BRCA2 mutations herald poor prognosis in screen-detected prostate cancer

By Joanna Lyford, Senior medwireNews Reporter

Among men with prostate cancer detected on screening, survival among those with a mutation in the BRCA2 gene is much poorer than in those without such a mutation, researchers report.

The findings suggest that BRCA2 mutation carriers may warrant additional treatments to improve their prognosis, say Steven Narod (Women’s College Hospital, Toronto, Ontario) and fellow authors writing in the British Journal of Cancer.

BRCA2 mutations are known to confer an increased risk for developing prostate cancer and also to be associated with more aggressive tumours. However, the effect of BRCA2 mutations status on mortality in the setting of screen-detected cancers is unclear.

In this study, Narod et al genotyped a cohort of 4187 Canadian men who underwent prostate biopsy because of an abnormal screening test – either elevated prostate-specific antigen (PSA) levels or an abnormal digital rectal examination – between 1998 and 2010.

At biopsy, 45.5% of the men were diagnosed with prostate cancer at biopsy (cases) and 54.5% were free of prostate cancer (controls). The researchers sequenced the entire 26 coding exons of BRCA2 in the germline DNA and a BRCA2 mutation was found in 1.4% of cases versus 0.4% of controls, giving a highly significant odds ratio of 3.5.

Among men with prostate cancer, various differences were found between men with and without a BRCA2 mutation. Average age at diagnosis was higher in carriers than noncarriers (67 vs 65 years), as was average PSA concentration at diagnosis (56.3 vs 13.3 ng/mL) and the proportion of men with high-grade disease (Gleason 7–9; 96 vs 54%).

The mean length of follow-up was 8.7 years. At the last follow-up, 73% of mutation carriers with prostate cancer were alive versus 96% of non-carriers. This translated into a significantly lower 12-year survival among BRCA2 mutation carriers, at 61.8% versus 94.3%.

After adjusting for confounders, the hazard ratio for prostate cancer-specific mortality associated with BRCA2 mutation carriage was 3.48; among men with high-grade disease, the hazard ratio was 4.38.

The authors note that while the survival of men with a BRCA2 mutation in this study was poor, it was better than has been previously reported in other cohorts. This could imply that screening is associated with improved survival; however, the potential impact of lead-time bias and of the relatively small samples must also be considered.

Noting that the 12-year mortality rate of just 38% among BRCA2-positive men “attests to the aggressive nature of these malignancies”, the authors write: “BRCA2 carriers with prostate cancer may benefit from additional therapies, such as with cis-platinum or a PARP [poly ADP-ribose polymerase] inhibitor.”

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