Prognostic value of Bcl-2 in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy

L. M. VARGAS ROIG; F. D. CUELLO CARRIÓN; N. FERNÁNDEZ ESCOBAR; P. DAGUERRE; M. LEUZZI; J. IBARRA; F. E. GAGO; S. B. NADIN; D. R. CIOCCA

Chicago, USA

Congreso; American Society of Clinical Oncology 44th Annual Meeting; 2008

American Society of Clinical Oncology (ASCO)

Background: Bcl-2 has important roles in breast cancer: high expression is proapoptotic while a relatively lower expression is antiapoptotic, Bcl-2 is anti-proliferative regulating G1/S transition and is related to cell differentiation. The value of Bcl-2 protein as predictive or prognostic factor to adjuvant treatment in breast cancer has been investigated. However, there are few analyses in a homogeneous group of patients treated with neoadjuvant chemotherapy. In this prospective study we analyzed Bcl-2 in paired pre- and post-chemotherapy biopsies, overall survival (OS) and disease-free survival (DFS) in patients treated with neoadjuvant chemotherapy. Methods: One hundred and ten patients were submitted to two different chemotherapeutic regimens: a) 5-fluorouracil, adriamycin or epirubicin, and cyclophosphamide (FAC/FEC) during 2 to 6 cycles before surgery and 3 or 4 additional cycles of FAC/FEC after surgery (n=40) and b) doxorubicin (D) 75 mg/m2 or epirubicin (E) 120 mg/m2 during 4 cycles before surgery, and 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) after surgey (n=70). Pre- and post-chemotherapy samples were immediately fixed in 10% buffered formalin and embedded in paraffin for studies (H&E, immunohistochemistry, TUNEL). Some samples were stored at -70°C until western blot analysis was performed. Statistical analyses were performed using the Prism computer program: Kaplan-Meier method, Wilcoxon signed rank non-parametric test, Spearman´s rank correlation coefficient, and Fisher’s exact test. Results: Bcl-2 expression, evaluated by immunohistochemistry, did not change significantly after chemotherapy and was not related to clinical/pathological response. A high apoptotic index (AI) was more frequently found among the cases with low Bcl-2 expression compared to the cases with high Bcl-2 content, but this inverse correlation was not statistically significant. The expression of Bcl-2, Bax and p53 evaluated before chemotherapy did not correlate with the clinical response of the tumor.  In FAC/FEC group, Bcl-2 positive expression after chemotherapy correlated with better DFS and OS (P = 0.008 and P = 0.001). In D/E group, Bcl-2 also correlated with better DFS and OS (P = 0.03 and P = 0.054) in the post-chemotherapy biopsies. ERa expression after chemotherapy was associated with longer DFS (P = 0.004) and OS (P = 0.04). An unusual nuclear localization of Bax was observed in some biopsies, but this localization did not correlate with the tumor response or outcome of the patients. Since WT p53 tends to activate Bax, we explored the correlation between Bax and p53 expression. We observed that mutated p53 correlated with lower Bax content in the pre-chemotherapy biopsies only (Spearman´s rank correlation coefficient r = -0.67, P = 0.003). Conclusions: We found that a high Bcl-2 expression had no predictive value anticipating better clinical/pathological response but had prognostic value anticipating better survival rates in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy.