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

Janet R. Vos*, Li Hsu, Richard M. Brohet, Marian J. E. Mourits, Jakob de Vries, Kathleen E. Malone, Jan C. Oosterwijk, Geertruida H. de Bock

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

16 Citations (Scopus)

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. (C) 2015 by American Society of Clinical Oncology

Original languageEnglish
Pages (from-to)2553-2562
Number of pages10
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume33
Issue number23
DOIs
Publication statusPublished - 10-Aug-2015

Keywords

  • ASHKENAZI JEWISH WOMEN
  • OVARIAN-CANCER
  • SEGREGATION ANALYSIS
  • FOUNDER MUTATIONS
  • CUMULATIVE RISK
  • GENE-MUTATIONS
  • LARGE SERIES
  • KIN-COHORT
  • FOLLOW-UP
  • PENETRANCE

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