Transformation to small‑cell lung cancer following treatment with icotinib in a patient with lung adenocarcinoma

Abstract

Abstract. The present study describes the case of a 48-year-old man who was diagnosed with lung adenocarcinoma with an epidermal growth factor receptor (EGFR) 21 L858R mutation. The patient received surgery and adjuvant chemotherapy. When multiple lung metastases appeared, icotinib was administered. Following resistance to icotinib, biopsy by endobroncheal ultrasonography for a right lung hilar lymph node revealed transformation to a neuroendocrine morphology. Neuron-specific enolase (NSE) levels were elevated, accompanied with disease progression following transformation to the neuroendocrine morphology. The post-operative and biopsy specimens were analyzed for 416 genes using next-generation sequencing, and phosphatidylinositol-3-kinase catalytic α mutation and retinoblastoma loss were evident. Five cycles of etoposide combined with cisplatin were administered and a partial response was achieved. The disease progressed again accompanied with an elevated NSE level, and bronchoscopy examination revealed small cell lung cancer (SCLC) after 3 months. The patient received chemotherapy consisting of irinotecan combined with carboplatin for two cycles and achieved stable disease. Overall, a secondary biopsy is important for the evaluation of genetic and histological changes and the selection of an appropriate treatment following tyrosine kinase inhibitor (TKI) resistance, and NSE may be useful for the early detection of SCLC transformation in cases that are resistant to EGFR-TKI therapy. IntroductionLung cancer, including small-cell lung cancer (SCLC) and non-SCLC (NSCLC), which is mainly comprised of adenocarcinoma, squamous cell carcinoma and large cell carcinoma, is the most common type of malignancy and the leading cause of cancer-associated mortality worldwide (1). Adenocarcinoma is the most common type of NSCLC, and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy, including erlotinib, gefitinib or icotinib, is the gold standard of treatment for EGFR-mutant lung adenocarcinoma (2-4). The incidence of EGFR mutation in NSCLC in 2005 was higher in East Asian populations when compared with the incidence in other ethnicities (30 vs. 8%) (5). Patients with lung adenocarcinoma harboring exon 19 deletions achieved longer progression-free survival (PFS) and overall survival time (OS) compared with those with L858R mutations (6). However, patients ultimately develop acquired resistance, and the most recently identified mechanism for this is transformation to SCLC (7). Ahn et al (8) reported six cases of transformation from lung adenocarcinoma to SCLC. Erlotinib, gefitinib, afatinib and icotinib were equally as efficient as each other but exhibited different efficacy-toxicity patterns (4). EGFR-TKI-resistant SCLCs are differentiated early from the lung adenocarcinoma clones that harbor completely inactivated retinoblastoma 1 (RB1) and TP53 (9). Molecular mechanisms involved in the transformation from NSCLC to SCLC include TP53 mutations, RB1 loss, lack of EGFR expression and MYC amplificatio...

Histologic Changes in Non–Small Cell Lung Cancer under Various Treatments: A Comparison of Histology and Mutation Status in Serial Samples

“…These pressures may also cause histologic changes and tumor cells settle in other organs in a changed histology. Histologic change from AdenoCa to SCC after surgery and adjuvant therapy has been previously described [ 17 ]. One patient (case 3) in our study is interesting because the diagnosis of primary lung cancer and its brain metastasis was confirmed by surgical resection, and both were pure AdenoCa and SCC, respectively.…”

Histological transformation of non-small cell lung cancer: Clinical analysis of nine cases

“…Gu et al [ 24 ] also reported that serum ProGRP and NSE levels were markedly elevated compared with normal levels when SCLC transformation occurred. In addition, many other literature reports have shown a significant increase in NSE levels, indicating SCLC or LCNEC transformation[ 11 , 18 , 32 , 33 ]. In our cases, NSE levels were detected in six cases at the time of SCLC transformation.…”

Small-cell lung cancer transformation from EGFR-mutant adenocarcinoma after EGFR-TKIs resistance

“…SCLC transformation is 1 resistance mechanism associated with first-generation EGFR-TKIs, and is more frequent in lung adenocarcinomas with EGFR-activating mutations than in EGFR wild-type tumors [7–9] . A number of mechanisms of acquired resistance to EGFR-TKI therapy in EGFR-mutant lung adenocarcinoma have been described, including the EGFR T790M mutation, EGFR amplification, MET gene amplification, PIK3CA mutation, and transformation to SCLC [10,11] . However, the potential mechanism underlying SCLC phenotype conversion after TKI therapy remains unclear.…”