This year’s final General Session on Friday afternoon featured two preclinical studies suggesting new approaches to both treating and identifying brain metastases in triple negative and inflammatory breast cancer.
GS5-07: Estradiol represses anti-tumoral immune response to promote progression of ER- brain metastases.
Diana M. Cittelly, PhD, Associate Professor of Pathology, University of Colorado Denver Anschutz Medical Campus School of Medicine, described the latest findings on the activity of estrogen in promoting the progression of brain metastases (BM) in triple negative breast cancer (TNBC). Younger age is a significant independent predictor of BM in breast cancer, she noted.
“Our hypothesis is that premenopausal hormones such as estradiol (E2) may promote brain metastasis by exerting effects on the microenvironment in the brain,” Dr. Cittelly said. “We already know that estradiol acts on ER+ astrocytes to secrete growth factors which can activate tumor promoting pathways in TNBC. Both brain and ovarian estrogen may influence the brain tumor microenvironment in younger women.”
It is not practical to study estrogen depletion and BM in the clinical setting, she noted, but mouse models of TNBC show that ovariectomy alone or in combination with letrozole prevent BM colonization and restoring premenopausal levels of E2 promotes BM colonization. Combining multiple murine models that mimic current standard of care for TNBC allowed researchers to examine the effect E2 depletion alone or in combination with brain irradiation might have on the progression of existing BM in TNBC.
E2 suppression + brain irradiation decreases BM progression in immune competent mouse models of ER- breast cancer. E2 suppression alone does not affect BM progression.
“The effectiveness of E2 suppression in decreasing progression of existing metastases depends on radiation to prime the system,” Dr. Cittelly said. “And E2 suppression with or without irradiation does not affect BM progression in immunocompromised mice.”
Suppressing E2 activates immune surveillance at the earliest stages of brain colonization by repressing microglia and macrophage activation, she explained. In the later stages of metastatic progression, E2 suppression recruits T and B cells to the brain. E2 suppression does not interact with anti-PD1 inhibitors to affect either brain or systemic metastases.
“These findings suggest that E2 depletion might be used in combination with radiation therapy to decrease BM in younger women with TNBC,” Dr. Cittelly said, “But we need further studies to determine any benefit of E2 depletion in combination with immunotherapies. Researchers need to use a combination of preclinical models mimicking the current standard of care in BM research.”
GS5-08: Soluble E-cadherin: a novel prognostic biomarker and driver of brain metastasis in inflammatory breast cancer.
Xiaoding Hu, MD, PhD, Instructor in Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at The University of Texas MD Anderson Cancer Center, presented data suggesting that soluble E-cadherin (sEcad), the extracellular domain of E-cadherin, appears to be a useful biomarker and driver of brain metastasis in inflammatory breast cancer (IBC).
E-cadherin is a cell-cell adhesion protein that is overexpressed in IBC tumors and tumor emboli and plays an oncogenic function in IBC, Dr. Hu said. High levels of sEcad are present in the serum, urine and plasma of cancer patients and are associated with poor prognosis.
“Higher sEcad independently correlates with poor overall survival and is strongly associated with the development of brain metastases with a hazard ratio of 2.0,” Dr. Hu said. “We saw that sEcad promotes migration and invasion in multiple IBC cell lines. sEcad also promotes anoikis resistance in IBC cells to drive brain metastatic growth and reduce survival in mice.”
Additional studies found that sEcad induces reactive astrocytes and interacts with X-linked inhibitor of apoptosis protein (XIAP) to activate the NF-κB pathway to promote cancer cell migration from the primary tumor, intravasation and survival in circulation and metastatic invasion of the brain microenvironment.
“These results suggest that sEcad is both a potential biomarker for metastasis in IBC and a potential therapeutic target in metastatic IBC,” Dr. Hu said.
On-Demand Session Availability
Daily sessions will be available for on-demand viewing 3-5 days following the 2022 Symposium (author permitting). They will be available exclusively to registered SABCS attendees until March 2023. Following March 2023, they will be available on SABCS.org under the “Resources” tab.