Abstract 1255: Identification of predictive biomarkers for neoadjuvant chemotherapy response in invasive breast cancer Latino patients
Authors: Guevara-Nieto Hedda Michelle , Parra-Medina Rafael , Mejia-Henao Juan Carlos , López-Correa Patricia Eugenia , Guío-Avila José Ismael , Diaz-Casas Sandra , Garai Jone , Zabaleta Jovanny , López-Kleine Liliana , Cómbita Alba Lucia 
Published: June 2022

Purpose: Breast cancer (BC) is the leading cause of morbidity and mortality in women in Colombia, constituting a major public health issue. Importantly, not all breast cancer patients respond to neoadjuvant chemotherapy (NAC), leading to an incomplete pathological response and suggesting that there are tumor characteristics that may explain the differences in response. The overarching goal of this study is to identify gene expression profiles associated with an incomplete pathological response to NAC in Colombian women with invasive BC.

Design: An integrative transcriptome analysis using Illumina high-throughput RNA sequencing was performed from 63 baseline and post-NAC (follow-up) paraffin-embedded samples from 46 different female patients with locally advanced BC (stage IIB to IIIC) treated at the Colombian National Cancer Institute. Gene expression data were obtained from 42 baseline and 21 follow-up samples. Two comparison analyses were conducted to identify differentially expressed genes (DEGs) first comparing baseline vs follow-up samples from nonresponders to NAC and second comparing to baseline samples from nonresponders vs responders to NAC. Additionally, enrichment analyses were performed in both comparative analyses.

Results: From 46 patients included, 20 had a pathological complete response (pCR), while 26 did not show pCR. By investigating the gene expression profiling, 1546 significantly DEGs and 174 DEGs were identified among non-responders and Baseline analyses, respectively. From these analyses, 24 DEGs were found in common and apoptosis as the only shared enrichment pathway (p=0.001). In both analyses, Histone associated genes were downregulated in nonresponders (Histone 3, p=0,001 and Histone 2B, p&lt;0,001). In addition, downregulation of Granzyme B and perforin were also found differentially expressed in apoptosis network pathways. CD8+ naïve T-cells, hematopoietic stem cells, Macrophages, Macrophages M1, Neurons, Th1 cells, activated dendritic cells and pro B cells were defined by the xCell algorithm and showed statistically significant association with non-response to NAC.

Conclusions: Changes in histones and tumor microenvironment cell populations elicits local immune response, which contributed to therapeutic efficacy. Downregulation of Granzyme B and perforin could block mechanism of resistance to carcinogenesis, leading to non-response to NAC. Furthermore, patients with tumors containing higher gene signatures of these DEGs may benefit from NAC. Additional validations are needed to confirm these data. If confirmed, these data may be relevant in elucidating the mechanisms that lead to therapy resistance as well as in selecting patients that will benefit from NAC in Latino (Colombian) patients.

Citation Format: Hedda Michelle Guevara-Nieto, Rafael Parra-Medina, Juan Carlos Mejia-Henao, Patricia Eugenia López-Correa, José Ismael Guío-Avila, Sandra Diaz-Casas, Jone Garai, Jovanny Zabaleta, Liliana López-Kleine, Alba Lucia Cómbita. Identification of predictive biomarkers for neoadjuvant chemotherapy response in invasive breast cancer Latino patients [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 1255.