Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor <i>EML4-ALK</i>

Shaw, Alice T.; Yeap, Beow Y.; Mino‐Kenudson, Mari; Digumarthy, Subba R.; Costa, Daniel B.; Heist, Rebecca S.; Solomon, Benjamin; Stubbs, Hannah; Admane, Sonal; McDermott, Ultan; Settleman, Jeffrey; Kobayashi, Susumu; Mark, Eugene J.; Rodig, Scott J.; Chirieac, Lucian R.; Kwak, Eunice L.; Lynch, Thomas J.; Iafrate, A. John

doi:10.1200/jco.2009.22.6993

Cited by 1,717 publications

(1,613 citation statements)

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“…The EML4-ALK fusion is a rare abnormality detected in B3-13% of patients with adenocarcinomas. 8,[146][147][148][149][150][151][152] The most common fusion results from the joining of exons 1-13 of EML4 to exons 20-29 of ALK. At least seven EML4-ALK variants (V1-V7) have been identified in lung adenocarcinomas.…”

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

“…[159][160][161][162] Compared with patients with wildtype ALK and EGFR, patients with the EML4-ALK fusion gene tend to be younger (median, 52 vs 64 years), of Asian ethnicity, diagnosed at an advanced clinical stage at presentation, male dominant (58 vs 32%), and more likely to be never-smokers (74 vs 26%), but with a comparable response rate to chemotherapy and overall survival. 8,148,159,160 The EML4-ALK fusion gene was detected in 19 of 141 (13%) tumor samples by FISH. 148 None of the 10 patients with an EML4-ALK rearrangement achieved an objective response to EGFR TKIs.…”

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

“…8,148,159,160 The EML4-ALK fusion gene was detected in 19 of 141 (13%) tumor samples by FISH. 148 None of the 10 patients with an EML4-ALK rearrangement achieved an objective response to EGFR TKIs. In contrast, 24% of responding patients in the EML4-ALKnegative cohort showed an objective response with an EGFR TKI.…”

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

“…In contrast, 24% of responding patients in the EML4-ALKnegative cohort showed an objective response with an EGFR TKI. 148,163 Tiseo et al 126 reported a 48-yearold Caucasian never-smoker man with lung adenosquamous carcinoma harboring EML4-ALK fusion and exon 19 deletion in EGFR gene. The patient manifested resistance to the erlotinib therapy.…”

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

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Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

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Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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“…The EML4‐ALK fusion gene is found in 2–7% of AC patients9 and generally occurs independently of other oncogenic drivers, including EGFR, KRAS or ERBB2 mutations 10. NSCLC patients carrying ALK rearrangements have shown resistance to anti‐EGFR TKIs but sensitivity to ALK inhibitors comprising crizotinib and ceritinib 11. Upcoming agents explored in preclinical and clinical studies target KRAS, BRAF, ERBB2, PI3KC and translocations involving RET, ROS and amplification of c‐MET 12…”

mentioning

confidence: 99%

KRAS driven expression signature has prognostic power superior to mutation status in non‐small cell lung cancer

Nagy

Pongor

Szabó

et al. 2016

Intl Journal of Cancer

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KRAS is the most frequently mutated oncogene in non‐small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer.We divided NSCLC patients with mutation and RNA‐seq data into KRAS mutated and wild type groups. Mann‐Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a “transcriptomic fingerprint” of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using univariate and multivariate Cox regression analysis.Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3 and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p < 0.01). The KRAS signature also remained significant (p < 0.01) in a multivariate analysis including age, gender, smoking history and tumor stage.We generated a “surrogate signature” of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself.

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Pulmonary-Respiratory Medicine

2001

JAMA

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Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK

Abstract: EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.

Cited by 1,717 publications

References 28 publications

Molecular pathology of lung cancer: key to personalized medicine

Molecular pathology of lung cancer: key to personalized medicine

KRAS driven expression signature has prognostic power superior to mutation status in non‐small cell lung cancer

Pulmonary-Respiratory Medicine

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