Re: p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy.

Abstract

Abnormal expression of the cell cycle regulatory proteins p27^Kip1 and cyclin E may be associated with breast cancer survival and relapse. We studied these markers in a clinical trial setting with patients with breast cancer treated by a uniform drug regimen so that treatment was not associated with variability in outcome. We used tissue microarrays to evaluate the expression of p27^Kip1 and cyclin E protein by immunohistochemistry in tumor tissue from 2123 (68%) of 3122 patients with moderate-risk primary breast cancer who were enrolled in Southwest Oncology Group/Intergroup Trial S9313, in which patients were assigned to receive doxorubicin and cyclophosphamide administered concurrently (n = 1595) or sequentially (n = 1527). Disease-free and overall survival were equivalent in the two arms. Expression of the proteins was rated on a scale of 1–7, and the median value was used as the cutpoint. Log-rank tests and Cox regression analyses were used to assess associations with survival. Overall survival was defined as time to death from all causes; disease-free survival was defined as time to recurrence or death. All <i>P</i> values were from two-sided statistical tests. Lower p27^Kip1 expression was associated with worse overall survival (unadjusted hazard ratio [HR] =1.50, 95% confidence interval [CI] = 1.21 to1.86) and disease-free survival (unadjusted HR = 1.31, 95% CI = 1.10 to 1.57) than higher p27^Kip1 expression. Among hormone receptor-positive patients, lower p27^Kip1 expression was associated with worse overall survival (HR = 1.42, 95% CI = 1.05 to 1.94) and worse disease-free survival (HR = 1.27, 95% CI = 0.99 to 1.63) than higher p27^Kip1 expression after adjustment for treatment, menopausal status, tumor size, and number of positive lymph nodes.. Among these patients, five year overall survival for higher p27 was 0.91 (95% CI 0.89–0.93) compared to 0.85 (95% CI 0.82–0.87) for lower p27. No association between p27^Kip1 expression and survival was found in hormone receptor-negative patients. Cyclin E expression was not statistically significantly associated with overall survival (HR = 1.12, 95% CI = 0.91 to 1.38) or disease-free survival (HR = 1.09, 95% CI = 0.92 to 1.29). Low p27^Kip1 expression appears to be associated with poor prognosis, especially among patients with steroid receptor-positive tumors.