Platinum Priority – Prostate CancerEditorial by XXX on pp. x–y of this issueClinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer
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.
References (30)
- et al.
Integrative clinical genomics of advanced prostate cancer
Cell
(2015) - et al.
Genomic hallmarks and structural variation in metastatic prostate cancer
Cell
(2018) - et al.
Compound genomic alterations of TP53, PTEN, and RB1 tumor suppressors in localized and metastatic prostate cancer
Eur Urol
(2019) - et al.
Role and therapeutic potential of CDK12 in human cancers
Cancer Treat Rev
(2016) - et al.
Circulating tumor DNA abundance and potential utility in de novo metastatic prostate cancer
Eur Urol
(2019) - et al.
Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer
Eur Urol
(2019) - et al.
Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer
Cell
(2018) - et al.
CDK12 regulates DNA repair genes by suppressing intronic polyadenylation
Nature
(2018) - et al.
The cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes
Genes Dev
(2011) - et al.
Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity
Cancer Res
(2014)
Ovarian cancers harboring inactivating mutations in CDK12 display a distinct genomic instability pattern characterized by large tandem duplications
Cancer Res
The tandem duplicator phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations
Cancer Cell
Differential impact of RB status on E2F1 reprogramming in human cancer
J Clin Invest
Clinical implications of PTEN loss in prostate cancer
Nat Rev Urol
Genomic correlates of clinical outcome in advanced prostate cancer
Proc Natl Acad Sci U S A
Cited by (0)
- †
These authors contributed equally to this manuscript.