Gender Disparities in Patients With Melanoma: Breaking the Glass Ceiling

The past decade has seen increased attention to gender and racial disparities in outcome for a wide variety of malignancies, and melanoma is no exception. Although cutaneous melanoma is predominantly a disease of whites, when it does occur in darker-skinned peoples, outcomes are clearly inferior stage for stage. There are also gender disparities in melanoma incidence and outcome. In the United States in 2011, there were an estimated 70,230 cases of invasive cutaneous melanoma, of which 43% (30,220 cases) occurred in women. However, of the 8,790 melanoma-related deaths, only 35% (3,040 deaths) occurred in women. In Journal of Clinical Oncology, Joosse et al add prospective clinical trial data to the large amount of retrospective information suggesting women with melanoma fare better, stage for stage, than men. In a pooled analysis of 2,672 patients with clinically localized (stage I/II) melanoma enrolled onto four European Organisation for Research and Treatment of Cancer prospective trials, women had observed advantages in overall survival, melanomaspecific survival, and time to lymph node and distant metastases. These advantages were consistently in the 30% range, even when adjusted for other prognostic factors, and were consistent across various subgroups and in younger (presumably premenopausal) and older (postmenopausal) age groups. As is so often the case in melanoma, these observations generate at least as many questions as they answer. A few of the most cogent questions are addressed herein. 1. Is this gender-based disparity real or artifactual? As previously alluded to, a great deal of prior retrospective single-institution and pooled data support improved outcomes for women with melanoma. Population-based data from most countries demonstrate similar trends, such as a recent study from Germany, which showed that women with melanoma were 38% more likely to survive than men and 32% less likely to have melanoma progression (with reduced risk for both nodal and visceral metastases). These results closely mirror those of Joosse et al and seem to strongly support that the gender-based disparity is real rather than artifactual. 2. If real, what is the cause of the disparity? Is the benefit confined to only a subset of women? Available data have addressed the potential cause(s) of a gender-based outcome disparity in melanoma by evaluating estrogen and estrogen-related factors—the contribution of which has been suspected for many years. Whereas previously the only known estrogen receptor (ER) was ER, now ERexpression has been shown to be significantly associated with mortality in melanoma. Furthermore, methylation of ERseems to be associated strongly with progression in melanoma. Additionally,otherdifferencesinhost-tumorinteractions, including potentialprotectivefactorsinwomenormelanoma-stimulatingfactorsin men, have been hypothesized. If the difference was purely based on hormonal influences, the age of onset should affect outcomes in women, in contrast to the findings of Joosse et al. Etiologic and site-specific differences could play a role, given different patterns of occupational and recreational ultraviolet light exposure between men and women. But perhaps most importantly, men consistently demonstrate lower awareness, resistance to screening, and less knowledgeseeking behavior when it comes to skin malignancies. Possibly as a direct consequence of these behavioral traits, men—especially older men—present with thicker tumors and an attendant increased mortality risk. Available data are limited and somewhat conflicting on whether there are subsets of women who fare better or worse. Pregnancy status at diagnosis or afterward was inversely associated with melanoma survival in Sweden. Inverse associations with parity were observed for melanoma and nonmelanoma skin cancer outcomes in a prospective Norwegian case-control study and for choroidal melanoma outcome in a single-institution study in Massachusetts. The possible influence of parity bears further scrutiny, because it could implicate either hormonal or immunologic influences on melanoma outcomes. 3. What if any therapeutic implications are there for this observation? Should men be treated differently than women (eg, more aggressively)? Should we revisit hormone receptor analysis and/or hormonal therapies such as tamoxifen? At present, the lack of definitive data implicating hormonal or other specific factors in melanoma outcome disparities makes any consideration of different therapeutic interventions for men and women with cutaneous melanoma premature. At one point, tamoxifen was frequently used along with systemic cytotoxic chemotherapy for stage IV melanoma, but prospective clinical trials have not supported its use. An intriguing area that should be further explored is whether the indications for sentinel lymph node biopsy should be different for men and women, given the observed greater propensity for lymphatic metastases in men. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 18 JUNE 2