Abstract P2-20-14: Relationship of HIF-1α and tumor infiltrating lymphocytes in patients with HER2-negative early-stage breast cancer treated with neoadjuvant chemotherapy
Authors: Oza Harsh , Grabinski Victoria , Ibanez Hector , Godet Ines , Gilkes Daniele , Cimino-Mathews Ashley , Gabrielson Edward , Shah Mirat , Zhi W. Iris , Pipa Zoe , Lehman Jennifer , Ke Suqi , Tsai Hua-Ling , Stearns Vered , Santa-Maria Cesar Augusto 
Published: March 2023

Abstract
Title: Relationship of HIF-1α and tumor infiltrating lymphocytes in patients with HER2-negative early-stage breast cancer treated with neoadjuvant chemotherapy Authors: Grabinski VF, Oza HH, Gilkes DM, Shah MY, Cimino-Mathews A, Gabrielson E, Zhi I, Pipa Z, Lehman J, Ibanez HE, Ke S, Tsai HL, Stearns V, Santa-Maria CA Introduction: Hypoxia inducible factor 1α (HIF-1α) is an oxygen-dependent transcription factor expressed in areas of hypoxia associated with regulation of immune escape mechanisms, metabolism (CAIX), and results in cancer treatment resistance. High stromal tumor infiltrating lymphocytes (sTILs) are associated with pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) in breast cancer. We investigated associations between HIF-1α, sTILs and their relationship with pCR after NACT in patients with HER2-negative early-stage breast cancer. Methods: We identified patients with early-stage HER2-negative breast cancer at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center from 2000-2009 who received NACT, and had accessible breast tissue from biopsy and/or surgery. A pathologist scored nuclear HIF-1α (0, 1, 2, or 3), membranous CAIX (0, 1, 2, or 3), sTILs (0-100) from baseline (ie pre-NACT) and surgical tissue (if non-pCR). Statistical analysis considered the following variables: age, histology, race, menopausal status, tumor size, and node status. Chemotherapy regimens were divided into either anthracycline AND taxane versus anthracycline OR taxane. Wilcoxon rank-sum, Fisher exact, and Jonckheere trends tests were utilized to assess differences between groups. Results: 43 patients met the predefined criteria and were included in the analysis, 16% (n=7) obtained a pCR. Patient race, ethnicity, clinical tumor size, histology, clinical subtype (estrogen receptor positive (ER+) vs. triple negative (TN)), and NACT regimen were not associated with pCR. Older age (p=0.019), postmenopausal status (p=0.009), smaller surgical tumor size (p &lt; 0.001), and surgical node-negative status (p &lt; 0.001) were associated with pCR. Mean TILs score was 32.5% in patients achieving pCR versus 20% in those with non-pCR (p=0.46); mean HIF-1α was 2.42 in pCR group versus 2.57 in non-pCR (p=0.84). There was a trend of lower baseline sTILs with increasing nuclear HIF-1α score (p=0.085). Membranous CAIX was not associated with nuclear HIF-1α or baseline TILs, however, in the small proportion of patients (n=11) with CAIX scoring, higher membranous CAIX score at baseline (1 vs. 0) was associated with pCR (p=0.024). Conclusions: We observed that patients with pCR had a numerically higher sTILs level at baseline consistent with other studies, but did not find a correlation of HIF-1α and pCR. Patients with higher HIF-1α scores tended to have lower sTILS, suggesting that hypoxia may be leading to an immunosuppressive tumor microenvironment. Further characterizing the HIF-1α pathway and its effects on the immune microenvironment may help identify resistance mechanisms to chemotherapy and immunotherapy.
Citation Format: Harsh Oza, Victoria Grabinski, Hector Ibanez, Ines Godet, Daniele Gilkes, Ashley Cimino-Mathews, Edward Gabrielson, Mirat Shah, W. Iris Zhi, Zoe Pipa, Jennifer Lehman, Suqi Ke, Hua-Ling Tsai, Vered Stearns, Cesar Augusto Santa-Maria. Relationship of HIF-1α and tumor infiltrating lymphocytes in patients with HER2-negative early-stage breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-14.