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• W1986180523 abstract "Many aspects of the clinical and pathological phenotype of non-small cell lung cancer (NSCLC) harboring rearrangements in the anaplastic lymphoma kinase (ALK) gene have been characterized following the description of the EML4-ALK fusion gene in NSCLC in 2007.1Soda M Choi YL Enomoto M et al.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.Nature. 2007; 448: 561-566Crossref PubMed Scopus (4302) Google Scholar, 2Rikova K Guo A Zeng Q et al.Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.Cell. 2007; 131: 1190-1203Abstract Full Text Full Text PDF PubMed Scopus (1914) Google Scholar These tumors most frequently occur in younger, never or light smokers with adenocarcinoma, are almost always mutually exclusive with EGFR or KRAS mutations, and demonstrate exquisite sensitivity to treatment with the ALK inhibitor crizotinib.3Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar However, there are few published data regarding the natural history and clinical outcomes of ALK-positive NSCLC. Two reports in this issue of the Journal of Thoracic Oncology, conducted in different patient populations using different methods to detect ALK rearrangements, provide apparently conflicting conclusions about the prognostic significance of ALK gene rearrangements in NSCLC and raise questions about the optimal method to detect ALK gene rearrangements in clinical samples. In the first study, Wu et al. performed a retrospective analysis using reverse transcription polymerase chain reaction (RT-PCR) to detect ALK gene rearrangements in cell pellets derived from malignant pleural effusions in 116 EGFR wild-type, Taiwanese patients with stage IIIB/IV NSCLC. Thirty-nine patients (34%) were found to have ALK gene rearrangements and, in contrast to other studies, these patients did not differ from ALK-negative patients with respect to age or smoking history. Wu et al. observed better median survival in the ALK-positive patients compared with the EGFR wild-type, ALK-negative patients (14.7 versus 10.3 months, p = 0.009). In the second study, Yang et al. screened 300 never smokers from the Mayo Clinic Lung Cancer Cohort with a two-staged process involving immunohistochemistry (IHC) using the commercially available monoclonal ALK1 antibody (Dako, Capinteria, Ca) followed by fluorescence in situ hybridization (FISH) using break-apart probes (Vysis, Des Plaines, IL). In this cohort of predominantly early-stage tumors (191/300 stage I/II, 62/300 stage II, and 47/300 stage IV), 22 patients (8.2%) were determined to be ALK-positive by FISH. No overall survival data are presented, but using a composite end point of 5-year progression-free survival (PFS) and recurrence-free survival, adjusted for stage and treatment modality, Yang et al. found inferior outcomes in the ALK-positive cohort, with a twofold increase in the risk of experiencing disease progression or recurrence within 5 years in ALK-positive compared with ALK-negative patients. How do these articles with apparently contradictory findings fit in with what is known about clinical outcomes in this patient population? Of note, assessment of the predictive and prognostic significance of ALK gene rearrangements in NSCLC is limited by the fact that, with the exception of one prospective, single-arm study,3Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar the published data are limited to relatively small retrospective studies. Furthermore, the possibility of ascertainment bias cannot be excluded because of potential differences in the populations screened for ALK rearrangements in these studies compared with the broader population of NSCLC patients. With these caveats in mind, retrospective data have been reported regarding outcomes in ALK-positive patients treated with platinum doublets, pemetrexed, or EGFR tyrosine kinase inhibitors (TKIs). Three retrospective studies have indicated that ALK rearrangements do not seem to predict additional benefit from platinum-based combination chemotherapy compared with other genotypes. Shaw et al.4Shaw AT Yeap BY Mino-Kenudson M et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1631) Google Scholar first reported that the response rate and time to progression in patients with ALK-rearranged tumors treated with platinum doublets were not different compared with patients whose tumors had EGFR mutations or were wild-type for both ALK and EGFR. This finding has since been replicated in two independent series reported from South Korea.5Kim HR, Shim HS, Chung JH, et al. Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Cancer In press.Google Scholar, 6Koh Y Kim DW Kim TM et al.Clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase-positive advanced pulmonary adenocarcinoma: suggestion for an effective screening strategy for these tumors.J Thorac Oncol. 2011; 6: 905-912Crossref PubMed Scopus (58) Google Scholar Intriguingly, two retrospective studies have reported improved response rates7Lee JO Kim TM Lee SH et al.Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer.J Thorac Oncol. 2011; 6: 1474-1480Crossref PubMed Scopus (146) Google Scholar and PFS7Lee JO Kim TM Lee SH et al.Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer.J Thorac Oncol. 2011; 6: 1474-1480Crossref PubMed Scopus (146) Google Scholar, 8Camidge DR Kono SA Lu X et al.Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed.J Thorac Oncol. 2011; 6: 774-780Crossref PubMed Scopus (209) Google Scholar after treatment with pemetrexed in ALK-positive patients compared with patients with tumors of other genotypes. Perhaps not surprisingly, ALK rearrangements seem to be negative predictors for benefit from EGFR TKIs. Across three retrospective studies, no patients with ALK gene rearrangements responded to EGFR TKIs.4Shaw AT Yeap BY Mino-Kenudson M et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1631) Google Scholar, 5Kim HR, Shim HS, Chung JH, et al. Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Cancer In press.Google Scholar, 6Koh Y Kim DW Kim TM et al.Clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase-positive advanced pulmonary adenocarcinoma: suggestion for an effective screening strategy for these tumors.J Thorac Oncol. 2011; 6: 905-912Crossref PubMed Scopus (58) Google Scholar Furthermore, PFS after erlotinib or gefitinib was inferior in ALK-positive tumors compared with other genotypes.4Shaw AT Yeap BY Mino-Kenudson M et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1631) Google Scholar, 5Kim HR, Shim HS, Chung JH, et al. Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Cancer In press.Google Scholar, 6Koh Y Kim DW Kim TM et al.Clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase-positive advanced pulmonary adenocarcinoma: suggestion for an effective screening strategy for these tumors.J Thorac Oncol. 2011; 6: 905-912Crossref PubMed Scopus (58) Google Scholar Due to crossover in the ongoing randomized phase III trials of crizotinib, and the recent accelerated approval of crizotinib by the U.S. Food and Drug Administration (FDA), the effects of ALK inhibitors on survival are unlikely to be prospectively established. However, data from crizotinib-treated and crizotinib-naive ALK-positive cohorts point to ALK gene rearrangements being (1) predictive of response to ALK inhibitors3Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar and (2) associated with survival benefit from these agents.9Shaw AT Yeap BY Solomon BJ et al.Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.Lancet Oncol. 2011; 12: 1004-1012Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar In NSCLC patient populations where ALK has been genotyped, there does not appear to be a positive prognostic effect of ALK rearrangements on survival in the absence of treatment with crizotinib. In a recent report of a cohort from United States and Australia, the median overall survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (20 versus 15 months, p = 0.244).9Shaw AT Yeap BY Solomon BJ et al.Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.Lancet Oncol. 2011; 12: 1004-1012Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar In an independent cohort of 229 Korean nonsmokers with NSCLC,5Kim HR, Shim HS, Chung JH, et al. Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Cancer In press.Google Scholar median overall survival in ALK-positive patients (14.3 months) was similar to patients with KRAS mutations (15.6 months) and inferior to patients with EGFR mutation (37.4 months) or “triple-negative” patients (33.3 months). Kim et al. also analyzed recurrence-free survival in 119 patients who were managed with surgery. Recurrence-free survival was 39.7 months for EGFR mutations, 20 months for ALK rearrangements, 21.4 months for KRAS mutations, and 26.8 months for the triple-negative patients. These findings are consistent with those reported by Yang et al. who showed a twofold increase in the risk of experiencing lung progression or recurrence within 5 years. Taken together, these data suggest that ALK-positive patients do not have improved outcomes compared with other genotypes and potentially provide an argument for clinical trials of ALK inhibitors in the adjuvant setting. The natural history of ALK-rearranged NSCLC does, however, seem to be modified by treatment with crizotinib with improved survival in crizotinib-treated patients compared with ALK-positive patients never exposed to crizotinib.9Shaw AT Yeap BY Solomon BJ et al.Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.Lancet Oncol. 2011; 12: 1004-1012Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar Survival in 30 ALK-positive patients who were given crizotinib in the second- or third-line setting was significantly longer than in 23 ALK-positive, crizotinib-naive controls given any second-line therapy (hazard ratio 0.36, 95% confidence interval 0.17–0.75; p = 0.004). In fact, survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy. These data appear to be supported by a recent study by Paik et al. of patients genotyped for EGFR, KRAS, and ALK in the “postcrizotinib era”: patients with ALK rearrangements had outcomes that were similar to patients with EGFR mutations and improved compared with those with KRAS mutations.10Paik PK, Johnson M, D'Angelo SP, et al. Prognostic Implications of Driver Mutations in Smokers and Never Smokers with Lung Adenocarcinoma. World Conference of Lung Cancer; O16.06, 2011.Google Scholar These two articles raise important questions about the optimal strategy to detect patients with ALK gene rearrangements, the subject of a recent editorial in this journal.11Camidge DR Hirsch FR Varella-Garcia M et al.Finding ALK-positive lung cancer: what are we really looking for?.J Thorac Oncol. 2011; 6: 411-413Crossref PubMed Scopus (30) Google Scholar The technique used by Wu et al. to identify ALK-positive patients was RT-PCR from frozen cell pellets derived from pleural effusions. This assay requires extraction of RNA from clinical samples, is not routinely performed in many diagnostic pathology laboratories, and suffers from some important limitations. Each PCR assay is ALK fusion-specific, and although assays may be multiplexed,12Takeuchi K Choi YL Soda M et al.Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts.Clin Cancer Res. 2008; 14: 6618-6624Crossref PubMed Scopus (432) Google Scholar they may not detect all possible ALK gene rearrangements, especially those involving novel fusion partners,13Mino-Kenudson M Chirieac LR Law K et al.A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry.Clin Cancer Res. 2010; 16: 1561-1571Crossref PubMed Scopus (388) Google Scholar a consequence of which may be false-negative results. Another important limitation is the possibility of contamination which might impair specificity and lead to false-positive results.14Mano H Takeuchi K EML4-ALK fusion in lung.Am J Pathol. 2010; 176: 1552-1553Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Discordant data in the small subset of patients who underwent both FISH and RT-PCR testing raises the possibility of both false positives and false negatives, a finding that could account for the discrepant findings regarding survival in the report by Wu et al. Yang et al. expand on previous experience15Yi ES Boland JM Maleszewski JJ et al.Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH.J Thorac Oncol. 2011; 6: 459-465Crossref PubMed Scopus (249) Google Scholar evaluating the approach of initial testing using IHC with the commercially available monoclonal ALK1 antibody and an enhanced detection system paired with subsequent FISH testing. They observed complete concordance between samples scored as IHC 3+ and FISH positivity and also between samples scored as IHC 0 and FISH negativity. However, in the case of IHC 2+, 14.3% of cases were FISH positive and in the case of IHC 1+ only 3.1% of cases were FISH positive, indicating that IHC was sensitive but not specific. On this basis, upfront testing of all patients with IHC coupled with confirmatory testing by FISH in IHC 2+ (and selected IHC 1+) cases is suggested. Similar strategies have been proposed using another commercially available antibody (Clone 5A4, Novocastra, Newcastle, United Kingdom)16Paik JH Choe G Kim H et al.Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization.J Thorac Oncol. 2011; 6: 466-472Crossref PubMed Scopus (254) Google Scholar and a novel antibody that is yet to be made commercially available (D5F3, Cell Signaling, Danvers, MA).13Mino-Kenudson M Chirieac LR Law K et al.A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry.Clin Cancer Res. 2010; 16: 1561-1571Crossref PubMed Scopus (388) Google Scholar The proposed algorithm, analogous to that recommended for the detection of HER2 amplification in breast cancer,17Wolff AC Hammond ME Schwartz JN et al.American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.J Clin Oncol. 2007; 25: 118-145Crossref PubMed Scopus (3032) Google Scholar is attractive and has advantages with respect to improving the accessibility and cost-effectiveness of screening for ALK rearrangements in NSCLC. However, large-scale multicenter prospective validation of this approach is essential. A cautionary note is provided by experience with HER2 testing in breast cancer where there has been at least a 20% discordance reported between community-based HER2 assays and central laboratory testing.18Paik S Bryant J Tan-Chiu E et al.Real-world performance of HER2 testing—National Surgical Adjuvant Breast and Bowel Project experience.J Natl Cancer Inst. 2002; 94: 852-854Crossref PubMed Scopus (439) Google Scholar, 19Roche PC Suman VJ Jenkins RB et al.Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831.J Natl Cancer Inst. 2002; 94: 855-857Crossref PubMed Scopus (357) Google Scholar This has led to recommendations to reduce preanalytic, analytic, and postanalytic variation including sample handling (e.g., tissue processing and method of fixation), standardization of reagents and protocols, standardized reporting criteria, and implementation of quality assurance procedures (including the requirement for laboratory accreditation and external proficiency assessments).17Wolff AC Hammond ME Schwartz JN et al.American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.J Clin Oncol. 2007; 25: 118-145Crossref PubMed Scopus (3032) Google Scholar Nonetheless, even in this arena, where the FDA has approved several IHC, FISH, and chromogenic in situ hybridization (CISH) assays for detection of HER2 amplification, controversy remains about whether the best diagnostic approach is a combination of IHC and FISH17Wolff AC Hammond ME Schwartz JN et al.American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.J Clin Oncol. 2007; 25: 118-145Crossref PubMed Scopus (3032) Google Scholar or whether all tumors should have primary testing with FISH or CISH.20Sauter G Lee J Bartlett JM et al.Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations.J Clin Oncol. 2009; 27: 1323-1333Crossref PubMed Scopus (436) Google Scholar NSCLC with ALK gene rearrangements represent a distinct entity with clinical and pathological features that are characteristic but overlap with other subsets of NSCLC. Molecular characterization of ALK status is essential as it identifies patients suitable for treatment with crizotinib, an agent that likely impacts the natural history of ALK-positive NSCLC. Development and validation of strategies to improve effective identification of this patient population with strategies incorporating IHC or other techniques are important and likely to assume a place in clinical practice. However, for now, FISH with break-apart probes remains the gold standard and is the only FDA-approved test for identification of NSCLC patients with ALK gene rearrangements who may be eligible for treatment with crizotinib." @default.
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• W1986180523 title "Are Anaplastic Lymphoma Kinase Gene Rearrangements in Non-small Cell Lung Cancer Prognostic, Predictive, or Both?" @default.
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