Bias Correction Methods Explain Much of the Variation Seen in Breast Cancer Risks of BRCA1/2 Mutation Carriers

Abstract

Purpose Recommendations for treating patients who carry a BRCA1/2 gene are mainly based on cumulative lifetime risks (CLTRs) of breast cancer determined from retrospective cohorts. These risks vary widely (27% to 88%), and it is important to understand why. We analyzed the effects of methods of risk estimation and bias correction and of population factors on CLTRs in this retrospective clinical cohort of BRCA1/2 carriers. Patients and Methods The following methods to estimate the breast cancer risk of BRCA1/2 carriers were identified from the literature: Kaplan-Meier, frailty, and modified segregation analyses with bias correction consisting of including or excluding index patients combined with including or excluding first-degree relatives (FDRs) or different conditional likelihoods. These were applied to clinical data of BRCA1/2 families derived from our family cancer clinic for whom a simulation was also performed to evaluate the methods. CLTRs and 95% CIs were estimated and compared with the reference CLTRs. Results CLTRs ranged from 35% to 83% for BRCA1 and 41% to 86% for BRCA2 carriers at age 70 years width of 95% CIs: 10% to 35% and 13% to 46%, respectively). Relative bias varied from −38% to +16%. Bias correction with inclusion of index patients and untested FDRs gave the smallest bias: +2% (SD, 2%) in BRCA1 and +0.9% (SD, 3.6%) in BRCA2. Conclusion Much of the variation in breast cancer CLTRs in retrospective clinical BRCA1/2 cohorts is due to the bias-correction method, whereas a smaller part is due to population differences. Kaplan-Meier analyses with bias correction that includes index patients and a proportion of untested FDRs provide suitable CLTRs for carriers counseled in the clinic.

The phenotype of SDHB germline mutation carriers: a nationwide study

“…The high proportion of unaffected mutation carriers in our study seems to reflect an active testing protocol in the Netherlands of at-risk family members of the index patients, who are advised to undergo genetic counseling and DNA testing for the family-specific SDHB mutation. Lower lifetime cancer risks have also been established for other genetic tumor syndromes following the inclusion of unaffected mutation carriers, one well-known example being pathogenic BRCA1/2 gene variants (23). Lower cumulative lifetime risks of breast cancer followed from analyses that excluded index patients while including first-degree relatives.…”

The association between cancer family history and ovarian cancer risk in BRCA1/2 mutation carriers: can it be explained by the mutation position?

“…The families of the study participants were relatively small (median of two female FDRs), and may not be as informative as larger families. We did not investigate the possible effect of family clustering in our results, however, we do not expect this to have a major impact on the observed associations, as the number of carriers per family was small [6,18].…”

“…Up to 24% of OC cases are due to a genetic predisposition, most often associated with BRCA1/2 mutations [2]. Numerous studies aimed at estimating the lifetime OC risk for BRCA1/2 mutation carriers [3][4][5] obtaining varying results according to the population studied and methodology applied [6], with estimates ranging between 31-59% in BRCA1 and 6-18% in BRCA2 mutation carriers [3][4][5]. Subsequent studies aimed to identify genetic and environmental factors associated with the observed risk variation in mutation carriers [7].…”

A review on age‐related cancer risks in PTEN hamartoma tumor syndrome

“…Case‐control studies were excluded because sample sizes are too limited to detect rare germline variants in both cases and controls 9 . Study quality was evaluated on common cancer risk estimate variation sources: methodology, patient recruitment, and population characteristics 10 . Overlapping cohorts were included because they provided complementary approaches or outcomes.…”