Rare transformation from lung adenocarcinoma to sarcomatoid carcinoma mediates resistance to inhibitors targeting different driver oncogenes.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.