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

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 ( = 0.12), but was significantly associated with worse progression-free survival (PFS) and overall survival following osimertinib treatment ( = 0.026,  = 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 ( = 0.65), but was significantly associated with worse PFS and showed a trend towards worse overall survival following osimertinib treatment ( < 0.001,  = 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, -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.