Pang Lanlan, Zhuang Weitao, Huang Yihua, Liao Jun, Yang Mengjuan, Zhang Li, Zhang Yaxiong, Fang Wenfeng
Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
J Natl Cancer Cent. 2024 Dec 17;5(1):75-81. doi: 10.1016/j.jncc.2024.12.005. eCollection 2025 Feb.
Phenotypic transition is a common resistance mechanism of targeted therapy. While transformations from lung adenocarcinoma (LUAD) to small-cell lung cancer or squamous-cell carcinoma have been extensively studied, the conversion into sarcomatoid carcinoma (SC) is rarely reported.
Genetic and histological examinations were systematically performed on tumor re-biopsy samples obtained from patients with advanced EGFR-mutant LUAD who progressed on EGFR-tyrosine kinase inhibitors (TKIs). EGFR wild-type patients were also identified who underwent the rare transformation from adenocarcinoma to SC following the ineffectiveness of inhibitors that target distinct driver oncogenes. Furthermore, we also retrospectively collected 42 cases diagnosed with primary pulmonary SC as a comparison cohort to comprehensively characterize the biological events and clinical outcomes of transformed SC.
The sarcomatoid transformation mediated drug resistance in 2.5 % and 4.8 % of patients after failure on the first/second, and third-generation EGFR-TKIs. Transformation of sarcomatoid carcinoma is characterized by a higher frequency of , and genetic alterations compared to cases lacking histological transformation; the PI3K signaling pathway was also significantly activated. Fifteen individuals were identified with a rare transition from adenocarcinoma to SC, consisting of seven cases with -activating mutations and eight cases without mutations. All sarcomatoid-transformed samples not only retained their original driver mutations but also shared specific genetic alterations with primary LUAD. Moreover, transformed sarcomatoid carcinomas mimic the primary SC in terms of immunochemical and molecular features.
The transformation from lung adenocarcinoma to SC is a resistance mechanism wildly applied to inhibitors targeting different driver oncogenes. Immunotherapy plus chemotherapy shows potential to benefit patients with sarcomatoid transformation and warrants further study in larger cohorts.
表型转变是靶向治疗常见的耐药机制。虽然肺腺癌（LUAD）向小细胞肺癌或鳞状细胞癌的转变已得到广泛研究，但向肉瘤样癌（SC）的转化鲜有报道。
对晚期EGFR突变型LUAD患者在接受EGFR酪氨酸激酶抑制剂（TKIs）治疗后病情进展时获得的肿瘤重新活检样本进行系统的基因和组织学检查。还鉴定了EGFR野生型患者，他们在针对不同驱动癌基因的抑制剂无效后经历了从腺癌到SC的罕见转变。此外，我们还回顾性收集了42例诊断为原发性肺SC的病例作为对照队列，以全面描述转化型SC的生物学事件和临床结局。
肉瘤样转化在第一代/第二代和第三代EGFR-TKIs治疗失败后的患者中分别介导了2.5%和4.8%的耐药。与无组织学转化的病例相比，肉瘤样癌的转化具有更高频率的 、 和 基因改变；PI3K信号通路也被显著激活。鉴定出15例从腺癌到SC的罕见转变个体，其中7例有 -激活突变，8例无 突变。所有肉瘤样转化样本不仅保留了其原始驱动突变，还与原发性LUAD共享特定的基因改变。此外，转化后的肉瘤样癌在免疫化学和分子特征方面与原发性SC相似。
肺腺癌向SC的转化是一种广泛应用于针对不同驱动癌基因的抑制剂的耐药机制。免疫治疗联合化疗显示有可能使肉瘤样转化患者受益，值得在更大队列中进一步研究。
