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

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

doi:10.3389/fonc.2023.1258365

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

Front Oncol. 2023 Nov 29:13:1258365. doi: 10.3389/fonc.2023.1258365. eCollection 2023.

Authors

Hazel Lote^{1

2}, Florentia Mousoullou³, George Vlachogiannis¹, Andrea Lampis¹, Laura Satchwell², Clare Peckitt², Caroline Fong², Ruwaida Begum², Shannon Kidd², Susan Cromarty², Anderley Gordon², Charlotte Fribbens², Sheela Rao², Naureen Starling², Ian Chau², David Cunningham², Nicola Valeri^{1

3}

Affiliations

¹ Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.
² Department of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.
³ Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom.

Abstract

Background: This study aimed to identify microRNAs (miRs) as circulating biomarkers of resistance to first-line trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.

Methods: 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 the FOrMAT (NCT02112357) and PLATFORM (NCT02678182) clinical trials. The primary endpoints were overall survival (OS) for plasma miR-148a-3p HIGH (>median) versus LOW (≤median). The secondary endpoints were progression-free survival (PFS) and 3-month progression-free rates (PFRs) miR-148a-3p HIGH versus LOW. PLATFORM sensitivity analysis normalised miR-148a-3p (NmiR-148a-3p).

Results: The 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 PFRs (n=23; OR, 0.11 [0.02-0.78]; p=0.027; aOR, 0.03 [0.001-0.71], p=0.029) but no difference in OS or PFS. There was no statistically significant relationship between miR-148-3p LOW versus HIGH for OS (PLATFORM, n=62; hazard ratio [HR], 0.98 [0.57-1.66]; p=0.933; FOrMAT, n=8; HR, 0.54 [0.13-2.31]; p=0.322), PFS (n=62; HR, 1.08 [0.65-1.81]; p=0.759; FOrMAT, n=8; HR, 1.26 [0.31-5.07]; p=0.714), or PFRs (PLATFORM, n=31; odds ratio [OR], 0.67 [0.2-2.8]; p=0.577).

Conclusion: Normalised miR-148a-3p may be a relevant biomarker for trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.

Keywords: HER2; biomarkers; gastric cancer; microRNA; oesophageal adenocarcinoma; trastuzumab.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. All authors would like to acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. HL would like to acknowledge National Health Service funding of a National Institute for Health Research Academic Clinical Fellowship, Academic Clinical Lectureship, and a Cancer Research UK Clinical Research PhD Fellowship. NV acknowledges support from Cancer Research UK (CEA A18052) and European Union FP7 (CIG 334261).