AUTHOR=Lote Hazel , Mousoullou Florentia , Vlachogiannis George , Lampis Andrea , Satchwell Laura , Peckitt Clare , Fong Caroline , Begum Ruwaida , Kidd Shannon , Cromarty Susan , Gordon Anderley , Fribbens Charlotte , Rao Sheela , Starling Naureen , Chau Ian , Cunningham David , Valeri Nicola 

TITLE=MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients

JOURNAL=Frontiers in Oncology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1258365

DOI=10.3389/fonc.2023.1258365

ISSN=2234-943X

ABSTRACT=This study aimed to identify microRNAs (miRs) as circulating biomarkers of resistance to firstline trastuzumab-based therapy in advanced HER2 positive oesophago-gastric cancer patients.A high-throughput 1015 Exiqon miRCURY LNA™ microRNA inhibitor library screen was performed in trastuzumab-treated HER2 positive NCI-N87 and HER2 negative FLO-1 oesophago-gastric cancer cell lines. NanoString nCounter ® miR analysis was performed in NCI-N87, FLO-1 and MAGIC trial (ISRCTN93793971) formalin-fixed paraffin-embedded (FFPE) oesophago-gastric cancer patient samples.MiR-148a-3p copies in plasma samples were quantified using Digital Droplet Polymerase Chain Reaction (ddPCR) from HER2 positive oesophago-gastric cancer patients treated with standard-of-care trastuzumab-based therapy within FOrMAT (NCT02112357) and PLATFORM (NCT02678182) clinical trials. Primary endpoints were overall survival (OS) plasma miR-148a-3p HIGH (>median) versus LOW (≤median); secondary endpoints were progression-free survival (PFS) and 3-month progression-free rates (PFR) miR-148a-3p HIGH versus LOW. PLATFORM sensitivity analysis normalised miR-148a-3p (NmiR-148a-3p).Inhibition of miR-148a-3p reduced NCI-N87 relative cell viability (<0.6) and expression was high (>242) in NCI-N87 and HER2 positive MAGIC trial patients (n=5).Normalised-miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in 3-month PFR (n=23, OR=0.