Female sex is associated with higher rates of dermatologic adverse events among patients with melanoma receiving immune checkpoint inhibitor therapy: A retrospective cohort study

To the Editor: The significance of sex as a risk factor for the development of dermatologic toxicities caused by immunotherapy remains unclear. In a study on non–small cell lung cancer patients receiving immune checkpoint inhibitors (ICIs), women were observed to have higher rates of nondermatologic immune-related adverse events (irAEs) (such as endocrinopathies and arthralgias), with premenopausal women appearing to be at a greatest risk.1Duma N. Abdel-Ghani A. Yadav S. et al.Sex differences in tolerability to anti-programmed cell death protein 1 therapy in patients with metastatic melanoma and non-small cell lung cancer: are we all equal?.Oncologist. 2019; 24: e1148-e1155https://doi.org/10.1634/theoncologist.2019-0094Crossref PubMed Scopus (59) Google Scholar We evaluated the impact of sex on the development of dermatologic toxicities in melanoma patients receiving ICIs. This retrospective cohort study included 243 adult patients with metastatic melanoma who received ipilimumab, nivolumab, pembrolizumab, or a combination of ipilimumab and nivolumab. They were evaluated by a health care provider at least every 4 weeks at the Dana-Farber Cancer Institute or Brigham and Women's Cancer Center between 2011 and 2016 (Supplemental Fig 1 available via Mendeley at https://data.mendeley.com/datasets/2jhhh83yxb/1.) Electronic medical records were reviewed to assess the development of dermatologic adverse events (dAEs) diagnosed by oncologists and/or dermatologists during and within 1 year of the last ICI treatment. Study staff, followed by 2 dermatologists, manually reviewed and confirmed the presence of the dAEs; for inclusion, a history of present illness, a physical examination, or an assessment or a plan based on oncology and/or dermatology notes was used to confirm the presence of rash and temporal association with ICI. Photography was considered a supportive documentation (available in 15.0% of the patients) but was not required. Multivariate logistic regression controlling for age, type of ICI, and number of infusion cycles was used to assess the impact of sex on the development of dAEs. Secondary analysis was used to investigate the effect of menopausal status; women aged ≥52 years were classified as postmenopausal based on epidemiologic studies.1Duma N. Abdel-Ghani A. Yadav S. et al.Sex differences in tolerability to anti-programmed cell death protein 1 therapy in patients with metastatic melanoma and non-small cell lung cancer: are we all equal?.Oncologist. 2019; 24: e1148-e1155https://doi.org/10.1634/theoncologist.2019-0094Crossref PubMed Scopus (59) Google Scholar The study included 235 adult patients with metastatic melanoma receiving ICIs (Table I), of whom 93 were women (39.6%; 27 pre- and 66 postmenopausal). dAEs developed in 127 (54.0%) of the 235 patients and in 58 (62.4%) of the 93 women compared with 69 (48.6%) of 142 men. Female sex was a significant risk factor for the development of dAEs compared with male sex (odds ratio [OR] 2.1; 95% CI, 1.2-3.8; P = .01) (Fig 1). In the secondary analyses, the effect of menopausal status, compared with the rates in men, was comparable for postmenopausal (OR 2.2; 95% CI 1.0-4.7; P = .05) and premenopausal women (OR 1.97; 95% CI 0.56-6.87; P = .40).Table IDemographic, clinical, and treatment characteristics of 235 patients with melanoma treated with immune checkpoint inhibitor therapy, categorized based on male or female sexPatient demographics of total study populationSex (n)Female (n = 93)Male (n = 142)P valueConfirmed ICI-associated dermatologic irAE Yes58 (62.4)69 (48.6) No35 (37.6)73 (51.4)Age, y (median [range])∗Age at the onset of ICI therapy.60 (22-88)65 (30-91).002 18-5330 (32.3)31 (21.8).03 54-6226 (28.0)31 (21.8) 63-7123 (24.7)36 (25.4) ≥7258 (15.1)44 (31.0)Race.99 White91 (97.8)139 (97.9) Asian/American or Pacific Islander1 (1.1)2 (1.4) Other1 (1.1)1 (0.7)Ethnicity Non-Hispanic93 (100)142 (100)Menopausal status Premenopausal27 (29.0)N/A Postmenopausal66 (71.0)N/AReported history of autoimmune skin disease Psoriasis0 (0.0)1 (0.7) Sarcoidosis0 (0.0)1 (0.7)ICI.89 Ipilimumab24 (25.8)43 (30.3) Nivolumab8 (8.6)12 (8.5) Pembrolizumab32 (34.4)44 (31.0) Nivolumab and ipilimumab combination29 (31.2)43 (30.3)Number of ICI infusion cycles†The number of infusion cycles was defined as the total number of cycles prior to irAE onset for patients in whom a dermatologic irAE developed; for those in whom dermatologic irAE did not develop, this was defined as the total number of cycles of their most recent ICI..88 122 (23.7)39 (27.5) 2-333 (35.5)44 (31.0) 4-716 (17.2)26 (18.3) ≥822 (23.7)33 (23.2)Clinical and treatment characteristics of 127 patients with dermatologic toxicities Sex (n, %)Female (n = 58)Male (n = 69) Number of dermatologic irAE(s) per individual141 (70.7)53 (76.8)216 (27.6)15 (21.7)31 (1.7)1 (1.4) Type of dermatologic irAE‡The following dermatologic irAEs had counts of n = 1 and, thus, were not reported in the table. Females: eczematous, folliculitis, inflamed seborrheic keratosis, lichen simplex chronicus/prurigo nodularis, macular, morbilliform, papular, petechial, psoriasis, and seborrheic dermatitis. Males: alopecia areata, bullous pemphigoid, eczematous, Grover, lichen simplex chronicus, macular, melasma, morbilliform, papulopustular rosacea, petechial, and plaques.Morbilliform21 (36.2)34 (49.3)Pruritus (without rash)14 (24.1)10 (14.5)Pruritic rash12 (20.7)12 (17.4)Vitiligo10 (17.2)10 (14.5)Nonspecific rash, morphology not well described3 (5.2)2 (2.9)Photo distributed2 (3.4)0 (0.0)Lichenoid2 (3.4)4 (5.8)Acneiform/papulopustular2 (3.4)1 (1.4) Referral to the dermatology department for the management of dermatologic irAEReferral to the dermatology department13 (22.4)20 (29.0)No referral to the dermatology department45 (77.6)49 (71.0) Treatment with systemic steroids for dermatologic irAEYes1 (1.7)2 (2.9) ICI interruption due to dermatologic irAENot interrupted55 (94.8)63 (91.3)Permanently discontinued2 (3.4)4 (5.8)Held and restarted at full dose1 (1.7)2 (2.9)ICI, Immune checkpoint inhibitor; irAE, immune-related adverse event; N/A, not applicable.∗ Age at the onset of ICI therapy.† The number of infusion cycles was defined as the total number of cycles prior to irAE onset for patients in whom a dermatologic irAE developed; for those in whom dermatologic irAE did not develop, this was defined as the total number of cycles of their most recent ICI.‡ The following dermatologic irAEs had counts of n = 1 and, thus, were not reported in the table. Females: eczematous, folliculitis, inflamed seborrheic keratosis, lichen simplex chronicus/prurigo nodularis, macular, morbilliform, papular, petechial, psoriasis, and seborrheic dermatitis. Males: alopecia areata, bullous pemphigoid, eczematous, Grover, lichen simplex chronicus, macular, melasma, morbilliform, papulopustular rosacea, petechial, and plaques. Open table in a new tab ICI, Immune checkpoint inhibitor; irAE, immune-related adverse event; N/A, not applicable. Herein, female sex was associated with twice the risk of the development of dAEs. Biologic differences involving sex hormones, sex-chromosome–related genes, as well as the innate and adaptive immune systems likely contribute; women elicit stronger immune responses and are more susceptible to autoimmune diseases.2Conforti F. Pala L. Bagnardi V. et al.Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis.Lancet Oncol. 2018; 19: 737-746https://doi.org/10.1016/s1470-2045(18)30261-4Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Klein S.L. Flanagan K.L. Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638https://doi.org/10.1038/nri.2016.90Crossref PubMed Scopus (2223) Google Scholar, 4Polanczyk M.J. Hopke C. Vandenbark A.A. Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway.J Neurosci Res. 2006; 84: 370-378https://doi.org/10.1002/jnr.20881Crossref PubMed Scopus (175) Google Scholar High estrogen levels enhance humoral and cell-mediated immunity by augmenting proinflammatory cytokines, antigen-presenting cells, and helper T cell type 2 responses.3Klein S.L. Flanagan K.L. Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638https://doi.org/10.1038/nri.2016.90Crossref PubMed Scopus (2223) Google Scholar Regulatory T cell levels differ between the sexes and fluctuate with hormonal status.4Polanczyk M.J. Hopke C. Vandenbark A.A. Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway.J Neurosci Res. 2006; 84: 370-378https://doi.org/10.1002/jnr.20881Crossref PubMed Scopus (175) Google Scholar In animal models, estrogen and antigen-presenting cells produce an inhibitory effect on the programmed death 1 pathway.4Polanczyk M.J. Hopke C. Vandenbark A.A. Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway.J Neurosci Res. 2006; 84: 370-378https://doi.org/10.1002/jnr.20881Crossref PubMed Scopus (175) Google Scholar Sex-chromosome–related genes may escape X inactivation, leading to higher levels of interferon α in women.3Klein S.L. Flanagan K.L. Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638https://doi.org/10.1038/nri.2016.90Crossref PubMed Scopus (2223) Google Scholar The comparable OR between premenopausal and postmenopausal women compared with that in men suggests that factors other than sex hormones are contributory. We were limited by the few referrals to the dermatology department, which restricted the comparison of more specifically classified eruptions. Differences in health-seeking behaviors may contribute; however, the patients were evaluated for toxicities at the time of infusion visits, regardless of sex. Clinicians should consider these findings while counseling female patients regarding the risk of dAEs due to immunotherapy. Dr LeBoeuf is a consultant and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, and Synox Therapeutics outside the submitted work. Drs Bougrine, Bui, Buchbinder, and Giobbie-Hurder have no conflicts of interest to declare. Dr LeBoeuf had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.