Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung Adenocarcinoma

Abstract

Introduction

Resistance to EGFR tyrosine kinase inhibitors is influenced by tumor-intrinsic and -extrinsic factors. We investigated the impact of tumor cell histology and tumor microenvironment on the efficacy of osimertinib.

Methods

We evaluated surgically resected adenocarcinoma from patients treated with first-line osimertinib at the National Cancer Center Hospital East (2016–2023), evaluating clinicopathologic characteristics, tumor cell histology, podoplanin expression in cancer-associated fibroblasts (CAFs) identified by immunohistochemistry, and outcomes. We also investigated HGF mRNA expression levels, using The Cancer Genome Atlas Program and Singapore Oncology Data Portal cohorts.

Results

The study included 93 patients. Solid (n = 19) versus non-solid predominant (n = 74) histology was not associated with worse disease-free survival after surgery (p = 0.12), but was significantly associated with worse progression-free survival (PFS) and overall survival following osimertinib treatment (p = 0.026, p = 0.004). Similarly, high-podoplanin (n = 31) versus low-podoplanin (n = 62) expression in CAFs was not associated with worse disease-free survival after surgery (p = 0.65), but was significantly associated with worse PFS and showed a trend towards worse overall survival following osimertinib treatment (p < 0.001, p = 0.11). In the multivariable analysis, solid predominant histology and high-podoplanin expression in CAFs were independently associated with worse PFS. In the cohorts of The Cancer Genome Atlas Program and Singapore Oncology Data Portal, EGFR-mutated lung adenocarcinoma with solid predominant histology or high-podoplanin expression exhibited significantly higher HGF expression.

Conclusions

Solid predominant histology and high-podoplanin expression in CAFs predicted osimertinib resistance, potentially guiding the selection of patients for more intensive treatments beyond osimertinib monotherapy.