Abstract P2-20-12: Abundance of tumor-infiltrating lymphocytes is associated with pathologic complete response to neoadjuvant chemotherapy but not with survival in ER-positive/HER2-negative breast cancer
Authors: Wu Rongrong , Nagahashi Masayuki , Oshi Masanori , Miyoshi Yasuo , Ishikawa Takashi , Takabe Kazuaki 
Published: March 2023

Abstract
INTRODUCTION: Abundance of tumor infiltrating lymphocytes (TILs) is well known to be associated with achievement of pathologic complete response (pCR) after neoadjuvant chemotherapy and is a surrogate of better survival in triple negative breast cancer (TNBC). However, the association remains unclear in ER-positive/HER2-negative, which is the most common subtype in breast cancer. Further, pathological quantification of TILs is known for its ambiguity. We hypothesized that abundance of TILs, quantified by transcriptomic signatures, in ER-positive/HER2-negative is associated with different biology and is not a surrogate of survival unlike in TNBC. METHODS: A total of 6035 primary breast cancer patients from three cohorts (TCGA, METABRIC, and SCAN-B) with full transcriptome and clinical data were analyzed. Lymphocyte fractionation in the tumor microenvironment of a bulk tumor was estimated from the transcriptome using two different deconvolution tools, CIBERSORTx and xCell. RESULTS: First, the correlation between TIL score measured histologically on TCGA patients and gene expression of CD3D, CD3E, CD3G, CD8A, CD4, and total lymphocytes, and total T-cells measured by xCell or CIBERSORTx were analyzed. Total sum of lymphocytes by xCell correlated the strongest, thus it was adopted as the TIL score. The TIL score strongly correlated with CD3G, CD3E, CD3D, CD8A, and CD4 gene expressions in both TCGA and GSE96058 cohorts (all r &gt; 0.48). Among the infiltrated cells; M1 and M2 macrophages, dendritic cells, mast cells and monocytes were all higher, and microvascular endothelial cells and pericytes were lower in TIL score high tumors in ER-positive/HER2-negative (all p &lt; 0.01) where M2 and mast cells were not in HER2+ and TNBC in both 2 cohorts. Enrichment of immune related gene sets IL2/Stat5 signaling, IL6/Jak/Stat3 signaling, inflammatory response, and Complement were less in high TIL group of ER-positive/HER2-negativethan HER2 and TNBC. In agreement, cytolytic activity was lower in TIL high of ER-positive/HER2-negative compared from TNBC. On the other hand, high TIL group in ER-positive/HER2-negative had significantly higher intratumor heterogeneity, homologous recombination deficiency, mutation burden, and neoantigens, which were not the case in the other subtypes. In agreement, all the cell proliferation-related gene sets; E2F targets, G2M checkpoint, mitotic spindle, Myc targets v1 and v2, were more strongly enriched in high TIL group of ER-positive/HER2-negative compared from HER2+ and TNBC. MKI67 gene expression and Nottingham histological Grade were uniformly elevated with high TIL regardless of subtypes. In three independent neoadjuvant cohorts, we found that pathologic complete response rates of high TIL group. On the other hand, high TIL group did not show any survival benefit compared with low TIL group in ER-positive/HER2-negative, unlike in HER2+ or TNBC. CONCLUSION: High tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer was associated with less immune response and higher genetic alteration and cell proliferation compared to the other subtypes, leading to better response of neoadjuvant chemotherapy, but no benefit in survival outcome.
Citation Format: Rongrong Wu, Masayuki Nagahashi, Masanori Oshi, Yasuo Miyoshi, Takashi Ishikawa, Kazuaki Takabe. Abundance of tumor-infiltrating lymphocytes is associated with pathologic complete response to neoadjuvant chemotherapy but not with survival in ER-positive/HER2-negative breast cancer [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 P2-20-12.