Abstract P2-07-08: Identification of UGT2B15 as a potential biomarker in response to neoadjuvant therapy in HER2+ breast cancer

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Abstract INTRODUCTION. In response to neoadjuvant therapy, pathological complete response (pCR; lack of residual disease in breast and lymph nodes), has been proposed as a prognostic marker for long-term clinical outcomes, such as disease-free (DFS) and overall survival (OS), in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer. In clinical practice, recognizing those patients likely to achieve such responses proves challenging to the oncologist, making the identification of new useful biomarkers vital. Here, we searched for potential biomarkers that anticipate pCR to neoadjuvant therapy in HER2-positive, hormone receptor-negative breast cancer tissue samples. METHODS. Patients with early and locally advanced breast cancer, diagnose as HER2-positive, hormone receptor-negative by immunohistochemistry (IHC) at the time of neoadjuvant treatment were included. All samples were collected from biobank at Hospital Universitario Virgen del Rocio. We defined two groups: responder (R) and non-responder (nR) and analyzed 18 samples in the discovery cohort (10 R vs 8 nR) and 12 samples in the validation cohort (6 R vs 6 nR).The RNA for the study was extracted from tissue fixed in formaldehyde and paraffin embedded. The extraction of the RNA was carried out using the commercial kit RecoverAll Total Nucleic Acid Isolation Kit from Ambion (Applied Biosystems). RNA was quantified by Qubit RNA HS Assay Kit (Molecular Probes). Before hybridization, RNA for the discovery cohort was amplified using GeneChip WT Pico Kit (Applied Biosystems).We analyzed transcript expression using ClariomD array. Differential expression between the two groups was analyzed using in-house R scripts (version 3.5.1). Data were corrected and normalized using Robust Multi-array Average method. Expression was summarized at gene level using the corresponding annotation for ClariomD BrainArray. Gene validation was performed by qPCR using TaqMan Gene Expression Assay (Applied Biosystem). RESULTS. Considering a fold change ≥ 2 and an adjusted p-value <0.05 as statistically significant, we found 53 differentially expressed transcripts: 51 downregulated transcripts (lower expression in R) and 2 upregulated transcripts (higher expression in R). The RNA was annotated as non-coding RNAs in over 25% of the cases. The distribution of such molecules was as followed: 8 long non-coding RNAs (56%); 3 non-coding RNAs (22%) and 3 pseudo-genes (22%). Regarding protein coding transcripts, gene ontology analysis revealed an enrichment of terms associated to metabolic processes and response to toxic substance.As expected, ERBB2, which encodes for HER2, appeared at the top of the list with a patent upregulation of expression in the responder group when compared with non-responder patients. To validate the data, we used qPCR and ERBB2 expression as a positive control of the results (p-value=0.0380). Our data showed a significant downregulation of UDP-glucuronosyltransferase 2B15 (UGT2B15; p-value= 0.0173), which encodes a glycosyltransferase, involved in the metabolism and elimination of toxic compounds. CONCLUSIONS. The ability to predict which patients will benefit from neoadjuvant therapy and achieve a pCR would allow for improved patient stratification and more personalized medicine. Here, we identified a set of transcript differentially expressed (FC>2; adjusted p-value<0.05) in patients that achieve pCR (R) when compared with tissue samples with residual disease (nR). We usedERBB2 expression as a positive control to validate the data and show that UGT2B15 is consistently upregulated in non-responder patients. Further work is needed to elucidate UGT2B15 role, but it is worth mentioning that an increased rate of glucuronidation has been associated with a loss of potency for the target drugs. Citation Format: Ana Gil-Torralvo, Marta Benavent, Maria A Dominguez-Cejudo, Alejandro Falcon, Begoña Vieites, Sonia Molina-Pinela, Manuel Ruiz, Álvaro Montaño, Rosario Gónzalez, Julia Martínez, Juan de la Haba, Antonio Rodríguez, Maria I Queipo, Begoña Jímenez, Javier Salvador-Bofill. Identification of UGT2B15 as a potential biomarker in response to neoadjuvant therapy in HER2+ breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-08.

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