Age-Dependent Female Survival Advantage in Hepatocellular Carcinoma: A Multicenter Cohort Study

Background & Aims Hepatocellular carcinoma (HCC) has higher incidence in males, but the association of sex with survival remains controversial. This study aimed to examine the effect of sex on HCC survival and its association with age. Methods Among 33,238 patients with HCC from 12 Chinese tertiary hospitals, 4,175 patients who underwent curative-intent hepatectomy or ablation were analyzed. Cancer-specific survival (CSS) was analyzed using Cox regression and Kaplan-Meier methods. Two propensity score methods and multiple mediation analysis were applied to mitigate confounding. To explore the effect of estrogen, a candidate sex-specific factor that changes with age, female participants’ history of estrogen use and survival were analyzed. Results There were 3,321 males and 854 females included. A sex-related disparity of CSS was present and showed a typical age-dependent pattern: female survival advantage over male appeared at the perimenopausal age (years) of 45-54 (HR 0.77, 5-year CSS 85.7% vs 70.6%, p = 0.018), peaked at early postmenopausal age of 55-59 (HR 0.57, 5-year CSS 89.8% vs 73.5%, p = 0.015) and was not present in the premenopausal (<45) and late postmenopausal groups (≥60). Consistent patterns were observed in patients after either ablation or hepatectomy. These results were sustained with propensity score analyses. Confounding or mediation effects accounted for only 19.5% of sex survival disparity. Female estrogen users had significantly longer CSS than non-users (HR 0.74, 5-year CSS 79.6% vs 72.5%, p = 0.038). Conclusion Female survival advantage in HCC depends on age, and this may be associated with age-dependent sex-specific factors.