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Placental Cadherin and the Basal Epithelial Phenotype of BRCA1-Related Breast Cancer

Authors' Affiliations: ¹ Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway; ² Hôpital du Sacré-Coeur de Montréal; ³ Program in Cancer Genetics; Department of ⁴ Medicine and ⁵ Pathology, ⁶ Research Institute of the McGill University Health Centre and ⁷ Cancer Prevention Centre, Sir M.B. Davis-Jewish General Hospital, McGill University, Montréal, Québec, Canada; ⁸ Services of Oncology and Medical Genetics, University Hospital of Geneva, Geneva, Switzerland; and ⁹ Algorithme Pharma, Laval, Québec, Canada

Requests for reprints: William D. Foulkes, Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Room L10-116, 1650 Cedar Avenue, Montreal, Quebec, Canada H3G 1A4. Phone: 514-937-1934 ext. 44121; Fax: 514-934-8273; E-mail: william.foulkes{at}mcgill.ca.

Purpose: BRCA1-related breast cancer frequently has a basal epithelial phenotype, and P-cadherin is a basal marker. We undertook a detailed evaluation of the relationship among P-cadherin, prognostic markers in breast cancer, and outcome.

Experimental Design: This study was restricted to 292 cases of first primary invasive breast cancer diagnosed in Ashkenazi Jewish women between 1980 and 1995. All available blocks were stained for P-cadherin, and 261 were included in the final statistical analyses, including 27 germ line BRCA1 mutation carriers and 8 BRCA2 mutation carriers. Descriptive analyses were done followed by survival analyses and a Poisson regression analysis.

Results: P-cadherin was present in 80 of the 261 breast cancers (31%) and was more frequently present in tumors that have a basal epithelial phenotype [i.e., high-grade, estrogen receptor– and KIP1 (p27^Kip1)–negative tumors, with expression of cytokeratin 5/6, cyclin E, TP53, and presence of BRCA1 mutations and vascular nests (all P < 0.001)]. In a univariate survival model, expression of P-cadherin was associated with a relative risk (RR) of death from breast cancer at a 10-year follow-up of 2.9 (95% confidence interval, 1.8-4.7; P < 0.0001) and was a predictor of poor univariate survival in both lymph node–negative and –positive breast cancers. In a multivariate analysis, the effect of P-cadherin levels was not independent of other basal-related markers. Multivariable interaction modeling showed that P-cadherin positivity was highly predictive of a poor prognosis in small, node-negative breast cancers (RR, 7.1; P = 0.006).

Conclusions: P-cadherin is a marker for basal-like breast cancers and is strongly associated with the presence of a BRCA1 mutation. It is an adverse prognostic factor, particularly in small, node-negative breast cancers.

Key Words: Hereditary breast cancer • stem cells • survival • immunohistochemistry

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