Abstract P5-02-37: Multi-omics approach to identify markers of resistance to endocrine therapy + CDK4/6 inhibitors in first line HR+/HER2- metastatic breast cancer (MBC) patients
Authors: FRENEL Jean Sebastien , Azzouz Fadoua Ben , Bigot Frederic , Dauve Jonathan , Heymann Marie Francoise , Gouraud Wilfried , Guette Catherine , Lasla Hamza , Michel Bertrand , Morel Alain , Patsouris Anne , Robert Marie , Siekaniec Grégoire , Colombie Mathilde , Jézéquel Pascal , Campone Mario 
Published: March 2023

Abstract
CONTEXT: Endocrine therapy combined with CDK4/6 inhibitor is the standard frontline treatment for the vast majority of HR+/HER2- MBC patients. Despite an overall survival benefit, patients eventually progress and mechanisms of resistance to this combination are not well identified. METHODS: EPICURE is an ongoing pilot prospective cohort study of heterogeneous and massive data integration, ie. multi-omics approach in MBC patients. The present study aims at identifying progression markers in patients with HR+/HER2- MBC receiving frontline endocrine therapy+iCDK4/6 by means of transcriptomics, genomics and proteomics data. All patients had a tumor biopsy at the entry in the study (B1) and a biopsy was repeated at progression if feasible (B2). Transcriptomic (RNAseq: NextSeq550, Illumina), genomic (whole exome sequencing: NextSeq550, Illumina) and proteomic (DIA mass spectrometry: TimsTOFPro2, Bruker) were performed on B1 and B2 according to available tumor tissue. RESULTS: Fifty-one patients matching inclusion criteria were included. B1 was done at inclusion for all patients (B1) (n = 51) and B2 was performed in 8 patients. (B2) (n = 8). Eight metastatic sites were biopsied: node (n = 17); liver (n = 16); bone (n = 8); breast local recurrence (n = 5); chest wall (n = 5); skin (n = 4); pleural (n = 3); ovary (n = 1). Transcriptomic, genomic and proteomic analysis of paired biopsies (B1 and B2) was performed in parallel and separately for 8, 7 and 2 patients, respectively. Exploratory data analysis of transcriptomic and proteomic data showed that liver biopsies clustered together. In order to eliminate this anatomic bias, specific genes and proteins of liver metastases were identified by means of DESeq2 analysis (12 liver vs 39 other sites) for transcriptomic data (n = 2654) and LIMMA (4 liver vs 14 other sites) for proteomic data (n = 227), and excluded for the rest of the analysis. Differential analyses (ie. gene expression, non-synonymous mutations and protein expression) between B1 and B2 were performed for each patient. These three kind of lists were finally submitted to ToppGene, DAVID and GOrilla for Gene Ontology terms enrichment analyses. Transcriptomic analyses of the 8 paired biopsies highlighted immune response (IR) in seven B1, IR in four B2 and neurogenesis in three B2. Genomics data evaluation between B1 and B2 pointed out “transposon integration” as an important pathway. Proteomic data of the 2 paired biopsies analysed underlined high immune response in B1, and muscle development/contraction and response to tumor necrosis factor in B2 for one patient. For the second one, liver metabolism in B1 and extracellular matrix and p38 MAPK cascade were emphasised. CONCLUSION: This preliminary study based on transcriptomic, genomic and proteomic data represents an encouraging first step of the EPICURE project. In a near future, additional paired biopsies and other kinds of omics data (epigenetics, radiomics, microbiomics, exposomics) will be available. Furthermore, omics data will be analysed in an integrated manner (ie. artificial intelligence), which will make it possible to detect synergies across the different omics data.
Citation Format: Jean Sebastien FRENEL, Fadoua Ben Azzouz, Frederic Bigot, Jonathan Dauve, Marie Francoise Heymann, Wilfried Gouraud, Catherine Guette, Hamza Lasla, Bertrand Michel, Alain Morel, Anne Patsouris, Marie Robert, Grégoire Siekaniec, Mathilde Colombie, Pascal Jézéquel, Mario Campone. Multi-omics approach to identify markers of resistance to endocrine therapy + CDK4/6 inhibitors in first line HR+/HER2- metastatic breast cancer (MBC) patients. [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 P5-02-37.