Background:: Abnormal expression of the cell cycle regulatory proteins p27Kip1 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.
Methods:: We used tissue microarrays to evaluate the expression of p27Kip1 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 P values were from two-sided statistical tests.
Results:: Lower p27Kip1 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 p27Kip1 expression. Among hormone receptor-positive patients, lower p27Kip1 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 p27Kip1 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 p27Kip1 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).
Conclusions:: Low p27Kip1 expression appears to be associated with poor prognosis, especially among patients with steroid receptor-positive tumors.