Abstract 4632: Molecular determinants to neoadjuvant chemotherapy resistance in breast cancer patients: Insights from a Latin-American cohort

Abstract Neoadjuvant chemotherapy (NAC) is vital in treating primary breast cancer, yet the mechanisms behind its success are not fully understood. Understanding transcriptomic changes associated with NAC resistance is crucial for improving treatment. This study sought to identify transcriptomic alterations linked to NAC resistance, enhance comprehension of treatment resistance, and lay the groundwork for developing targeted strategies for patients unresponsive to standard NAC protocols.We analyzed the transcriptomes of 44 matched breast cancer specimens from nonresponder patients to NAC at the Colombian National Cancer Institute. Samples were collected before and after NAC, representing luminalA, luminalB/HER2-positive, luminalB/HER2-negative, and TNBC subtypes. We performed differential gene expression and enrichment analyses and compared hallmark gene sets. Furthermore, we used deconvolution algorithms to estimate tumor microenvironment (TME) infiltration and assess immune population activity within the TME. Our findings were compared with publicly available GEO database data.Gene expression patterns before and after treatment were distinct across subtypes, with FOS and NR4A1 common to all, and ZBTB16 unique to luminalB. FOSB was found in all luminal samples. ATF3, DUSP1, EGR1, and JUN were shared among HER2-negative subtypes. GEM was common to luminalA and LuminalB/HER2-negative subtypes. Pathway variations included complement and coagulation cascades, and IL-17, TNF, MAPK, and NF-κB signaling pathways among subtypes and post-NAC specimens. Post-treatment LuminalA samples had increased CD4 memory cells, Tregs, and neutrophils. The LuminalB/HER2+ group showed higher CD8+ and CD4+ memory-activated cells post-treatment. In LuminalB/HER2- post-treatment samples, B cell CD4 memory resting, Macrophages M2, and neutrophils were elevated. TNBC post-treatment samples had higher resting mast cells and CD4+ memory cells. MSIGBD comparison of gene sets linked to cisplatin, docetaxel, and doxorubicin resistance identified several shared genes. GeoDatabases confirmed FOS and NR4A1 across all groups, with other DEGs shared among subtypes.Our research indicates that NAC affects gene expression, cell function, and interactions within the TME, potentially contributing to treatment resistance. Assessing TME components is crucial for predicting NAC effectiveness and reducing the risk of recurrence. These results highlight the importance of studying diverse patient populations to gain fresh perspectives and address disparities in treatment outcomes. This investigation emphasizes the need to understand how TME influences chemotherapy resistance, paving the way for the development of more precise and efficient therapeutic strategies. Citation Format: H Michelle Guevara-Nieto, Carlos A. Orozco, Rafael S. Parra-Medina, Jovanny Zabaleta, Liliana Lopez-Kleine, Alba L. Combita. Molecular determinants to neoadjuvant chemotherapy resistance in breast cancer patients: Insights from a Latin-American cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4632.