Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-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 tr...
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Elsevier
2025-03-01
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| Series: | JTO Clinical and Research Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666364324001498 |
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| author | Yuji Uehara, MD Hiroki Izumi, MD, PhD Tetsuro Taki, MD, PhD Tetsuya Sakai, MD, PhD Hibiki Udagawa, MD, PhD Eri Sugiyama, MD, PhD Shigeki Umemura, MD, PhD Yoshitaka Zenke, MD, PhD Shingo Matsumoto, MD, PhD Kiyotaka Yoh, MD, PhD Shoko Kubota, MD, PhD Keiju Aokage, MD, PhD Naoya Sakamoto, MD, PhD Shingo Sakashita, MD, PhD Motohiro Kojima, MD, PhD Michiko Nagamine, MD, PhD Yukio Hosomi, MD, PhD Masahiro Tsuboi, MD, PhD Koichi Goto, MD, PhD Genichiro Ishii, MD, PhD |
| author_facet | Yuji Uehara, MD Hiroki Izumi, MD, PhD Tetsuro Taki, MD, PhD Tetsuya Sakai, MD, PhD Hibiki Udagawa, MD, PhD Eri Sugiyama, MD, PhD Shigeki Umemura, MD, PhD Yoshitaka Zenke, MD, PhD Shingo Matsumoto, MD, PhD Kiyotaka Yoh, MD, PhD Shoko Kubota, MD, PhD Keiju Aokage, MD, PhD Naoya Sakamoto, MD, PhD Shingo Sakashita, MD, PhD Motohiro Kojima, MD, PhD Michiko Nagamine, MD, PhD Yukio Hosomi, MD, PhD Masahiro Tsuboi, MD, PhD Koichi Goto, MD, PhD Genichiro Ishii, MD, PhD |
| author_sort | Yuji Uehara, MD |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-43b3efbd1ded427bb4b931c2e0bb7030 |
| institution | Kabale University |
| issn | 2666-3643 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JTO Clinical and Research Reports |
| spelling | doaj-art-43b3efbd1ded427bb4b931c2e0bb70302025-02-09T05:01:28ZengElsevierJTO Clinical and Research Reports2666-36432025-03-0163100779Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung AdenocarcinomaYuji Uehara, MD0Hiroki Izumi, MD, PhD1Tetsuro Taki, MD, PhD2Tetsuya Sakai, MD, PhD3Hibiki Udagawa, MD, PhD4Eri Sugiyama, MD, PhD5Shigeki Umemura, MD, PhD6Yoshitaka Zenke, MD, PhD7Shingo Matsumoto, MD, PhD8Kiyotaka Yoh, MD, PhD9Shoko Kubota, MD, PhD10Keiju Aokage, MD, PhD11Naoya Sakamoto, MD, PhD12Shingo Sakashita, MD, PhD13Motohiro Kojima, MD, PhD14Michiko Nagamine, MD, PhD15Yukio Hosomi, MD, PhD16Masahiro Tsuboi, MD, PhD17Koichi Goto, MD, PhD18Genichiro Ishii, MD, PhD19Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan; Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, JapanDepartment of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, JapanDepartment of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JapanDepartment of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan; Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan; Corresponding author. Address for correspondence: Genichiro Ishii, MD, PhD, Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan.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.http://www.sciencedirect.com/science/article/pii/S2666364324001498Solid predominant subtypeLung adenocarcinomaEGFR mutationCancer associated fibroblasts (CAFs)Podoplanin |
| spellingShingle | Yuji Uehara, MD Hiroki Izumi, MD, PhD Tetsuro Taki, MD, PhD Tetsuya Sakai, MD, PhD Hibiki Udagawa, MD, PhD Eri Sugiyama, MD, PhD Shigeki Umemura, MD, PhD Yoshitaka Zenke, MD, PhD Shingo Matsumoto, MD, PhD Kiyotaka Yoh, MD, PhD Shoko Kubota, MD, PhD Keiju Aokage, MD, PhD Naoya Sakamoto, MD, PhD Shingo Sakashita, MD, PhD Motohiro Kojima, MD, PhD Michiko Nagamine, MD, PhD Yukio Hosomi, MD, PhD Masahiro Tsuboi, MD, PhD Koichi Goto, MD, PhD Genichiro Ishii, MD, PhD Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung Adenocarcinoma JTO Clinical and Research Reports Solid predominant subtype Lung adenocarcinoma EGFR mutation Cancer associated fibroblasts (CAFs) Podoplanin |
| title | Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung Adenocarcinoma |
| title_full | Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung Adenocarcinoma |
| title_fullStr | Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung Adenocarcinoma |
| title_full_unstemmed | Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung Adenocarcinoma |
| title_short | Solid Predominant Histology and High Podoplanin Expression in Cancer-Associated Fibroblast Predict Primary Resistance to Osimertinib in EGFR-Mutated Lung Adenocarcinoma |
| title_sort | solid predominant histology and high podoplanin expression in cancer associated fibroblast predict primary resistance to osimertinib in egfr mutated lung adenocarcinoma |
| topic | Solid predominant subtype Lung adenocarcinoma EGFR mutation Cancer associated fibroblasts (CAFs) Podoplanin |
| url | http://www.sciencedirect.com/science/article/pii/S2666364324001498 |
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