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Authors
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Vellano CP, White MG, Andrews MC, Chelvanambi M, Witt RG, Daniele JR, Titus M, McQuade JL, Conforti F, Burton EM, Lastrapes MJ, Ologun G, Cogdill AP, Morad G, Prieto P, Lazar AJ, Chu Y, Han G, Khan MAW, Helmink B, Davies MA, Amaria RN, Kovacs JJ, Woodman SE, Patel S, Hwu P, Peoples M, Lee JE, Cooper ZA, Zhu H, Gao G, Banerjee H, Lau M, Gershenwald JE, Lucci A, Keung EZ, Ross MI, Pala L, Pagan E, Segura RL, Liu Q, Borthwick MS, Lau E, Yates MS, Westin SN, Wani K, Tetzlaff MT, Haydu LE, Mahendra M, Ma X, Logothetis C, Kulstad Z, Johnson S, Hudgens CW, Feng N, Federico L, Long GV, Futreal PA, Arur S, Tawbi HA, Moran AE, Wang L, Heffernan TP, Marszalek JR, Wargo JA
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Abstract Text
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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.
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