Abstract Background: Patients with breast cancer are susceptible to coronavirus disease (COVID-19), which affects cancer treatment efficacy and prognosis. However, its effects on neoadjuvant chemotherapy (NAC) response and its genetic correlation with breast cancer remain unclear. We aimed to clarify these effects and investigate potential genetic associations and shared pathogenic mechanisms. Μethods: In this ambidirectional (retrospective and prospective) cohort study involving 856 breast cancer patients receiving NAC, with and without COVID-19, we evaluated the impact of COVID-19 on NAC response using multivariable logistic regression and three matching methods: propensity score matching, inverse probability of treatment weighting, and overlap weighting. Using single-cell and bulk transcriptome data from the Gene Expression Omnibus and genetic variants from the Genome-Wide Association Study databases, we conducted Mendelian randomization (MR) analysis to explore the core cellular subsets, shared genes, causal relationships, and common pathogenic mechanisms between COVID-19 and breast cancer. Results: Patients with breast cancer and COVID-19 showed poor NAC responses, including a low objective response rate and reduced likelihood of achieving RCB class 0-I in the HR+/HER2+ subgroup (OR=0.46, P=0.028, P for interaction=0.024). The consistent findings from the three matching models support these results. Integrating single-cell and bulk transcriptome data with MR analyses revealed genetic correlations between COVID-19 and breast cancer and identified ABLIM1 and GZMM as potential genes linked to NAC resistance. Conclusions: SARS-CoV-2 infection during NAC may compromise therapeutic efficacy in patients with breast cancer. ABLIM1 and GZMM may be causal genes in the genetic correlation between COVID-19 and breast cancer. Citation Format: Y. Wang, J. Zhan, S. Liu, W. Cai, Y. Qiu, P. He, M. Chen, L. Chen, F. Fu, C. Wang. Impact of COVID-19 on neoadjuvant chemotherapy efficacy in patients with breast cancer: an ambidirectional cohort study and Mendelian randomization analysis abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-02-02.
Wang et al. (Tue,) studied this question.