Abstract 812: High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer
Authors: Wu Rongrong , Patel Ankit , Tokumaru Yoshihisa , Asaoka Mariko , Oshi Masanori , Yan Li , Ishikawa Takashi , Takabe Kazuaki 
Published: June 2022

Abstract
INTRODUCTION: Homologous recombination deficiency (HRD) is involved in breast cancer carcinogenesis, however, activation of DNA repair in cancer cells may promote its survival and progression. RAD51 plays an essential role in homologous recombination with BRCA2. Recently, RAD51 has been highlighted to play a role in resistance to DNA-damaging chemotherapy or PARP inhibitors. We hypothesized that RAD51 as a prognostic and predictive biomarker of drug sensitivity in breast cancer.
MATERIALS AND METHODS: Total of 4500 primary breast cancer patients from three independent cohorts were examined. High and low expression of RAD51 were divided by median RNA expression. Response to treatments were assessed in total of 3000 patients across 11 independent cohorts of breast cancer patients that received neoadjuvant chemotherapy.
RESULTS: RAD51 was upregulated in cancer compared to normal tissues in the TCGA cohort and was positively correlated with HRD. Cancer with high RAD51 group enriched DNA repair gene set in gene set enrichment analysis (GSEA) in all cohorts and had high expression of HRD-related genes including BRCA1 and BRCA2. Histological grade and Ki67 expression were positively correlated with RAD51, and all cancer proliferation gene sets from Hallmark (E2F target, G2M checkpoint, Myc Targets v1 and v2, and Mitotic Spindle) were strongly enriched in the high RAD51 expression breast cancer in all cohorts. In TCGA, tumor mutation burden and neoantigen were also higher in tumor with high RAD51 expression, but RAD51 expression was not elevated in BRCA1 or BRCA2 mutant tumors. Cytolytic activity score, a marker of cancer immunity, was elevated high RAD51 group in two cohorts, and the immune cell fraction calculated by the xCell algorithm showed increase in immune cell infiltration, including CD4 memory T cells, Th1 cells, M1 macrophages and activated dendritic cells, in all cohorts, suggesting a certain level of activation of cancer immunity in this RAD51 high breast cancer group. However, contrary to previous reports, RAD51 expression in breast cancer cell lines did not show any association between sensitivity to chemotherapy or PARP inhibitors. Neither for the breast cancer NAC cohort, RAD51 expression was not increased in the residual burden group, but conversely increase in RAD51expression was observed in pathological complete response group in some cohorts. Surprisingly, RAD51 was significantly associated with worse overall survival in all three large cohorts included in this analysis, and with worse disease-specific survival in two cohorts.
CONCLUSIONS: RAD51 expression was significantly associated with worse survival, but did not with treatment-responsive, suggesting its usefulness as prognostic, but not predictive, biomarker.
Citation Format: Rongrong Wu, Ankit Patel, Yoshihisa Tokumaru, Mariko Asaoka, Masanori Oshi, Li Yan, Takashi Ishikawa, Kazuaki Takabe. High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 812.