Germline BRCA1/2 mutations and p27Kip1 protein levels independently predict outcome after breast cancer

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 inversive 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 wets 6.4 years. Results: Thirty-two tumors (16%) were positive for a BRCA 1/2 mutation, Low p27(Kip1) expression was seen in 110 tumors (63%) and was significantly associated with BRCA 1/2 mutations (odds ratio, 4.0; 95% confidence in terval [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, J Clin Oncol 18:4045-4052, (C) 2000 by American Society of Clinical Oncology.