Sex Is an Independent Prognostic Indicator for Survival and Relapse/Progression-Free Survival in Metastasized Stage III to IV Melanoma: A Pooled Analysis of Five European Organisation for Research and Treatment of Cancer Randomized Controlled Trials

Abstract

The persistent independent female advantage, even after metastasis to lymph nodes and distant sites, contradicts theories about sex behavioral differences as an explanation for this phenomenon. A biologic sex trait seems to profoundly influence melanoma progression and survival, even in advanced disease.

Prognostic instrument for survival outcome in melanoma patients: based on data from the population-based Swedish Melanoma Register

“…Also after adjusting for tumour thickness, Clark's level of invasion and tumour ulceration, women had a 30% lower risk of CMM-related death than men. This superior non-stage effect for women has previously been found in studies with similar HR (19,20). Surprisingly, sex was not included in the final prognostic model in two of the largest published prognostic instruments based on AJCC data and from Queensland Australia respectively (3,4).…”

Effect of biology on the outcome of female melanoma patients

“…In a subsequent study on stage I/II melanoma, it was observed that men had worse prognostic characteristics at diagnosis, and they retained a progression disadvantage of ~30% after diagnosis (7). In 2013, the same group analyzed survival differences across sexes in stage III and IV melanoma patients (8). They again demonstrated the continuity of independent female survival advantage following adjustment for known prognostic factors, despite lymph node and distant metastasis.…”

“…The first hypothesis was controverted and the second hypothesis was advocated by the fact that the female survival advantage persisted even following adjustment for factors such as Breslow's thickness, and that lymph node and visceral organ metastases did not affect the higher survival rate of female patients (4,(5)(6)(7)(8)(9)(10)(11). Thus, it was concluded that the aggressiveness of the disease did not affect the survival benefit of female melanoma patients.…”

“…In order to explain this difference, researchers have suggested two major hypotheses so far: The first hypothesis is based on behavioral characteristics, such as that men have more advanced disease at diagnosis due to certain lifestyle characteristics (i.e., men are exposed to the sun more often and for longer periods compared with women, and are less conscious of skin care and skin cancer, thus not taking sufficient preventive measures) that may result in delays in screening, detection and diagnosis of the disease (4). The second hypothesis is that there is a biological trait that has yet to be elucidated, which accounts for the sex-related survival difference in melanoma; this unclear biological trait is believed to be associated with either the tumor per se (namely, the disease in female patients is naturally less aggressive), or with factors within the host (namely, female sex prevents disease progression and spread) (5)(6)(7)(8)(9).…”

1244 Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

“…There is an acute need for new therapeutic strategies that augment the efficacy of standard-of-care immune checkpoint inhibitors. Clues to potential new therapeutic targets for melanoma may be found in 50 year old observations (White, 1959), validated in recent studies, that female sex, history of multiple pregnancies, and decreased maternal age at first birth are associated with decreased melanoma incidence and favorable prognosis (Bannister-Tyrrell et al, 2015;Gandini et al, 2011;Hersey et al, 1977;Joosse et al, 2013;Karagas et al, 2006;Magnus, 1977). Although the mechanism of this protective effect is unknown, the clinical association suggests that sex hormone signaling is involved.…”