Men with metastatic disease found more likely to harbor mutations in genes mediating DNA-repair processes, according to results published Wednesday in the New England Journal of Medicine. The multicenter study funded by Stand Up to Cancer (SU2C), the Prostate Cancer Foundation (PCF), and others, isolated germline DNA from 692 men and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes. The majority of patients came from Prostate Cancer Clinical Trials Consortium (PCCTC) clinical research sites. In addition, the PCCTC played a critical role in coordinating the distribution and analysis of patient samples.
The particular genes analyzed in this study including BRCA1, BRCA1, and ATM have been linked to autosomal dominant cancer-predisposition syndromes and are commonly associated with breast and ovarian cancers. Mutated DNA-repair genes lead to tumor growth and survival and are also associated with an increased risk of lethal prostate cancer.
The findings – the frequency of mutations in men with metastatic prostate cancer (11.8%) significantly exceeded the prevalence in men with localized disease (4.6%) – suggest a greater role for genetic testing to guide treatment for men diagnosed with prostate cancer, and supports further development of drugs targeting these genetic aberrations (e.g., PARP inhibitors). Moreover, the frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to family history of prostate cancer, and in fact the rate of these particular aberrations was found substantially higher than the 7.3% incidence of mutations in 22 tumor-suppressor genes in familial prostate cancer, which would advocate universal genetic testing to assess the risk of developing disease.
The American Cancer Society estimates approximately 180,890 new cases of prostate cancer and 26,120 deaths from the disease in the United States for 2016. Critically, the findings from this study may lead to earlier diagnosis and improved treatment selection for men with aggressive disease.
The full article was published on July 6, 2016, at NEJM.org.
Source: Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. DOI: 10.1056/NEJMoa1603144