Gene Mutations as a Target in Metastatic Prostate Cancer

Summary and Comment |
July 8, 2016

Gene Mutations as a Target in Metastatic Prostate Cancer

  1. Robert Dreicer, MD, MS, FACP, FASCO

The incidence of germline mutations in DNA-repair genes was significantly higher in men with metastatic versus localized disease.

  1. Robert Dreicer, MD, MS, FACP, FASCO

The recent report of a high response to PARP1 inhibitors among heavily treated metastatic castration-resistant prostate cancer patients with DNA-repair defects (NEJM JW Oncol Hematol Dec 2015 and N Engl J Med 2015; 373:1697) has led to additional efforts to more fully characterize the potential role of germline DNA-repair mutations, which, although limited in unselected patients with localized prostate cancer, is undefined in advanced disease.

To analyze DNA-repair genes associated with autosomal-dominant cancer-predisposition syndromes, investigators added 542 men from six different international cohorts to a previous reported series of 150 men with metastatic prostate cancer (Cell 2015; 161:1215). Patients were unselected regarding family history, age, or genetic background.

Of the 692 men, 11.8% had at least one presumed pathogenic germline mutation in a gene involved in DNA-repair processes. Mutations were identified in 16 different genes, including more than half of the mutations in BRCA2 and ATM. Among men who provided family history data, 22% of those either with or without DNA-repair gene mutations had a first-degree relative with prostate cancer. Of note, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence among 499 men from the Cancer Genome Atlas prostate cancer study (Cell 2015; 163:1011) with localized prostate cancer (4.6%; P<0.001).

Comment

As noted by the authors, this study has some potentially important limitations, including possible issues regarding comparability of DNA sequencing analyses across several institutions using public data, the potential for bias in the seven unselected cohorts, and the relative dearth of patients 70 years or older. Nevertheless, the findings may lead to novel methods of improving prostate cancer-risk identification and identification of patients who may benefit from PARP1 inhibition and cisplatin-based chemotherapy.

Editor Disclosures at Time of Publication

  • Disclosures for Robert Dreicer, MD, MS, FACP, FASCO at time of publication Consultant / Advisory board Medivation; Genentech/Roche; Ferring; Asana; Churchill Pharma; Tokai Editorial boards Urology; Clinical Genitourinary Cancer; Current Urology Reports Leadership positions in professional societies National Cancer Institute (Co-Chair, GU Oncology Steering Committee); Bladder Cancer Advocacy Network (Member, Scientific Advisory Board)

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