Abstract P1-04-18: Identification of UGT2B family genes as potential biomarkers of response to neoadjuvant therapy in HER2+ breast cancer

Abstract INTRODUCTION Human Epidermal Growth Factor Receptor (HER2) is overexpressed and/or amplified in 15-20% of breast cancer at time of first diagnosis and is associated with an aggressive clinical progression disease. Management of HER2+ early breast cancer, include a combination of sequential chemotherapy and HER2-targeted therapy, which is currently the gold standard of care. Achieving pathological complete response (pCR) to after neoadjuvant therapy has been proposed as a prognostic marker for the prediction of disease-free survival (DFS). Although there are different criteria to define pCR, in general pathological complete response is the absence of residual disease in breast and lymph nodes in the pathology analysis of the surgical piece resection (ypTo/is ypN0). However, there is a compelling need to identify molecular biomarkers that will help determine which patients will benefit from neoadjuvant therapy. Considering that the UGT2B family plays an important role in drug metabolism, our aim is to analyze its role as potential predictive biomarkers of pCR to neoadjuvant therapy in breast cancer. METHODS We included 18 female patients diagnosed as early breast cancer HER2+ at the time of neoadjuvant treatment. Tissue samples were obtained from the surgical resection performed at Virgen del Rocio Hospital (Seville, Spain) and were formalin-fixed paraffin-embedded (FFPE) to subsequently carry out the pertinent analyses of the study. All patients were treated with chemotherapy plus anti-HER2-targeted therapy and were stratified according to response to neoadjuvant treatment. We defined two groups: responder (R; RCB-0; n=14) and non-responder (NR; RCB-II/III; n=4). Total RNA from FFPE tissue was extracted using the RecoverAll Total Nucleic Acid Isolation commercial kit (Ambion, Austin, TX, USA) following the manufacturer’s instructions. RNA concentration was measured using the NanoDrop ND-1000 spectrophotometer (Nanodrop Tech, DE, USA). A total of 18 samples were labeled and hybridized with a Clariom D pico Array microarray (Affymetrix, Santa Clara, CA, USA) following the manufacturer’s instructions. Differences in expressed genes according to response were identified using the Mann–Whitney U test where p -values. < 0.05 were considered significant and ROC curve was used to determine predictor value of complete response for each member of UGT2 family. Differential expression between the two groups was analyzed using the statistical packages SPSS version 28 and R 4.1.1.1. Statistical significance was established for p-values ​​< 0.05 and fold change ≥ 2 RESULTS We found 954 differentially expressed transcripts: 311 downregulated transcripts (lower expression in R) and 643 upregulated transcripts (higher expression in R). Our data showed a significant upregulation in 5 genes of the UGT2B family in non-responder patients (p-value< 0.05). 3 genes of the UGT2b family showed an acceptable ability to discriminate responders and non-responders to neoadjuvant treatment of HER2-positive in the ROC (receiver operating characteristic curve) analysis. CONCLUSIONS We identified a set of transcript differentially expressed (FC>2; adjusted p-value< 0.05) in patients with residual disease (nR) when compared with tissue samples in patients that achieve pCR (R). UGT2B family genes are consistently upregulated in non-responder patients. UGT2B genes encode enzymes involved in glucuronidation. They are phase II drug-metabolizing enzymes with steroids removal capabilities in the liver and various steroid target tissues. An increased rate of glucuronidation is been associated with a loss of potency for the target drugs. These genes would be used as predictive biomarkers of pCR to neoadjuvant therapy in breast cancer. Citation Format: Ana Gil-Torralvo, Marta Benavent, Maria A Dominguez-Cejudo, Alejandro Falcon, Mónica Cejuela, Begoña Vieites, Sonia Molina-Pinelo, Manuel Ruiz Borrego, Juan de la Haba-Rodríguez, Maria I Queipo, Francisco Javier Salvador Bofill. Identification of UGT2B family genes as potential biomarkers of response to neoadjuvant therapy in HER2+ 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 P1-04-18.