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Major Improvement in the Efficacy of BRCA1 Mutation Screening Using Morphoclinical Features of Breast Cancer¹

Unit of Cancer Molecular Genetics/Institut National de la Santé et de la Recherche Médicale (INSERM) EPI 00317 (R. L., M-H. C., C. N., I. B.), and Department of Pathology (C. P.), René Huguenin Center, 92210 Saint-Cloud, France; Department of Genetic Oncology/INSERM EPI 9939 (F. E., J. J., H. S.), Laboratory of Tumor Biology (D. B., J. J., H. S.), and Department of Pathology (J. J.), Paoli-Calmettes Institute, 13273 Marseille Cedex 9, France; and INSERM U 119, 13009 Marseille, France (D. B.)

A family history of breast and/or ovarian cancer is the main criterion used in screening BRCA1 gene carriers. However, ascertaining a patient’s family history is a difficult task, which significantly restricts the use of this parameter in clinical practice. Alternative individual criteria that can be used to identity BRCA1 gene carriers would, therefore, be of great value. In this context, it was recently established that BRCA1-associated breast cancers (BRCA1-BCs) show a specific morphoclinical pattern. In multivariate analyses, the two most discriminant morphoclinical parameters available for establishing the BRCA1 status, in addition to an early age at onset, are estrogen receptor negativity (ER-) and poor tumor differentiation (TD3). Here we tested the efficacy of these two morphological parameters as BRCA1 mutation indicators and investigated their economic impact, in a population-based survey on a series of women who developed invasive breast cancer by the age of 35 years, regardless of their family history. A high rate of 28.6% of BRCA1 mutations was found to have occurred in the group of tumors with both ER- and TD3 versus only 3.6% in tumors with other profiles (P = 0.007; odds ratio, 10.8). When the sole criterion used was early onset by the age of 35 years, the mutation rate was found to be 8.6%. The resulting cost of testing only women with ER- and TD3 tumors worked out at 30% that of testing the whole population of women with cancer by the age of 35 years, and the sensitivity was found to be of 66%. Lastly, the family history of ER- and TD3 cases with a BRCA1 mutation was investigated retrospectively, and none of these cases was found to have a particularly extensive family history of breast and/or ovarian cancer. The use of these morphological features of BRCA1-BCs that are currently typed in clinical practice, therefore, provides a helpful and cost-effective tool for those making decisions about genetic screening. This strategy makes it possible to identify gene carriers who would be overlooked using current criteria.

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