Standardizing Biomarker Testing for Canadian Patients with Advanced Lung Cancer
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STANDARDIZING MOLECULAR TESTING FOR CANADIAN PATIENTS WITHPRACTICE ADVANCED NSCLC, GUIDELINE Melosky et al. Standardizing biomarker testing for Canadian patients with advanced lung cancer † ‡ § B. Melosky MD FRCPC*, N. Blais MD MSc FRCPC , P. Cheema MD Mbiotech FRCPC , C. Couture MD MSc , || # # R. Juergens MD PhD , S. Kamel-Reid PhD FACMG , M.-S. Tsao MD FPCPC , P. Wheatley-Price BSc MB ChB FRCP †† (UK) MD**, Z. Xu MD FRCPC FCAP , and D.N. Ionescu MD FRCPC FCAP* ABSTRACT Background The development and approval of both targeted and immune therapies for patients with advanced non-small cell lung cancer (nsclc) has significantly improved patient survival rates and quality of life. Biomarker testing for patients newly diagnosed with nsclc, as well as for patients progressing after treatment with epidermal growth factor receptor (EGFR) inhibitors, is the standard of care in Canada and many parts of the world. Methods A group of thoracic oncology experts in the field of thoracic oncology met to describe the standard for biomarker testing for lung cancer in the Canadian context, focusing on evidence-based recommendations for standard- of-care testing for EGFR, anaplastic lymphoma kinase (ALK), ROS1, BRAF V600 and programmed death-ligand (PD- L1) at the time of diagnosis of advanced disease and EGFR T790M upon progression. As well, additional exploratory molecules and targets are likely to impact future patient care, including MET exon 14 skipping mutations and whole gene amplification, RET translocations, HER2 (ERBB2) mutations, NTRK, RAS (KRAS and NRAS), as well as TP53. Results The standard of care must include the incorporation of testing for novel biomarkers as they become available, as it will be difficult for national guidelines to keep pace with technological advances in this area. Conclusions Canadian patients with nsclc should be treated equally; the minimum standard of care is defined in this paper. Key Words Biomarker testing, lung cancer, EGFR, ALK, ROS1, BRAF V600X, MET, PD-L1, Canada Curr Oncol. 2018 Feb;25(1):73-82 www.current-oncology.com INTRODUCTION been identified in lung cancer2. The Lung Cancer Mutation Consortium found that two-thirds of non-small cell lung According to Canadian Cancer Statistics 20171, lung cancer cancer (nsclc) patients with adenocarcinomas (adcs) have is one of the most common malignancies, accounting for an oncogenic driver, and that when these patients receive 14% of all newly diagnosed cancers in both genders. To- the corresponding targeted agent, they will have improved bacco consumption is still the most important risk factor survival and quality of life3. Thus, biomarker testing is for this disease. Incidence rates for lung cancer also dif- essential to identify patients eligible for targeted therapy. fer across the country for the same reason1. Lung cancer Molecular testing is reserved for those mutations with remains the leading cause of cancer-related mortality, evidence to support their characterization as predictive accounting for 26% of all cancer deaths in both genders biomarkers indicative of therapeutic efficacy4. in 2017. The purpose of this article is to articulate the stan- Our understanding of lung cancer has advanced over dard-of-care molecular testing for advanced lung cancer the last decade. The development and approval of small- in the Canadian context, focusing specifically on action- molecule tyrosine kinase inhibitors (tkis) and immune able driver mutations. Key pathology issues with sample therapies has significantly improved patient outcomes. selection and analytics are described elsewhere5. A key A multitude of actionable gene alterations have already challenge in this area is the rapid change with respect to Correspondence to: Dr. Barbara Melosky, British Columbia Cancer Agency, Vancouver Centre, 600-10th Avenue West, Vancouver, BC V5Z 4E6 E-mail: [email protected] n DOI: https://doi.org/10.3747/co.25.3867 Current Oncology, Vol. 25, No. 1, February 2018 © 2018 Multimed Inc. 73 STANDARDIZING MOLECULAR TESTING FOR CANADIAN PATIENTS WITH ADVANCED NSCLC, Melosky et al. new targets and technologies, and recommendations need Genetic alterations can be found in all nsclc his- to accommodate new and emerging data. Suggestions for tologies, including adc, sqcc, asqc and lcc, with various general improvements for molecular testing in the Cana- mutation rates and in current, former, and never-smokers. dian landscape will also be extended and discussed. This Although associations have been made between specific project was initiated by Lung Cancer Canada, Canada’s gene mutations and ethnic background, sex, age, and smok- only charitable organization solely focused on lung cancer. ing history, none of these clinical characteristics are strong enough to enable patient selection6. Therefore, all patients METHODS with nsclc ideally need to be tested for gene mutations re- gardless of clinical characteristics. Only genetic alterations Process and Panel Composition with an associated targeted therapy are recommended as Lung Cancer Canada selected an Expert Committee from standard-of-care testing. across Canada, on the basis of interest and expertise. The The following biomarkers should be considered as Expert Committee identified and reviewed lung cancer standard of care today for every patient diagnosed with molecular testing guidelines, meta-analyses, and other advanced lung cancer across the country (Table I). relevant documents from the literature to determine which standards are appropriate for Canadian patients. During EGFR molecular testing at diagnosis the review process, the Expert Committee discussed points of disagreement and reached consensus for testing recom- Recommendation 1 mendations suitable for the Canadian context. All patients with advanced non-squamous nsclc as well This article describes biomarker testing for advanced as non-smokers with other histology (squamous and small nsclc only. More specifically, only actionable mutations cell carcinoma) need to be tested for the presence of EGFR and immunotherapy will be discussed. mutations at diagnosis. Identifying both the common EGFR mutations and any individual mutations that are reported STANDARD-OF-CARE BIOMARKER TESTING with a frequency of at least 1% of EGFR-mutated lung ad- IN CANADA: EGFR, ALK, ROS1, PD-L1 AND enocarcinomas is standard of care. EGFR T790M The epidermal growth factor receptor (EGFR) gene en- codes a receptor tyrosine kinase. Epidermal growth factor In the era of targeted and immune therapies, lung cancer receptor mutations were the first targetable mutations to diagnosis is based on a combination of histological, im- be discovered in lung cancer. They are present in approxi- munohistochemical, and molecular analysis6. Multidisci- mately 20% of patients with nsclc in Canada8 and range plinary collaboration should aim at, first, achieving precise from 35 to 51% in East Asia9-12. Two EGFR mutations in lung histopathological subtyping and then biomarker testing, cancer are considered common: 90% of epidermal growth both in a timely manner. To achieve these goals, complete factor receptor mutations are either the exon 21 L858R point clinical information should be provided to pathologists mutation or an exon 19 deletion (del19)13. Uncommon mu- on pathology request forms by clinicians to help limit the tations which are present at low frequency, and which also number of immunohistochemical stains needed to make sensitize tumours to EGFR tkis include the exon 18 G719X, the diagnosis with precise histopathological subtype in exon 20 S768I, and exon 21 L861Q point mutations14-16. Not order to maximize the amount of residual tissue available all EGFR mutations confer sensitivity to EGFR tkis. Exon for subsequent biomarker testing. In the same manner, 20 T790M mutation and deletions are almost invariably pathologists should use a limited panel of diagnostic im- resistant to EGFR tkis17. Gene amplifications and other munohistochemical markers (i.e., ttf-1 and p40) to resolve types of mutations can be present; however these are not most cases. On small biopsies and cytology specimens, this currently detected with standard testing. allows for obtaining a diagnosis of adc, squamous cell car- Methods for detecting EGFR mutations include poly- cinoma (sqcc) or non-small cell carcinoma not otherwise merase chain reaction (pcr)-based methods on either specified nscc-nos( ) in the vast majority of cases in a matter formalin-fixed, paraffin-embeddedffpe ( ) tissue or fresh, of days. In the past, only samples with adc histology were frozen, or alcohol-fixed specimens. Other tissue treat- sent for testing. Standard practice now consists of evaluat- ments (e.g., acidic or heavy metal fixatives, mordants, or ing non-squamous histologies (i.e., adc, nscc-nos, adeno- decalcifying solutions) should be avoided in specimens squamous carcinoma [asqc], and large cell carcinoma [lcc]) destined for EGFR testing. Cytology samples are suitable for targetable molecular alterations. Never-smokers with for EGFR testing, with cell blocks being widely preferred other histologies (i.e., sqcc and small cell lung carcinoma over smears. A recent study compared the reliability of [sclc]) should also be considered for testing. fine needle aspirations (cytology) and core needle biopsy Lung cancers have a very high number of point muta- specimens (histology specimens) for molecular testing tions, chromosomal rearrangements, and copy number using next generation sequencing (ngs). The study dem- changes compared with other tumours7.