Abstract 7515: Enhancing immune checkpoint inhibitor efficacy with fulvestrant in estrogen receptor-positive breast cancer
Authors: Arima Jun , Chida Kohei , Oshi Masanori , Roy Arya Mariam , Taniguchi Kohei , Lee Sang-Woong , Takabe Kazuaki 
Published: March 2024

Abstract
Introduction: Breast cancer (BC) recurs decades after initial treatment that consists majority of the annual 43,000 BC deaths. Thus, Immune Checkpoint Inhibitor (ICI) therapy that bolster anti-cancer immunity is expected to improve long-term survival with reduced recurrence. Neoadjuvant ICI revolutionized management of triple negative breast cancer (TNBC); however, this represents only 5-7% of all BC cases, where estrogen receptor (ER)-positive subtype that consists of 70% of all BCs is not indicated due to less tumor-infiltrating lymphocytes (TILs). Using I-SPY2 trial we aim to investigate the potency of ER-alpha gene (ESR1) expression as a predictive biomarker, and whether the inhibition of the ER with fulvestrant enhances the efficacy of ICIs in ER+ BC.
Methods:Total of 1157 BC patients from two independent cohorts (ISPY2 trial; n= 73, TCGA; n = 1084) were included, encompassing both clinical and transcriptomic profiles. The TIL score was determined using the xCell algorithm.
Results:Using the transcriptome of the ISPY2 trial, we found that compared to ESR1 low expression patients, ESR1 high patients were associated with significantly lower pCR rates after neoadjuvant immunotherapy with ICI in whole cohort (n=71, pCR rate=30%, p&lt;0.05) and HR+ subtype (n=50, pCR rate=20%, p&lt;0.001), but not in triple-negative breast cancer (TNBC). ESR1 expression outperformed PD-1, PD-L1, and CTLA4 in Area Under the Curve (AUC) of the whole ISPY2 cohort (AUC=0.75, 0.68, 0.48, and 0.62, respectively), and further pronounced in HR+ BC (AUC=0.88, 0.73, 0.55, and 0.65, respectively), suggesting the potency of ESR1 expression as a predictive biomarker for ICI in HR+ BC. In agreement, ESR1 expression inversely correlated with the amount of intratumoral TILs consistently in both ISPY2 and TCGA cohorts in HR+ BC, but only in TCGA in whole cohort (all p&lt;0.05). Among the intratumoral TILs, CD8+ T cell and M1 Macrophages were found to be less infiltrated in HR+ BC in TCGA. Given that ESR1 expression was associated with less intratumoral TILs and a poor response to ICI, we hypothesized that suppression of ER-alpha would enhance the effectiveness of ICI in HR+ BC in vitro. ER-alpha positive MCF7 cells were incubated with activated peripheral blood mononuclear cells with 1:1 ratio, and treated with 0.1 microgram of anti-PDL1, and 1nM of ER antagonist, fulvestrant, which demonstrated minimum cell killing. We found that ICI therapy with anti-PDL1 significantly decreased the cell viability of the MCF7 cells when ER-alpha expression was suppressed by fulvestrant, while activated peripheral blood mononuclear cells or anti-PDL1 alone or the combination did not exhibit any significant cell killing.
Conclusion: We found that ESR1 expression is a predictive biomarker of ICI, and ER antagonist fulvestrant enhances the response of HR+ BC to ICI, suggesting that this combination could expand ICI indications to HR+ BC.
Citation Format: Jun Arima, Kohei Chida, Masanori Oshi, Arya Mariam Roy, Kohei Taniguchi, Sang-Woong Lee, Kazuaki Takabe. Enhancing immune checkpoint inhibitor efficacy with fulvestrant in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7515.