<i>ALK</i> Fusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy

Ross, Jeffrey S.; Ali, Siraj M.; Fasan, Omotayo; Block, Jared; Pal, Sumanta K.; Elvin, Julia A.; Schrock, Alexa B.; Suh, James; Nozad, Sahar; Kim, Sungeun; Lee, Hwa Jeong; Sheehan, Christine E.; Jones, David; Vergilio, Jo‐Anne; Ramkissoon, Shakti; Severson, Eric Allan; Daniel, Sugganth; Fabrizio, David; Frampton, Garrett M.; Miller, V. A.; Stephens, Philip J.

doi:10.1634/theoncologist.2016-0488

Cited by 90 publications

(99 citation statements)

References 56 publications

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“…ALK rearrangement is often seen in NSCLC (3.1%), whereas its incidence in other tumors is only 0.2% . The data in this study showed that the percentage of Chinese patients with ALK rearrangement was 7.8%, quite high compared with the published data mentioned above.…”

Section: Discussioncontrasting

confidence: 47%

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Dai

Wang

et al. 2019

The Oncologist

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Background Non‐small cell lung cancer (NSCLC) is one of the most common human malignancies and the leading cause of cancer‐related death. Over the past few decades, genomic alterations of cancer driver genes have been identified in NSCLC, and molecular testing and targeted therapies have become standard care for lung cancer patients. Here we studied the unique genomic profile of driver genes in Chinese patients with NSCLC by next‐generation sequencing (NGS) assay. Materials and Methods A total of 1,200 Chinese patients with NSCLC were enrolled in this study. The median age was 60 years (range: 26–89), and 83% cases were adenocarcinoma. NGS‐based genomic profiling of major lung cancer‐related genes was performed on formalin‐fixed paraffin‐embedded tumor samples and matched blood. Results Approximately 73.9% of patients with NSCLC harbored at least one actionable alteration recommended by the National Comprehensive Cancer Network guideline, including epidermal growth factor receptor (EGFR), ALK, ERBB2, MET, BRAF, RET, and ROS1. Twenty‐seven patients (2.2%) harbored inherited germline mutations of cancer susceptibility genes. The frequencies of EGFR genomic alterations (both mutations and amplification) and ALK rearrangement were identified as 50.1% and 7.8% in Chinese NSCLC populations, respectively, and significantly higher than the Western population. Fifty‐six distinct uncommon EGFR mutations other than L858R, exon19del, exon20ins, or T790M were identified in 18.9% of patients with EGFR‐mutant NSCLC. About 7.4% of patients harbored both sensitizing and uncommon mutations, and 11.6% of patients harbored only uncommon EGFR mutations. The uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. In patients <40 years of age, the ALK‐positive percentage was up to 28.2%. Moreover, 3.2% of ALK‐positive patients harbored multi ALK rearrangements, and seven new partner genes were identified. Conclusion More unique features of cancer driver genes in Chinese NSCLC were identified by next‐generation sequencing. These findings highlighted that NGS technology is more feasible and necessary than other molecular testing methods, and suggested that the special strategies are needed for drug development and targeted therapy for Chinese patients with NSCLC. Implications for Practice Molecular targeted therapy is now the standard first‐line treatment for patients with advanced non‐small cell lung cancer (NSCLC). Samples of 1,200 Chinese patients with NSCLC were analyzed through next‐generation sequencing to characterize the unique feature of uncommon EGFR mutations and ALK fusion. The results showed that 7.4% of EGFR‐mutant patients harbored both sensitizing and uncommon mutations and 11.6% harbored only uncommon mutations. Uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. ALK fusion was more common in younger patients, and the frequency decreased monotonically with age. 3.2% of ALK‐positive patien...

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Section: Discussioncontrasting

confidence: 47%

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Dai

Wang

et al. 2019

The Oncologist

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“…NT: mutations were not tested. (2020) 10:2707 | https://doi.org/10.1038/s41598-020-59744-3 www.nature.com/scientificreports www.nature.com/scientificreports/ common mutation sites: EGFR exon 19 deletion (del19) and exon 21 (L858R) 35,36 , KRAS exon 2 (G12C) 37 , BRAF V600E 38 and ALK-EML4 fusion 39 . The frequencies of ALK (5.4%) and ROS1 (2.9%) mutations determined in our study (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…EGFR del19, EGFR L858R, BRAF V600E, ALK-EML4 and ROS1 fusion mutations in combined (139 cases) accounted for 39.7% of cases in the Vietnamese cohort. They were known as activating mutations and clinically proven to be sensitive to treatments with available TKI drugs 5,6,11,39 . Thus, our findings suggested that approximately 40% of Vietnamese patients would carry such mutations and therefore would benefit from available targeted drugs.…”

Section: Discussionmentioning

confidence: 99%

Actionable Mutation Profiles of Non-Small Cell Lung Cancer patients from Vietnamese population

Dang

Tran²,

Tran³

et al. 2020

Sci Rep

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Comprehensive profiling of actionable mutations in non-small cell lung cancer (NSCLC) is vital to guide targeted therapy, thereby improving the survival rate of patients. Despite the high incidence and mortality rate of NSCLC in Vietnam, the actionable mutation profiles of Vietnamese patients have not been thoroughly examined. Here, we employed massively parallel sequencing to identify alterations in major driver genes (EGFR, KRAS, NRAS, BRAF, ALK and ROS1) in 350 Vietnamese NSCLC patients. We showed that the Vietnamese NSCLC patients exhibited mutations most frequently in EGFR (35.4%) and KRAS (22.6%), followed by ALK (6.6%), ROS1 (3.1%), BRAF (2.3%) and NRAS (0.6%). Interestingly, the cohort of Vietnamese patients with advanced adenocarcinoma had higher prevalence of EGFR mutations than the Caucasian MSK-IMPACT cohort. Compared to the East Asian cohort, it had lower EGFR but higher KRAS mutation prevalence. We found that KRAS mutations were more commonly detected in male patients while EGFR mutations was more frequently found in female. Moreover, younger patients (<61 years) had higher genetic rearrangements in ALK or ROS1. In conclusions, our study revealed mutation profiles of 6 driver genes in the largest cohort of NSCLC patients in Vietnam to date, highlighting significant differences in mutation prevalence to other cohorts. Lung cancer is the most common malignancy and the leading cause of cancer related deaths worldwide (18.4% of total cancer deaths), with non-small cell lung cancer (NSCLC) being the most common subtype, accounting for approximately 85% of all diagnosed cases 1,2. The majority of NSCLC patients display advanced disease when diagnosed and thus have poor prognosis 2,3. It is well established that acquired genetic alterations in certain driver genes result in tumour growth and invasiveness, and that patients harboring certain mutations may benefit from targeted therapies 4,5. Indeed, a randomized clinical trial reported that advanced NSCLC patients harboring activating mutations in EGFR, one of the major driver genes of NSCLC, exhibited longer progression-free period when treated with a tyrosine kinase inhibitor (TKI), gefitinib, compared to those treated with standard platinum based chemotherapy 6. However, those who were treated with TKI drugs can acquire secondary resistant mutations, in which case a new treatment regimen is needed to maintain therapeutic effect 7,8. In addition to EGFR, NSCLC patients carrying ALK or ROS1 rearrangement were shown to respond well to a different TKI drug,

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“…Most ALK-positive NSCLCs result from the juxtaposition of EML4 to ALK and ALK fusions primarily occur at a highly conserved breakpoint in intron 19. 4 In contrast, a multitude of ROS1 breakpoints and fusion partners have been described in ROS1-positive NSCLC. 1,4 Diagnostic approaches that can reliably identify ROS1 fusions are as critical as therapies that selectively and effectively target ROS1.…”

Section: Introductionmentioning

confidence: 99%

Molecular Analysis of Plasma From Patients With ROS1-Positive NSCLC

Dagogo‐Jack

Rooney

Nagy

et al. 2019

Journal of Thoracic Oncology

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Introduction: Circulating tumor DNA analysis is an emerging genotyping strategy that can identify tumorspecific genetic alterations in plasma including mutations and rearrangements. Detection of ROS1 fusions in plasma requires genotyping approaches that cover multiple breakpoints and target a variety of fusion partners. Compared to other molecular subsets of NSCLC, experience with detecting ROS1 genetic alterations in plasma is limited. Methods: To describe the spectrum of ROS1 fusions in NSCLC and determine sensitivity for detecting ROS1 fusions in plasma, we queried the Guardant Health plasma dataset and an institutional tissue database and compared plasma findings to tissue results. In addition, we used the Guar-dant360 NGS assay to detect potential genetic mediators of resistance in plasma from patients with ROS1-positive NSCLC who were relapsing on crizotinib. Results: We detected seven distinct fusion partners in plasma, most of which (n ¼ 6 of 7) were also represented in the tissue dataset. Fusions pairing CD74 with ROS1 predominated in both cohorts (plasma: n ¼ 35 of 56, 63%; tissue: n ¼ 26 of 52, 50%). There was 100% concordance between the specific tissue-and plasmadetected ROS1 fusion for seven patients genotyped with both methods. Sensitivity for detecting ROS1 fusions in plasma at relapse on ROS1-directed therapy was 50%. Six (33%) of 18 post-crizotinib plasma specimens harbored ROS1 kinase domain mutations, five of which were ROS1 G2032R. Two (11%) post-crizotinib plasma specimens had genetic alterations (n ¼ 1 each BRAF V600E and PIK3CA E545K) potentially associated with ROS1independent signaling. Conclusions: Plasma genotyping captures the spectrum of ROS1 fusions observed in tissue. Plasma genotyping is a promising approach to detecting mutations that drive resistance to ROS1-directed therapies.

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ALK Fusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy

Cited by 90 publications

References 56 publications

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Actionable Mutation Profiles of Non-Small Cell Lung Cancer patients from Vietnamese population

Molecular Analysis of Plasma From Patients With ROS1-Positive NSCLC

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