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BRCA2 Mutations Linked to Poor Treatment Response, Outcomes in Prostate Cancer

NEW YORK (GenomeWeb) – BRCA2 mutations are associated with poorer treatment responses and outcomes among men with aggressive prostate cancer, according to a new study.

The Spanish National Cancer Research Center (CNIO) launched the PROREPAIR-B study in 2013 to uncover genetic markers associated with prostate cancer progression and treatment response. In a study published yesterday in the Journal of Clinical Oncology, the researchers found that about 16 percent of the men in their cohort had a germline mutation in a DNA repair damage gene such as BRCA2. They also found that men with germline BRCA2 mutations and prostate cancer had shorter cause-specific survival and they responded differently to treatment.

"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," CNIO's Elena Castro, the first author of the study, said in a statement.

She and her colleagues enrolled 419 patients diagnosed with metastatic castration-resistant prostate cancer into their prospective, multi-center study and screened them for germline mutations within DNA damage repair genes, including BRCA1, BRCA2, ATM, and PALB2. Their aim was to gauge how germline mutations in those specific genes affected cause-specific survival among prostate cancer patients.

Within their cohort, the researchers identified 68 men who carried germline mutations, including 14 BRCA2 mutation carriers, eight ATM mutation carriers, and four BRCA1 mutation carriers.

While they found the median cause-specific survival among BRCA1, BRCA2, ATM, and PALB2 germline mutation carriers was 10 months shorter than non-carriers, it was not a statistically significant difference and the researchers were unable to meet the primary endpoint of their study.

However, they did find differences between germline BRCA2 mutation carriers and non-carriers. They reported a median 17.4 months of cause-specific survival among BRCA2 mutation carriers, as compared to 33.2 months among non-carriers. BRCA2, the researchers added, is an independent prognostic factor for cause-specific survival among metastatic castration-resistant prostate cancer patients.

BRCA status also appeared to influence treatment response, the researchers found. More than 360 patients in this cohort were treated with at least one androgen signaling inhibitor. At the same time, a taxane — usually docetaxel — was given to 326 patients.

BRCA2 mutation carriers treated with taxane and then with an androgen signaling inhibitor had worse cause-specific survival and progression-free survival as compared to non-carriers, while BRCA2 carriers treated with androgen signaling inhibitor and then a taxane had similar cause-specific survival and progression-free survival as compared to non-carriers. This indicated to the researchers that the order of treatment might make a difference among BRCA2 carriers.

However, the researchers noted that their study was limited because it was observational and not randomized, may not be extrapolated to other cohorts because of differences in the prevalence of germline mutations in different populations, and needs to be validated.

Still, they suggested that their findings indicated that current treatment approaches could be optimized and that other drugs such as PARP inhibitors could also be effective in prostate cancer, which they noted is the subject of ongoing clinical trials.

"Our study shows that treatment and follow-up protocols used in patients with advanced prostate cancer may be inadequate for men with BRCA2 mutations. We are currently studying the characteristics that make these tumors more aggressive and trying to establish new strategies to improve patient prognosis," senior author and CNIO researcher David Olmos said in a statement.

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