肿瘤相关成纤维细胞的固体优势组织学和高Podoplanin表达可预测egfr突变肺腺癌患者对奥西替尼的原发性耐药

IF 3 Q2 ONCOLOGY

JTO Clinical and Research Reports Pub Date : 2024-12-18 DOI:10.1016/j.jtocrr.2024.100779

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

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引用次数: 0

摘要

对EGFR酪氨酸激酶抑制剂的耐药性受肿瘤内源性和外源性因素的影响。我们研究了肿瘤细胞组织学和肿瘤微环境对奥希替尼疗效的影响。方法：我们评估了2016-2023年在国家癌症中心东医院接受一线奥西替尼治疗的手术切除腺癌患者的临床病理特征、肿瘤细胞组织学、免疫组织化学鉴定的癌症相关成纤维细胞（CAFs）中podoplanin的表达和结果。我们还研究了HGF mRNA表达水平，使用癌症基因组图谱计划和新加坡肿瘤数据门户队列。结果纳入93例患者。实性组织学（n = 19）与非实性组织学（n = 74）与手术后较差的无病生存无关（p = 0.12），但与奥西替尼治疗后较差的无进展生存（PFS）和总生存显著相关（p = 0.026, p = 0.004）。同样，CAFs中高podoplanin （n = 31）与低podoplanin （n = 62）表达与术后更差的无病生存无关（p = 0.65），但与更差的PFS显著相关，并且在奥西替尼治疗后显示出更差的总生存趋势(p <；0.001, p = 0.11)。在多变量分析中，CAFs中坚实的主要组织学和高podoplanin表达与较差的PFS独立相关。在癌症基因组图谱计划和新加坡肿瘤数据门户网站的队列中，具有坚实主导组织学或高podoplanin表达的egfr突变肺腺癌表现出显著更高的HGF表达。结论CAFs中坚实的组织学优势和高podoplanin表达预测了奥西替尼耐药性，可能指导患者选择在奥西替尼单药治疗之外进行更强化的治疗。

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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 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.

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