Case report and literature review: histologic transformation from EGFR-mutant lung adenocarcinoma to squamous cell carcinoma with newly detected SMAD4 and ATM variants

Background Adenocarcinoma-to-squamous cell carcinoma transdifferentiation (AST) is an uncommon but clinically important form of histologic evolution in EGFR-mutant lung adenocarcinoma. Its underlying molecular mechanisms remain incompletely understood. Longitudinal genomic profiling may help characterize molecular alterations accompanying lineage transdifferentiation. Case presentation A 60-year-old woman with lung adenocarcinoma previously underwent surgical resection, and molecular testing identified an EGFR exon 19 deletion (EGFR 19del). After multiple lines of EGFR tyrosine kinase inhibitors and systemic therapy, she developed pleural recurrence. Repeat biopsy revealed a squamous phenotype, with positive p40 and CK5/6 staining and loss of TTF-1 and Napsin A expression, supporting AST. Longitudinal next-generation sequencing (NGS) showed that EGFR 19del and a TP53 p.R175H mutation were present both at baseline and after transformation, whereas SMAD4 p.D351V and ATM p.E1139K variants were newly detected only in the post-transformation tumor. After transformation, the patient received carboplatin, nab-paclitaxel, and tislelizumab and achieved a partial response. Conclusion We report a case of AST after multiple lines of therapy in a patient with EGFR-mutant lung adenocarcinoma and summarize potential molecular mechanisms and treatment developments in AST. Longitudinal NGS identified SMAD4 p.D351V and ATM p.E1139K variants in the post-transformation tumor. Functional evidence suggests that SMAD4 p.D351V may impair SMAD4-dependent BMP/TGF-β signaling, whereas the functional significance of ATM p.E1139K remains unclear. Further studies are needed to determine whether either variant contributes to AST.