Subscribers Conquer Cancer Foundation 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. The raw data are analysed using software to generate the DNA sequence. This information does not mandate any particular course of medical care. Importance of EGFR Testing . Categories for disclosure include Employment; Leadership; Stock or Other Ownership; Honoraria, Consulting or Advisory Role; Speaker’s Bureau; Research Funding; Patents, Royalties, Other Intellectual Property; Expert Testimony; Travel, Accommodations, Expenses; and Other Relationships. EGFR Mutation Testing in plasma (cfDNA) Introduction. 11 Diagnostics Advisory Committee members and NICE project team, 12 Sources of evidence considered by the Committee. Reprint requests: American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; [email protected]org. Drives the growth and spread of metastatic NSCLC; Can be targeted with therapy specific to the mutation 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. 14. [6] Evidence-based recommendations on testing for epidermal growth factor receptor tyrosine kinase (EGFR–TK) mutations in untreated, locally advanced or metastatic non-small-cell-lung cancer.. Is this guidance up to date? An Expert Panel was convened to endorse clinical practice guideline recommendations that were based on a systematic review of the medical literature. The information therein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. EGFR mutation testing in non-small cell lung cancer (NSCLC). Patents, Royalties, Other Intellectual Property: I have a patent for a cell block device. EGFR mutations are less frequent in squamous cell carcinomas therefore the guidelines suggest testing only those patients with squamous histology whose clinical or demographic characteristics (e.g., absence of smoking history, Asian descent) indicate an increased likelihood of mutations. ASCO Connection This guideline includes the following provisional recommendation, “In patients with a sensitizing EGFR mutation, disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy, and T790M mutation, osimertinib is recommended; if NSCLC lacks the T790M mutation, then chemotherapy is recommended.” 4.12 Pyrosequencing involves extracting DNA from the sample and amplifying it using PCR. detect the presence of EGFR mutations in patients with advanced NSCLC. The total amount of DNA in the sample is assessed by a control assay. Expert Consensus Opinion: Laboratories should use, or have available at an external reference laboratory, clinical lung cancer biomarker molecular testing assays that are able to detect molecular alterations in specimens with as little as 20% cancer cells. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki. 1 Australian Clinical Practice Guidelines for the … National Comprehensive Cancer Network ® (NCCN ®) recommends clinicopathologic features such as ethnicity, smoking status, or histology NOT be used to select patients for EGFR mutational testing 4; BE SURE. Patient information is available at www.cancer.net. However, the ASCO Endorsement Panel did consider the new US Food and Drug Administration (FDA) approval of stand-alone BRAF testing in 2017 during its endorsement process. The searches identified 21 studies for inclusion in the guideline’s update of the 2013 CAP/IASLC/AMP recommendations and 118 articles that met the inclusion criteria for the questions that were new to this update. 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. were Expert Panel co-chairs. Finally, each of the three organizations instituted a separate review process to approve the guideline. The Endorsement Panel agreed with the conclusions of the CAP/IASLC/AMP Expert Panel that there was adequate evidence to support the recommendation for ROS1 testing in patients with advanced-stage adenocarcinoma.1 ROS1 testing has been approved by the FDA based on a 50-person phase I clinical trial that demonstrated a 72% response rate to targeted therapy with crizotinib in patients with ROS1-rearranged non–small-cell lung cancer.5 An additional 32-patient retrospective study demonstrated an 80% rate of response for patients with ROS1-rearranged non–small-cell lung cancer who were treated with crizotinib.6. Detailed results of the scoring for this guideline are available upon request at [email protected]. The therascreen EGFR RGQ PCR Kit then uses 2 technologies for detecting mutations: ARMS (amplification-refractory mutation system) for mutation-specific DNA amplification; and Scorpions for detecting amplified regions. 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. Also, KRAS mutations Mutation correlate with smoking history and poor prognosis. The fluorescence intensity is monitored as a function of time, and analysis software can determine the size of the fragments. The PCR product is then precisely warmed so that the 2 strands of DNA 'melt' apart. ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate. The Japanese guidelines for the testing of KRAS mutations in colorectal cancer have been used for the past 5 years. An EGFR mutation test may be ordered by itself or as part of a panel (a series of tests to detect mutations in other genes such as KRAS, ALK and ROS1). No Recommendation: There is currently insufficient evidence to support a recommendation for or against routine testing for ALK mutational status for patients with lung adenocarcinoma with sensitizing ALK mutations who have progressed after treatment with an ALK-targeted TKI. Therefore, the ASCO panel chose to incorporate this into the recommendations and to recommend BRAF testing for all patients with advanced lung adenocarcinoma. Key Question 1: Which genes should be tested for patients with lung cancer? If EGFR testing is negative, Alkfusion Test should be performed. Molecular testing should be capable of identifying EGFR mutation, anaplastic lymphoma kinase (ALK) gene rearrangements, and, for the first time, ROS1 and programmed death ligand-1 (PD-L1) expression. 8. The clinical practice guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (“ASCO”) to assist providers in clinical decision making. Expert Consensus Opinion: ROS1 IHC may be used as a screening test in patients with advanced lung adenocarcinoma; however, positive ROS1 IHC results should be confirmed by a molecular or cytogenetic method. JCO Global Oncology Maybe you didn’t have a TP53 mutation before, but now you do. EGFR ± ALK testing should be conducted as part of a multiplex/next-generation sequencing. Recommendations for Endorsement That Have Been Reaffirmed or Updated From the 2013 Version, Table 2. 4.3 The limits of detection (the per cent mutant DNA present in a background of wild-type DNA, at which 95% or more replicates were determined positive) reported by the manufacturer for the different mutations ranged from 0.5% to 7.0%. 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. Al Dayel F(1). OpenUrl CrossRef PubMed ↵ Lindeman NI, Cagle PT, Beasley MB, et al. 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. Thus, a standard set of guideline recommendations for liquid biopsy for EGFR mutation testing suitable for the Korean medical community is necessary. It should be noted that sequencing only works well when viable tumour cells constitute 25% or more of the sample. It strongly recommends against evaluating epidermal growth factor receptor (EGFR) expression by immunohistochemistry for selection of patients for EGFR-targeted therapy. Key Question 5: What is the role of testing for circulating cell-free DNA (cfDNA) for patients with lung cancer? Key Question 3: Is molecular testing appropriate for lung cancers that do not have an adenocarcinoma component? Visit www.asco.org/guidelineswiki to provide comments on the guideline or to submit new evidence. The guideline Bottom Line Box was designed to facilitate implementation of recommendations. The sequencing reaction uses dideoxynucleotides labelled with coloured dyes, which randomly terminate DNA synthesis, creating DNA fragments of various lengths. Recommendation: Physicians should use molecular testing for the appropriate genetic targets on either primary or metastatic lung lesions to guide initial therapy selection. A series of enzymes incorporates nucleotides into the complementary DNA strand, generates light proportional to the number of nucleotides added and degrades unincorporated nucleotides. The Panel discussed each recommendation and agreed that the recommendations were generally clear, thorough, and based on the most relevant scientific evidence in this content area and that they present options that will be acceptable to patients. EGFR mutations are the approved predictive biomarker for EGFR TKI therapy. Strong Recommendation: Laboratories should not use epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) testing to select patients for EGFR-targeted TKI therapy. CancerLinQ Expert Consensus Opinion: RET molecular testing is not recommended as a routine stand-alone assay outside the context of a clinical trial. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. It is appropriate to include RET as part of larger testing panels performed either initially or when routine EGFR, ALK, BRAF, and ROS1 testing is negative. Expert Consensus Opinion: Laboratories should ensure that test results that are unexpected, discordant, equivocal, or otherwise of low confidence are confirmed or resolved by using an alternative method or sample. The Diagnostics Advisory Committee considered clinical and cost-effectiveness evidence from a systematic review of epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small-cell lung cancer (NSCLC) prepared by an External Review Group. The type of evidence supporting the recommendations is not specifically stated. Recommendation: ROS1 testing should be performed on all patients with advanced lung adenocarcinoma, irrespective of clinical characteristics. According to ASCO and NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ), newly diagnosed patients with mNSCLC should be tested for sensitizing EGFR mutations and, if positive, treated with an EGFR-TKI 1-3. 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. Testing for EGFR mutations has become a critical first step in personalised treatment of lung cancer. Research Questions 1. 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. An initial methodology review of the Molecular Testing for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors was completed using the Rigour of Development subscale from the AGREE II instrument. 9. Then an ASCO Expert Panel reviewed the content and the recommendations. 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). Most guidelines recommend that all patients with an adenocarcinoma, probable or possible adenocarcinoma should have their tumour tested for EGFR mutations in exons 18-21. 4.13 In fragment length analysis, DNA is extracted from the sample, and then amplified and labelled with fluorescent dye using PCR. All relationships are considered compensated. 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. In cases where an initial activating EGFR mutation was present, T790M mutations were identified by cfDNA in approximately 30% to 40% of cases. 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. 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 For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Expert Consensus Opinion: MET molecular testing is not indicated as a routine stand-alone assay outside the context of a clinical trial. 16. Cancer.Net, ASCO.org A quality assessment of the guidelines on testing for EGFR mutations in patients with advanced NSCLC will also be presented. DOI: 10.1200/JCO.2017.76.7293 Journal of Clinical Oncology - CAP/IASLC/AMP chose to update the joint guideline on molecular testing to incorporate advances in the field that have occurred since publication of the previous version.2 ASCO endorses this update with minor modifications by the ASCO Expert Panel, as presented in the Bottom Line Box and discussed here. These changes are documented as melt curves and the presence or absence of a mutation can be reported. 12. Molecular testing of genomic alterations in the EGFR gene is critical to personalized treatment decisions for patients with advanced non-small cell lung cancer (NSCLC). 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. 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. The Diagnostics Advisory Committee considered clinical and cost-effectiveness evidence from a systematic review of epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small-cell lung cancer (NSCLC) prepared by an External Review Group. B). EGFR mutation testing rates were high for newly diagnosed patients (81%) but rates varied between regions For nearly one in four patients tested for EGFR mutations, results were not available in time to guide treatment decisions – with significant differences between regions (range: 12% in … Tumor testing for mutations in the epidermal growth factor receptor (EGFR) gene is indicated for all newly diagnosed, metastatic lung cancer patients, who may be candidates for first-line treatment with an EGFR tyrosine kinase inhibitor. The goal of guideline endorsement is to increase the number of high-quality, ASCO-vetted guidelines available to the ASCO membership. 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. OBJECTIVE: We aimed to determine population-based trends in the real-world uptake and impact in routine practice of these recently updated testing guidelines. Acti-vating mutations in KRAS gene were shown to be of negative predictive value to TKIs. (4) What testing is indicated for patients with a targetable mutation who have relapsed on targeted therapy? G.P.K. Overall, the ASCO Expert Panel agreed with the recommendations as stated in the guideline, with minor qualifications, which are outlined in the Bottom Line Box and described in the Endorsement Recommendation section. Permissions, Authors 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. Strong Recommendation: In patients with lung adenocarcinoma who harbor sensitizing EGFR mutations and have progressed after treatment with an EGFR-targeted TKI, physicians must use EGFR T790M mutational testing when selecting patients for third-generation EGFR-targeted therapy. 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. Don’t settle for an unknown molecular status Patients with advanced lung cancer (ie, stage IV or other incurable lung cancer). 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. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions. 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]. 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 4: What testing is indicated for patients with targetable mutations who have relapsed on targeted therapy? 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. Testing for EGFR mutations and rearrangements involving the ALK and ROS1 genes are now considered mandatory in most European countries. First-lineTest for sensitizing EGFR mutations. 4.7 The limits of detection (lowest amount of DNA [nanogram] per reaction well to achieve a 95% or higher 'mutation detected' rate), as reported by the manufacturer for the different mutations, ranged from 0.78 nanograms to 3.13 nanograms of DNA per well. This guideline will be distributed widely through the ASCO Practice Guideline Implementation Network. It is appropriate to include ERBB2 (HER2) mutation analysis as part of a larger testing panel performed either initially or when routine EGFR, ALK, BRAF, and ROS1 testing is negative. However, the FDA has since granted approval for stand-alone BRAF testing. 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