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Resistance to EGFR tyrosin kinase inhibitors (TKI) inevitably occurs. Here it is reported the case of a young patient affected by lung adenocarcinoma harboring the L858R EGFR sensitive mutation. The patient developed multiple TKI resistance mechanisms: T790M EGFR resistance mutation, detected only on tumor cell-free DNA, squamous cell transformation and MET amplification, both detected on a tumor re-biopsy. The co-occurrence of squamous cell transformation and de novo MET amplification is an extremely rare event, and this case confirms how dynamic and heterogeneous can be the temporal and spatial tumor evolution under treatment pressure.

Resistance to EGFR tyrosin kinase inhibitors (TKI) inevitably occurs. Here it is reported the case of a young patient affected by lung adenocarcinoma harboring the L858R EGFR sensitive mutation. The patient developed multiple TKI resistance mechanisms: T790M EGFR resistance mutation, detected only on tumor cell-free DNA, squamous cell transformation and MET amplification, both detected on a tumor re-biopsy. The co-occurrence of squamous cell transformation and de novo MET amplification is an extremely rare event, and this case confirms how dynamic and heterogeneous can be the temporal and spatial tumor evolution under treatment pressure. [ABSTRACT FROM AUTHOR]

Pathological transformation to squamous cell carcinoma after epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor treatment has been reported, but details of the transformation remain unclear. We report two cases with transformation to squamous cell carcinoma. The first case was a 61‐year‐old man who was an ex‐smoker with stage IV lung adenocarcinoma harbouring EGFR exon 19 insertion. He experienced squamous cell transformation after 28 months of erlotinib therapy. Next‐generation sequencing (NGS) analysis showed EGFR T790M and genomic alterations in PTEN, PDGFR, and HRAS. The second case was a 72‐year‐old man who was an ex‐smoker with stage IV lung adenocarcinoma harbouring EGFR exon 21 L858R. He experienced squamous cell transformation after nine months of erlotinib therapy. NGS analysis showed EGFR T790M and genomic alterations in PTEN, SMARCB1, TP53, and KIT. Both patients had PTEN genomic alterations and the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway might play an important role in squamous cell transformation.

We herein report a case of squamous cell transformation combined with the epidermal growth factor receptor (EGFR) mutation T790M associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in a 73-year-old male patient diagnosed with stage IVA lung adenocarcinoma. Gene alterations were analyzed by collecting and studying pleural effusion at the time of diagnosis. Examination revealed an exon 19 deletion in the EGFR gene. Following treatment with the second-generation EGFR-TKI afatinib, squamous cell carcinoma was identified by performing a re-biopsy of the recurrent site. Although the levels of cytokeratin 19 fragment, which is a tumor marker for the follow-up of squamous cell carcinoma, were increased at that point, the levels of carcinoembryonic antigen, a marker particularly associated with adenocarcinoma, remained within normal limits. The T790M mutation and the original exon 19 deletion were detected simultaneously. The patient received treatment with the third-generation EGFR-TKI osimertinib, achieving a good clinical response. These findings suggest that osimertinib is beneficial for lung adenocarcinoma patients with squamous cell transformation harboring the T790M mutation. [ABSTRACT FROM AUTHOR]