Patients with microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI (TMB-H/MSS).
We sequenced 3,244 tumors from 2,257 prostate cancer patients. MSI-H/dMMR prostate cancer was defined as MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival (OS) and radiographic progression-free survival (rPFS) were compared using log rank test.
63 (2.8%) men had MSI-H/dMMR and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel and neoantigen burden compared with TMB-H/MSS. 27 patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored POLE mutations. 45% of MSI-H/dMMR patients had a RECIST response and 65% had a PSA50 response. No TMB-H/MSS patient had a RECIST response and 50% had a PSA50 response. rPFS tended to be longer in MSI-H/dMMR patients than in TMB-H/MSS patients who received immunotherapy. Pronounced differences in genomics, TMB or MSIsensor score were not detected between MSI-H/dMMR responders and non-responders.
MSI-H/dMMR prostate cancers have greater TMB, indel and neoantigen burden compared with TMB-H/MSS prostate cancers, and these differences may contribute to more profound and durable responses to ICB.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Jul 01 [Epub ahead of print]
Andrew T Lenis, Vignesh Ravichandran, Samantha Brown, Syed M Alam, Andrew Katims, Hong Truong, Peter A Reisz, Samantha Vasselman, Barbara Nweji, Karen A Autio, Michael J Morris, Susan F Slovin, Dana Rathkopf, Daniel Danila, Howard I Scher, Sungmin Woo, Hebert Alberto Vargas, Vincent P Laudone, Behfar Ehdaie, Victor Reuter, Maria Arcila, Michael F Berger, Agnes Viale, Nikolaus Schultz, Anuradha Gopalan, Mark T A Donoghue, Irina Ostrovnaya, Konrad H Stopsack, David B Solit, Wassim Abida
Columbia University Medical Center, New York, NY, United States., Memorial Sloan Kettering Cancer Center, New York, NY, United States., Memorial Sloan Kettering Cancer Center, New York, United States., Memorial Sloan Kettering Cancer Center, New York, New York, United States., Memorial Sloan Kettering Cancer Center; Weill Cornell College of Medicine, New York, NY, United States., New York University Langone Medical Center, New York, NY, United States., New York University Langone Medical Center, United States., Massachusetts General Hospital, Boston, MA, United States.