EGFR mutation testing based on plasma ctDNA in combination with tumor tissue (when required and feasible) is necessary to decide whether TKIs can be used in a patient diagnosed with NSCLC. Fragment length analysis to detect exon 19 deletions and real-time PCR to detect the exon 21 mutation L858R are then used on samples that produce a negative result using Sanger sequencing. The Expert Panel wishes to thank Scott Tagawa, MD, MS, Paul Hesketh, MD, and the Clinical Practice Guidelines Committee for their thoughtful reviews and insightful comments on this guideline. Idylla TM EGFR provides fast, reliable information on the EGFR tumor mutation status reducing the clinical turnaround time from sample to result report significantly. 4.13 In fragment length analysis, DNA is extracted from the sample, and then amplified and labelled with fluorescent dye using PCR. Procedure addressed by this guideline Procedure code EGFR Targeted Mutation Analysis 81235 What is EGFR testing in non-small cell lung cancer Definition Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and is associated with exposure to cigarette smoking.1 Recommendations are also provided for testing methods for lung cancers that have a nonadenocarcinoma non–small-cell component, for patients with targetable mutations who have relapsed on targeted therapy, and for testing the presence of circulating cell-free DNA. Recommendation: ROS1 testing should be performed on all patients with advanced lung adenocarcinoma, irrespective of clinical characteristics. A region of DNA with a mutation will 'melt' at a different temperature from the same region of DNA without a mutation. Further, an earlier version of the therascreen EGFR PCR Kit, which did include an assay for T790M, was used to analyse all samples in the IPASS trial. The molecular testing guideline was reviewed for developmental rigor by methodologists. EGFR ± ALK testing should be conducted as part of a multiplex/next-generation sequencing. The ASCO Post The first EGFR mutation test was commercialized in 2005, however EGFR testing recommendations were not included in the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines until 2010 [9, 10]. Additional searches were conducted in Scopus (Amsterdam, the Netherlands) to identify publications not indexed in MEDLINE. Expert Consensus Opinion: KRAS molecular testing is not indicated as a routine stand-alone assay as a sole determinant of targeted therapy. Each section, including the Introduction, Methods, Results, Recommendations, Conclusions, and Supplemental Material were clear and well referenced from the systematic review. Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. February 5, 2018. Despite sensitive assays, detection of circulating tumour deoxyribonucleic acid (ctDNA) is variable and influenced by clinical factors. Clinical guidelines recommend routine mutation testing and identification of EGFR mutations in all patients with NSCLC of non-squamous cell carcinoma (non-SCC) histology to identify who may benefit from approved EGFR-TKIs [6,7,8]. If they have an EGFR mutation right now and the patient relapses in 2, 3, or 4 years, you are still going to see that EGFR driver mutation. The limit of detection claimed by the manufacturer for the therascreen EGFR PCR Kit is 1% mutant DNA in a background of wild-type DNA. The PCR product is then cleaned up and sequenced in both forward and reverse directions. Expert Consensus Opinion: BRAF testing should be performed on all patients with advanced lung adenocarcinoma, irrespective of clinical characteristics. Comparison of CAP/IASLC/AMP Recommendations and ASCO Endorsed Recommendations. In many oncology services, BRAF V600E mutations as testing is also mandated as first-line BRAF/MEK inhibitors are more widely approved. Remember, those are clonal mutations. The fluorescence intensity is monitored as a function of time, and analysis software can determine the size of the fragments. For updates and the most recent information and to submit new evidence, please visit www.asco.org/thoracic-cancer-guidelines and the ASCO Guidelines Wiki (www.asco.org/guidelineswiki). Key Question 5: What is the role of testing for circulating cell-free DNA (cfDNA) for patients with lung cancer? When CAP/IASLC/AMP originally drafted updated recommendations, BRAF testing had not yet been approved by the FDA. JCO Oncology Practice Meeting Abstracts, About published online before print 911-919. However, a detailed discussion of this aspect is beyond the scope of the current guideline and endorsement. Recommendation: Laboratories testing for EGFR T790M mutation in patients with secondary clinical resistance to EGFR-targeted kinase inhibitors should deploy assays capable of detecting EGFR T790M mutations in as little as 5% of viable cells. Institutions Additional information, including a Methodology Supplement, slide sets, clinical tools and resources, and links to patient information at www.cancer.net, is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki. This endorsement reinforces the recommendations provided in the CAP/IASLC/AMP guideline and acknowledges the effort put forth by CAP/IASLC/AMP to produce an evidence-based guideline informing practitioners who care for patients with lung cancer. 1–4 Diagnostic tests are available that look for the presence or absence of mutations in tumour DNA encoding the EGFR gene. Expert Consensus Opinion: Physicians may use cfDNA methods to identify EGFR T790M mutations in patients with lung adenocarcinoma who have progression or secondary clinical resistance to EGFR-targeted TKIs; testing of the tumor sample is recommended if the plasma result is negative. Optimal treatment starts with a full molecular profile ~1 in 3 patients with metastatic lung adenocarcinoma has an actionable mutation, a genetic alteration that 1-4. The PCR product is then precisely warmed so that the 2 strands of DNA 'melt' apart. The three participating organizations convened an Expert Panel that included practicing pathologists and oncologists with expertise in lung carcinoma, which met three times by teleconference and two times in person to develop the scope, draft recommendations, review and respond to solicited feedback, and assess the quality of evidence. This article considers the use of pretest probability in non-small cell lung cancer (NSCLC) and how its use in EGFR testing has helped establish clinical guidelines on selecting patients for EGFR testing. Newest Articles Research Questions 1. Following this modification to the CAP/IASLC/AMP recommendations, the ASCO Expert Panel also chose to add BRAF testing to the routine tests listed in recommendations 4 through 7 for other molecular markers as well as to recommendation 9 for multiplexed genetic sequencing panels. 4.17 High-resolution melt analysis is a screening method of mutation detection. Recommendation: Laboratories testing for EGFR T790M mutation in patients with secondary clinical resistance to EGFR-targeted kinase inhibitors should deploy assays capable of detecting EGFR T790M mutations in as little as 5% of viable cells. What is the clinical effectiveness of epidermal growth factor receptor mutation analysis using polymerase chain reaction for All members of the Expert Panel completed ASCO’s disclosure form, which requires disclosure of financial and other interests, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. 1,2 In patients diagnosed with advanced non-small cell lung cancer (NSCLC), the most common EGFR mutations are exon 19 deletions and an L858R point mutation in exon 21. Key Question 2: What methods should be used to perform molecular testing? Mutations in the EGFR gene that lead to overexpression of the protein have been associated with an adverse cancer prognosis. (5) What is the role of testing for circulating cell-free DNA (cfDNA) for patients with lung cancer? However, the testing landscape is complex. If EGFR testing is negative, Alkfusion Test should be performed. Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard of care in EGFR mutation–positive non–small cell lung cancer, most patients will develop resistance to first-line therapy with use of these agents.. Clinical efficacy, safety, and cost-effectiveness are important considerations when selecting a first- or subsequent-line EGFR TKI treatment. PURPOSE To compare the results of plasma cell-free DNA (cfDNA) droplet digital PCR (ddPCR) and next-generation sequencing (NGS) on detection of epidermal growth factor receptor (EGFR) primary activating mutations and p.T790M with results of tissue analysis in patients with EGFR mutated non–small-cell lung cancer. The DNA sequence is determined from the resulting pyrogram trace. This update clarifies that any sample with adequate cellularity and preservation may be tested and that analytical methods must be able to detect mutation in a sample with as little as 20% cancer cells. 4.10 Sanger sequencing of exons 18 to 21 is used as an initial test to screen for mutations. A comparison of the CAP/IASLC/AMP and ASCO recommendations can be found in Tables 1 and 2. [2,5] Still, discordance rates of 20% to 30% when comparing cfDNA testing with tissue-based testing have been reported. Results: Overall, 782 patients (1 L = 435; 2 L+ =347) were included. Clinical Practice Guideline Committee approval: October 2, 2017. The ASCO Expert Panel determined that the recommendations from the CAP/IASLC/AMP molecular testing guideline are clear, thorough, and based upon the most relevant scientific evidence. (March 20, 2018) Introduction Guidelines for management of non-small cell lung cancer (NSCLC) strongly recommend EGFR mutation testing. Since 2013, clinical practice guidelines recommend EGFR mutation testing of non-squamous NSCLC to select advanced-stage patients for first-line treatment using EGFR-TKIs. 9 Because the ASCO Endorsement Panel was aware that the CAP/IASLC/AMP Expert Panel would be continuously monitoring the literature for signals that the guideline should be updated, the ASCO Panel chose not to conduct an additional review of the literature as part of this endorsement process. The second step is PCR amplification and detection of EGFR‑TK mutations using complementary primer pairs and fluorescently labelled probes. Diagnostics guidance [DG9] The PCR product is then prepared for analysis by heat denature and analysed using capillary electrophoresis under non-denaturing conditions. 4.11 This test strategy combines in-house methods of pyrosequencing (to detect point mutations) with in-house methods of fragment length analysis (to detect deletions and insertions) for EGFR‑TK mutation detection. 4.9 In this test strategy, Sanger sequencing of exons 18 to 21 (described in section 4.19) is used to detect EGFR‑TK mutations in test samples with more than 30% tumour cells, and the cobas EGFR Mutation Test (described in sections 4.5 to 4.7) is used to detect EGFR‑TK mutations in samples with less than 30% tumour cells. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. In cases where an initial activating EGFR mutation was present, T790M mutations were identified by cfDNA in approximately 30% to 40% of cases. Expected median survival for patients with advanced lung cancer is approximately 1 year; however, treatment with targeted tyrosine kinase inhibitor (TKI) therapy can improve outcomes for patients who have certain molecular alterations that can be identified by molecular testing.1 In 2013, the College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) issued a joint guideline for molecular testing for the selection of patients with lung cancer for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) TKIs.2 ASCO endorsed that guideline,3 which included recommendations for selecting patients for testing, samples to be tested, and testing methodology. There was discussion within the Expert Panel and the ASCO Clinical Practice Guidelines Committee regarding the cost of multiplexed genomic sequencing panels, and it was concluded that multiplexed panels are likely to be more efficient in terms of cost and tumor tissue requirements. Methods. ASCO Daily News Therefore, the ASCO panel chose to incorporate this into the recommendations and to recommend BRAF testing for all patients with advanced lung adenocarcinoma. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki. An EGFR mutation does not refer to a single gene abnormality. 8. Expert Consensus Opinion: ERBB2 (HER2) molecular testing is not indicated as a routine stand-alone assay outside the context of a clinical trial. detect the presence of EGFR mutations in patients with advanced NSCLC. CancerLinQ This study aims to explore current testing practices, logistics of testing, types of EGFR mutation, and prevalence of EGFR mutations in patients with advanced NSCLC … Mutation testing and subsequent therapies following first-/second-generation EGFR-TKI were described. Strong Recommendation: Laboratories should not use epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) testing to select patients for EGFR-targeted TKI therapy. JCO Precision Oncology, ASCO Educational Book With regard to osimertinib, a third-generation EGFR TKI that was approved by the China Food and Drug Administration as second-line treatment of EGFR-mutant advanced NSCLC, the Chinese guidelines recommend that the T790M mutation should be detected by … Also, KRAS mutations Mutation correlate with smoking history and poor prognosis. This older version uses the same methods as the newer therascreen EGFR RGQ PCR Kit, and detects 28 of the same mutations, but is not designed to detect the resistance mutation T790M. The full CAP/IASLC/AMP guideline is available at http://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2017-0388-CP. The first EGFR mutation test was commercialized in 2005, however EGFR testing recommendations were not included in the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines until 2010 [9, 10]. Research paper by Hyo Sup HS Shim, Jin-Haeng JH Chung, Lucia L Kim, Sunhee S Chang, Wan-Seop WS Kim, Geon Kook GK Lee, Soon-Hee SH Jung, Se Jin SJ Jang This may particularly be true for the statements that lack robust evidence and are either primarily consensus opinions or for statements that have no recommendation for or against a particular issue. : pathologists may use either cell blocks or smear preparations as suitable specimens for cancer! 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