Which cyclin E prevails as prognostic marker for breast cancer? Results from a retrospective study involving 635 lymph node-negative breast cancer patients

Purpose: To evaluate the prognostic value of cyclin E with a quantitative method for lymph node - negative primary breast cancer patients. Patients and Methods: mRNA transcripts of full-length and splice variants of cyclin El (CCNE1) and cyclin E2 (CCNE2) were measured by real-time PCR in frozen tumor samples from 635 lymph node - negative breast cancer patients who had not received neoadjuvant or adjuvant systemic therapy. Results: None of the PCR assays designed for the specific splice variants of the cyclins gave additional prognosis-related information compared with the common assays able to detect all variants. In Cox multivariate analysis, corrected for the traditional prognostic factors, high levels of cyclin E were independently associated with a short distant metastasis-free survival [hazard ratio (HR), 3.40; P < 0.001 for CCNE1 and HR, 1.76; P < 0.001 for CCNE2, respectively]. After dichotomizing the tumors at the median level of 70% tumor cells, the multivariate analysis showed particularly strong results for CCNE1 in the group of 433 patients with stroma-enriched primary tumors (HR, 5.12; P < 0.001). In these tumors, the worst prognosis was found for patients with estrogen receptor - negative tumors expressing high CCNE1 (HR, 9.89; P < 0.001) and for patients with small (T-1) tumors expressing high CCNE1 (HR, 8.47; P < 0.001). Conclusion: Our study shows that both CCNE1 and CCNE2 qualify as independent prognostic markers for lymph node - negative breast cancer patients, and that CCNE1 may provide additional information for specific subgroups of patients.