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Eur Urol. 2019 Oct 20. pii: S0302-2838(19)30764-X. doi: 10.1016/j.eururo.2019.09.036. [Epub ahead of print]

Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer.

Author information

1
Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
2
BC Cancer, Vancouver Cancer Centre, Vancouver, British Columbia, Canada.
3
Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
4
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
5
Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
6
Department of Medicine, University of Washington, Seattle, WA, USA; Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, WA, USA.
7
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
8
BC Cancer, Vancouver Cancer Centre, Vancouver, British Columbia, Canada; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
9
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
10
Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. Electronic address: Ajjai@med.umich.edu.
11
Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA; Department of Urology, University of California San Francisco, San Francisco, CA, USA. Electronic address: Felix.Feng@ucsf.edu.

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.

KEYWORDS:

Cyclin-dependent kinase 12; Genomics; Next-generation sequencing; Prostate cancer

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