A pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response

A. Ari Hakimi (), Kyrollis Attalla, Renzo G. DiNatale, Irina Ostrovnaya, Jessica Flynn, Kyle A. Blum, Yasser Ged, Douglas Hoen, Sviatoslav M. Kendall, Ed Reznik, Anita Bowman, Jason Hwee, Christopher J. Fong, Fengshen Kuo, Martin H. Voss, Timothy A. Chan and Robert J. Motzer
Additional contact information
A. Ari Hakimi: Memorial Sloan Kettering Cancer Center
Kyrollis Attalla: Memorial Sloan Kettering Cancer Center
Renzo G. DiNatale: Memorial Sloan Kettering Cancer Center
Irina Ostrovnaya: Memorial Sloan Kettering Cancer Center
Jessica Flynn: Memorial Sloan Kettering Cancer Center
Kyle A. Blum: Memorial Sloan Kettering Cancer Center
Yasser Ged: Memorial Sloan Kettering Cancer Center
Douglas Hoen: Memorial Sloan Kettering Cancer Center
Sviatoslav M. Kendall: Memorial Sloan Kettering Cancer Center
Ed Reznik: Memorial Sloan Kettering Cancer Center
Anita Bowman: Memorial Sloan Kettering Cancer Center
Jason Hwee: Memorial Sloan Kettering Cancer Center
Christopher J. Fong: Memorial Sloan Kettering Cancer Center
Fengshen Kuo: Memorial Sloan Kettering Cancer Center
Martin H. Voss: Memorial Sloan Kettering Cancer Center
Timothy A. Chan: Memorial Sloan Kettering Cancer Center
Robert J. Motzer: Memorial Sloan Kettering Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.

Date: 2020
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DOI: 10.1038/s41467-020-17965-0

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