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Germline BRCA1/2 Mutations and p27^Kip1 Protein Levels Independently Predict Outcome After Breast Cancer

From the Departments of Medicine, Oncology, Pathology, and Surgery, Sir M.B. Davis-Jewish General Hospital, and Departments of Medicine and Human Genetics, McGill University Health Centre Research Institute, McGill University, Montreal, Quebec; and Departments of Medicine and Pathology and Centre for Research in Women’s Health, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

Address reprint requests to William D. Foulkes, MD, Cancer Prevention Research Unit, Room A-803, Sir M.B. Davis-Jewish General Hospital McGill University, 3755 chemin Côte Ste-Catherine, Montreal, Quebec H3T 1E2, Canada; email MDWF{at}musica .mcgill.ca.

PURPOSE: Decreased levels of the cyclin-dependent kinase inhibitor p27^Kip1 in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27^Kip1 protein levels, and outcome has not been studied.

PATIENTS AND METHODS: Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27^Kip1 expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years.

RESULTS: Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27^Kip1 expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P = .009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P = .003). Similar results were seen for women whose tumors expressed low levels of p27^Kip1, compared with those with high levels (5-year DDFS, 68% v 93%; P < .0001). In a multivariate analysis, both BRCA1/2 mutation and low p27^Kip1 expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P = .05; and RR, 3.9; 95% CI, 1.4 to 11.1; P = .01, respectively).

CONCLUSION: In this study, we showed that BRCA1/2 mutations were associated with low levels of p27^Kip1 in breast cancer. Both BRCA1/2 and p27^Kip1 status were identified as independent prognostic factors.

Presented at the American Society of Human Genetics meeting, October 19-23, 1999.

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