| Literature DB >> 35705814 |
Christopher P Vellano1, Michael G White2, Miles C Andrews2,3, Manoj Chelvanambi2, Russell G Witt2, Joseph R Daniele1, Mark Titus4, Jennifer L McQuade5, Fabio Conforti6, Elizabeth M Burton2, Matthew J Lastrapes2, Gabriel Ologun2,7, Alexandria P Cogdill2,8, Golnaz Morad2, Peter Prieto2,9, Alexander J Lazar10,11,12, Yanshuo Chu11, Guangchun Han11, M A Wadud Khan2, Beth Helmink2,13, Michael A Davies5, Rodabe N Amaria5, Jeffrey J Kovacs1, Scott E Woodman11, Sapna Patel5, Patrick Hwu5,14, Michael Peoples1, Jeffrey E Lee2, Zachary A Cooper2,15, Haifeng Zhu11, Guang Gao1, Hiya Banerjee16, Mike Lau17, Jeffrey E Gershenwald2, Anthony Lucci2, Emily Z Keung2, Merrick I Ross2, Laura Pala6, Eleonora Pagan18, Rossana Lazcano Segura12, Qian Liu19, Mikayla S Borthwick20, Eric Lau19, Melinda S Yates20, Shannon N Westin20, Khalida Wani12, Michael T Tetzlaff10,21, Lauren E Haydu2, Mikhila Mahendra1, XiaoYan Ma1, Christopher Logothetis4, Zachary Kulstad2, Sarah Johnson2, Courtney W Hudgens12, Ningping Feng1, Lorenzo Federico1, Georgina V Long22, P Andrew Futreal11, Swathi Arur23, Hussein A Tawbi5, Amy E Moran24, Linghua Wang11, Timothy P Heffernan25, Joseph R Marszalek26, Jennifer A Wargo27,28.
Abstract
Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.Entities:
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Year: 2022 PMID： 35705814 DOI： 10.1038/s41586-022-04833-8
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 69.504