Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas

Lee, Jake June-Koo; Lee, Junehawk; Kim, Sehui; Kim, Soyeon; Youk, Jeonghwan; Park, Seongyeol; An, Yohan; Keam, Bhumsuk; Kim, Dong Wan; Heo, Dae Seog; Kim, Young Tae; Kim, Jin-Soo; Kim, Se Hyun; Lee, Jong Seok; Lee, Se‐Hoon; Park, Keunchil; Ku, Ja Lok; Jeon, Yoon Kyung; Chung, Doo Hyun; Park, Peter J.; Kim, Joon; Kim, Tae Min; Ju, Young Seok

doi:10.1200/jco.2016.71.9096

Cited by 364 publications

(409 citation statements)

References 31 publications

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“…NOTCH alterations promote ASCL1 and CD56 overexpression (9). These changes induce cyclin-dependent kinase 5 (CDK5) activity and inactivation of RB by phosphorylation (9). The present study reports a case of acquired resistance to icotinib therapy through transformation to SCLC.…”

Section: Introductionmentioning

confidence: 87%

“…The most studied signaling pathway is the achaete-scute homolog 1 (ASCL1) which is regulated by four different neurogenic locus notch homolog (NOTCH) receptors. NOTCH alterations promote ASCL1 and CD56 overexpression (9). These changes induce cyclin-dependent kinase 5 (CDK5) activity and inactivation of RB by phosphorylation (9).…”

Section: Introductionmentioning

confidence: 99%

“…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 amplification.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Lee et al have recently described predictors of transformation into small-cell carcinomas from lung adenocarcinomas under treatment by tyrosine kinase inhibitor (1). Their very interesting work raises several reflections about tumor transformation and the clinical management of tumor drug resistance.…”

mentioning

confidence: 99%

“…The article by Lee et al provides important advancements about the pathogenesis of such mechanism of EGFRinhibitor resistance (1). Through the genomic analysis of repeat biopsy of patients diagnosed with EGFR-mutated lung adenocarcinoma, the authors found that the alterations of the cancer gene drivers RB1 and TP53 are present even in early stage lung adenocarcinoma.…”

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confidence: 99%

Molecular mechanisms of pathological tumor transformation and their clinical implications: predictors of pulmonary adenocarcinoma transformation into small cell carcinoma

Ghigna

Montpréville

2017

J. Thorac. Dis.

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J Thorac Dis 2017;9(10):3469-3472 jtd.amegroups.com effective first-line therapy. Nevertheless, along the treatment, cancer cells acquire a resistant phenotype, through different mechanisms, consisting either in the gain of new EGFR mutations or in the acquisition of other oncogenic drivers bypassing EGFR signaling (10,11). Thr790Met mutation in EGFR gene enhances the affinity of the EGFR for ATP, leading to the continuous activation of EGFR signaling even in presence of the inhibitor (12). The acquisition of T790M represents the most common molecular mechanism of TKI resistance in EGFR mutated adenocarcinoma, occurring in half of the resistant tumors (12). The development of PIK3CA mutations has also been identified as a mechanism of EGFR drug resistance (13) in 5% of cases. MET or HER2 amplification constitute two additional biological mechanisms inducing EGFR inhibitor resistance, accounting for about 15-20% of cases (10,14).The histological analysis of tissue specimen from patients having developed an EGFR inhibitor resistant tumor has disclosed significant histological modifications, leading to the description of an additional mechanism of drug resistance: the transformation of adenocarcinoma to small cell lung cancer (15). This process, initially, described in case reports (16), has been increasingly characterized in case series, in which repeat biopsies were performed in patients with acquired resistance to EGFR inhibitors. The prevalence of this mechanism of resistance is difficult to evaluate: in a large case series, SCLC was identified in 14% of patients with EGFR mutated adenocarcinoma (17). The genomic analysis of SCLC developed in this setting has disclosed that the EGFR mutations originally detected in adenocarcinoma were retained in SCLC, together with classic oncogenetic drivers such as RB1, TP53 and MYC. This finding has raised the question about SCLC origin: are SCLCs the result of EGFR inhibitors treatment or are EGFR mutated adenocarcinomas more likely to evolve toward SCLC? It has been previously reported that the development of small cell lung carcinomas in association with pulmonary adenocarcinoma, either synchronously or metachronously, could be linked to EGFR mutations, regardless of tyrosine kinase inhibitors use (15). The description of synchronous adenocarcinoma and SCLC before the administration of EGFR inhibitors has suggested that SCLC are not the mere consequence of EGFR inhibitors. Moreover, the progression of NSCLC to SCLC has been documented before the introduction of EGFR inhibitors, with a reported frequency of 5% in a case series (18).The biological mechanisms underlying the transformation of adenocarcinoma into SCLC are largely unknown. The hypothesis about the existence of a "pool" of pluripotent cancer cell, giving rise to a phenotypically distinct cancer population, constitutes an attractive biological mechanism potentially related with cancer cell therapeutic resistance (19,20).Moreover, in the field of pulmonary oncology, the hypothesis of the existence of common cells...

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Estimating Recurrence Risk in Resected Early-Stage Epidermal Growth Factor Receptor–Positive Non–Small Cell Lung Cancer

Davella

Bodor

2021

JAMA Netw Open

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Estimating prognosis in patients with resected non-small cell lung cancer (NSCLC) remains an area of active research, as risk of recurrence is substantial. Even with the addition of adjuvant platinumbased chemotherapy, the risk of recurrence or death remains high. 1 Findings from prior studies on the prognostic impact of epidermal growth factor receptor (EGFR) alterations in early stage NSCLC are conflicting, and factors associated with recurrence risk in patients with EGFR-positive NSCLC need further elucidation. The cohort study by Tan et al 2 included patients with EGFR-positive and wildtype EGFR early-stage NSCLC with the primary goal to compare disease-free survival (DFS) between cohorts and identify clinicopathologic and molecular factors associated with recurrence among patients with EGFR-positive NSCLC. Tan et al 2 found that 2-year DFS was similar between patients with EGFR-positive NSCLC (70.2%) and those with wildtype EGFR NSCLC (67.6%), and several risk factors for recurrence were identified in the EGFR-positive population. This research is especially timely and relevant, given the recent Food and Drug Administration (FDA) approval in December 2020 of adjuvant osimertinib in patients with stage IB to IIIA resected EGFR-positive NSCLC. The impressive DFS benefit with adjuvant osimertinib seen in the ADAURA trial 3 in patients with resected EGFR-positive NSCLC led to this approval; however, many researchers still await mature overall survival data from this landmark study.In this large pre-ADAURA cohort, Tan et al 2 found DFS to be similar between the wildtype EGFR and altered EGFR groups, which questions the prognostic significance of EGFR alterations in terms of recurrence risk. However, overall survival was significantly improved in EGFR-positive NSCLC compared with wildtype EGFR NSCLC, which is likely explained by the number of efficacious targeted treatment options in the metastatic setting for EGFR-positive NSCLC. Tan et al 2 found similar DFS for patients with stage IA (81%) and IB (78%) NSCLC in the EGFR-positive cohort. This is notable, given that patients with stage IA NSCLC were not included in ADAURA 3 and are otherwise not eligible for osimertinib, per the FDA label. Even among patients with very early-stage disease, nearly 20% of patients still experience early recurrence or death. On the other hand, Tan et al 2 note that 37% of their overall cohort of patients with stage IB to IIIA NSCLC were disease free at 5 years and cured, without the benefit of receiving adjuvant osimertinib. 2 Since the publication of the ADAURA findings, 3 much debate has been centered around which patients benefit most from adjuvant osimertinib, given the differences in absolute DFS benefits observed by stage. Many oncologists admit a greater enthusiasm for offering this additional therapy to patients with stage II to IIIA disease and acknowledge the need for more nuanced discussions regarding the risks and benefits in stage I disease. The findings by Tan et al 2 highlight that stage of disease is only a part of t...

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Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas

Cited by 364 publications

References 31 publications

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

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

Molecular mechanisms of pathological tumor transformation and their clinical implications: predictors of pulmonary adenocarcinoma transformation into small cell carcinoma

Estimating Recurrence Risk in Resected Early-Stage Epidermal Growth Factor Receptor–Positive Non–Small Cell Lung Cancer

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