Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent

Abstract

The BRCAPRO, Couch, Myriad I and II, Ontario Family History Assessment Tool (FHAT), and Manchester models have been used to predict BRCA1 or BRCA2 mutation carrier status of women at high risk for developing the heritable form of breast and ovarian cancers. We have evaluated these models for their accuracy in classifying 224 French Canadian families with at least three cases of breast cancer (diagnosed before the age of 65 years), ovarian cancer, or male breast cancer where mutation status was known for an index affected case used to assess the model. This series includes 44 BRCA1 and 52 BRCA2 mutation-positive families. Using receiver operator characteristics analyses, the C-statistics were found to be 0.81, 0.80, 0.79, and 0.74 for the BRCAPRO, FHAT, Manchester, and Myriad II models, respectively, when incorporating both BRCA1 and BRCA2 mutation carrier predictions. For the BRCAPRO model, 75% scored greater than a 0.43 probability in the mutation-positive group and 75% scored less than 0.50 in the mutation-negative group. Only 38 of 128 (30%) mutation-negative group had a probability greater than 0.43 with the BRCAPRO model. While all models were highly predictive of carrier status, the BRCAPRO model was the most accurate where a cut-off of 10% would have eliminated 60 of 128 (47%) mutation-negative families for genetic testing and only miss 10 of 96 (10%) mutation-positive families. A review of the cancer phenotypes with high BRCAPRO probabilities showed that significantly more metachronous bilateral breast cancer cases occurred in BRCA1/2 mutation carrier families in comparison to mutation-negative families, a feature which is not discriminated in the BRCAPRO model.