Small cell lung cancer transformation and the T790M mutation: A case report of 2 acquired mechanisms of TKI resistance detected in a tumor rebiopsy and plasma sample of EGFR-mutant lung adenocarcinoma

Authors: Greta Alì Rossella Bruno Mirella Giordano Irene Prediletto Letizia Marconi Simonetta Zupo Franco Fedeli Alessandro Ribechini Antonio Chella Gabriella Fontanini

Affiliations: Unit of Pathological Anatomy, University Hospital of Pisa, I‑56126 Pisa, Italy, Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, I‑56126 Pisa, Italy, Unit of Pneumology, University Hospital of Pisa, I‑56124 Pisa, Italy, Unit of Molecular Diagnostics, Institute of Hospitalization and Scientific Care, National Institute for Cancer Research, I‑16132 Genova, Italy, Unit of Pathological Anatomy, Sant'Andrea Hospital, I‑19124 La Spezia, Italy, Endoscopic Section of Pneumology, University Hospital of Pisa, I‑56124 Pisa, Italy

The present study describes the case of a 45-year-old man diagnosed with metastatic lung adenocarcinoma, which harbored a deletion within exon 19 of the epidermal growth factor receptor (EGFR) gene. The patient was subsequently treated with gefitinib (250 mg/day orally from May 2013 to March 2014), but developed acquired resistance to the drug following 11 months of treatment. Tumor burden molecular analysis was performed on a tumor rebiopsy and plasma sample, and histological analysis was also performed on the tumor rebiopsy. A small cell transformation retaining the original EGFR mutation was detected in the tumor rebiopsy, while the T790M mutation together with the activating ex19del mutation were identified only in the plasma sample. The patient was treated with cytotoxic chemotherapy (off‑label schedule with epirubicin 80 mg/mq and paclitaxel 160 mg/mq every 21 days for 6 cycles) and radiation (50.4 Gy administered in 28 fractions of 1.8 Gy once daily for 5.5 weeks) specific for small cell lung cancer, and may also have benefitted from treatment with a third generation T790M‑specific EGFR‑TKI. To better describe the mechanisms of resistance to TKI inhibitors and to optimize therapeutic regimens, the simultaneous analysis of tumor biopsies and circulating tumor DNA should be considered.

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