Features of Tumor-Microenvironment Images Predict Targeted Therapy Survival Benefit in Patients With EGFR-Mutant Lung Cancer

Authors

Shidan Wang
Ruichen Rong
Donghan M Yang
Junya Fujimoto
Justin A Bishop
Shirley Yan
Ling Cai
Carmen Behrens
Lynne D Berry
Clare Wilhelm
Dara Aisner
Lynette Sholl
Bruce E Johnson
David J Kwiatkowski
Ignacio I Wistuba
Paul A Bunn
John Minna
Guanghua Xiao
Mark G Kris
Yang Xie

Publication Date

1-17-2023

Journal

Journal of Clinical Investigation

Abstract

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.

Keywords

Humans, Phosphatidylinositol 3-Kinases, Tumor Microenvironment, Protein Kinase Inhibitors, Lung Neoplasms, ErbB Receptors, Drug Resistance, Neoplasm, Mutation, Lung Cancer, Oncology

DOI

\10.1172/JCI160330

PMID

36647832

PMCID

PMC9843059

PubMedCentral® Posted Date

1-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes