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Annals of Oncology Advance Access published online on March 31, 2005
Annals of Oncology, doi:10.1093/annonc/mdi149
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© 2005 European Society for Medical Oncology
Received September 8, 2004
Revised December 17, 2004
Accepted December 22, 2004

Original article

Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment

P. O. Chappuis 1* {dagger},, E. Donato 2, J. R. Goffin 3 {ddagger}, N. Wong 4, L. R. Bégin 5 #, L. R. Kapusta 6 ¶, J.-S. Brunet 7, P. Porter 2, and W. D. Foulkes 8

1 Departments of Human Genetics, McGill University Health Centre, Montreal, Canada; Departments of Research Institute of the McGill University Health Centre, Montreal, Canada
2 Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center and Department of Pathology, University of Washington, Seattle, WA, USA
3 Departments of Oncology, McGill University Health Centre, Montreal, Canada
4 Departments of Human Genetics, McGill University Health Centre, Montreal, Canada; Departments of Cancer Prevention Centre, Sir M. B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
5 Departments of Surgery, McGill University Health Centre, Montreal, Canada; Departments of Pathology, McGill University Health Centre, Montreal, Canada
6 Department of Pathology, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Toronto, ON, Canada
7 Departments of Program in Cancer Genetics, Montreal, Canada, Algorithme Pharma, Montreal, QC, Canada
8 Departments of Human Genetics, McGill University Health Centre, Montreal, Canada; Departments of Oncology, McGill University Health Centre, Montreal, Canada; Departments of Medicine, McGill University Health Centre, Montreal, Canada; Departments of Research Institute of the McGill University Health Centre, Montreal, Canada; Departments of Program in Cancer Genetics, Montreal, Canada; Departments of Cancer Prevention Centre, Sir M. B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada

* To whom correspondence should be addressed.
P. O. Chappuis, E-mail: pierre.chappuis{at}hcuge.ch


  Abstract

Background: Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, p27Kip1, have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27Kip1 levels, BRCA1 status and outcome has not been studied in detail.

Patients and methods: We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27Kip1 were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured.

Results: The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P <0.001] and low p27Kip1 protein levels (OR 2.8; P=0.03) than tumors from patients without BRCA1/2 mutations. High cyclin E expression level was the strongest predictor of BRCA1 germline mutations (multivariate OR 4.7; P=0.004). On univariate analysis, high cyclin E protein levels [relative risk (RR) 2.6; P <0.001] and low p27Kip1 protein levels (RR 2.3; P=0.006) were significant prognostic factors for a poorer BCSS. In Cox multivariate models, high cyclin E levels remained an independent indicator of poor outcome only in the subgroup of patients who did not receive chemotherapy (P=0.002).

Conclusions: In this ethnically restricted cohort, a high level of cyclin E is a characteristic of BRCA1-related breast cancer, and is a marker of poor prognosis following breast cancer, particularly in the absence of adjuvant chemotherapy.

Keywords: BRCA1; breast cancer; chemotherapy; cyclin E; KIP1; prognosis.

{dagger} Present address: Service of Oncology and Service of Medical Genetics, University Hospitals of Geneva, 1211 Geneva 14, Switzerland

{ddagger} Present address: Division of Hematology/Oncology, Department of Medicine, Tufts University, Tufts-New England Medical Center, Boston, MA 02115, USA

# Present address: Hôpital du Sacré-Coeur de Montréal, Montreal, QC H4J 1C5, Canada

¶ Present address: Credit Valley Hospital, Mississauga, ON L5M 2N1, Canada


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