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Optimal Selection of Individuals for BRCA Mutation Testing: A Comparison of Available Methods

From the Familial Cancer Centre and Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre; and Genetic Health Services Victoria, Murdoch Children's Research Institute, Melbourne, Australia

Address reprint requests to Paul A. James, MD, Department of Human Anatomy and Genetics, Oxford University, South Parks Rd, Oxford, OX1 3QX, United Kingdom; e-mail: paul.james{at}anat.ox.ac.uk

PURPOSE: Several methods have been described that estimate the likelihood that a family history of cancer is a result of a mutation in the BRCA1 or BRCA2 genes. We examined the performance of six different methods with the aim of identifying an optimal strategy for selecting individuals for mutation testing in clinical practice.

PATIENTS AND METHODS: Two hundred fifty-seven families who had completed BRCA1 and BRCA2 mutation screening were assessed by six models representing the major methodologies used to assess the likelihood of a pathogenic mutation. The performance of each method as a selection criterion was compared with the result of mutation testing to produce sensitivity, specificity, and receiver operating curve data. The impact of incorporating breast cancer pathology data in the assessment was also analyzed.

RESULTS: The highest accuracy was achieved by the Bayesian probabilistic model (BRCAPRO). The formal probabilistic methods were significantly more accurate than clinical scoring methods. The methods were further improved by the incorporation of information on breast cancer pathology (tumor grade and estrogen receptor/progesterone receptor status). The resulting combined probability figure was highly accurate when selecting individuals for BRCA1 testing. Some BRCA2 mutation carriers were missed by all of the models examined.

CONCLUSION: Formal probabilistic models provide significantly greater accuracy in the selection of families for gene testing than the use of clinical criteria or scoring methods. The accuracy is further enhanced by incorporating information on the pathology of breast cancers occurring in the families.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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