ONCOLOGY LETTERS 14: 593-598, 2017
Resistance to epithelial growth factor receptor tyrosine kinase inhibitors in a patient with transformation from lung adenocarcinoma to small cell lung cancer: A case report LIYING FANG1,2*, JIAN HE1*, JINGWEN XIA1, LIANG DONG1, XIUJUAN ZHANG1, YAQIN CHAI1,3, YING LI1,4, MENGJIE NIU1, TIANXING HANG1 and SHENGQING LI1 1
Department of Respiratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040; Department of Respiratory Medicine, The Fourth People's Hospital of Shaanxi, Xi'an, Shaanxi 710043; 3 Department of Respiratory Medicine, Xi'an Aerospace General Hospital, Xi'an, Shaanxi 710100; 4 Department of Respiratory Medicine, The Second People's Hospital of Shaanxi, Xi'an, Shaanxi 710005, P.R. China 2
Received June 1, 2016; Accepted February 23, 2017 DOI: 10.3892/ol.2017.6229 Abstract. First‑generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR‑TKIs) have markedly improved the treatment of non‑small cell lung cancer (non‑SCLC) with EGFR‑sensitive mutations. However, acquired resistance to these drugs was inevitable. The transformation of lung adenocarcinoma to SCLC following treatment with EGFR‑TKIs is a rare phenomenon that contributes to resistance to EGFR‑TKIs. The present case concerns a 74‑year‑old man previously diagnosed with and treated for pneumonia; however, this was later pathologically confirmed as lung adenocarcinoma by transbronchial lung biopsy. Deletion of exon 19 of EGFR was identified by next‑generation sequencing technology. The patient improved markedly when treated with gefitinib, but relapsed after 1 year, with markedly increased serum levels of neuron‑specific enolase (NSE). Transformation to SCLC was detected by endobronchial ultrasound transbronchial needle aspiration (EBUS‑TBNA) re‑biopsy, which was negative for the deletion of exon 19 of EGFR. The patient was positive for vimentin expression and refractory to etoposide and cisplatin chemotherapy, and succumbed to the disease 18 months after diagnosis. Transformation of the disease from adenocarcinoma to SCLC may have been due to cancer heterogeneity. Re‑biopsy is therefore important in EGFR‑TKI‑resistant patients for genetic and
Correspondence to: Professor Shengqing Li, Department of
Respiratory Medicine, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai 200040, P.R. China E‑mail: [email protected] *
Contributed equally
Key words: epithelial growth factor receptor tyrosine kinase inhibitor, lung adenocarcinoma, small cell lung cancer, resistance
histological re‑evaluation. NSE serum levels may also be useful for detecting early SCLC transformation. Introduction Lung cancer, particularly non‑small‑cell lung cancer (NSCLC), remains the leading cause of global cancer‑associated mortality, with a 5‑year survival rate of 50% of patients (6); the compensatory contribution of other receptor tyrosine kinases, including c‑MET amplification (7) and activating mutations in human epidermal growth factor receptor 2 (HER‑2) (8); the activation of compensatory signaling pathways, including the phosphoinositide‑3 kinase/AKT/mammalian target of rapamycin signaling pathway (9) and the TOPK‑c‑Jun pathway (10); and histological transformation, including EMT phenotypic transforming (11) and SCLC transformation (12). The transformation of lung adenocarcinoma to SCLC, as described by the present case report, is a relatively rare TKI resistance mechanism. Case report A 74‑year‑old male with a 50‑pack‑year smoking history presented to the Department of Respiratory Medicine (Huashan Hospital, Shanghai, China) with a 3‑year history of coughing, sputum production and shortness of breath in March 2014. A computed tomography (CT) scan revealed multiple patchy and
594
FANG et al: LUNG ADENOCARCINOMA TRANSFORMATION TO SMALL CELL LUNG CANCER
Table I. Driver gene profile of primary lung adenocarcinoma and secondary small cell lung cancer. Driver gene
Primary lung adenocarcinoma
Secondary small cell lung cancer
EGFR exon 19 deletion + ‑ ALK rearrangement ‑ ‑ HER2 mutations ‑ ‑ BRAF V600E mutation ‑ ‑ High‑level MET amplification or MET exon 14 ‑ ‑ skipping mutation RET rearrangements ‑ ‑ ROS1 rearrangements ‑ ‑ KRAS mutation ‑ ‑ EGFR, epithelial growth factor receptor; ALK, anaplastic lymphoma kinase; HER2, human epidermal growth factor receptor 2; BRAF, B‑Raf proto‑oncogene, serine/threonine kinase; MET, MET proto‑oncogene, receptor tyrosine kinase; RET, ret proto‑oncogene; ROS, ROS proto‑oncogene 1, receptor tyrosine kinase; KRAS, KRAS proto‑oncogene, GTPase.
nodular high‑density shadows, and bilateral lung bronchiectasis with consolidation in the left lower lobe (Fig. 1A). The structure of the mediastinum was clear and the lymph nodes were not enlarged (Fig. 1B). The patient was administered ceftazidime and levofloxacin to treat the suspected infection prior to hospitalization. However, the patient did not respond to treatment and the symptoms and CT scan images gradually worsened. Following admission, adenocarcinoma cells and a Lophomonasblattarum infection were detected by pathological cytology following a bronchoalveolar lavage (BAL) that was performed in the right middle lobe of the lung (Fig. 1C). A subsequent transbronchial lung biopsy was performed on the basal segment of the left lower lobe, which detected well‑differentiated adenocarcinoma cells (Fig. 1D). Next‑generation sequencing (NGS, Illumina Hiseq 4000; Illumina, Inc., San Diego, CA, USA) was employed to check the 8 driver genes with targeted drugs and it was found that exon 19 of EGFR was deleted (Table I). A positron emission tomography (PET)/CT scan revealed intense uptake of 18F‑fluorodeoxyglucose in the left lower lobe, no hypermetabolic lymph nodes, and no hypermetabolic lesions in the brain, abdomen or bone. The patient was prescribed 500 mg metronidazole once a day for 3 months to cure the L. blattarum infection and 250 mg gefitinib once a day for lung cancer treatment, and was followed up every 2‑3 months. The patient's symptoms improved markedly, the serum carcinoembryonic antigen level decreased from 5.52 ng/ml to within the normal range (
Resistance to epithelial growth factor receptor tyrosine kinase inhibitors in a patient with transformation from lung adenocarcinoma to small cell lung cancer: A case report LIYING FANG1,2*, JIAN HE1*, JINGWEN XIA1, LIANG DONG1, XIUJUAN ZHANG1, YAQIN CHAI1,3, YING LI1,4, MENGJIE NIU1, TIANXING HANG1 and SHENGQING LI1 1
Department of Respiratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040; Department of Respiratory Medicine, The Fourth People's Hospital of Shaanxi, Xi'an, Shaanxi 710043; 3 Department of Respiratory Medicine, Xi'an Aerospace General Hospital, Xi'an, Shaanxi 710100; 4 Department of Respiratory Medicine, The Second People's Hospital of Shaanxi, Xi'an, Shaanxi 710005, P.R. China 2
Received June 1, 2016; Accepted February 23, 2017 DOI: 10.3892/ol.2017.6229 Abstract. First‑generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR‑TKIs) have markedly improved the treatment of non‑small cell lung cancer (non‑SCLC) with EGFR‑sensitive mutations. However, acquired resistance to these drugs was inevitable. The transformation of lung adenocarcinoma to SCLC following treatment with EGFR‑TKIs is a rare phenomenon that contributes to resistance to EGFR‑TKIs. The present case concerns a 74‑year‑old man previously diagnosed with and treated for pneumonia; however, this was later pathologically confirmed as lung adenocarcinoma by transbronchial lung biopsy. Deletion of exon 19 of EGFR was identified by next‑generation sequencing technology. The patient improved markedly when treated with gefitinib, but relapsed after 1 year, with markedly increased serum levels of neuron‑specific enolase (NSE). Transformation to SCLC was detected by endobronchial ultrasound transbronchial needle aspiration (EBUS‑TBNA) re‑biopsy, which was negative for the deletion of exon 19 of EGFR. The patient was positive for vimentin expression and refractory to etoposide and cisplatin chemotherapy, and succumbed to the disease 18 months after diagnosis. Transformation of the disease from adenocarcinoma to SCLC may have been due to cancer heterogeneity. Re‑biopsy is therefore important in EGFR‑TKI‑resistant patients for genetic and
Correspondence to: Professor Shengqing Li, Department of
Respiratory Medicine, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai 200040, P.R. China E‑mail: [email protected] *
Contributed equally
Key words: epithelial growth factor receptor tyrosine kinase inhibitor, lung adenocarcinoma, small cell lung cancer, resistance
histological re‑evaluation. NSE serum levels may also be useful for detecting early SCLC transformation. Introduction Lung cancer, particularly non‑small‑cell lung cancer (NSCLC), remains the leading cause of global cancer‑associated mortality, with a 5‑year survival rate of 50% of patients (6); the compensatory contribution of other receptor tyrosine kinases, including c‑MET amplification (7) and activating mutations in human epidermal growth factor receptor 2 (HER‑2) (8); the activation of compensatory signaling pathways, including the phosphoinositide‑3 kinase/AKT/mammalian target of rapamycin signaling pathway (9) and the TOPK‑c‑Jun pathway (10); and histological transformation, including EMT phenotypic transforming (11) and SCLC transformation (12). The transformation of lung adenocarcinoma to SCLC, as described by the present case report, is a relatively rare TKI resistance mechanism. Case report A 74‑year‑old male with a 50‑pack‑year smoking history presented to the Department of Respiratory Medicine (Huashan Hospital, Shanghai, China) with a 3‑year history of coughing, sputum production and shortness of breath in March 2014. A computed tomography (CT) scan revealed multiple patchy and
594
FANG et al: LUNG ADENOCARCINOMA TRANSFORMATION TO SMALL CELL LUNG CANCER
Table I. Driver gene profile of primary lung adenocarcinoma and secondary small cell lung cancer. Driver gene
Primary lung adenocarcinoma
Secondary small cell lung cancer
EGFR exon 19 deletion + ‑ ALK rearrangement ‑ ‑ HER2 mutations ‑ ‑ BRAF V600E mutation ‑ ‑ High‑level MET amplification or MET exon 14 ‑ ‑ skipping mutation RET rearrangements ‑ ‑ ROS1 rearrangements ‑ ‑ KRAS mutation ‑ ‑ EGFR, epithelial growth factor receptor; ALK, anaplastic lymphoma kinase; HER2, human epidermal growth factor receptor 2; BRAF, B‑Raf proto‑oncogene, serine/threonine kinase; MET, MET proto‑oncogene, receptor tyrosine kinase; RET, ret proto‑oncogene; ROS, ROS proto‑oncogene 1, receptor tyrosine kinase; KRAS, KRAS proto‑oncogene, GTPase.
nodular high‑density shadows, and bilateral lung bronchiectasis with consolidation in the left lower lobe (Fig. 1A). The structure of the mediastinum was clear and the lymph nodes were not enlarged (Fig. 1B). The patient was administered ceftazidime and levofloxacin to treat the suspected infection prior to hospitalization. However, the patient did not respond to treatment and the symptoms and CT scan images gradually worsened. Following admission, adenocarcinoma cells and a Lophomonasblattarum infection were detected by pathological cytology following a bronchoalveolar lavage (BAL) that was performed in the right middle lobe of the lung (Fig. 1C). A subsequent transbronchial lung biopsy was performed on the basal segment of the left lower lobe, which detected well‑differentiated adenocarcinoma cells (Fig. 1D). Next‑generation sequencing (NGS, Illumina Hiseq 4000; Illumina, Inc., San Diego, CA, USA) was employed to check the 8 driver genes with targeted drugs and it was found that exon 19 of EGFR was deleted (Table I). A positron emission tomography (PET)/CT scan revealed intense uptake of 18F‑fluorodeoxyglucose in the left lower lobe, no hypermetabolic lymph nodes, and no hypermetabolic lesions in the brain, abdomen or bone. The patient was prescribed 500 mg metronidazole once a day for 3 months to cure the L. blattarum infection and 250 mg gefitinib once a day for lung cancer treatment, and was followed up every 2‑3 months. The patient's symptoms improved markedly, the serum carcinoembryonic antigen level decreased from 5.52 ng/ml to within the normal range (
