Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Abstract

IntroductionThe distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.MethodsSelection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.ResultsER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).ConclusionsThese results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0474-y) contains supplementary material, which is available to authorized users.

Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53

“…The relationship between TNBC and BRCA1 mutation status is similar in this population to that observed elsewhere. [7] Across all genes, 41 different damaging mutations were identified in the mutation discovery series. Genotyping these 41 mutations in the general population series yielded 1.0% (4/422) additional mutation carriers.…”

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

“…If no age at last update was provided by the submitting center for unaffected individuals, test date was used to infer current age. Breast tumor pathology LRs were assigned based on the estimates in Spurdle et al (), and considered age at diagnosis. When multiple tumors were present in one individual, the first diagnosed tumor with information available was taken, and only a single LR was assigned according to the extent of information available (out of the variables tumor grade, ER, PR, and HER2), following previous recommendations (Spurdle et al, ).…”

Cost Effectiveness of Risk-Reducing Mastectomy versus Surveillance in BRCA Mutation Carriers with a History of Ovarian Cancer

“…Among BRCA1 mutation carriers, we assumed that 80% would be estrogen receptor/progesterone receptor/HER2-negative (triple-negative breast cancer) and 20% would be non-triple-negative breast cancer. 28,29 Modeled breast cancer-specific survival was based on long-term follow-up from a retrospective cohort analysis by Dent et al 30 …”