Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin

Oser, Matthew G.; Niederst, Matthew J.; Sequist, Lecia V.; Engelman, Jeffrey A.

doi:10.1016/s1470-2045(14)71180-5

Cited by 734 publications

(736 citation statements)

References 64 publications

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“…As NSCLC typically grows and spreads more slowly compared with SCLC, it does not frequently respond to chemotherapy, in contrast to SCLC (10). Therefore, there are numerous efforts to develop NSCLC targeted chemotherapy based on oncogenic mutations, including those in epidermal growth factor receptor (EGFR) (10).…”

Section: Introductionmentioning

confidence: 99%

Mutation of the TERT promoter leads to poor prognosis of patients with non-small cell lung cancer

et al. 2017

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Abstract. Mutations in the promoter region of telomerase reverse transcriptase (TERT) and alterations in telomere length (TL) have been the focus of research in various types of cancer. In the present study, the frequency and clinical characteristics of TERT promoter mutations and TL were studied in non-small cell lung cancers (NSCLC). TERT promoter mutations and TL were analyzed in 188 patients using DNA sequencing and the reverse transcription-quantitative polymerase chain reaction, respectively. The TERT promoter mutation rate was observed to be 2.2% (4/188 NSCLC cases), and it was significantly associated with regional lymph node invasion (P<0.001). No significant difference in TL was observed between the patients with and without TERT promoter mutations. TL was decreased in males (P=0.058 vs. females) and smokers (P=0.008 vs. non-smokers). Survival analyses demonstrated poor prognoses for patients with NSCLC with TERT promoter mutations (P<0.001). Multivariate survival analyses demonstrated that TERT promoter mutations were an independent prognostic marker for poor overall survival (P=0.045). The results of the present study demonstrated that TERT promoter mutation was not frequent in NSCLC; however, it may have value as a prognostic marker in NSCLC.

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Section: Introductionmentioning

confidence: 99%

Mutation of the TERT promoter leads to poor prognosis of patients with non-small cell lung cancer

et al. 2017

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“…It is currently indicated that combined-histology tumors and transformation occur more frequently in lung cancer types with EGFR-activating mutations compared with EGFR wild-type tumors. The reason for this may be that the cell of origin of certain EGFR-mutant adenocarcinomas, type II alveolar cells, also have the potential to become SCLC (17). Mixed EGFR-mutant NSCLC/SCLC histology has been reported in a number of cases, indicating a certain degree of dynamic plasticity between the two histologies in specific cases, without the selective pressure of the EGFR TKI (18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Qin

et al. 2018

Oncol Lett

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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...

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“…Initially described in 2006, observations of small-cell lung cancer (sclc) transformation after egfr tki treatment represents a consistent acquired resistance mechanism, with a prevalence of 5% -14% in multiple case series 22 . The absence of response to egfr tkis is explained by decreased levels of egfr protein expression, a well-known feature of sclc [23][24][25] .…”

Section: Figurementioning

confidence: 99%

Management of Egfr-Mutated Non-Small-Cell Lung Cancer: Practical Implications from a Clinical and Pathology Perspective

Cabanero

Sangha²,

Sheffield

et al. 2017

Current Oncology

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Starting in the early 2000s, non-small-cell lung cancer (nsclc) subtypes have evolved from being histologically described to molecularly defined. Management of lung adenocarcinomas now generally requires multiple molecular tests at baseline to define the optimal treatment strategy. More recently, second biopsies performed at progression in patients treated with tyrosine kinase inhibitors (tkis) have further defined the continued use of molecularly targeted therapy.In the present article, we focus on one molecular subtype: EGFR-mutated nsclc. For that patient population, multiple lines of tki therapy are now available either clinically or in clinical trials. Each line of treatment is guided by the specific mutations (for example, L858R, T790M, C797S) identified in EGFR. We first describe the various mechanisms of acquired resistance to EGFR tki treatment. We then focus on strategies that clinicians and pathologists can both use during tissue acquisition and handling to optimize patient results. We also discuss future directions for the molecular characterization of lung cancers with driver mutations, including liquid biopsies. Finally, we provide an algorithm to guide treating physicians managing patients with EGFR-mutated nsclc. The same framework can also be applied to other molecularly defined nsclc subgroups as resistance patterns are elucidated and additional lines of treatment are developed.

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Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin

Cited by 734 publications

References 64 publications

Mutation of the TERT promoter leads to poor prognosis of patients with non-small cell lung cancer

Mutation of the TERT promoter leads to poor prognosis of patients with non-small cell lung cancer

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

Management of Egfr-Mutated Non-Small-Cell Lung Cancer: Practical Implications from a Clinical and Pathology Perspective

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