Abstract P3-07-62: Association of overexpression of hypoxia inducible factor 1α with response to neoadjuvant chemotherapy in early stage breast cancer

Abstract Background: Hypoxia inducible factor 1 alpha (HIF-1α) is a master transcription factor involved in multiple oncogenic processes. In breast cancer, HIF-1α overexpression is associated with increased resistance to radiation therapy, chemotherapy, and inferior disease-free and overall survival. Patients who achieve a pathologic complete response (pCR) following neoadjuvant therapy have improved survival outcomes. Limited data are available regarding the association between HIF-1α expression and rates of pCR. We investigated the relationship between HIF-1α overexpression and pCR rates following neoadjuvant chemotherapy for early breast cancer. Methods: Eligible women were those with HER2-negative, stage II-III breast cancer, who received anthracycline- and taxane-based neoadjuvant chemotherapy from 2002 to 2012, and were included in an institutional review board-approved Integrated Breast Cancer Research Database at Johns Hopkins. The database includes patient age, sex, menopausal status, breast cancer diagnosis, tumor histopathology, treatment history, laboratory data, and outcomes. Both diagnostic and surgical tissue blocks were retrieved from pathology archives. Whole section slides were prepared and analyzed by immunohistochemical staining with appropriate negative and positive controls. The intensity of cells positive for HIF-1α was estimated visually by a pathologist blinded to clinical data. A semi-quantitative scoring of nucleus expression was used to score HIF-1α expression: score 0 is defined as less than 1%, 1 is defined as 1-5%, 2 as 5-20% and 3 as >20% tumor cells positive for HIF-1α. Overall tumor HIF-1α negativity was defined as (0, 1) and positivity as (2, 3). We compared baseline HIF-1α status among responders (pCR defined as no invasive tumor in the breast or lymph nodes) and non-responders (no pCR) using Fisher's exact test, and evaluate the association between baseline and surgical specimens in those who did not achieve pCR using NcNemar's test. Results: A total of 122 women meeting the eligibility criteria underwent a definitive surgical procedure following neoadjuvant chemotherapy. Of those, 50 patients had no tissue blocks available at baseline and additional 16 patients' blocks did not contain sufficient tissue for analysis. Thus, tumors from 56 women were available for analysis. Median age was 50 (range 33-78), 54% were White and 35% Black; 41% and 59% of women had triple negative and hormone receptor-positive tumors, respectively; 71% women had Ki67>30%, and 80% were node-positive. Overall pCR was observed in 12 women (21%). We did not detect a significant association between HIF-1α score on the diagnostic specimen with pCR status (p=0.627). However, a positive HIF-1α score was significantly associated with positive lymph nodes (p=0.01). We observed a significant decrease in HIF-1α score following chemotherapy (p<0.001). Conclusions: We did not observe a clear association between HIF-1α expression and response to neoadjuvant chemotherapy. However, HIF-1α expression on a diagnostic specimen was statistically higher than following chemotherapy and was associated with lymph node positivity. Our study is limited by its retrospective nature and a small sample size. Citation Format: Zhi WI, Huang C-Y, Gabrielson E, Tully E, Cimino-Mathews A, Santa-Maria C, Jeter S, Kai C, Semenza G, Stearns V. Association of overexpression of hypoxia inducible factor 1α with response to neoadjuvant chemotherapy in early stage breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-62.