Abstract PS14-14: Distinct tumor microenvironments of breast cancer bone metastases in pre- and post-menopausal patients
Authors: Ihle Claire , Provera Meredith , Straign Desiree , Zolman Katy , Smith Erin , Van Bokhoven Adrie , Lucia Scott , Owens Philip 
Published: February 2021

Breast cancer (BC) patient prognosis has improved over the past 2 decades with a 99% 5 year survival rate for localized BC, yet metastatic BC continues to cause high mortality with a 5 year survival rate of 27%. Recent advances have been made in the treatment of primary BC, providing an opportunity to apply this positive momentum towards treating metastatic disease. Approximately 70% of BC metastases occur in the bone, with the majority of patients retaining estrogen receptor positive (ER+) disease. The BC tumor microenvironment (TME) in bone exhibits an osteolytic bone pathology of bone destruction and is composed of primarily four cellular groups including the cancer, immune, vascular and bone cells. These cellular constituents are uniquely responsive to estradiol (E2) and exhibit unique TMEs dependent on menopause status, when circulating E2 is lost. Both menopause and BC endocrine therapies induce an E2-deprived post-menopausal state in patients. However, studying the distinctions of pre- and post-menopausal BC patient TMEs is still necessary to understand how natural menopause status impacts non-treatment naïve ER+ BC that is already in a therapy induced menopausal state. In particular the full extent of the unique phenotypes harbored by pre- versus post-menopausal ER+ BC tumor induced bone disease (TIBD) remains unknown, and elucidation of these difference may identify novel mechanisms of TIBD.

We investigated a cohort of demineralized formalin-fixed and paraffin-embedded (FFPE) pre- and post-menopausal lytic bone metastasis biopsies from non-treatment naïve ER+ BC patients. We utilized immunohistochemistry (IHC), NanoString nCounter gene expression panels and GeoMx Digital Spatial Profiling (DSP) to observe distinct TMEs in our archival biopsy cohort. IHC staining of pre- and post-menopausal samples displayed alterations to immune cell infiltration and composition. Differential gene expression analysis revealed enrichment of myeloid function in pre-menopausal patients compared to post-menopausal patients. Alterations to immune signaling pathways and cell profiles were also exhibited in pre-menopausal patients compared to post-menopausal patients. DSP analysis presented changes in both the tumor and microenvironment, and unique immune cell infiltration with checkpoint proteins in both pre-menopausal and post-menopausal ER+ BC bone metastases. The identification of these targetable markers unique to pre- and post-menopausal TIBD could provide new therapeutic strategies for ER+ BC patients with bone lesions. Thus, we propose that bone biopsies could be performed to guide selection for metastatic BC patients into appropriate therapeutic interventions, with pre- and post-menopausal patients receiving tailored treatments based on their distinct protein and RNA expression of available therapies. This personalized approach to treating metastatic disease could enhance patient quality of life and survival.

Citation Format: Claire Ihle, Meredith Provera, Desiree Straign, Katy Zolman, Erin Smith, Adrie Van Bokhoven, Scott Lucia, Philip Owens. Distinct tumor microenvironments of breast cancer bone metastases in pre- and post-menopausal patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-14.