Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.

作者：Michael G. White, Christopher P. Vellano, Miles C. Andrews, Russell G. Witt, Manoj Chelvanambi, Jennifer L. McQuade, Elizabeth M. Burton, Yanshuo Chu, Matthew Lastrapes, Mike Lau, Hiya Banerjee, Alexander J. Lazar, Michael A. Davies, Scott E. Woodman, Linghua Wang, Amy E. Moran, Georgina V. Long, Timothy P. Heffernan, Joe Marszalek, Jennifer A. Wargo · 发表于：Journal of Clinical Oncology · 年份：2022 · DOI：10.1200/jco.2022.40.16_suppl.9523 · 被引用次数：4 · 研究领域：Melanoma and MAPK Pathways、Protein Degradation and Inhibitors、Cutaneous Melanoma Detection and Management

9523 Background: Treatment with BRAF+/-MEK inhibition (BRAF+/-MEKi) has revolutionized treatment in melanoma and other cancers, but resistance is common and innovative treatment strategies are needed. Sexual dimorphism in response to BRAF+/-MEKi have been noted, but mechanisms behind this are poorly understood and hormonal modulation has not been well-studied in this setting. Methods: We examined outcomes by sex in five clinical cohorts of patients (pts) (total n = 792, 362 female, 430 male) with BRAF-mutated melanoma who were treated with BRAF/MEKi in either the neoadjuvant or metastatic setting. Rates of major pathologic response (MPR), clinical benefit (CB), progression free survival (PFS) relapse-free survival (RFS) and overall survival (OS) were assessed. Translational research studies were performed on available pre- and on-treatment tumor samples (n = 27 pts) including RNA sequencing and profiling androgen receptor (AR) expression. Parallel studies were performed in preclinical models to assess the effect of sex and AR modulation on response to BRAF+/-MEKi. Results: In this study, improved rates of MPR, CB, PFS and OS were observed in female vs male pts. Specifically, female patients treated with neoadjuvant BRAF+MEKi showed significantly higher rates of MPR (66% v. 14%, p = 0.001), and improved RFS (64% versus 32% at 2 years, p = 0.021) vs male pts in the neoadjuvant setting (n = 51). These findings were not observed in a 2 nd smaller trial of pts (n = 35), but were v...