Elsevier

European Urology

Volume 77, Issue 3, March 2020, Pages 333-341
European Urology

Platinum Priority – Prostate Cancer
Editorial by XXX on pp. x–y of this issue
Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer

https://doi.org/10.1016/j.eururo.2019.09.036Get rights and content

Abstract

Background

Cyclin-dependent kinase 12 (CDK12) loss occurs in 3–7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are not well established.

Objective

To determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes.

Design, setting, and participants

A retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (n = 172) or circulating tumor DNA (n = 145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%).

Outcome measurements and statistical analysis

Patients were stratified by mutation status (CDK12, homologous recombination deficiency [HRD; BRCA1/2 and ATM], TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset.

Results and limitations

The median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (median = 34.9 mo, p =  0.004) and development of castration-resistant disease (median = 32.7 mo, p <  0.001), compared with other genomic subtypes, with shorter time to PSA progression on first-line ARPI treatment of metastatic castration-resistant disease (median = 3.6 mo, p =  0.0219). CDK12 mutant patients did not have overall shorter time on treatment compared with other mutation subgroups, and CDK12 status did not demonstrate statistical significance in multivariate analysis. Limitations include variable center-dependent practice patterns and heterogeneity due to combining tumor and liquid biopsy data.

Conclusions

Our data suggest that advanced prostate cancers harboring CDK12 mutations display aggressive clinical behavior, underscoring the need to fully delineate the molecular and clinical characteristics, and appropriate therapeutic approaches for distinct subtypes of advanced prostate cancers.

Patient summary

In this report, we evaluate the clinical characteristics and outcomes of patients with prostate cancer and CDK12 mutation in their tumors. These patients seem to have more aggressive disease, with more high-grade Gleason ≥8 cancers and shorter time to developing metastatic cancer. Cases of advanced CDK12-mutated prostate cancer may warrant consideration of therapy intensification or combination approaches.

Introduction

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease despite six Food and Drug Administration–approved therapies that prolong survival. While whole-exome and -genome sequencing studies have provided insights into the heterogeneous landscape of mutations and structural variants within advanced prostate cancer [1], [2], the impact of these genomic alterations on clinical outcomes requires further investigation [3], [4]. Recently, a novel molecular subtype of advanced prostate cancer harboring cyclin-dependent kinase 12 (CDK12) mutations has been reported in 3–7% of patients with mCRPC [1], [2], [5]. CDK12 functions in transcriptional regulation and RNA splicing [6], and regulates DNA damage repair genes involved in homologous recombination (HR [ie, BRCA1 and ATM]), suppresses intronic polyadenylation, and may increase susceptibility to poly ADP-ribose polymerase (PARP) inhibitors [7], [8], [9]. Recently, we and others showed that biallelic CDK12 loss in prostate cancer patients results in genomic instability and increased tandem duplications [2], [5], which is also observed in CDK12-mutated ovarian cancer [10], [11], but is distinct from tumors characterized by BRCA2 loss [2].

PTEN loss, RB loss, and TP53 mutations have been associated with poor outcomes in mCRPC [3], [12], [13], [14]. The effects of alterations in the canonical HR gene BRCA2 remain an area of ongoing investigation [15]. BRCA2 mutations lead to decreased cancer-specific survival and poor clinical outcomes in the mCRPC setting, with a variable impact on response to therapy [16], [17], [18]. However, the prognostic relevance of CDK12 mutations remains unexplored. Therefore, we evaluated the clinical characteristics and outcomes of a multicenter cohort of patients with CDK12-mutated prostate cancer, comparing this genomic subtype with prostate cancers characterized by deficiency in canonical HR genes (ie, BRCA1, BRCA2, and ATM) and TP53.

Section snippets

Patients and methods

We conducted a retrospective chart review of patients with advanced prostate cancer at the University of Michigan (MI), University of California San Francisco (UCSF), and University of British Columbia (UBC). University of Washington patients sequenced at MI via Stand up to Cancer (SU2C) were included in the MI cohort. CDK12 mutant and HRD patients were identified from each institution’s available next-generation sequencing (NGS) and clinical data. The remaining patients had previously

Results

Baseline characteristics are shown in Table 1. A total of 317 patients were included in this analysis. At the time of censoring, 305 developed metastatic disease and 296 developed CRPC. Detailed mutation data were available for 43 of 46 patients with CDK12 mutations (Fig. 1A and 2, and Supplementary Table 1) with two distinct mutations in 34/43 patients (79%), consistent with biallelic loss (Supplementary Table 1). A significantly higher proportion (88%) of men with CDK12 mutations presented

Discussion

This study represents the largest assessment to date of clinical outcome measures in CDK12 mutant advanced prostate cancer. Of note, we report that 14.5% of patients in this cohort harbored CDK12 mutations. Given that we have purposefully included all available CDK12 patients at our institutions, we would expect our proportion of patients with CDK12 mutations to be artificially higher than the previously reported prevalence [1], [5]. We identified several characteristics that suggest that CDK12

Conclusions

CDK12-mutated prostate cancers are a molecularly distinct subset of advanced prostate cancer, displaying clinical features suggestive of more aggressive disease and may warrant intensification of therapy. Overall, our study illustrates the importance of molecularly subtyping advanced prostate cancers, given the apparent heterogeneity in clinical behavior, and serves as the foundation for future prospective investigations to further characterize the CDK12-mutated subtype of prostate cancer.


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  • Cited by (0)

    These authors contributed equally to this manuscript.

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