Abstract 685: ALDH1 and hypoxia inducible factors in locally advanced breast cancer patients subjected to neoadjuvant chemotherapy
Authors: Daniel G. Tiezzi, Willian S. Clagnan, Heitor RC Marana, Marcelo G. Tiezzi, Jurandyr M. Andrade
Journal: Cancer Research (2012)

Abstract The presence of stem-like cells within malignant tumors has been reported as a prognostic factor in patients with solid tumors. Recent studies suggest that hypoxia promotes tumor stemness. This mechanism can be regulated by hypoxia inducible factors such as HIF1A and HIF2A. In breast carcinomas, the aldehyde dehydrogenase 1 (ALDH1) was identified as a potential stem-like cell marker and prognostic factor. However, the association of HIFs and ALDH1 expressions in breast cancer patients subjected to neoadjuvant treatment has not been studied yet. Methods: we retrospectively analyzed the expression of ALDH1, HIF1A and HIF2A proteins in 80 tumors from patients with histologically confirmed stage II and III breast carcinomas treated with neoadjuvant chemotherapy in the Hospital das Clínicas of the University of São Paulo from 2000 to 2005 [stage IIa: 12 patients (14%); stage IIb: 30 patients (35.5%); stage IIIa: 15 patients (17.5%) and stage IIIb: 28 patients (33%)]. The patients’ mean age was 48.9 ± 11.7 years old with a mean follow-up of 100 months. The ER, PgR and HER2 positive expression rates were 63%, 43% and 32%, respectively. The immunohistochemistry for ALDH1, HIF1A and HIF2A was performed in tumors samples before and after neoadjuvant treatment. We analyzed the influence of clinical and pathological features on clinical and pathological response, disease free survival and overall survival. Results: the objective clinical response (partial and complete response) to neoadjuvant therapy was 80% with 12% of complete pathological response. Among all clinical and pathological parameters, only HIF1A expression was associated with pathological response (21% of complete pathological response in HIF1A positive vs 5% in HIF1A negative; p= 0.04). There was a positive association between ALDH1 and HIF1A expression before and after chemotherapy (p= 0.038 and p= 0.03, respectively). The ALDH1 expression was associated with HIF2A expression in tumors after neoadjuvant treatment (p= 0.01). In univariate analysis, the prognostic was influenced by age (p= 0.01), pathological response (p= 0.01), metastasis to axillary lymph nodes after neoadjuvant chemotherapy (p= 0.006), HER2 overexpression (p= 0.03) and by the presence of ALDH1+ cells within the primary tumor after neoadjuvant chemotherapy (p= 0.01). In multivariate analysis, only the presence of ALDH1+ cells after chemotherapy and age were associated with reduced overall survival (p= 0.04 and p= 0.01, respectively). Conclusion: the presence of ALDH1 positive cells within the residual tumor after neoadjuvant chemotherapy is associated with and increase in HIF2A expression and poor prognostic in patients with locally advanced breast cancer. There is a association between ALDH1 expression in tumor cells and the expression of HIF1A in locally advanced breast carcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 685. doi:1538-7445.AM2012-685