacceptably high incidence of these disease complications, a 2014 FDA regulation categorized tanning beds as class II, requiring that tanning bed users be informed of the risk of skin cancer in an effort to reverse the growing trend of indoor tanning.¹² Despite these regulatory interventions, it is not clear if this knowledge of cancer risk deters patients from indoor tanning.

The purpose of this study was to investigate the patients’ perspective on indoor tanning behaviors as associated with the severity of their melanoma and the time frame in which they were diagnosed as well as their perceived views on the safety of indoor tanning and the frequency in which they continue to tan indoors. This information is highly relevant in helping to determine if requiring a warning of the risk of skin cancer will deter patients from this unhealthy habit, especially given recent reclassification of sunbeds as class II by the FDA. Additional insights from these data may clarify if indoor tanning decreases the time frame in which melanoma is diagnosed or increases the severity of the resulting melanoma. Moreover, it will help elucidate whether or not the age at which indoor tanning is initiated affects the time frame to melanoma onset and corresponding severity.

Methods

An original unvalidated online survey was conducted worldwide via a link distributed to the following supporting institutions: Advanced Dermatology & Cosmetic Surgery, Ameriderm Research, Melanoma Research Foundation (a melanoma patient advocacy group), Florida State University Department of Dermatology, Moffitt Cancer Center Cutaneous Oncology Program, Cleveland Clinic, Ohio State University Division of Medical Oncology, Harvard Medical School Department of Dermatology, The University of Texas MD Anderson Cancer Center Department of Dermatology, University of Colorado Department of Dermatology, and Northwestern University Department of Dermatology. However, there was not confirmation that all of these institutions promoted the survey. Additionally, respondents were recruited through patient advocacy groups and social media sites including Facebook, Twitter, LinkedIn, Tumblr, and Instagram. The patient advocacy groups and social media sites invited participation through recruitment announcements, including DermNetNZ (a global dermatology patient information site), with additional help from the International Federation of Dermatology Clinical Trial Network.

The survey was restricted to those who were self-identified as 18 years or older and who self-reported a diagnosis of melanoma following the use of indoor tanning devices. The survey was hosted by SurveyMonkey, which allowed consent to be obtained and responses to remain anonymous. Access to the survey was sponsored by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. The University of Central Florida (Orlando, Florida) institutional review board reviewed and approved this study as exempt human research.

Survey responses collected from January 2014 to June 2015 were analyzed herein. The survey contained 58 questions and was divided into different topics including indoor tanning background (eg, states/countries in which participants tanned indoors, age when they first tanned, frequency of tanning), consenting process (eg, length, did someone review the consent with participants, what was contained in the consent), indoor tanning and melanoma (eg, how long after tanning did melanoma develop, age at development, location of melanoma), indoor tanning postmelanoma (eg, did participants tan after diagnosis and why), and other risk factors (eg, did participants smoke or drink pre- or postmelanoma).

Statistical Analysis
The data consist of both categorical and continuous variables. The categorical variables included age (<35 years or ≥35 years), frequency of indoor tanning (≤1 time weekly or >1 time weekly), and onset of melanoma diagnosis (within or after 5 years of indoor tanning). The continuous variables consisted of current age, age at start of indoor tanning, age at melanoma diagnosis, Breslow depth, and Clark level. Frequency of indoor tanning and warning of the risk of skin cancer were converted to be used as both categorical and continuous variables. For frequency of indoor tanning, the variables less than or equal to once weekly and more than once weekly were used as categorical variables, whereas less than monthly, 1 time monthly, 4 times monthly, 2 times weekly, and more than 2 times weekly were used as continuous variables. For warning of the risk of skin cancer, no and yes were converted to 0 and 1 for use in the Spearman correlations, which allowed for greater analyses among other variables. Spearman correlation was used to determine if a significant relationship existed among the age at melanoma diagnosis, age at start of indoor tanning, Breslow depth, Clark level, frequency of indoor and outdoor tanning, and knowledge and warning of the risk of skin cancer. All data were analyzed by use of IBM SPSS Statistics (version 21.0).

Difference in proportions among groups, age, frequency of tanning, onset of melanoma diagnosis within or after 5 years of starting indoor tanning, and knowledge of cancer risks was tested for significance using the χ² test. Reported P values were 2-tailed, corresponding with a significance level of P<.05. All data were analyzed using SPSS (version 21.0). All statistical analyses were conducted independent of the participants’ sex.

Results

Of the 454 participants who accessed the survey, 448 were analyzed in this study; 6 participants did not complete the questionnaire. Both males and females were analyzed: 289 females, 12 males, and 153 who did not report gender. The age range of participants was 18 to 69 years. The age at start of indoor tanning ranged from 8 to 54 years, with a mean of 22 years. Additional participant characteristics are described in Table 1. The mean frequency of indoor tanning was reported as 2 times weekly. When participants were asked if they were warned of the risk of skin cancer, 21.5% reported yes while 78.4% reported not being told of the risk. This knowledge was compared to their frequency of indoor tanning. Having the knowledge of the risk of skin cancer had no influence on their frequency of indoor tanning (Table 2).

Among responders, those who perceived indoor tanning as safer than outdoor tanning tanned indoors more frequently than those who do not (Spearman r=−0.224; P<.05)(Table 3). The frequency of indoor tanning was divided into those who tanned indoors more than once weekly and those who tanned indoors once a week or less. This study showed that the frequency of indoor tanning had no effect on the latency time between the commencement of indoor tanning and diagnosis of melanoma (Table 4). The time frame from the onset of melanoma diagnosis also was compared to the age at which the participants started to tan indoors. Age was divided into those younger than 35 years and those 35 years and older. There was no correlation between the age when indoor tanning began and the time frame in which the melanoma was diagnosed (eTable).

Comment

Thirty million Americans utilize indoor tanning devices at least once a year.¹³ UVA light comprises the majority of the spectrum used by indoor tanning devices, with a fraction (<5%) being UVB light. Until recently, UVB light was the only solar spectrum considered carcinogenic. In 2009, the International Agency for Research on Cancer classified the whole spectrum as carcinogenic to humans.^5,11 Despite this evidence, indoor tanning facilities have promoted indoor tanning as damage free.³ The goal of this study was to collect the patient perspective on the safety of indoor tanning, indoor tanning behaviors, time frame of onset of melanoma, and the severity (ie, Breslow depth) of those melanomas.

Melanoma is the most prevalent cancer in females aged 25 to 29 years.³ The median age of diagnosis of melanoma (with and without the use of indoor tanning devices) is approximately 60 years¹⁴ versus our study, which found the average age at diagnosis was 37.6 years. Our findings are consistent with other literature in that those who start indoor tanning earlier (<35 years of age) develop melanoma at an earlier age.^14,15 Cust et al¹⁴ also promoted the idea that patients develop melanoma earlier because younger individuals are more biologically susceptible to the carcinogenic effects of artificial UV light. However, our study found that those who started indoor tanning at an older age reported being diagnosed with a melanoma of greater Breslow depth, seemingly incongruent with the aforementioned hypothesis. One limitation is the age range for this research sample (18–69 years). The young age range may be attributable to the recruitment through social media, which is geared toward a younger population. Additionally, indoor tanning is a relatively new phenomenon practiced since the 1980s,² which may contribute to the younger sample size. However, 2.7 billion individuals use social media worldwide with 40% of those older than 65 years on social media.¹⁶

Prior research has shown that those who start indoor tanning before the age of 35 years have a 75% increased risk of developing melanoma.¹⁴ Another study also has suggested that UVA-rich sunlamps may shorten the latency period for induction of melanoma and nonmelanoma skin cancers.³ Our study used similar age cutoffs in concluding that there was no earlier onset of melanoma diagnosis between those who started indoor tanning before the age of 35 years and those who started at the age of 35 years or older. Limitations include that our study is cross-sectional, and therefore time course cannot be established. Also, survey responses were self-reported, allowing the possibility of recall bias.

A plethora of research has been conducted to determine if there is a connection between the use of indoor tanning devices and developing melanoma. Cust et al¹⁴ suggested the risk of melanoma was 41% higher for those who had ever used a sunbed in comparison to those who had not. Other studies describe the difficulty in making the connection between indoor tanning and melanoma, as those who more frequently tan indoors also more frequently tan outdoors,¹¹ as suggested by this study. However, there is a paucity of literature on the patients’ perspectives on the safety of indoor tanning. This study determined that those who more frequently tan indoors believed that indoor tanning is safer than outdoor tanning. With this altered perception promoted by the indoor tanning industry, the FDA has added a warning label to all indoor tanning devices about the risk of skin cancer. Our study revealed that having the knowledge of the risk of skin cancer had no influence on the frequency of indoor tanning. This concerning finding highlights a pressing need for an alternative approach to increase awareness of the harmful consequences that accompany indoor tanning. Further studies may elaborate on potential effective methods and messages to relate to an indoor tanning population comprised mostly of young females.

Acknowledgments
Supported and funded by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. This research project was completed as part of the FIRE Module at the University of Central Florida, College of Medicine. We thank the FIRE Module faculty and staff for their assistance with this project.

The Food and Drug Administration has approved nivolumab for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection.

Nivolumab was previously approved for the treatment of patients with unresectable or metastatic melanoma, the FDA said in a press statement.

Approval was based on results from the CHECKMATE-238 trial, where 906 patients with completely resected stage IIIB/C or stage IV melanoma received either nivolumab or ipilimumab for up to 1 year. Recurrence-free survival was superior in patients who received nivolumab, with 34% of patients in the nivolumab group experiencing recurrence/death, compared to 45.5% in the ipilimumab group.

Wikimedia Commons/FitzColinGerald/Creative Commons License

lfranki@frontlinemedcom.com

The Food and Drug Administration has approved nivolumab for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection.

Nivolumab was previously approved for the treatment of patients with unresectable or metastatic melanoma, the FDA said in a press statement.

Approval was based on results from the CHECKMATE-238 trial, where 906 patients with completely resected stage IIIB/C or stage IV melanoma received either nivolumab or ipilimumab for up to 1 year. Recurrence-free survival was superior in patients who received nivolumab, with 34% of patients in the nivolumab group experiencing recurrence/death, compared to 45.5% in the ipilimumab group.

Wikimedia Commons/FitzColinGerald/Creative Commons License

lfranki@frontlinemedcom.com

The Food and Drug Administration has approved nivolumab for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection.

Nivolumab was previously approved for the treatment of patients with unresectable or metastatic melanoma, the FDA said in a press statement.

Approval was based on results from the CHECKMATE-238 trial, where 906 patients with completely resected stage IIIB/C or stage IV melanoma received either nivolumab or ipilimumab for up to 1 year. Recurrence-free survival was superior in patients who received nivolumab, with 34% of patients in the nivolumab group experiencing recurrence/death, compared to 45.5% in the ipilimumab group.

Wikimedia Commons/FitzColinGerald/Creative Commons License

lfranki@frontlinemedcom.com

Skin adnexal tumors (SAT) are rare tumors that make up about 1%-2% of all cutaneous malignancies. They represent a various group of benign and malignant tumors that arise from skin adnexal epithelial structures: hair follicle, pilosebaceous unit, and apocrine or eccrine sweat glands. Although this derivation provides a practical basis for classification, some tumors may exhibit a mixed or more than one line of differentiation, rendering precise classification of those neoplasms difficult, and such cases should be categorized according to prevailing phenotype. In this report, we present a patient with metastatic eccrine carcinoma. Clinical experience for metastatic disease treatment is derived from a few reports, and there are no universal treatment guidelines. Given the few reported cases and the absence of randomized clinical trials for these patients, it is important to collect clinical experiences.

Case presentation and summary

A 56-year-old African man presented with a 5-week history of multiple nontender subcutaneous skin nodules all over his body except for his palms and soles, and associated with generalized itching. He had a mass in the sole of his right foot 35 years previously in another country. The mass had recurred 15 years later and was excised again. The exact etiology of the mass was unknown to the patient. He had no other medical problems. He was on no medications and did not smoke, drink, or use recreational drugs.

His vital signs on admission were normal. Examination was significant for innumerable superficial skin nodules in the scalp, back, torso, and abdomen. The largest was in the neck and measured 4 x 2 cm. A firm right inguinal mass of 7 x 4 cm was palpable. An abdominal exam revealed large ascites but no organomegaly.

The results of laboratory tests were significant for hyponatremia 126 mEq/L (normal, 135-145), hypercalcemia of 12.2 mg/dL (8.5-10.5), with normal phosphorous of 2.5 mg/dL (2.5-4.5), parathyroid of 11.5 pg/ml (6-65), and low vitamin D level of <7 ng/ml (30-100). Other test results were: carcinoembryonic antigen (CEA), 4.36 ng/ml (0.00-2.99); alpha fetoprotein, 2.39 IU/ml (0.00-9.0); calcium 11.6 mg/dL (8.5-10.2); lactate dehydrogenase, 325 U/L (85-210); aspartate aminotransferase, 59 U/L (0-40); alanine aminotransferase 43 U/L (5-35); alkaline phosphatase, 65 u/L (50-120); albumin, 2.7 g/dL (3.8-5.2); white blood cell count, 14.1 k/uL (4.4-10.6); hemoglobin, 12.6 g/dL; and platelets, 339 k/uL (161-369).

A chest and abdomen computed-tomography scan on presentation showed presence of innumerable subcutaneous and intramuscular nodules throughout the chest, abdomen, and pelvis (Figure 1).

Discussion

Sweat gland carcinomas are very rare malignant tumors of the adnexal epithelial structures of the skin, sebaceous, hair follicle, apocrine or eccrine glands that were first described by Cornil in 1865.¹ They occur primarily in adult patients, with a peak incidence in fifth and sixth decades of life.^2,3 The etiology is unknown, but some cases have been reported to be a consequence of radiation therapy.⁴ They are almost always an incidental histologic diagnosis.^2,5 The tumors usually appear as single nodule, and multinodularity usually associated with both local and metastatic disease.⁶ There are no characteristic findings to suggest that a particular nodule may represent sweat gland carcinoma, and even if sweat gland tumor is suspected, benign counterparts are more common.

Eccrine carcinoma is the most aggressive among skin adnexal tumors. They can arise on the lower limbs, trunk, head and neck, scalp and ears, upper extremities, abdomen, and genital sites.⁷

The cells of eccrine sweat glands express low molecular weight keratin, epithelial membrane antigen, carcinoembryonic antigen, as well as S100 protein, smooth muscle actin, p63, calponin, cytokeratin 14, and bcl-2.⁸ Skin tumors with eccrine differentiation may stain for estrogen and progesterone, which has important clinical implications because those patients can be treated with hormonal therapy.⁹ Positivity for estrogen receptors does not differentiate cutaneous eccrine tumors from cutaneous metastases of breast cancers.^8,9 Androgen receptor evaluation in these cases can help distinguish between the two.¹⁰ Human epidermal growth factor receptor 2 (HER-2) is expressed in 3.5% of skin adnexal tumors.¹¹

The molecular pathogenesis of malignant adnexal tumors is not clear, but overexpression of tumor suppressor protein p16 has been described as a common feature in eccrine carcinomas.¹²

Prognostic factors for sweat gland carcinoma are difficult to identify, because of the small number of reported cases. The likely prognostic factors include size, histological type, lymph node involvement, and presence of distant metastasis. Absent of lymph node involvement correlates with 10-year disease-free survival rate of 56%, which falls to 9% if nodes are involved.¹³

There are no uniform guidelines for the treatment sweat gland carcinomas, and the clinical experience described in the literature is the only source of available information.

The treatment of choice of all subtypes of localized sweat gland carcinomas is wide surgical excision with broad tumor margins, given the propensity for local recurrences along with regional lymph node dissection in the presence of clinically positive nodes. Prophylactic lymph node resection does not seem to improve survival or decrease recurrence rates.⁷ The use of adjuvant radiotherapy to prevent local recurrence also is not well established. One report suggested radiosensitivity of these tumors, and adjuvant radiation was therefore recommended in high-risk cases (ie, large tumors of 5 cm and positive surgical margins of 1 cm) and moderate to poorly differentiated tumors with lymphovascular invasion.¹⁴ Adjuvant radiation to the involved lymph node basin is suggested in the setting of extranodal extension or extensive involvement, that is, 4 lymph nodes.¹⁵ The role of lymphadenectomy has not been adequately addressed in the literature.

The role of chemotherapy in metastatic disease is not clear, but sweat gland carcinomas are considered chemoresistant (Table). Several combinations have been used with short-term responses. In one case treated with doxorubicin, mitomycin, vincristine, and 5-FU followed by maintenance therapy, the patient achieved a complete response that lasted for 16 months.¹⁶ In another report, the treatment response was 2 years with treatment consisted of anthracyclin, cyclophosphamide, vincristine, and bloemycin.¹⁷ Other combinations used in the literature include carboplatin and paclitaxel, which led to prolonged remission.¹⁴ Cisplatin and 5-FU, or cisplatin plus cetuximab have been reported but with discouraging results.¹⁸ Results to taxanes showed conflicting results.^19,20

Skin adnexal tumors (SAT) are rare tumors that make up about 1%-2% of all cutaneous malignancies. They represent a various group of benign and malignant tumors that arise from skin adnexal epithelial structures: hair follicle, pilosebaceous unit, and apocrine or eccrine sweat glands. Although this derivation provides a practical basis for classification, some tumors may exhibit a mixed or more than one line of differentiation, rendering precise classification of those neoplasms difficult, and such cases should be categorized according to prevailing phenotype. In this report, we present a patient with metastatic eccrine carcinoma. Clinical experience for metastatic disease treatment is derived from a few reports, and there are no universal treatment guidelines. Given the few reported cases and the absence of randomized clinical trials for these patients, it is important to collect clinical experiences.

Case presentation and summary

A 56-year-old African man presented with a 5-week history of multiple nontender subcutaneous skin nodules all over his body except for his palms and soles, and associated with generalized itching. He had a mass in the sole of his right foot 35 years previously in another country. The mass had recurred 15 years later and was excised again. The exact etiology of the mass was unknown to the patient. He had no other medical problems. He was on no medications and did not smoke, drink, or use recreational drugs.

His vital signs on admission were normal. Examination was significant for innumerable superficial skin nodules in the scalp, back, torso, and abdomen. The largest was in the neck and measured 4 x 2 cm. A firm right inguinal mass of 7 x 4 cm was palpable. An abdominal exam revealed large ascites but no organomegaly.

The results of laboratory tests were significant for hyponatremia 126 mEq/L (normal, 135-145), hypercalcemia of 12.2 mg/dL (8.5-10.5), with normal phosphorous of 2.5 mg/dL (2.5-4.5), parathyroid of 11.5 pg/ml (6-65), and low vitamin D level of <7 ng/ml (30-100). Other test results were: carcinoembryonic antigen (CEA), 4.36 ng/ml (0.00-2.99); alpha fetoprotein, 2.39 IU/ml (0.00-9.0); calcium 11.6 mg/dL (8.5-10.2); lactate dehydrogenase, 325 U/L (85-210); aspartate aminotransferase, 59 U/L (0-40); alanine aminotransferase 43 U/L (5-35); alkaline phosphatase, 65 u/L (50-120); albumin, 2.7 g/dL (3.8-5.2); white blood cell count, 14.1 k/uL (4.4-10.6); hemoglobin, 12.6 g/dL; and platelets, 339 k/uL (161-369).

A chest and abdomen computed-tomography scan on presentation showed presence of innumerable subcutaneous and intramuscular nodules throughout the chest, abdomen, and pelvis (Figure 1).

Discussion

Sweat gland carcinomas are very rare malignant tumors of the adnexal epithelial structures of the skin, sebaceous, hair follicle, apocrine or eccrine glands that were first described by Cornil in 1865.¹ They occur primarily in adult patients, with a peak incidence in fifth and sixth decades of life.^2,3 The etiology is unknown, but some cases have been reported to be a consequence of radiation therapy.⁴ They are almost always an incidental histologic diagnosis.^2,5 The tumors usually appear as single nodule, and multinodularity usually associated with both local and metastatic disease.⁶ There are no characteristic findings to suggest that a particular nodule may represent sweat gland carcinoma, and even if sweat gland tumor is suspected, benign counterparts are more common.

Eccrine carcinoma is the most aggressive among skin adnexal tumors. They can arise on the lower limbs, trunk, head and neck, scalp and ears, upper extremities, abdomen, and genital sites.⁷

The cells of eccrine sweat glands express low molecular weight keratin, epithelial membrane antigen, carcinoembryonic antigen, as well as S100 protein, smooth muscle actin, p63, calponin, cytokeratin 14, and bcl-2.⁸ Skin tumors with eccrine differentiation may stain for estrogen and progesterone, which has important clinical implications because those patients can be treated with hormonal therapy.⁹ Positivity for estrogen receptors does not differentiate cutaneous eccrine tumors from cutaneous metastases of breast cancers.^8,9 Androgen receptor evaluation in these cases can help distinguish between the two.¹⁰ Human epidermal growth factor receptor 2 (HER-2) is expressed in 3.5% of skin adnexal tumors.¹¹

The molecular pathogenesis of malignant adnexal tumors is not clear, but overexpression of tumor suppressor protein p16 has been described as a common feature in eccrine carcinomas.¹²

Prognostic factors for sweat gland carcinoma are difficult to identify, because of the small number of reported cases. The likely prognostic factors include size, histological type, lymph node involvement, and presence of distant metastasis. Absent of lymph node involvement correlates with 10-year disease-free survival rate of 56%, which falls to 9% if nodes are involved.¹³

There are no uniform guidelines for the treatment sweat gland carcinomas, and the clinical experience described in the literature is the only source of available information.

The treatment of choice of all subtypes of localized sweat gland carcinomas is wide surgical excision with broad tumor margins, given the propensity for local recurrences along with regional lymph node dissection in the presence of clinically positive nodes. Prophylactic lymph node resection does not seem to improve survival or decrease recurrence rates.⁷ The use of adjuvant radiotherapy to prevent local recurrence also is not well established. One report suggested radiosensitivity of these tumors, and adjuvant radiation was therefore recommended in high-risk cases (ie, large tumors of 5 cm and positive surgical margins of 1 cm) and moderate to poorly differentiated tumors with lymphovascular invasion.¹⁴ Adjuvant radiation to the involved lymph node basin is suggested in the setting of extranodal extension or extensive involvement, that is, 4 lymph nodes.¹⁵ The role of lymphadenectomy has not been adequately addressed in the literature.

The role of chemotherapy in metastatic disease is not clear, but sweat gland carcinomas are considered chemoresistant (Table). Several combinations have been used with short-term responses. In one case treated with doxorubicin, mitomycin, vincristine, and 5-FU followed by maintenance therapy, the patient achieved a complete response that lasted for 16 months.¹⁶ In another report, the treatment response was 2 years with treatment consisted of anthracyclin, cyclophosphamide, vincristine, and bloemycin.¹⁷ Other combinations used in the literature include carboplatin and paclitaxel, which led to prolonged remission.¹⁴ Cisplatin and 5-FU, or cisplatin plus cetuximab have been reported but with discouraging results.¹⁸ Results to taxanes showed conflicting results.^19,20

Skin adnexal tumors (SAT) are rare tumors that make up about 1%-2% of all cutaneous malignancies. They represent a various group of benign and malignant tumors that arise from skin adnexal epithelial structures: hair follicle, pilosebaceous unit, and apocrine or eccrine sweat glands. Although this derivation provides a practical basis for classification, some tumors may exhibit a mixed or more than one line of differentiation, rendering precise classification of those neoplasms difficult, and such cases should be categorized according to prevailing phenotype. In this report, we present a patient with metastatic eccrine carcinoma. Clinical experience for metastatic disease treatment is derived from a few reports, and there are no universal treatment guidelines. Given the few reported cases and the absence of randomized clinical trials for these patients, it is important to collect clinical experiences.

Case presentation and summary

A 56-year-old African man presented with a 5-week history of multiple nontender subcutaneous skin nodules all over his body except for his palms and soles, and associated with generalized itching. He had a mass in the sole of his right foot 35 years previously in another country. The mass had recurred 15 years later and was excised again. The exact etiology of the mass was unknown to the patient. He had no other medical problems. He was on no medications and did not smoke, drink, or use recreational drugs.

His vital signs on admission were normal. Examination was significant for innumerable superficial skin nodules in the scalp, back, torso, and abdomen. The largest was in the neck and measured 4 x 2 cm. A firm right inguinal mass of 7 x 4 cm was palpable. An abdominal exam revealed large ascites but no organomegaly.

The results of laboratory tests were significant for hyponatremia 126 mEq/L (normal, 135-145), hypercalcemia of 12.2 mg/dL (8.5-10.5), with normal phosphorous of 2.5 mg/dL (2.5-4.5), parathyroid of 11.5 pg/ml (6-65), and low vitamin D level of <7 ng/ml (30-100). Other test results were: carcinoembryonic antigen (CEA), 4.36 ng/ml (0.00-2.99); alpha fetoprotein, 2.39 IU/ml (0.00-9.0); calcium 11.6 mg/dL (8.5-10.2); lactate dehydrogenase, 325 U/L (85-210); aspartate aminotransferase, 59 U/L (0-40); alanine aminotransferase 43 U/L (5-35); alkaline phosphatase, 65 u/L (50-120); albumin, 2.7 g/dL (3.8-5.2); white blood cell count, 14.1 k/uL (4.4-10.6); hemoglobin, 12.6 g/dL; and platelets, 339 k/uL (161-369).

A chest and abdomen computed-tomography scan on presentation showed presence of innumerable subcutaneous and intramuscular nodules throughout the chest, abdomen, and pelvis (Figure 1).

Discussion

Sweat gland carcinomas are very rare malignant tumors of the adnexal epithelial structures of the skin, sebaceous, hair follicle, apocrine or eccrine glands that were first described by Cornil in 1865.¹ They occur primarily in adult patients, with a peak incidence in fifth and sixth decades of life.^2,3 The etiology is unknown, but some cases have been reported to be a consequence of radiation therapy.⁴ They are almost always an incidental histologic diagnosis.^2,5 The tumors usually appear as single nodule, and multinodularity usually associated with both local and metastatic disease.⁶ There are no characteristic findings to suggest that a particular nodule may represent sweat gland carcinoma, and even if sweat gland tumor is suspected, benign counterparts are more common.

Eccrine carcinoma is the most aggressive among skin adnexal tumors. They can arise on the lower limbs, trunk, head and neck, scalp and ears, upper extremities, abdomen, and genital sites.⁷

The cells of eccrine sweat glands express low molecular weight keratin, epithelial membrane antigen, carcinoembryonic antigen, as well as S100 protein, smooth muscle actin, p63, calponin, cytokeratin 14, and bcl-2.⁸ Skin tumors with eccrine differentiation may stain for estrogen and progesterone, which has important clinical implications because those patients can be treated with hormonal therapy.⁹ Positivity for estrogen receptors does not differentiate cutaneous eccrine tumors from cutaneous metastases of breast cancers.^8,9 Androgen receptor evaluation in these cases can help distinguish between the two.¹⁰ Human epidermal growth factor receptor 2 (HER-2) is expressed in 3.5% of skin adnexal tumors.¹¹

The molecular pathogenesis of malignant adnexal tumors is not clear, but overexpression of tumor suppressor protein p16 has been described as a common feature in eccrine carcinomas.¹²

Prognostic factors for sweat gland carcinoma are difficult to identify, because of the small number of reported cases. The likely prognostic factors include size, histological type, lymph node involvement, and presence of distant metastasis. Absent of lymph node involvement correlates with 10-year disease-free survival rate of 56%, which falls to 9% if nodes are involved.¹³

There are no uniform guidelines for the treatment sweat gland carcinomas, and the clinical experience described in the literature is the only source of available information.

The treatment of choice of all subtypes of localized sweat gland carcinomas is wide surgical excision with broad tumor margins, given the propensity for local recurrences along with regional lymph node dissection in the presence of clinically positive nodes. Prophylactic lymph node resection does not seem to improve survival or decrease recurrence rates.⁷ The use of adjuvant radiotherapy to prevent local recurrence also is not well established. One report suggested radiosensitivity of these tumors, and adjuvant radiation was therefore recommended in high-risk cases (ie, large tumors of 5 cm and positive surgical margins of 1 cm) and moderate to poorly differentiated tumors with lymphovascular invasion.¹⁴ Adjuvant radiation to the involved lymph node basin is suggested in the setting of extranodal extension or extensive involvement, that is, 4 lymph nodes.¹⁵ The role of lymphadenectomy has not been adequately addressed in the literature.

The role of chemotherapy in metastatic disease is not clear, but sweat gland carcinomas are considered chemoresistant (Table). Several combinations have been used with short-term responses. In one case treated with doxorubicin, mitomycin, vincristine, and 5-FU followed by maintenance therapy, the patient achieved a complete response that lasted for 16 months.¹⁶ In another report, the treatment response was 2 years with treatment consisted of anthracyclin, cyclophosphamide, vincristine, and bloemycin.¹⁷ Other combinations used in the literature include carboplatin and paclitaxel, which led to prolonged remission.¹⁴ Cisplatin and 5-FU, or cisplatin plus cetuximab have been reported but with discouraging results.¹⁸ Results to taxanes showed conflicting results.^19,20

NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.

Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.

Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.

In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).

During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.

Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.

Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.

“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.

In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.

A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.

In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).

“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.

The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.

“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.

Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.

sworcester@frontlinemedcom.com

NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.

Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.

Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.

In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).

During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.

Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.

Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.

“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.

In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.

A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.

In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).

“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.

The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.

“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.

Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.

sworcester@frontlinemedcom.com

NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.

Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.

Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.

In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).

During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.

Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.

Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.

“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.

In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.

A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.

In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).

“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.

The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.

“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.

Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.

sworcester@frontlinemedcom.com

Coastal travel accounts for 80% of all tourism worldwide, a number that continues to grow. The number of travelers to the Mediterranean Sea alone is expected to rise to 350 million individuals per year within the next 20 years.¹ As the number of tourists visiting the world’s oceans increases, the rate of sunscreen unintentionally washed into these marine environments also rises. One study estimated that approximately one-quarter of the sunscreen applied to the skin is washed off over a 20-minute period spent in the water.² Four of the most common sunscreen agents—benzophenone-3 (BP-3), 4-methylbenzylidene camphor (4-MBC), and the nanoparticles titanium dioxide and zinc oxide—have been considered to be risks to marine environments. As this topic has received increasing media scrutiny over the last few years, we summarize the general conclusions that can be drawn from current research and note the questions that still remain to better address patient concerns.

Benzophenone-3

Benzophenone-3, or oxybenzone, is a widely studied UV filter and its effects on marine ecosystems have received the media’s attention over the last few years. Benzophenone-3 is known to cause a bleaching effect to coral, which can inhibit growth and possibly kill the organism.³ Further, oxybenzone sunscreens can promote viral infections in coral, resulting in additional bleaching events.² In a recent study, exposure to BP-3 caused mobile planulae, the larval form of coral, to become clearly deformed, trapped within its own calcium carbonate skeleton.³ The concentration of BP-3 needed to induce these physiological changes is as small as 62 parts per trillion, which is the equivalent of a single drop of water in 6.5 Olympic-sized swimming pools. Levels of BP-3 contamination in the waters off of the US Virgin Islands’ beaches have been recorded as high as 1.4 parts per million, with average concentrations closer to 250 parts per billion.³ High BP-3 concentrations have also been recorded in the waters off the Canary Islands,⁴ Hawaii,³ and South Carolina.⁵

4-Methylbenzylidene Camphor

Environmental concerns have also been raised about another common chemical UV filter: 4-MBC, or enzacamene. In laboratory studies, 4-MBC has been shown to cause oxidative stress to Tetrahymena thermophila, an aquatic protozoan, which results in inhibited growth. At higher concentrations, damage to the cellular membrane was seen as soon as 4 hours after exposure.⁶ In embryonic zebrafish, elevated 4-MBC levels were correlated to improper nerve and muscular development, resulting in developmental defects.⁷ Another study demonstrated that 4-MBC was toxic to Mytilus galloprovincialis, known as the Mediterranean mussel, and Paracentrotus lividus, a species of sea urchin.⁸ Although these studies utilized highly controlled laboratory settings, further studies are needed to examine the effects of 4-MBC on these species at environmentally relevant concentrations.

Physical Sunscreens

Physical sunscreens, as compared to the chemical filters referenced above, use either zinc or titanium to protect the skin from the sun’s rays. Nanoparticles, in particular, are preferred because they do not leave a white film on the skin.⁹ Both titanium dioxide and zinc oxide nanoparticles have been found to inhibit the growth and photosynthesis of marine phytoplankton, the most abundant primary producers on Earth.^10,11 These metal contaminants can be transferred to organisms of higher trophic levels, including zooplankton,¹² and filter-feeding organisms, including marine abalone¹³ and the Mediterranean mussel.¹⁴ These nanoparticles have been shown to cause oxidative stress to these organisms, making them less fit to withstand environmental stressors. It is difficult to show their true impact, however, as it is challenging to accurately detect and quantify nanoparticle concentrations in vivo.¹⁵

Final Thoughts

A recent study showed that 7% of consumers (N=325) regarded environmental agencies’ recommendations as an important factor in their sunscreen purchase.¹⁶ When treating patients with these concerns, the ability to provide sound and informed advice will likely impact their sunscreen use and future sun protection behaviors. Although studies have shown the potential for sunscreen pollution to cause environmental harm, it is important to note that a portion of this research is not correlated to in vivo findings, and further work is required to determine the magnitude and importance of these studies.¹⁵ Regardless, legislation has already been submitted in both Hawaii and the European Union calling for a ban on oxybenzone-containing sunscreens, so knowledge of the subject is prudent when counseling patients.¹⁷ One potential solution may be to recommend sun-protective clothing during water-intensive activities to both increase skin protection and reduce the environmental impact. Furthermore, recommendations could be tailored to specific settings, such as coastal resorts and populated beaches, where these sunscreen ingredients are found in much higher concentrations. At this time, more data must be collected before making any definitive claims or recommendations, but knowledge of the current research will be an important tool in educating patients going forward.

Coastal travel accounts for 80% of all tourism worldwide, a number that continues to grow. The number of travelers to the Mediterranean Sea alone is expected to rise to 350 million individuals per year within the next 20 years.¹ As the number of tourists visiting the world’s oceans increases, the rate of sunscreen unintentionally washed into these marine environments also rises. One study estimated that approximately one-quarter of the sunscreen applied to the skin is washed off over a 20-minute period spent in the water.² Four of the most common sunscreen agents—benzophenone-3 (BP-3), 4-methylbenzylidene camphor (4-MBC), and the nanoparticles titanium dioxide and zinc oxide—have been considered to be risks to marine environments. As this topic has received increasing media scrutiny over the last few years, we summarize the general conclusions that can be drawn from current research and note the questions that still remain to better address patient concerns.

Benzophenone-3

Benzophenone-3, or oxybenzone, is a widely studied UV filter and its effects on marine ecosystems have received the media’s attention over the last few years. Benzophenone-3 is known to cause a bleaching effect to coral, which can inhibit growth and possibly kill the organism.³ Further, oxybenzone sunscreens can promote viral infections in coral, resulting in additional bleaching events.² In a recent study, exposure to BP-3 caused mobile planulae, the larval form of coral, to become clearly deformed, trapped within its own calcium carbonate skeleton.³ The concentration of BP-3 needed to induce these physiological changes is as small as 62 parts per trillion, which is the equivalent of a single drop of water in 6.5 Olympic-sized swimming pools. Levels of BP-3 contamination in the waters off of the US Virgin Islands’ beaches have been recorded as high as 1.4 parts per million, with average concentrations closer to 250 parts per billion.³ High BP-3 concentrations have also been recorded in the waters off the Canary Islands,⁴ Hawaii,³ and South Carolina.⁵

4-Methylbenzylidene Camphor

Environmental concerns have also been raised about another common chemical UV filter: 4-MBC, or enzacamene. In laboratory studies, 4-MBC has been shown to cause oxidative stress to Tetrahymena thermophila, an aquatic protozoan, which results in inhibited growth. At higher concentrations, damage to the cellular membrane was seen as soon as 4 hours after exposure.⁶ In embryonic zebrafish, elevated 4-MBC levels were correlated to improper nerve and muscular development, resulting in developmental defects.⁷ Another study demonstrated that 4-MBC was toxic to Mytilus galloprovincialis, known as the Mediterranean mussel, and Paracentrotus lividus, a species of sea urchin.⁸ Although these studies utilized highly controlled laboratory settings, further studies are needed to examine the effects of 4-MBC on these species at environmentally relevant concentrations.

Physical Sunscreens

Physical sunscreens, as compared to the chemical filters referenced above, use either zinc or titanium to protect the skin from the sun’s rays. Nanoparticles, in particular, are preferred because they do not leave a white film on the skin.⁹ Both titanium dioxide and zinc oxide nanoparticles have been found to inhibit the growth and photosynthesis of marine phytoplankton, the most abundant primary producers on Earth.^10,11 These metal contaminants can be transferred to organisms of higher trophic levels, including zooplankton,¹² and filter-feeding organisms, including marine abalone¹³ and the Mediterranean mussel.¹⁴ These nanoparticles have been shown to cause oxidative stress to these organisms, making them less fit to withstand environmental stressors. It is difficult to show their true impact, however, as it is challenging to accurately detect and quantify nanoparticle concentrations in vivo.¹⁵

Final Thoughts

A recent study showed that 7% of consumers (N=325) regarded environmental agencies’ recommendations as an important factor in their sunscreen purchase.¹⁶ When treating patients with these concerns, the ability to provide sound and informed advice will likely impact their sunscreen use and future sun protection behaviors. Although studies have shown the potential for sunscreen pollution to cause environmental harm, it is important to note that a portion of this research is not correlated to in vivo findings, and further work is required to determine the magnitude and importance of these studies.¹⁵ Regardless, legislation has already been submitted in both Hawaii and the European Union calling for a ban on oxybenzone-containing sunscreens, so knowledge of the subject is prudent when counseling patients.¹⁷ One potential solution may be to recommend sun-protective clothing during water-intensive activities to both increase skin protection and reduce the environmental impact. Furthermore, recommendations could be tailored to specific settings, such as coastal resorts and populated beaches, where these sunscreen ingredients are found in much higher concentrations. At this time, more data must be collected before making any definitive claims or recommendations, but knowledge of the current research will be an important tool in educating patients going forward.

Coastal travel accounts for 80% of all tourism worldwide, a number that continues to grow. The number of travelers to the Mediterranean Sea alone is expected to rise to 350 million individuals per year within the next 20 years.¹ As the number of tourists visiting the world’s oceans increases, the rate of sunscreen unintentionally washed into these marine environments also rises. One study estimated that approximately one-quarter of the sunscreen applied to the skin is washed off over a 20-minute period spent in the water.² Four of the most common sunscreen agents—benzophenone-3 (BP-3), 4-methylbenzylidene camphor (4-MBC), and the nanoparticles titanium dioxide and zinc oxide—have been considered to be risks to marine environments. As this topic has received increasing media scrutiny over the last few years, we summarize the general conclusions that can be drawn from current research and note the questions that still remain to better address patient concerns.

Benzophenone-3

Benzophenone-3, or oxybenzone, is a widely studied UV filter and its effects on marine ecosystems have received the media’s attention over the last few years. Benzophenone-3 is known to cause a bleaching effect to coral, which can inhibit growth and possibly kill the organism.³ Further, oxybenzone sunscreens can promote viral infections in coral, resulting in additional bleaching events.² In a recent study, exposure to BP-3 caused mobile planulae, the larval form of coral, to become clearly deformed, trapped within its own calcium carbonate skeleton.³ The concentration of BP-3 needed to induce these physiological changes is as small as 62 parts per trillion, which is the equivalent of a single drop of water in 6.5 Olympic-sized swimming pools. Levels of BP-3 contamination in the waters off of the US Virgin Islands’ beaches have been recorded as high as 1.4 parts per million, with average concentrations closer to 250 parts per billion.³ High BP-3 concentrations have also been recorded in the waters off the Canary Islands,⁴ Hawaii,³ and South Carolina.⁵

4-Methylbenzylidene Camphor

Environmental concerns have also been raised about another common chemical UV filter: 4-MBC, or enzacamene. In laboratory studies, 4-MBC has been shown to cause oxidative stress to Tetrahymena thermophila, an aquatic protozoan, which results in inhibited growth. At higher concentrations, damage to the cellular membrane was seen as soon as 4 hours after exposure.⁶ In embryonic zebrafish, elevated 4-MBC levels were correlated to improper nerve and muscular development, resulting in developmental defects.⁷ Another study demonstrated that 4-MBC was toxic to Mytilus galloprovincialis, known as the Mediterranean mussel, and Paracentrotus lividus, a species of sea urchin.⁸ Although these studies utilized highly controlled laboratory settings, further studies are needed to examine the effects of 4-MBC on these species at environmentally relevant concentrations.

Physical Sunscreens

Physical sunscreens, as compared to the chemical filters referenced above, use either zinc or titanium to protect the skin from the sun’s rays. Nanoparticles, in particular, are preferred because they do not leave a white film on the skin.⁹ Both titanium dioxide and zinc oxide nanoparticles have been found to inhibit the growth and photosynthesis of marine phytoplankton, the most abundant primary producers on Earth.^10,11 These metal contaminants can be transferred to organisms of higher trophic levels, including zooplankton,¹² and filter-feeding organisms, including marine abalone¹³ and the Mediterranean mussel.¹⁴ These nanoparticles have been shown to cause oxidative stress to these organisms, making them less fit to withstand environmental stressors. It is difficult to show their true impact, however, as it is challenging to accurately detect and quantify nanoparticle concentrations in vivo.¹⁵

Final Thoughts

A recent study showed that 7% of consumers (N=325) regarded environmental agencies’ recommendations as an important factor in their sunscreen purchase.¹⁶ When treating patients with these concerns, the ability to provide sound and informed advice will likely impact their sunscreen use and future sun protection behaviors. Although studies have shown the potential for sunscreen pollution to cause environmental harm, it is important to note that a portion of this research is not correlated to in vivo findings, and further work is required to determine the magnitude and importance of these studies.¹⁵ Regardless, legislation has already been submitted in both Hawaii and the European Union calling for a ban on oxybenzone-containing sunscreens, so knowledge of the subject is prudent when counseling patients.¹⁷ One potential solution may be to recommend sun-protective clothing during water-intensive activities to both increase skin protection and reduce the environmental impact. Furthermore, recommendations could be tailored to specific settings, such as coastal resorts and populated beaches, where these sunscreen ingredients are found in much higher concentrations. At this time, more data must be collected before making any definitive claims or recommendations, but knowledge of the current research will be an important tool in educating patients going forward.

The Food and Drug Administration approved a new genetic sequencing test that detects mutations across 324 genes in tumor biopsy specimens with an accuracy of 94.6%.

The FoundationOne CDx (F1CDx) test from Foundation Medicine “can identify which patients with any of five tumor types” – non–small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer – “may benefit from 15 different FDA-approved targeted treatment options,” as well as clinical trial eligibility, “with one test report, avoiding duplicative biopsies,” the agency said in a statement.

aotto@frontlinemedcom.com

The Food and Drug Administration approved a new genetic sequencing test that detects mutations across 324 genes in tumor biopsy specimens with an accuracy of 94.6%.

The FoundationOne CDx (F1CDx) test from Foundation Medicine “can identify which patients with any of five tumor types” – non–small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer – “may benefit from 15 different FDA-approved targeted treatment options,” as well as clinical trial eligibility, “with one test report, avoiding duplicative biopsies,” the agency said in a statement.

aotto@frontlinemedcom.com

The Food and Drug Administration approved a new genetic sequencing test that detects mutations across 324 genes in tumor biopsy specimens with an accuracy of 94.6%.

The FoundationOne CDx (F1CDx) test from Foundation Medicine “can identify which patients with any of five tumor types” – non–small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer – “may benefit from 15 different FDA-approved targeted treatment options,” as well as clinical trial eligibility, “with one test report, avoiding duplicative biopsies,” the agency said in a statement.

aotto@frontlinemedcom.com

The gut microbome may influence responses to immune checkpoint inhibitors, based on results from two studies, and one of the investigators is now gearing up for the next step - evaluating in a clinical trial whether altering the microflora will actually improve responses.

In the first study, investigators carried out a series of experiments using fecal microbiome samples from patients with metastatic melanoma embarking on therapy with a PD-1 (programmed cell death protein 1) inhibitor.

“In melanoma patients, there were differential signals in the gut microbiome of responders versus nonresponders, and I think the clincher was when we transplanted fecal samples from responders to nonresponders in germ-free mice, essentially reconstituting the microbiome and showing that it equally affected the systemic immunity and antitumor immunity when we implanted tumors, as well as response to checkpoint blockade,” lead author Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center in Houston, said in an interview.

Dr. Wargo and her colleagues first collected buccal and fecal microbiome samples from 112 patients with metastatic melanoma before they began therapy with a PD-1 inhibitor. After performing taxonomic profiling on all samples, they found that there was a clustering effect by response status in the gut microbiome, but not the oral microbiome, and because changes in the oral microbiome did not appear to be related to treatment response, they focused on the gut.

When Dr. Wargo and her colleagues studied the posttherapy microbiomes of 43 patients (30 responders and 13 nonresponders) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they found that the responders had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01). In addition, responders had a relative abundance of Ruminococcaceae, commonly occurring gut microbes that break down complex carbohydrates, the investigators reported (Science. 2017 Nov. 2. doi: 10.1126/science.aan4236).

They found that patients whose microbiomes were diverse in general, and in particular were enriched with Faecalibacterium and Clostridiales species, were more likely to respond to immunotherapy with a PD-1 inhibitor and have a longer duration of progression-free survival. In contrast, patients whose microbiomes were more enriched with Bacteroidales species were more likely to be nonresponders.

To get a better understanding of the mechanisms whereby gut bacteria may influence response to PD-1 inhibitors, they performed metagenomic analysis on samples from 14 responders and 11 nonresponders, and found that responders had micro-organisms predominantly associated with anabolic functions that may support host immunity, whereas nonresponders had microbiomes where catabolic functions were more common.

The investigators next performed immune profiling, and found that both systemic immunity and local immunity in the tumor microenvironment in responders were associated with the aforementioned favorable gut microbiome.

The researchers then transplanted feces from the human donors into germ-free mice and then injected tumor cells into the mice, and found that tumor growth was significantly reduced, and response to PD-1 inhibition was significantly enhanced, in mice who received feces from responders.

“An obvious next step is to run a clinical trial to test the hypothesis that by modulating the microbiome, you can actually enhance responses to therapy,” Dr. Wargo said. Details of the clinical trial are still being worked out, but will likely involve fecal transfers and other mechanisms for modulating the microbiome in hopes of improving responses to PD-1 inhibitors.

“It’s going to be a very biomarker-heavy trial,” she said. “We’re going to look, certainly, for changes in the microbiome, and will also do a lot of profiling in the blood, the tumor, and in the microbiome to see if there are changes that occur by modulating that microbiome. Then of course we’ll look for differences in response rates in patients as well.”
 

Bacteria also affect epithelial cancers

In a separate study, also published in Science, investigators led by Bertrand Routy, MD, of the Gustave Roussy Cancer Institute in Villejuif, France, reported that patients with non–small cell lung cancer and urothelial carcinoma who had previously used systemic antibiotics had reduced survival when treated with a PD-1 inhibitor, compared with patients who had never taken antibiotics (Science. 2017 Nov. 2 doi: 10.1126/science.aan3706).

Analysis of the gut microbiome in these patients showed that higher levels of Akkermansia muciniphila were associated with the best clinical outcomes, with the species detectable in the microbiome of 69% of patients who had partial responses to anti–PD-1 therapy, and in 58% of those with stable disease. In contrast, the bacterium was detectable in only 34% of patients who experienced disease progression.

As in the experiments by Dr. Wargo and her associates, when the French investigators first treated mice with antibiotics and then gave them oral supplements containing the bacteria, the supplements restored response to PD-1 blockade,

“We conclude from the study that the gut microbiome markedly influences the outcome of PD-1 blockade in mice and patients,” Dr. Routy and his associates wrote.

They acknowledged that the mechanism whereby a common organism such as Akkermansia muciniphila might have an immunomodulatory effect is still unknown,

“Irrespective of these remaining questions, our findings suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer[s] novel avenues for manipulating the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors],” they wrote.

The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his associates was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.

The gut microbome may influence responses to immune checkpoint inhibitors, based on results from two studies, and one of the investigators is now gearing up for the next step - evaluating in a clinical trial whether altering the microflora will actually improve responses.

In the first study, investigators carried out a series of experiments using fecal microbiome samples from patients with metastatic melanoma embarking on therapy with a PD-1 (programmed cell death protein 1) inhibitor.

“In melanoma patients, there were differential signals in the gut microbiome of responders versus nonresponders, and I think the clincher was when we transplanted fecal samples from responders to nonresponders in germ-free mice, essentially reconstituting the microbiome and showing that it equally affected the systemic immunity and antitumor immunity when we implanted tumors, as well as response to checkpoint blockade,” lead author Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center in Houston, said in an interview.

Dr. Wargo and her colleagues first collected buccal and fecal microbiome samples from 112 patients with metastatic melanoma before they began therapy with a PD-1 inhibitor. After performing taxonomic profiling on all samples, they found that there was a clustering effect by response status in the gut microbiome, but not the oral microbiome, and because changes in the oral microbiome did not appear to be related to treatment response, they focused on the gut.

When Dr. Wargo and her colleagues studied the posttherapy microbiomes of 43 patients (30 responders and 13 nonresponders) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they found that the responders had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01). In addition, responders had a relative abundance of Ruminococcaceae, commonly occurring gut microbes that break down complex carbohydrates, the investigators reported (Science. 2017 Nov. 2. doi: 10.1126/science.aan4236).

They found that patients whose microbiomes were diverse in general, and in particular were enriched with Faecalibacterium and Clostridiales species, were more likely to respond to immunotherapy with a PD-1 inhibitor and have a longer duration of progression-free survival. In contrast, patients whose microbiomes were more enriched with Bacteroidales species were more likely to be nonresponders.

To get a better understanding of the mechanisms whereby gut bacteria may influence response to PD-1 inhibitors, they performed metagenomic analysis on samples from 14 responders and 11 nonresponders, and found that responders had micro-organisms predominantly associated with anabolic functions that may support host immunity, whereas nonresponders had microbiomes where catabolic functions were more common.

The investigators next performed immune profiling, and found that both systemic immunity and local immunity in the tumor microenvironment in responders were associated with the aforementioned favorable gut microbiome.

The researchers then transplanted feces from the human donors into germ-free mice and then injected tumor cells into the mice, and found that tumor growth was significantly reduced, and response to PD-1 inhibition was significantly enhanced, in mice who received feces from responders.

“An obvious next step is to run a clinical trial to test the hypothesis that by modulating the microbiome, you can actually enhance responses to therapy,” Dr. Wargo said. Details of the clinical trial are still being worked out, but will likely involve fecal transfers and other mechanisms for modulating the microbiome in hopes of improving responses to PD-1 inhibitors.

“It’s going to be a very biomarker-heavy trial,” she said. “We’re going to look, certainly, for changes in the microbiome, and will also do a lot of profiling in the blood, the tumor, and in the microbiome to see if there are changes that occur by modulating that microbiome. Then of course we’ll look for differences in response rates in patients as well.”
 

Bacteria also affect epithelial cancers

In a separate study, also published in Science, investigators led by Bertrand Routy, MD, of the Gustave Roussy Cancer Institute in Villejuif, France, reported that patients with non–small cell lung cancer and urothelial carcinoma who had previously used systemic antibiotics had reduced survival when treated with a PD-1 inhibitor, compared with patients who had never taken antibiotics (Science. 2017 Nov. 2 doi: 10.1126/science.aan3706).

Analysis of the gut microbiome in these patients showed that higher levels of Akkermansia muciniphila were associated with the best clinical outcomes, with the species detectable in the microbiome of 69% of patients who had partial responses to anti–PD-1 therapy, and in 58% of those with stable disease. In contrast, the bacterium was detectable in only 34% of patients who experienced disease progression.

As in the experiments by Dr. Wargo and her associates, when the French investigators first treated mice with antibiotics and then gave them oral supplements containing the bacteria, the supplements restored response to PD-1 blockade,

“We conclude from the study that the gut microbiome markedly influences the outcome of PD-1 blockade in mice and patients,” Dr. Routy and his associates wrote.

They acknowledged that the mechanism whereby a common organism such as Akkermansia muciniphila might have an immunomodulatory effect is still unknown,

“Irrespective of these remaining questions, our findings suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer[s] novel avenues for manipulating the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors],” they wrote.

The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his associates was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.

The gut microbome may influence responses to immune checkpoint inhibitors, based on results from two studies, and one of the investigators is now gearing up for the next step - evaluating in a clinical trial whether altering the microflora will actually improve responses.

In the first study, investigators carried out a series of experiments using fecal microbiome samples from patients with metastatic melanoma embarking on therapy with a PD-1 (programmed cell death protein 1) inhibitor.

“In melanoma patients, there were differential signals in the gut microbiome of responders versus nonresponders, and I think the clincher was when we transplanted fecal samples from responders to nonresponders in germ-free mice, essentially reconstituting the microbiome and showing that it equally affected the systemic immunity and antitumor immunity when we implanted tumors, as well as response to checkpoint blockade,” lead author Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center in Houston, said in an interview.

Dr. Wargo and her colleagues first collected buccal and fecal microbiome samples from 112 patients with metastatic melanoma before they began therapy with a PD-1 inhibitor. After performing taxonomic profiling on all samples, they found that there was a clustering effect by response status in the gut microbiome, but not the oral microbiome, and because changes in the oral microbiome did not appear to be related to treatment response, they focused on the gut.

When Dr. Wargo and her colleagues studied the posttherapy microbiomes of 43 patients (30 responders and 13 nonresponders) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they found that the responders had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01). In addition, responders had a relative abundance of Ruminococcaceae, commonly occurring gut microbes that break down complex carbohydrates, the investigators reported (Science. 2017 Nov. 2. doi: 10.1126/science.aan4236).

They found that patients whose microbiomes were diverse in general, and in particular were enriched with Faecalibacterium and Clostridiales species, were more likely to respond to immunotherapy with a PD-1 inhibitor and have a longer duration of progression-free survival. In contrast, patients whose microbiomes were more enriched with Bacteroidales species were more likely to be nonresponders.

To get a better understanding of the mechanisms whereby gut bacteria may influence response to PD-1 inhibitors, they performed metagenomic analysis on samples from 14 responders and 11 nonresponders, and found that responders had micro-organisms predominantly associated with anabolic functions that may support host immunity, whereas nonresponders had microbiomes where catabolic functions were more common.

The investigators next performed immune profiling, and found that both systemic immunity and local immunity in the tumor microenvironment in responders were associated with the aforementioned favorable gut microbiome.

The researchers then transplanted feces from the human donors into germ-free mice and then injected tumor cells into the mice, and found that tumor growth was significantly reduced, and response to PD-1 inhibition was significantly enhanced, in mice who received feces from responders.

“An obvious next step is to run a clinical trial to test the hypothesis that by modulating the microbiome, you can actually enhance responses to therapy,” Dr. Wargo said. Details of the clinical trial are still being worked out, but will likely involve fecal transfers and other mechanisms for modulating the microbiome in hopes of improving responses to PD-1 inhibitors.

“It’s going to be a very biomarker-heavy trial,” she said. “We’re going to look, certainly, for changes in the microbiome, and will also do a lot of profiling in the blood, the tumor, and in the microbiome to see if there are changes that occur by modulating that microbiome. Then of course we’ll look for differences in response rates in patients as well.”
 

Bacteria also affect epithelial cancers

In a separate study, also published in Science, investigators led by Bertrand Routy, MD, of the Gustave Roussy Cancer Institute in Villejuif, France, reported that patients with non–small cell lung cancer and urothelial carcinoma who had previously used systemic antibiotics had reduced survival when treated with a PD-1 inhibitor, compared with patients who had never taken antibiotics (Science. 2017 Nov. 2 doi: 10.1126/science.aan3706).

Analysis of the gut microbiome in these patients showed that higher levels of Akkermansia muciniphila were associated with the best clinical outcomes, with the species detectable in the microbiome of 69% of patients who had partial responses to anti–PD-1 therapy, and in 58% of those with stable disease. In contrast, the bacterium was detectable in only 34% of patients who experienced disease progression.

As in the experiments by Dr. Wargo and her associates, when the French investigators first treated mice with antibiotics and then gave them oral supplements containing the bacteria, the supplements restored response to PD-1 blockade,

“We conclude from the study that the gut microbiome markedly influences the outcome of PD-1 blockade in mice and patients,” Dr. Routy and his associates wrote.

They acknowledged that the mechanism whereby a common organism such as Akkermansia muciniphila might have an immunomodulatory effect is still unknown,

“Irrespective of these remaining questions, our findings suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer[s] novel avenues for manipulating the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors],” they wrote.

The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his associates was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.

In antitumor immunity and immunotherapy, quality and fitness count.

Specifically, the quality and fitness of neoantigens – tumor-specific mutated peptides on the surface of cancer cells – can influence a patient’s response to immune checkpoint inhibitors, and mathematical models of neoantigen fitness can serve as biomarkers for response to immunotherapy, according to investigators of two separate but related studies published in Nature.

In one study, Marta Łuksza, PhD, from the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, N.J., and colleagues propose a neoantigen fitness model that can predict tumor response to checkpoint blockade immunotherapy.

“Our model predicts survival in anti-CTLA4–treated melanoma patients and anti-PD-1–treated lung cancer patients. Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies,” they wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24473).

In a related study, Vinod P. Balachandran, MD, from the David M. Rubinstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York and colleagues, including Dr. Łuksza and others, looked at T-cell antigens in long-term survivors of pancreatic cancer and identified specific neoantigens as T-cell targets.

“More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may guide the application of immunotherapies,” Dr. Balachandran and colleagues wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24462).
 

Proof of concept

The studies provide a proof of concept that mathematical modeling of tumor evolution and the interactions of tumors with the immune system may soon provide clinicians with valuable and actionable information about responses to immunotherapy, Benjamin Greenbaum, PhD, senior author on the study by Łuksza et al., and a coauthor on the pancreatic cancer study said in an interview.

“We’re trying to come up with measures that take into account what we think the underlying processes are and what lies behind therapy response, and that should lead to better predictive models associated with response in the future,” said Dr. Greenbaum, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Medical Center, New York.

One of the key findings of the studies is that neoantigen quality – the ability of neoantigens to spark T-cell recognition – seems to be as or more important than neoantigen quantity for influencing immune responses during tumor evolution.

“The general logic behind the idea that mutational burden can be a good predictor of response is that the more mutations you have, the more likely that you have a neoantigen, a peptide generated by a tumor mutation, that elicits productive T-cell recognition. We tried to model that process that might lead to productive T-cell recognition, to assign a kind of number to every neoantigen to provide some estimate of how likely it was to undergo a productive process,” Dr. Greenbaum explained.
 

Melanoma and lung cancer survivors

In the study by Łuksza et al., the investigators created a mathematical fitness model that can predict how tumors respond to immunotherapy based on how neoantigens interact with the immune system and applied the model to data on three previously reported patient cohorts, including two groups of patients with malignant melanoma treated with a cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint such as ipilimumab (Yervoy), and one group of patients with non–small cell lung cancer treated with a programmed death-1 (PD-1) inhibitor (for example, nivolumab [Opdivo]).

They found that their proposed model is more accurate than genomic biomarkers for predicting how a specific tumor may respond to immunotherapy.

“Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumors and rapidly evolving pathogens,” they wrote.
 

Pancreatic cancer survivors

Fewer than 7% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years, despite the best surgical and medical therapy. But a few lucky patients are long-term survivors, and Dr. Balachandran and associates sought to examine what aspects of T-cell immunity contributed to their longevity.

Rather than relying on genomic analysis of tumor samples, however, they used a combination of genetic, immunohistochemical, and transcriptional immunoprofiling, as well as computational biophysics and function to identify T-cell antigens in the long-term survivors.

When they compared surgically resected patients matched by tumor stage, they found that tumors from those with a median overall survival (OS) of 6 years had a 3-fold greater density of CD8-positive T cells and a 12-fold greater density of cytolytic CD8-positive cells, as well as more mature dendritic cells, regulatory T cells, and macrophages, but decreased numbers of CD4-positive T cells, compared with patients with a more typical course of survival (median OS, 0.8 years). There were no differences between long- and short-term survivors in either B cells or major histocompatibility complex (MHC) class I–positive cells.

They then performed whole-exome sequencing on tumor samples to determine the frequency of neoantigens and found a median of 38 predicted neoantigens per tumor.

“Notably, patients with both the highest predicted neoantigen number and either the greatest CD3+, CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival,” they wrote.

When they looked for qualities of neoantigens responsible for promoting T-cell activation in the long-term survivors, they found that the tumors from the survivors, compared with others, were enriched in neoantigen qualities that could be described by a mathematical fitness model.

“Our results provide insight into the heterogeneous immunobiology of PDAC, a presumed poorly immunogenic and checkpoint blockade–refractory tumor, demonstrating that neoantigens may be T-cell targets in [long-term survivors]”, they wrote.

The investigators propose that immunity to neoantigens that are generated during the outgrowth of a primary tumor could at least partially explain the lower incidence of relapse and prolonged survival of a small minority of patients with pancreatic cancer.

“Our findings support the development of strategies to harness neoantigen-specific immunity to treat checkpoint blockade–refractory cancers, and the identification of immunogenic hot spots for directed neoantigen targeting,” they concluded.

The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.

In antitumor immunity and immunotherapy, quality and fitness count.

Specifically, the quality and fitness of neoantigens – tumor-specific mutated peptides on the surface of cancer cells – can influence a patient’s response to immune checkpoint inhibitors, and mathematical models of neoantigen fitness can serve as biomarkers for response to immunotherapy, according to investigators of two separate but related studies published in Nature.

In one study, Marta Łuksza, PhD, from the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, N.J., and colleagues propose a neoantigen fitness model that can predict tumor response to checkpoint blockade immunotherapy.

“Our model predicts survival in anti-CTLA4–treated melanoma patients and anti-PD-1–treated lung cancer patients. Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies,” they wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24473).

In a related study, Vinod P. Balachandran, MD, from the David M. Rubinstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York and colleagues, including Dr. Łuksza and others, looked at T-cell antigens in long-term survivors of pancreatic cancer and identified specific neoantigens as T-cell targets.

“More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may guide the application of immunotherapies,” Dr. Balachandran and colleagues wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24462).
 

Proof of concept

The studies provide a proof of concept that mathematical modeling of tumor evolution and the interactions of tumors with the immune system may soon provide clinicians with valuable and actionable information about responses to immunotherapy, Benjamin Greenbaum, PhD, senior author on the study by Łuksza et al., and a coauthor on the pancreatic cancer study said in an interview.

“We’re trying to come up with measures that take into account what we think the underlying processes are and what lies behind therapy response, and that should lead to better predictive models associated with response in the future,” said Dr. Greenbaum, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Medical Center, New York.

One of the key findings of the studies is that neoantigen quality – the ability of neoantigens to spark T-cell recognition – seems to be as or more important than neoantigen quantity for influencing immune responses during tumor evolution.

“The general logic behind the idea that mutational burden can be a good predictor of response is that the more mutations you have, the more likely that you have a neoantigen, a peptide generated by a tumor mutation, that elicits productive T-cell recognition. We tried to model that process that might lead to productive T-cell recognition, to assign a kind of number to every neoantigen to provide some estimate of how likely it was to undergo a productive process,” Dr. Greenbaum explained.
 

Melanoma and lung cancer survivors

In the study by Łuksza et al., the investigators created a mathematical fitness model that can predict how tumors respond to immunotherapy based on how neoantigens interact with the immune system and applied the model to data on three previously reported patient cohorts, including two groups of patients with malignant melanoma treated with a cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint such as ipilimumab (Yervoy), and one group of patients with non–small cell lung cancer treated with a programmed death-1 (PD-1) inhibitor (for example, nivolumab [Opdivo]).

They found that their proposed model is more accurate than genomic biomarkers for predicting how a specific tumor may respond to immunotherapy.

“Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumors and rapidly evolving pathogens,” they wrote.
 

Pancreatic cancer survivors

Fewer than 7% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years, despite the best surgical and medical therapy. But a few lucky patients are long-term survivors, and Dr. Balachandran and associates sought to examine what aspects of T-cell immunity contributed to their longevity.

Rather than relying on genomic analysis of tumor samples, however, they used a combination of genetic, immunohistochemical, and transcriptional immunoprofiling, as well as computational biophysics and function to identify T-cell antigens in the long-term survivors.

When they compared surgically resected patients matched by tumor stage, they found that tumors from those with a median overall survival (OS) of 6 years had a 3-fold greater density of CD8-positive T cells and a 12-fold greater density of cytolytic CD8-positive cells, as well as more mature dendritic cells, regulatory T cells, and macrophages, but decreased numbers of CD4-positive T cells, compared with patients with a more typical course of survival (median OS, 0.8 years). There were no differences between long- and short-term survivors in either B cells or major histocompatibility complex (MHC) class I–positive cells.

They then performed whole-exome sequencing on tumor samples to determine the frequency of neoantigens and found a median of 38 predicted neoantigens per tumor.

“Notably, patients with both the highest predicted neoantigen number and either the greatest CD3+, CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival,” they wrote.

When they looked for qualities of neoantigens responsible for promoting T-cell activation in the long-term survivors, they found that the tumors from the survivors, compared with others, were enriched in neoantigen qualities that could be described by a mathematical fitness model.

“Our results provide insight into the heterogeneous immunobiology of PDAC, a presumed poorly immunogenic and checkpoint blockade–refractory tumor, demonstrating that neoantigens may be T-cell targets in [long-term survivors]”, they wrote.

The investigators propose that immunity to neoantigens that are generated during the outgrowth of a primary tumor could at least partially explain the lower incidence of relapse and prolonged survival of a small minority of patients with pancreatic cancer.

“Our findings support the development of strategies to harness neoantigen-specific immunity to treat checkpoint blockade–refractory cancers, and the identification of immunogenic hot spots for directed neoantigen targeting,” they concluded.

The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.

In antitumor immunity and immunotherapy, quality and fitness count.

Specifically, the quality and fitness of neoantigens – tumor-specific mutated peptides on the surface of cancer cells – can influence a patient’s response to immune checkpoint inhibitors, and mathematical models of neoantigen fitness can serve as biomarkers for response to immunotherapy, according to investigators of two separate but related studies published in Nature.

In one study, Marta Łuksza, PhD, from the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, N.J., and colleagues propose a neoantigen fitness model that can predict tumor response to checkpoint blockade immunotherapy.

“Our model predicts survival in anti-CTLA4–treated melanoma patients and anti-PD-1–treated lung cancer patients. Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies,” they wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24473).

In a related study, Vinod P. Balachandran, MD, from the David M. Rubinstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York and colleagues, including Dr. Łuksza and others, looked at T-cell antigens in long-term survivors of pancreatic cancer and identified specific neoantigens as T-cell targets.

“More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may guide the application of immunotherapies,” Dr. Balachandran and colleagues wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24462).
 

Proof of concept

The studies provide a proof of concept that mathematical modeling of tumor evolution and the interactions of tumors with the immune system may soon provide clinicians with valuable and actionable information about responses to immunotherapy, Benjamin Greenbaum, PhD, senior author on the study by Łuksza et al., and a coauthor on the pancreatic cancer study said in an interview.

“We’re trying to come up with measures that take into account what we think the underlying processes are and what lies behind therapy response, and that should lead to better predictive models associated with response in the future,” said Dr. Greenbaum, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Medical Center, New York.

One of the key findings of the studies is that neoantigen quality – the ability of neoantigens to spark T-cell recognition – seems to be as or more important than neoantigen quantity for influencing immune responses during tumor evolution.

“The general logic behind the idea that mutational burden can be a good predictor of response is that the more mutations you have, the more likely that you have a neoantigen, a peptide generated by a tumor mutation, that elicits productive T-cell recognition. We tried to model that process that might lead to productive T-cell recognition, to assign a kind of number to every neoantigen to provide some estimate of how likely it was to undergo a productive process,” Dr. Greenbaum explained.
 

Melanoma and lung cancer survivors

In the study by Łuksza et al., the investigators created a mathematical fitness model that can predict how tumors respond to immunotherapy based on how neoantigens interact with the immune system and applied the model to data on three previously reported patient cohorts, including two groups of patients with malignant melanoma treated with a cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint such as ipilimumab (Yervoy), and one group of patients with non–small cell lung cancer treated with a programmed death-1 (PD-1) inhibitor (for example, nivolumab [Opdivo]).

They found that their proposed model is more accurate than genomic biomarkers for predicting how a specific tumor may respond to immunotherapy.

“Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumors and rapidly evolving pathogens,” they wrote.
 

Pancreatic cancer survivors

Fewer than 7% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years, despite the best surgical and medical therapy. But a few lucky patients are long-term survivors, and Dr. Balachandran and associates sought to examine what aspects of T-cell immunity contributed to their longevity.

Rather than relying on genomic analysis of tumor samples, however, they used a combination of genetic, immunohistochemical, and transcriptional immunoprofiling, as well as computational biophysics and function to identify T-cell antigens in the long-term survivors.

When they compared surgically resected patients matched by tumor stage, they found that tumors from those with a median overall survival (OS) of 6 years had a 3-fold greater density of CD8-positive T cells and a 12-fold greater density of cytolytic CD8-positive cells, as well as more mature dendritic cells, regulatory T cells, and macrophages, but decreased numbers of CD4-positive T cells, compared with patients with a more typical course of survival (median OS, 0.8 years). There were no differences between long- and short-term survivors in either B cells or major histocompatibility complex (MHC) class I–positive cells.

They then performed whole-exome sequencing on tumor samples to determine the frequency of neoantigens and found a median of 38 predicted neoantigens per tumor.

“Notably, patients with both the highest predicted neoantigen number and either the greatest CD3+, CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival,” they wrote.

When they looked for qualities of neoantigens responsible for promoting T-cell activation in the long-term survivors, they found that the tumors from the survivors, compared with others, were enriched in neoantigen qualities that could be described by a mathematical fitness model.

“Our results provide insight into the heterogeneous immunobiology of PDAC, a presumed poorly immunogenic and checkpoint blockade–refractory tumor, demonstrating that neoantigens may be T-cell targets in [long-term survivors]”, they wrote.

The investigators propose that immunity to neoantigens that are generated during the outgrowth of a primary tumor could at least partially explain the lower incidence of relapse and prolonged survival of a small minority of patients with pancreatic cancer.

“Our findings support the development of strategies to harness neoantigen-specific immunity to treat checkpoint blockade–refractory cancers, and the identification of immunogenic hot spots for directed neoantigen targeting,” they concluded.

The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.

In patients with advanced, unresectable melanoma, the combination of talimogene laherparepvec (T-VEC) and ipilimumab yielded a higher objective response rate vs. ipilimumab alone, with a similar rate of severe or life-threatening ipilimumab-related toxicities, according to results of a 198-patient randomized phase II study.

Moreover, the incidence of grade 3/4 toxicities attributed to ipilimumab was similar between the two arms of the study, with no unexpected increases in treatment-related adverse events (AEs), reported Jason A. Chesney, MD, PhD, of the James Graham Brown Cancer Center, University of Louisville (Ky.), and his coinvestigators.

Taken together, the efficacy and safety findings suggest that the combination of T-VEC and ipilimumab “may have significant clinical utility in treatment of advanced melanoma,” Dr. Chesney and his colleagues wrote (J Clin Oncol. 2017 Oct. 5 doi: 10.1200/JCO.2017.73.7379).

The study included patients with unresectable stage IIIB/IV melanoma who had received no more than one previous treatment if BRAF wild type and no more than two treatments if BRAF mutant. Patients randomized to the combination arm received T-VEC starting in week 1 of the study and ipilimumab starting on week 6, while those in the single-agent arm received ipilimumab starting on week 1.

The primary endpoint of the phase II study was objective response rate by immune-related response criteria. Objective responses were seen in 38 of the 98 patients (39%) receiving T-VEC/ipilimumab, vs. 18 of the 100 patients (18%) who received ipilimumab alone (P = 0.002), the investigators said.

The incidence of grade 3 or greater AEs was 45% for the combination arm and 35% for the single-agent arm. There were three fatal AEs in the combination arm, but none was related to treatment, according to the investigators.

“Overall, combination treatment was not associated with unexpected AEs or increase in incidence or severity of AEs, suggesting that the combination therapy is tolerable for patients with advanced melanoma,” Dr. Chesney and his associates wrote.

Median progression-free survival (PFS) was 8.2 months for the combination arm and 6.4 months for ipilimumab alone (P = .35). Although the difference was not statistically significant, investigators remarked that ipilimumab was started later in the combination arm, per study design. Moreover, the 8.2-month median PFS exceeds the 2.8- to 2.9-month median PFS seen in previous ipilimumab studies, they said.

Combination immunotherapy is of great interest now in melanoma research. Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 antibody, while T-VEC is an attenuated herpes simplex 1 virus that expresses the immunostimulatory cytokine granulocyte–macrophage colony-stimulating factor. Some other combinations have shown promise, but with higher rates of toxicity, including the combination of ipilimumab plus nivolumab, which resulted in an increase in clinically significant AEs of grade 3 or greater, Dr. Chesney and his colleagues said.

“Combination regimens with lower toxicity may allow for their use in a broader range of patients,” they added.

The study was funded by Amgen, which manufactures talimogene laherparepvec. Dr. Chesney has a relationship with Amgen that involves consulting or advising; research funding; and travel, accommodation, and expenses. His associates reported financial relationships with Amgen and other companies; three of the investigators are Amgen employees.

op@frontlinemedcom.com

In patients with advanced, unresectable melanoma, the combination of talimogene laherparepvec (T-VEC) and ipilimumab yielded a higher objective response rate vs. ipilimumab alone, with a similar rate of severe or life-threatening ipilimumab-related toxicities, according to results of a 198-patient randomized phase II study.

Moreover, the incidence of grade 3/4 toxicities attributed to ipilimumab was similar between the two arms of the study, with no unexpected increases in treatment-related adverse events (AEs), reported Jason A. Chesney, MD, PhD, of the James Graham Brown Cancer Center, University of Louisville (Ky.), and his coinvestigators.

Taken together, the efficacy and safety findings suggest that the combination of T-VEC and ipilimumab “may have significant clinical utility in treatment of advanced melanoma,” Dr. Chesney and his colleagues wrote (J Clin Oncol. 2017 Oct. 5 doi: 10.1200/JCO.2017.73.7379).

The study included patients with unresectable stage IIIB/IV melanoma who had received no more than one previous treatment if BRAF wild type and no more than two treatments if BRAF mutant. Patients randomized to the combination arm received T-VEC starting in week 1 of the study and ipilimumab starting on week 6, while those in the single-agent arm received ipilimumab starting on week 1.

The primary endpoint of the phase II study was objective response rate by immune-related response criteria. Objective responses were seen in 38 of the 98 patients (39%) receiving T-VEC/ipilimumab, vs. 18 of the 100 patients (18%) who received ipilimumab alone (P = 0.002), the investigators said.

The incidence of grade 3 or greater AEs was 45% for the combination arm and 35% for the single-agent arm. There were three fatal AEs in the combination arm, but none was related to treatment, according to the investigators.

“Overall, combination treatment was not associated with unexpected AEs or increase in incidence or severity of AEs, suggesting that the combination therapy is tolerable for patients with advanced melanoma,” Dr. Chesney and his associates wrote.

Median progression-free survival (PFS) was 8.2 months for the combination arm and 6.4 months for ipilimumab alone (P = .35). Although the difference was not statistically significant, investigators remarked that ipilimumab was started later in the combination arm, per study design. Moreover, the 8.2-month median PFS exceeds the 2.8- to 2.9-month median PFS seen in previous ipilimumab studies, they said.

Combination immunotherapy is of great interest now in melanoma research. Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 antibody, while T-VEC is an attenuated herpes simplex 1 virus that expresses the immunostimulatory cytokine granulocyte–macrophage colony-stimulating factor. Some other combinations have shown promise, but with higher rates of toxicity, including the combination of ipilimumab plus nivolumab, which resulted in an increase in clinically significant AEs of grade 3 or greater, Dr. Chesney and his colleagues said.

“Combination regimens with lower toxicity may allow for their use in a broader range of patients,” they added.

The study was funded by Amgen, which manufactures talimogene laherparepvec. Dr. Chesney has a relationship with Amgen that involves consulting or advising; research funding; and travel, accommodation, and expenses. His associates reported financial relationships with Amgen and other companies; three of the investigators are Amgen employees.

op@frontlinemedcom.com

In patients with advanced, unresectable melanoma, the combination of talimogene laherparepvec (T-VEC) and ipilimumab yielded a higher objective response rate vs. ipilimumab alone, with a similar rate of severe or life-threatening ipilimumab-related toxicities, according to results of a 198-patient randomized phase II study.

Moreover, the incidence of grade 3/4 toxicities attributed to ipilimumab was similar between the two arms of the study, with no unexpected increases in treatment-related adverse events (AEs), reported Jason A. Chesney, MD, PhD, of the James Graham Brown Cancer Center, University of Louisville (Ky.), and his coinvestigators.

Taken together, the efficacy and safety findings suggest that the combination of T-VEC and ipilimumab “may have significant clinical utility in treatment of advanced melanoma,” Dr. Chesney and his colleagues wrote (J Clin Oncol. 2017 Oct. 5 doi: 10.1200/JCO.2017.73.7379).

The study included patients with unresectable stage IIIB/IV melanoma who had received no more than one previous treatment if BRAF wild type and no more than two treatments if BRAF mutant. Patients randomized to the combination arm received T-VEC starting in week 1 of the study and ipilimumab starting on week 6, while those in the single-agent arm received ipilimumab starting on week 1.

The primary endpoint of the phase II study was objective response rate by immune-related response criteria. Objective responses were seen in 38 of the 98 patients (39%) receiving T-VEC/ipilimumab, vs. 18 of the 100 patients (18%) who received ipilimumab alone (P = 0.002), the investigators said.

The incidence of grade 3 or greater AEs was 45% for the combination arm and 35% for the single-agent arm. There were three fatal AEs in the combination arm, but none was related to treatment, according to the investigators.

“Overall, combination treatment was not associated with unexpected AEs or increase in incidence or severity of AEs, suggesting that the combination therapy is tolerable for patients with advanced melanoma,” Dr. Chesney and his associates wrote.

Median progression-free survival (PFS) was 8.2 months for the combination arm and 6.4 months for ipilimumab alone (P = .35). Although the difference was not statistically significant, investigators remarked that ipilimumab was started later in the combination arm, per study design. Moreover, the 8.2-month median PFS exceeds the 2.8- to 2.9-month median PFS seen in previous ipilimumab studies, they said.

Combination immunotherapy is of great interest now in melanoma research. Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 antibody, while T-VEC is an attenuated herpes simplex 1 virus that expresses the immunostimulatory cytokine granulocyte–macrophage colony-stimulating factor. Some other combinations have shown promise, but with higher rates of toxicity, including the combination of ipilimumab plus nivolumab, which resulted in an increase in clinically significant AEs of grade 3 or greater, Dr. Chesney and his colleagues said.

“Combination regimens with lower toxicity may allow for their use in a broader range of patients,” they added.

The study was funded by Amgen, which manufactures talimogene laherparepvec. Dr. Chesney has a relationship with Amgen that involves consulting or advising; research funding; and travel, accommodation, and expenses. His associates reported financial relationships with Amgen and other companies; three of the investigators are Amgen employees.

op@frontlinemedcom.com