Abstract 1308: CDK12 alterations define a distinct molecular subtype of prostate cancers with unique genomic and clinical characteristics

Background:CDK12 alterations are present in several tumor types but little is known regarding their oncogenic role and their clinical significance. Here we sought to describe the landscape of CDK12 alterations across solid cancers and the clinical features of CDK12-altered prostate cancer. Methods: A total of 26,743 patients across 25 solid tumor types with available targeted sequencing data from MSK-IMPACT as part of their clinical care were included. Clinicopathological features and outcomes were assessed in prostate cancer. CDK12 alterations and association with genomic characteristics are described. For prostate cancer patients, overall survival from the date of metastasis and time to castration-resistance from the start of androgen deprivation therapy were assessed using univariable and multivariable Cox regression analysis. Results:CDK12 alterations were identified in 404/26,743 (1.5%) patients overall, but were most frequent in prostate (100/1875, 5.3%) and ovarian cancer (43/1034, 4.2%) where they were associated with a high prevalence of truncating variants and biallelic inactivation. CDK12 alterations defined a distinct subtype of prostate cancer with more aggressive clinical features, a unique copy number alteration profile and involvement of distinct oncogenic pathway alterations, including cell cycle pathway genes. Independent of standard clinical factors and genomic instability, CDK12-altered prostate cancer patients were associated with shorter overall survival (median 64.4 vs 74.9 months, adjusted hazard ratio [aHR] 1.65, 95% CI 1.07-2.53, p = 0.03) and shorter time to the development of castration-resistant disease (median 10.8 months vs 13.1, aHR 1.43, 95%CI 1.07-1.8, p = 0.02). Conclusions:CDK12 loss of function is a rare event across solid cancers but defines a distinct molecular subtype of prostate cancer that is associated with more aggressive clinical features and unique genomic alterations. Citation Format: Bastien Nguyen, Jose Mauricio Mota, Subhiksha Nandakumar, Konrad H. Stopsack, Emily Weg, Dana Rathkopf, Michael J. Morris, Howard Scher, Philip W. Kantoff, Anuradha Gopalan, Dmitriy Zamarin, David B. Solit, Nikolaus Schultz, Wassim Abida. CDK12 alterations define a distinct molecular subtype of prostate cancers with unique genomic and clinical characteristics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1308.