Abstract 67: Chemotherapy induced pro-metastatic changes in the primary breast tumors of racially diverse patients

Abstract

Abstract Neoadjuvant chemotherapy (NAC) induces influx of bone marrow-derived proangiogenic Tie2hi monocytes into the primary tumor, resulting in increased density of perivascular Tie2hi macrophages (1). Perivascular Tie2hi/Vegfhi macrophages in physical contact with Mena expressing cancer cells create micro-anatomic sites of transient vascular permeability called TMEM, which mediate cancer cell intravasation and dissemination (2). Cancer cells capable of intravasation via TMEM sites express high level of MenaINV, an isoform of Mena, induced by macrophage contact, which renders tumor cells intravasation-competent (3, 4). Consequently, breast cancers from mice and patients treated with NAC have increased density of TMEM sites and show increased expression of MenaINV (1) Moreover, in PyMT mouse mammary carcinoma and patient derived xenografts, NAC increases the number of circulating tumor cells and lung metastasis (1). The Tie2-inhibitor rebastinib, which inhibits TMEM function, can reverse chemotherapy-induced increases in the number of CTCs and lung metastasis in mouse mammary carcinoma (1, 5). Although NAC induces pro-metastatic changes in breast cancer microenvironment, large randomized prospective studies did not find significant differences in distant-recurrence free survival (DRFS) and overall survival (OS) between breast cancer patients treated with adjuvant and neoadjuvant chemotherapy in predominantly white populations. Since the breast cancer microenvironment in black women has higher microvascular density and density of Tie2hi macrophages, suggesting that black women may be more prone to develop TMEM-associated pro-metastatic changes in response to NAC, we questioned if there is a difference in DRFS in black women treated with NAC compared to AC. We evaluated DRFS in 1,211 racially diverse patients with localized or regionally advanced breast cancer treated with neoadjuvant or adjuvant chemotherapy between January 2000 and December 2016 and found that black patients with localized breast cancer treated with systemic neoadjuvant chemotherapy not only have inferior DRFS compared to white patients, but also worse DRFS when compared to black patients treated with adjuvant chemotherapy, after adjustment for clinical covariates in multivariate analysis. The biologic factors contributing to this finding, in particular TMEM-mediated pro-metastatic changes have been evaluated and will be discussed. 1. Karagiannis et al, Sci Transl Med. 2017;9:397. 2. Harney et al, Cancer discovery. 2015;5:932. 3. Pignatelli J et al, Sci Rep. 2016;6:37874. 4. Pignatelli J et al, Sci Signal. 2014;7:353. 5. Harney et al, Mol Cancer Ther. 2017;16:2486. Citation Format: George S. Karagiannis, Jessica M. Pastoriza, Sonali Lanjawar, Yarong Wang, David Entenberg, Esther Cheng, Timothy M. Dalfonso, Joan G. Jones, Jesus Anampa, Thomas E. Rohan, Joseph A. Sparano, John S. Condeelis, Maja H. Oktay. Chemotherapy induced pro-metastatic changes in the primary breast tumors of racially diverse patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 67.