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Germline DNA Repair Mutations and Outcomes in Metastatic Castration-Resistant Prostate Cancer

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Key Points

  • 16.2% (n = 68) of 419 patients in the study were carriers of germline DNA damage repair mutations; 3% of the 419 patients (n =14) carried BRCA2 mutations.
  • Cause-specific survival was 17.4 months in germline BRCA2 carriers vs 33.2 months in noncarriers.
  • Cause-specific survival and disease progression on second systemic therapy were greater in germline BRCA2 carriers who received first-line treatment with abiraterone or enzalutamide compared with taxanes—24.0 vs 17.9 months and 18.9 vs 18.6 months, respectively.

A subset of patients with aggressive prostate cancer are carriers of germline BRCA2 mutations, which are also linked to hereditary breast cancer, ovarian cancer, and pancreatic cancer. Study findings also showed family members of patients with prostate cancer who carry BRCA2 and DNA-repair gene mutations have an increased risk of developing cancer and should be evaluated in familial cancer prevention programs. Furthermore, the new study shows that prostate cancer in men with BRCA2 mutations is associated with worse outcomes and poor responses to standard treatments.

These findings were confirmed in the PROREPAIR-B study. Its results were published by Castro et al in the Journal of Clinical Oncology.

PROREPAIR-B Methods

PROREPAIR-B is a study coordinated by researchers at the Spanish National Cancer Research Centre (CNIO) and conducted at the Instituto de Investigación Biomédica de Málaga (IBIMA) and the Instituto de Genética Médica y Molecular (INGEMM) with the participation of 38 Spanish hospitals. More than 400 men diagnosed with castration-resistant prostate cancer were followed for 5 years starting in 2013 in order to analyze their genetic characteristics and the impact of these traits on the progression of the disease and response to treatments.

The primary aim was to assess the impact of ATM/BRCA1/BRCA2/PALB2 germline mutations on cause-specific survival from diagnosis of metastatic castration-resistant prostate cancer. Secondary aims included the association of germline DNA damage repair subgroups with treatment responses and combined progression-free survival from the first systemic therapy  until disease progression on the second systemic therapy.

Study Findings

The study found that 16.2% of 419 patients (n = 68) in the study were carriers of germline DNA damage repair mutations. About 3% of the 419 patients (n =14) carried BRCA2 mutations. “This proportion may seem comparatively low, but it comprises a significant number of patients, given the high incidence of prostate cancer,” said Dr. Castro.

Cause-specific survival was 17.4 months in germline BRCA2 carriers vs 33.2 months in noncarriers (P = .027), and germline BRCA2 mutations were identified as an independent prognostic factor for cause-specific survival (hazard ratio [HR] = 2.11; P = .033). Interactions between germline BRCA2 status and treatment type were observed. Cause-specific survival and disease progression on second systemic therapy were greater in germline BRCA2 carriers who received first-line treatment with abiraterone or enzalutamide compared with taxanes—24.0 vs 17.9 months and 18.9 vs 18.6 months, respectively.

The researchers who participated in the study believe treatment strategies should be improved by optimizing existing therapies and finding new drugs. In some patients, drugs interfering with DNA-repair mechanisms might be effective, as the cells that cannot repair their genetic defects die.

“This is the first prospective study … that shows BRCA2 mutations themselves, regardless of other factors, are responsible for poor prognosis and can have an impact on treatment responses,” explained Elena Castro, MD, PhD, the article’s first author, in a CNIO press release. “It should be noted that we identified germline mutations, although in a number of patients there were no familial cancer cases that might have indicated the presence of such genetic alterations. These mutations should be identified in patients with metastatic prostate cancer, since detecting such alterations is important for the diagnosis and management of the disease and for the patients’ families, whose risk of developing breast, ovarian, or pancreatic cancer is increased.”

The researchers concluded, “Germline BRCA2 mutations have a deleterious impact on metastatic castration-resistant prostate cancer outcomes that may be affected by the first line of treatment used. Determination of germline BRCA2 status may be of assistance for the selection of the initial treatment in metastatic castration-resistant prostate cancer. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.”

Disclosure: PROREPAIR-B received funding from the Prostate Cancer Foundation, CRIS Cancer Foundation, the Health Institute Carlos III, the Spanish Ministry of Science, Innovation and Universities, the Spanish Ministry of Education, Culture and Sports, and the Spanish Association Against Cancer. The study authors’ full disclosures can be found at jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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