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

Aged Cyclin-Dependent Kinases / genetics Humans Male Middle Aged Mutation Neoplasm Staging Prostatic Neoplasms / genetics Retrospective Studies Treatment Outcome
Cyclin-dependent kinase 12 Genomics Next-generation sequencing Prostate cancer

Journal

European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719

Informations de publication

Date de publication:
03 2020
Historique:
received: 01 05 2019
accepted: 27 09 2019
pubmed: 24 10 2019
medline: 28 5 2021
entrez: 24 10 2019
Statut: ppublish

Résumé

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

Sections du résumé

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.

Identifiants

DOI: 10.1016/j.eururo.2019.09.036 PMID: 31640893 PMC: PMC7365609
pubmed: 31640893
pii: S0302-2838(19)30764-X
doi: 10.1016/j.eururo.2019.09.036
pmc: PMC7365609
mid: NIHMS1544791
pii:
doi:

Substances chimiques

CDK12 protein, human EC 2.7.11.22
Cyclin-Dependent Kinases EC 2.7.11.22

Types de publication

Comparative Study Journal Article Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

333-341

Subventions

Organisme : NCI NIH HHS
ID : R01 CA227025
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA231996
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214170
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230516
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA108462
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA186786
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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Auteurs

Melissa A Reimers (MA)

Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Steven M Yip (SM)

BC Cancer, Vancouver Cancer Centre, Vancouver, British Columbia, Canada.

Li Zhang (L)

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.

Marcin Cieslik (M)

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Mallika Dhawan (M)

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.

Bruce Montgomery (B)

Department of Medicine, University of Washington, Seattle, WA, USA; Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, WA, USA.

Alexander W Wyatt (AW)

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Kim N Chi (KN)

BC Cancer, Vancouver Cancer Centre, Vancouver, British Columbia, Canada; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Eric J Small (EJ)

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.

Arul M Chinnaiyan (AM)

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.

Ajjai S Alva (AS)

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.

Felix Y Feng (FY)

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.

Jonathan Chou (J)

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.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Clinical Outcomes in Cyclin-dependent Kinase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Proline-directed protein kinases › Kinases cyclines-dépendantes › Clinical Outcomes in Cyclin-dependent Kinase...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Clinical Outcomes in Cyclin-dependent Kinase...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Clinical Outcomes in Cyclin-dependent Kinase...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Clinical Outcomes in Cyclin-dependent Kinase...
questionsmedicales.fr › Diagnostic › Pronostic › Stadification tumorale › Clinical Outcomes in Cyclin-dependent Kinase...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Clinical Outcomes in Cyclin-dependent Kinase...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études rétrospectives › Clinical Outcomes in Cyclin-dependent Kinase...
questionsmedicales.fr › Qualité, accès, évaluation des soins de santé › Qualité des soins de santé › Mécanismes d'évaluation des soins de santé › Évaluation des résultats et des processus en soins de santé › Évaluation de résultat (soins) › Résultat thérapeutique › Clinical Outcomes in Cyclin-dependent Kinase...