Worse Breast Cancer Prognosis of <i>BRCA1/BRCA2</i> Mutation Carriers: What's the Evidence? A Systematic Review with Meta-Analysis

<div><p>Objective</p><p>Conflicting conclusions have been published regarding breast cancer survival of <i>BRCA1/2</i> mutation carriers. Here we provide an evidence-based systematic literature review.</p><p>Methods</p><p>Eligible publications were observational studies assessing the survival of breast cancer patients carrying a <i>BRCA1/2</i> 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.</p><p>Results</p><p>Sixty-six relevant studies were identified. Moderate evidence for a worse unadjusted recurrence-free survival for <i>BRCA1</i> mutation carriers was found. For <i>BRCA1</i> and <i>BRCA2</i> 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.</p><p>Conclusions</p><p>In contrast to currently held beliefs of some oncologists, current evidence does not support worse breast cancer survival of <i>BRCA1/2</i> mutation carriers in the adjuvant setting; differences if any are likely to be small. More well-designed studies are awaited.</p></div

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

<p>Separate forest plots are shown of studies reporting overall survival (panels A and B), breast cancer-specific survival (panels C and D) of <i>BRCA2</i> 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). <i>Size of the bullet represents the number of included carriers; black bullet = HQ study; round bullet (●) and * = A</i>. <i>Jewish study population</i>, <i>only founder mutations tested; square bullet (■) and ** = specific study population (but not A</i>. <i>Jewish)</i>, <i>in which only founder mutations were tested; — = 95% Confidence interval (only for hazard ratios); CGC based studies with ext</i>. <i>ref</i>. = <i>CGC based studies with external reference group; CGC based studies with int</i>. <i>ref</i>. = <i>CGC based studies with internal reference group; Sign = statistically significant (P < 0</i>.<i>05); NS = not statistically significant; NR = not reported; †Adjusted for clinico-pathological characteristics and/or treatment</i>.</p

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

<p>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). <i>CGC based studies with ext</i>. <i>ref</i>. = <i>CGC based studies with external reference group; CGC based studies with int</i>. <i>ref</i>. = <i>CGC based studies with internal reference group</i>.</p

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

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

Comparing the number of hospitals meeting (or failing) the 3 different measures.

<p>O/E =  Observed/Expected outcome ratio.</p><p>N =  Hospital procedural volume.</p><p>*) using O/E ratio of >2 as the threshold for substandard care for mortality, and O/E ratio of >1.5 as the threshold for substandard care for morbidity.</p

Patient, tumour and treatment characteristics and outcome in the DSCA 2010 and 2011.

<p>ASA =  American Society of Anaesthesiologists classification BMI =  Body Mass Index, TNM =  Tumour Node Metastasis classification system, gy =  gray LAR =  Low anterior resection, *  =  including transverse colectomies, ∧  =  including subtotal or proctocolectectomy.</p

Meaning making themes and key-issues and themes of perceived changes in meaning making and meaning related issues.

<p>Meaning making themes and key-issues and themes of perceived changes in meaning making and meaning related issues.</p

Observed/Expected (O/E) mortality ratio of all hospitals in the Dutch Surgical Colorectal Audit in 2010 and 2011.

<p><i>Measure of ‘Outcome only’</i>: requires that a hospital's O/E ratio, regardless of its confidence interval, is below or equal to 2 (red fat printed line), met the ‘outcome only’ criterion. <i>Measure of ‘Volume only’</i>: requires that a hospital meets the ‘volume only’ criterion of >50 procedures per year (red squares) <i>Combined measure of ‘volume and outcome (CM-V&O)’</i>: the lower limit of the confidence interval around the hospitals O/E ratio is below or equal to 1, i.e. that the hospital is not significantly worse than average. In addition CM-V&O requires that the higher limit of the confidence interval is below 2 (fat printed red line), i.e. that the hospital is significantly better than substandard.</p

Number of hospitals meeting the measure of ‘outcome-only’ (better than substandard), of ‘volume-only’ (50 procedures or more), or the combined measure of volume and outcome’ in 2010, using different thresholds for ‘substandard care’.

<p>N =  number of patients.</p><p>O/E =  Observed/Expected outcome ratio.</p><p>CI95min  =  Lower limit of 95% confidence interval around the O/E ratio.</p><p>CI95max  =  Upper limit of 95% confidence interval around the O/E ratio.</p

Verification: Outcomes in 2011 of hospitals meeting the different measures in 2010.

<p>CM-V&O =  combined measure for volume and outcome.</p><p>O/E =  Observed/Expected outcome ratio.</p><p>CI95% = 95% confidence interval around the O/E ratio.</p><p>* P<0.05.</p