p27 enters the clinical arena as a prognostic factor for node negative breast cancer

C. Catzavelos1, W. Hanna1, I Andrulis2, S. Bull2 and J.M. Slingerland3

1Department of Pathology, St Mary’s Hospital, Montreal, Quebec
2Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto
3Braman Breast Cancer Institute, UMSCCC and Depts of Medicine and Biochemistry, U of Miami School of Medicine, Miami FL.

One of the molecular hallmarks of cancer is the deregulation of the cell proliferation cycle.  A better understanding of how cell growth is altered in breast cancer may not only reveal important new prognostic markers, but also lead to the generation of novel, molecular-based therapies.  Progression of a cell through the cell cycle, is governed by a family of cyclin-dependent kinases (cdks).  p27 is an important inhibitor of cell cycle progression.  This negative regulator of cell growth, p27, may prove to be one of the most important molecular markers of breast cancer prognosis yet identified (Tan et al., 1997; Porter et al., 1997; Catzavelos et al., 1997).  The p27 protein is highly expressed in the nuclei of normal mammary epithelial tissues suggesting a role of p27 in maintaining proliferative quiescence in the breast. Our initial study of p27 in 168 primary breast cancers, multivariate analysis showed reduced levels of p27 (<50% tumor nuclei staining p27 positive) to confer an increased risk of disease relapse and death (risk for relapse 2.315, p=0.01) (Catzavelos et al., 1997). Although some subsequent studies with multivariate analysis in breast and other types of cancers (Slingerland and Pagano, 2000) have shown reduced levels of p27 in the primary cancer to be associated with a poor prognosis (Wu et al., 1999; Chappuis et al., 2000), others failed to confirm these findings (Gillett et al., 1999). The majority of the studies investigating the prognostic significance of p27 levels in breast cancer performed to date have been retrospective, and some have had limited statistical power due to ascertainment of relatively small numbers of patients and short patient follow up. As a result, there has been insufficient data to initiate prospective trials to test the clinical utility of p27 levels. Recent work suggests an association between reduced p27 and other molecular markers, such as BRCA-1 mutation (Chappuis et al., 2000) and increased expression of Skp2 (Gstaiger et al., 2001).

In an effort to establish the prognostic role of p27 in node negative breast cancer, we have recently completed immunohistochemical analysis of p27 protein levels in 1015 node-negative primary breast cancers. Reduced p27 levels (p27 staining positive in <25% tumor nuclei) was a prognostic factor on multivariate analysis conferring a increase risk of relapse of 1.54 fold over patients with higher p27 protein expression (p=0.02, CI, 1.06-2.25). The median follow up period for this cohort of patients was over 9 years. Tumor size, lymphatic invasion and histologic grade were also of prognostic significance in this study.

Her2/neu status is a prognostic factor and a predictive factor for responsiveness to Herceptin therapy for breast cancer. Ascertainment of Her2 status has become a part of the routine histopathologic assessment of newly diagnosed breast cancers. When p27 value was assayed together with Her2/neu status, patients whose tumors showed reduced p27 levels together with Her2 amplification had a 4.5 fold higher risk of breast cancer recurrence and death than did patients with tumors showing high p27 and no Her2 amplifications (RR 4.5, CI 1.67-12.1 p<0.05).

This study confirms that reduced p27 levels are an independent predictor of disease free survival in node negative breast cancer patients. The combination of reduced p27 levels and Her-2/neu overexpression provides a more powerful predictor of tumor behavior than either factor alone. We present the first, large, confirmatory study demonstrating the independent prognostic value of p27 levels in a prospectively accrued patient cohort. Our data suggests that the combined assessment of p27 levels and Her-2/neu over-expression may have significant clinical utility in the management of lymph node negative breast cancer patients.

Reference List

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