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

Abstract

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.

Keywords: circulating free tumor DNA; epidermal growth factor receptor T790M mutation; epidermal growth factor receptor/tyrosine kinase inhibitor-acquired resistance; lung adenocarcinoma; small cell carcinoma transformation.

Figure 1.

(A) Presence of lung adenocarcinoma in the bronchial biopsy (staining, hematoxylin and eosin). (B) Immunohistochemical staining of thyroid transcription factor 1 demonstrating strong nuclear expression in neoplastic cells. (C) Presence of small cell lung cancer in a computed tomography-guided biopsy (staining, hematoxylin and eosin) (D) with strong cytoplasmic immunoreactivity for chromogranin. All sections were analyzed at a magnification of ×20.

Figure 2.

Analysis of the EGFR T790M mutation in the (A) cftDNA and (B) tumor rebiopsy using a polymerase chain reaction assay specifically for T790M. The WT (detected using a TET-labelled probe) and mutant T790M (detected using a FAM-labelled probe) populations are circled in each panel. The EGFR T790M mutation was observed only in the cftDNA sample with a count number of 13 and was not detected in the corresponding rebiopsy. The counts for the WT allele were 169 and 2459 in the cftDNA and tumor rebiopsy, respectively. EGFR, epidermal growth factor receptor; TET, tetrachloro fluorescein; FAM, 6-carboxyfluorescein; cft, circulating free tumor; WT, wild-type.