Morphological predictors of BRCA1 germline mutations in young women with breast cancer

Southey, M.C., Ramus, S.J., Dowty, J.G., Smith, L.D., Tesoriero, A.A., Wong, E.E.M., Dite, G.S., Jenkins, M.A., Byrnes, G.B., Winship, I., Phillips, K-A., Giles, G.G., and Hopper, J.L. (2011) Morphological predictors of BRCA1 germline mutations in young women with breast cancer. British Journal of Cancer, 104 (6). pp. 903-909.

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Background: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.

Methods: We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation.

Results: The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6–47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7–25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3–5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01). The area under the ROC curve was 0.87 (0.83–0.90).

Conclusion: Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.

Item ID: 35577
Item Type: Article (Research - C1)
ISSN: 1532-1827
Keywords: BRCA1, early-onset breast cancer, tumour morphology
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From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit

Funders: National Health and Medical Research Council of Australia (NHMRC), New South Wales Cancer Council, Victorian Health Promotion Foundation (Australia), National Cancer Institute, National Institutes of Health
Projects and Grants: RFA-CA-06–503
Date Deposited: 01 Oct 2014 15:51
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111203 Cancer Genetics @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110316 Pathology (excl Oral Pathology) @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 100%
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