Abstract 1563P
Background
Effective treatment of esophageal adenocarcinoma (EAC) is hampered by a high degree of mesenchymal plasticity that contributes to acquired therapy resistance and disease recurrence. Many trials are or have been investigating new treatments, such as additional epidermal growth factor signaling inhibition, to improve patient outcome. However, patient selection methods are limited. The existence of a tissue-level molecular subtype that could be used to stratify patients has remained elusive, in large part due to an abundance of non-tumor cells confounding bulk gene expression data.
Methods
We profiled gene expression from 186 esophageal cancer samples and applied non-negative matrix factorization to identify tumor-intrinsic features. Subgroups were discovered using consensus clustering of the tumor-intrinsic gene expression signatures and single-nucleus RNA sequencing analysis.
Results
Two subtypes were identified; intestinal-like (IL) and mesenchymal-like (ML). The latter enriched following neoadjuvant treatment and during disease progression. In a separate cohort of RNA-sequenced metastatic EAC, the ML subtype was found to predict poor response to treatment. Conversely, IL subtype cancer cells were highly dependent on epidermal growth factor signalling, and sensitive to receptor tyrosine kinase inhibition. Mechanisms behind the dependence on epidermal growth factor signalling are currently elucidated using comprehensive analyses.
Conclusions
Targeting of epidermal growth factor signaling is currently only available for HER2-positive patients, about 15% of all cases. Based on our tumor-intrinsic subtypes, a larger fraction of EAC patients seem to benefit from epidermal growth factor inhibition. Therefore, the ability to assign subtype labels in the clinic will be an important step forward to identify patients who may benefit from additional epidermal growth factor inhibition.
Clinical trial identification
NCT05188313.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
KWF.
Disclosure
H.W.M. van Laarhoven: Financial Interests, Institutional, Advisory Board: BMS, MSD; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Institutional, Writing Engagement: Nordic Pharma; Financial Interests, Institutional, Invited Speaker: Servier; Financial Interests, Institutional, Research Grant, REPEAT study: Bayer; Financial Interests, Institutional, Research Grant: BMS, Philips; Financial Interests, Institutional, Local PI, FRACTION study: BMS; Financial Interests, Institutional, Research Grant, ACTION study: Celgene; Financial Interests, Institutional, Research Grant, DECO study: Janssen; Financial Interests, Institutional, Local PI, RAINFALL study: Lilly; Financial Interests, Institutional, Local PI, KEYNOTE 062 and KEYNOTE 181 study: Merck/MSD; Financial Interests, Institutional, Research Grant, SOX study: Nordic Pharma; Financial Interests, Institutional, Research Grant, TRAP study, PERFECT study; local PI of JACOB study: Roche; Financial Interests, Institutional, Research Grant, LyRICX study: Servier; Financial Interests, Institutional, Research Grant, TAPESTRY study: Merck; Financial Interests, Institutional, Research Grant, Research money and investigational product: Incyte; Non-Financial Interests, Institutional, Product Samples, For all clinical study mentioned, study medication is provided: See 'research funding'. M.F. Bijlsma: Financial Interests, Institutional, Other, Consultant: Servier; Financial Interests, Institutional, Funding: Celgene, Lead Pharma. All other authors have declared no conflicts of interest.
Resources from the same session
1498P - HGF/MET pathway is associated with poor efficacy of Immune checkpoint inhibitors (ICIs) in advanced-stage NSCLC
Presenter: Assya Akli
Session: Poster session 21
1499P - Wnt5-ROR2 signalling mediated resistance to immune checkpoint inhibitors in advanced non-small cell lung cancer
Presenter: Etienne Giroux-Leprieur
Session: Poster session 21
1500TiP - REFINE-Lung is a multicentre phase III study to determine the optimal frequency of pembrolizumab in non-small cell lung cancer utilising a novel multi-arm design
Presenter: Ehsan Ghorani
Session: Poster session 21
1502TiP - A phase I/IIa trial of ChAdOx1 and MVA vaccines against MAGE-A3 and NY-ESO-1
Presenter: Fiona Blackhall
Session: Poster session 21
1503TiP - A phase II study of cemiplimab plus BNT116 versus cemiplimab alone in first-line treatment of patients with advanced non-small cell lung cancer with PD-L1 expression ≥50%
Presenter: Mark Awad
Session: Poster session 21
1504TiP - HARMONi: Randomized, double-blind, multi-center, phase III clinical study of ivonescimab or placebo combined with pemetrexed and carboplatin in patients with EGFR-mutant locally advanced or metastatic non-squamous NSCLC who have progression following EGFR-TKI treatment
Presenter: WenFeng Fang
Session: Poster session 21
1505TiP - TROPION-Lung07: A phase III trial of datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy in advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC) with PD-L1 expression
Presenter: Isamu Okamoto
Session: Poster session 21
1506TiP - A single-arm, phase II study of amivantamab (AMI), lazertinib (L) and pemetrexed (P) for first-line treatment of recurrent/metastatic non-small cell lung cancers (NSCLCS) with epidermal growth factor receptor mutations in Exons 19 or 21 (EGFR 19/21): AMIGO 1 (LACOG0821)
Presenter: William Nassib William Junior
Session: Poster session 21
1507TiP - Phase Ib multicenter study of trastuzumab deruxtecan (T-DXd) and immunotherapy with or without chemotherapy in first-line treatment of patients (pts) with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) and HER2 overexpression (OE): DESTINY-Lung03
Presenter: David Planchard
Session: Poster session 21