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The Prognostic Implication of the Basal-Like (Cyclin E^high/p27^low/p53⁺/Glomeruloid-Microvascular-Proliferation⁺) Phenotype of BRCA1-Related Breast Cancer

¹ Program in Cancer Genetics and Departments of ² Oncology, ³ Human Genetics, ⁴ Medicine, ⁵ Surgery, and ⁶ Pathology, ⁷ Research Institute of the McGill University Health Centre, and ⁸ Cancer Prevention Centre, Sir M. B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada; ⁹ Algorithme Pharma, Montreal, Quebec, Canada; ¹⁰ Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway; ¹¹ Department of Pathology, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; and ¹² Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center and Department of Pathology, University of Washington, Seattle, Washington

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27^Kip1, or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27^Kip1, p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27^Kip1 levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.

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