Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: what's the evidence? A systematic review with meta-analysis

Abstract

Objective: Conflicting conclusions have been published regarding breast cancer survival of BRCA1/2 mutation carriers. Here we provide an evidence-based systematic literature review.

Methods: Eligible publications were observational studies assessing the survival of breast cancer patients carrying a BRCA1/2 mutation compared to non-carriers or the general breast cancer population. We performed meta-analyses and best-evidence syntheses for survival outcomes taking into account study quality assessed by selection bias, misclassification bias and confounding.

Results: Sixty-six relevant studies were identified. Moderate evidence for a worse unadjusted recurrence-free survival for BRCA1 mutation carriers was found. For BRCA1 and BRCA2 there was a tendency towards a worse breast cancer-specific and overall survival, however, results were heterogeneous and the evidence was judged to be indecisive. Surprisingly, only 8 studies considered adjuvant treatment as a confounder or effect modifier while only two studies took prophylactic surgery into account. Adjustment for tumour characteristics tended to shift the observed risk estimates towards a relatively more favourable survival.

Conclusions: In contrast to currently held beliefs of some oncologists, current evidence does not support worse breast cancer survival of BRCA1/2 mutation carriers in the adjuvant setting; differences if any are likely to be small. More well-designed studies are awaited.

Fig 1. Flow diagram of the inclusion process of papers and studies in the review.

OS = Overall survival; BCSS = Breast cancer-specific survival; MFS = Metastasis-free survival; RFS = Recurrence-free survival.

Fig 2. Quality distribution based on selection bias, misclassification bias and confounding/accounting for mediating variables in all included studies (n = 66).

The scores for selection bias and misclassification bias were taken into account for the analysis of the univariate outcomes (panel A). The scores for selection bias, misclassification bias and confounding accounting for mediating variables were taken into account for the analysis of multivariate outcomes (panel B). CGC based studies with ext. ref. = CGC based studies with external reference group; CGC based studies with int. ref. = CGC based studies with internal reference group.

Fig 3. Forest plots of studies reporting survival estimates for BRCA1 mutation carriers compared to ‘non-carriers’, classified per study type and sorted by quality score.

Separate forest plots are shown of studies reporting overall survival (panels A and B), breast cancer-specific survival (panels C and D), metastasis-free survival (panels E and F) and recurrence-free survival (panel G) of BRCA1 mutation carriers compared to ‘non-carriers’. Additionally, the results for each type of survival outcome are stratified per reported risk estimate: the 5-year and 10-year absolute overall survival difference (panels A, C, E, G) and the adjusted and unadjusted hazard ratios for overall survival (panels B, D, F). Size of the bullet represents the number of included carriers; black bullet = HQ study; round bullet (●) and * = A. Jewish study population, only founder mutations tested; square bullet (■) and ** = specific study population (but not A. Jewish), in which only founder mutations were tested;— = 95% Confidence interval (only for hazard ratios); CGC based studies with ext. ref. = CGC based studies with external reference group; CGC based studies with int. ref. = CGC based studies with internal reference group; Sign = statistically significant (P < 0.05); NS = not statistically significant; NR = not reported; †Adjusted for clinico-pathological characteristics and/or treatment.

Fig 4. Forest plots of studies reporting survival estimates for BRCA2 mutation carriers compared to ‘non-carriers’, classified per study type and sorted by quality score.

Separate forest plots are shown of studies reporting overall survival (panels A and B), breast cancer-specific survival (panels C and D) of BRCA2 mutation carriers compared to ‘non-carriers’. Additionally, the results for each type of survival outcome are stratified per reported risk estimate: the 5-year and 10-year absolute overall survival difference (panels A and C) and the adjusted and unadjusted hazard ratios for overall survival (panels B and D). Size of the bullet represents the number of included carriers; black bullet = HQ study; round bullet (●) and * = A. Jewish study population, only founder mutations tested; square bullet (■) and ** = specific study population (but not A. Jewish), in which only founder mutations were tested; — = 95% Confidence interval (only for hazard ratios); CGC based studies with ext. ref. = CGC based studies with external reference group; CGC based studies with int. ref. = CGC based studies with internal reference group; Sign = statistically significant (P < 0.05); NS = not statistically significant; NR = not reported; †Adjusted for clinico-pathological characteristics and/or treatment.