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

Abstract

Background: Abnormal expression of the cell cycle regulatory proteins p27(Kip1) (p27) 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 p27 and cyclin E proteins 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 cut point. 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 p27 expression was associated with worse overall survival (unadjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.21 to 1.86) and disease-free survival (unadjusted HR = 1.31, 95% CI = 1.10 to 1.57) than higher p27 expression. Among hormone receptor-positive patients, lower p27 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 expression after adjustment for treatment, menopausal status, tumor size, and number of positive lymph nodes. Among these patients, 5-year overall survival associated with higher p27 expression (0.91, 95% CI = 0.89 to 0.93) was similar to that associated with lower p27 expression (0.85, 95% CI = 0.82 to 0.87). No association between p27 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 p27 expression appears to be associated with poor prognosis, especially among patients with steroid receptor-positive tumors.

Fig. 1

Kaplan-Meier plots of overall survival and disease-free survival by treatment assignment in 2120 women enrolled in S9313 and tested for this study. A) Overall survival. Overall survival was defined as the time to death from any cause. B) Disease-free survival. Disease-free survival was defined as the time to first recurrence (local, regional, or distant), new primary cancer in the contralateral breast, or death due to any cause. All statistical tests were two-sided. The 95% confidence intervals are shown at 1, 3, 5, and 7 years for both treatment groups. The numbers of patients at risk for death due to any cause (overall survival) at 0, 1, 3, 5, or 7 years were 2020, 1995, 1833, 1706, or 1037. The numbers of patients at risk for death or recurrence (disease-free survival) at 0, 1, 3, 5, or 7 years were 2020, 1951, 1699, 1551, or 940 for the entire sample.

Fig. 2

Kaplan-Meier plots of overall survival and disease-free survival by p27 and cyclin E expression in tumors from women enrolled in S9313. A and B) p27 expression. C and D) Cyclin E expression. Overall survival was defined as the time to death from any cause. Disease-free survival was defined as the time to first recurrence (local, regional, or distant), new primary cancer in the contralateral breast, or death due to any cause. All statistical tests were two-sided. The 95% confidence intervals are shown at 1, 3, 5, and 7 years for both treatment groups. The numbers of patients at risk for death due to any cause (overall survival) at 0, 1, 3, 5, or 7 years were 2020, 1995, 1833, 1706, or 1037. The numbers of patients at risk for death or recurrence (disease-free survival) at 0, 1, 3, 5, or 7 years were 2020, 1951, 1699, 1551, or 940 for the entire sample.

Fig. 3

Kaplan-Meier plots of overall survival and disease-free survival by p27 expression in steroid receptor-positive and -negative tumors from women enrolled in S9313. A and B) p27 expression in steroid receptor-positive tumors. C and D) p27 expression in steroid receptor-negative tumors. Overall survival was defined as the time to death from any cause. Disease-free survival was defined as the time to first recurrence (local, regional, or distant), new primary cancer in the contralateral breast, or death due to any cause. All statistical tests were two-sided. The 95% confidence intervals are shown at 1, 3, 5, and 7 years for both treatment groups. The numbers of patients at risk for death due to any cause (overall survival) at 0, 1, 3, 5, or 7 years were 2020, 1995, 1833, 1706, or 1037. The numbers of patients at risk for death or recurrence (disease-free survival) at 0, 1, 3, 5, or 7 years were 2020, 1951, 1699, 1551, or 940 for the entire sample.