Gender-based differences in the efficacy of anti-EGFR/BRAF/MEK targeted therapy in patients with BRAF-mutated metastatic colorectal cancer.

Objectives: We previously showed that men with melanoma harboring BRAF mutations had significantly lower benefit from targeted therapy as compared with women Here we explored the hypothesis that such gender-based dimorphism in the efficacy of BRAF-pathway blockade extends to other tumor histotypes carrying pathogenic BRAF-mutations.

Methods: We retrospectively analyzed data from a cohort of patients with advanced colorectal-cancer (CRC) harboring BRAF V600E mutations, treated with anti-EGFR/BRAF/MEK targeted therapy. The primary objective was to assess the association between gender and outcome of patients treated with targeted therapy, in terms of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).A multivariable Cox proportional hazard regression model was used to assess the association between gender and PFS and OS, adjusted for other relevant clinical, pathological and molecular prognostic factors, including ECOG PS (0 vs 1-2), primary tumor site (right-side vs left-side), microsatellite instability status (instable [MSI] vs stable [MSS]), number of metastatic sites at treatment start, treatment type (double targeted therapy [ie, anti-EGFR + anti-BRAF] vs triple targeted therapy [ie, anti-EGFR + anti-BRAF + anti-MEK]) and mutational status of the RNF43 gene (wild type vs mutated).

Results: Ninety-eight patients with advanced CRC were included in the analysis: 59 (60%) were women and 39 (40%) men. The ORR was 43.1% in women vs only 23.7% in men (p-value = .05). Multivariable analysis adjusted for relevant clinical, pathological, and molecular variables associated with patients' prognosis, showed a significantly shorter PFS and OS in men as compared with women: the adjusted-HR was, respectively, 1.65 (95%CI,1.00-2.69; p = .04) for PFS and 1.83 (95%CI,1.08-3.08; p-value = .02) for OS.

Conclusions: We confirmed a significant gender-based dimorphism in the efficacy of anti-EGFR/BRAF/MEK therapy in patients with advanced-CRC harboring BRAF mutations that warrant further investigation.