{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:38:20Z","timestamp":1787027900273,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>ROS1 rearrangements are identified in 1\u20132% of lung adenocarcinoma cases, and reflex testing is guideline-recommended. We developed a decision model for population-based ROS1 testing from a Canadian public healthcare perspective to determine the strategy that optimized detection of true-positive (TP) cases while minimizing costs and turnaround time (TAT). Eight diagnostic strategies were compared, including reflex single gene testing via immunohistochemistry (IHC) screening, fluorescence in-situ hybridization (FISH), next-generation sequencing (NGS), and biomarker-informed (EGFR\/ALK\/KRAS wildtype) testing initiated by pathologists and clinician-initiated strategies. Reflex IHC screening with FISH confirmation of positive cases yielded the best results for TAT, TP detection rate, and cost. IHC screening saved CAD 1,000,000 versus reflex FISH testing. NGS was the costliest reflex strategy. Biomarker-informed testing was cost-efficient but delayed TAT. Clinician-initiated testing was the least costly but resulted in long TAT and missed TP cases, highlighting the importance of reflex testing. Thus, reflex IHC screening for ROS1 with FISH confirmation provides a cost-efficient strategy with short TAT and maximizes the number of TP cases detected.<\/jats:p>","DOI":"10.3390\/curroncol28050284","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:19:26Z","timestamp":1629937166000},"page":"3268-3279","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Reflex ROS1 IHC Screening with FISH Confirmation for Advanced Non-Small Cell Lung Cancer\u2014A Cost-Efficient Strategy in a Public Healthcare System"],"prefix":"10.3390","volume":"28","author":[{"given":"Maisam","family":"Makarem","sequence":"first","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada"},{"name":"Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doreen A.","family":"Ezeife","sequence":"additional","affiliation":[{"name":"Tom Baker Cancer Centre, University of Calgary, Calgary, AB T2N 4N2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9927-4914","authenticated-orcid":false,"given":"Adam C.","family":"Smith","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5700-2889","authenticated-orcid":false,"given":"Janice J. N.","family":"Li","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer H.","family":"Law","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9160-5405","authenticated-orcid":false,"given":"Ming-Sound","family":"Tsao","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha B.","family":"Leighl","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada"},{"name":"Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.5858\/arpa.2017-0388-CP","article-title":"Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology","volume":"142","author":"Lindeman","year":"2018","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1634\/theoncologist.2013-0095","article-title":"Novel Targets in Non-Small Cell Lung Cancer: ROS1 and RET Fusions","volume":"18","author":"Gainor","year":"2013","journal-title":"Oncologist"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1200\/JCO.2011.35.6345","article-title":"ROS1 rearrangements define a unique molecular class of lung cancers","volume":"30","author":"Bergethon","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_4","unstructured":"(2020, January 24). Regulatory Decision Summary\u2013Xalkori\u2013Health Canada. Available online: https:\/\/hpr-rps.hres.ca\/reg-content\/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00285."},{"key":"ref_5","unstructured":"(2021, May 16). ROZLYTREK (Entrectinib) Product Monograph. Available online: https:\/\/www.rochecanada.com\/content\/dam\/rochexx\/roche-ca\/products\/ConsumerInformation\/MonographsandPublicAdvisories\/Rozlytrek\/Rozlytrek_PM_E.pdf."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1093\/annonc\/mdz131","article-title":"Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): Updated results, including overall survival, from PROFILE 1001","volume":"30","author":"Shaw","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1097\/PAS.0b013e3182960fa7","article-title":"ROS1 Immunohistochemistry for Detection of ROS1-Rearranged Lung Adenocarcinomas","volume":"37","author":"Sholl","year":"2013","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"45","DOI":"10.2147\/LCTT.S120172","article-title":"Detection of ROS1 rearrangement in non-small cell lung cancer: Current and future perspectives","volume":"8","author":"Rossi","year":"2017","journal-title":"Lung Cancer Targets Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1200\/JOP.18.00035","article-title":"Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement Summary of the College of American Pathologists\/International Association for the Study of Lung Cancer\/Association for Molecular Pathology Clinical Practice Guideline Update","volume":"14","author":"Kalemkerian","year":"2018","journal-title":"J. Oncol. Pract."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"iv192","DOI":"10.1093\/annonc\/mdy275","article-title":"Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"29","author":"Planchard","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1093\/annonc\/mdy554","article-title":"Pan-Asian adapted Clinical Practice Guidelines for the management of patients with metastatic non-small-cell lung cancer: A CSCO\u2013ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS","volume":"30","author":"Wu","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1200\/JCO.20.03570","article-title":"Therapy for Stage IV Non\u2013Small-Cell Lung Cancer with Driver Alterations: ASCO and OH (CCO) Joint Guideline Update","volume":"39","author":"Hanna","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"254","DOI":"10.6004\/jnccn.2021.0013","article-title":"NCCN Guidelines Insights: Non\u2013Small Cell Lung Cancer, Version 2.2021","volume":"19","author":"Ettinger","year":"2021","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_14","unstructured":"(2021, August 22). Rozlytrek\u2014Notice of Compliance with Conditions\u2014Qualifying Notice. Available online: https:\/\/www.canada.ca\/en\/health-canada\/services\/drugs-health-products\/drug-products\/notice-compliance\/conditions\/rozlytrek-qualifying-notice.html."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Rautenberg, T., Gerritsen, A., and Downes, M. (2020). Health Economic Decision Tree Models of Diagnostics for Dummies: A Pictorial Primer. Diagnostics, 10.","DOI":"10.3390\/diagnostics10030158"},{"key":"ref_16","unstructured":"Canadian Cancer Society\u2019s Advisory Committee on Cancer Statistics (2017). Canadian Cancer Statistics, Special Topic: Pancreatic Cancer, Canadian Cancer Society."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cheung, C.C., Smith, A.C., Albadine, R., Bigras, G., Bojarski, A., Couture, C., Cutz, J.-C., Huang, W.-Y., Ionescu, D., and Itani, D. (2021). Canadian ROS proto-oncogene 1 Study (CROS) for multi-institutional implementation of ROS1 testing in non-small cell lung cancer. Lung Cancer, in press.","DOI":"10.1016\/j.lungcan.2021.08.003"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1016\/j.jtho.2017.08.002","article-title":"Recent Advances in Targeting ROS1 in Lung Cancer","volume":"12","author":"Lin","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Shan, L., Lian, F., Guo, L., Qiu, T., Ling, Y., Ying, J., and Lin, D. (2015). Detection of ROS1 Gene Rearrangement in Lung Adenocarcinoma: Comparison of IHC, FISH and Real-Time RT-PCR. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120422"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.jtho.2016.03.019","article-title":"A Validation Study for the Use of ROS1 Immunohistochemical Staining in Screening for ROS1 Translocations in Lung Cancer","volume":"11","author":"Viola","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.prp.2018.02.001","article-title":"Targeted next-generation-sequencing for reliable detection of targetable rearrangements in lung adenocarcinoma-a single center retrospective study","volume":"214","author":"Velizheva","year":"2018","journal-title":"Pathol. Res. Pract."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lanman, R.B., Mortimer, S.A., Zill, O.A., Sebisanovic, D., Lopez, R., Blau, S., Collisson, E.A., Divers, S.G., Hoon, D., and Kopetz, S. (2015). Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140712"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1097\/FPC.0000000000000061","article-title":"Cancer patients\u2019 acceptance, understanding, and willingness-to-pay for pharmacogenomic testing","volume":"24","author":"Cuffe","year":"2014","journal-title":"Pharm. Genom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4043","DOI":"10.1002\/cncr.32422","article-title":"Anaplastic lymphoma kinase 5A4 immunohistochemistry as a diagnostic assay in lung cancer: A Canadian reference testing center\u2019s results in population-based reflex testing","volume":"125","author":"Fiset","year":"2019","journal-title":"Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/bjc.2016.22","article-title":"Clinical impact of mutation fraction in epidermal growth factor receptor mutation positive NSCLC patients","volume":"114","author":"Martin","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4691","DOI":"10.1158\/1078-0432.CCR-19-0624","article-title":"Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non\u2013small Cell Lung Cancer","volume":"25","author":"Leighl","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1097\/JTO.0b013e31829f6a43","article-title":"Challenges to implementation of an epidermal growth factor receptor testing strategy for non-small-cell lung cancer in a publicly funded health care system","volume":"8","author":"Ellis","year":"2013","journal-title":"J. Thorac. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nrc3580","article-title":"Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology","volume":"13","author":"Hallberg","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"CRA7506","DOI":"10.1200\/jco.2011.29.18_suppl.cra7506","article-title":"Identification of driver mutations in tumor specimens from 1000 patients with lung adenocarcinoma: The NCI\u2019s Lung Cancer Mutation Consortium (LCMC)","volume":"29","author":"Kris","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s40880-017-0187-6","article-title":"Proportion and clinical features of never-smokers with non-small cell lung cancer","volume":"36","author":"Cho","year":"2017","journal-title":"Chin. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1093\/jnci\/djw295","article-title":"Proportion of Never-Smoker Non\u2013Small Cell Lung Cancer Patients at Three Diverse Institutions","volume":"109","author":"Pelosof","year":"2017","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1590\/S1807-59322011001100005","article-title":"Non-small cell lung cancer in never smokers: A clinical entity to be identified","volume":"66","author":"Santoro","year":"2011","journal-title":"Clinics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1080\/0284186X.2017.1287944","article-title":"Lung cancer in never-smokers\u2013what are the differences?","volume":"56","author":"Dias","year":"2017","journal-title":"Acta Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"22559","DOI":"10.18632\/oncotarget.25176","article-title":"Lung cancer in never smokers from the Princess Margaret Cancer Centre","volume":"9","author":"Korpanty","year":"2018","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.16.00010","article-title":"ROS1 Gene Fusion in Advanced Lung Cancer in Women: A Systematic Analysis, Review of the Literature, and Diagnostic Algorithm","volume":"2017","author":"Marchetti","year":"2017","journal-title":"JCO Precis. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3747\/co.24.3495","article-title":"Improving molecular testing and personalized medicine in non-small-cell lung cancer in Ontario","volume":"24","author":"Lim","year":"2017","journal-title":"Curr. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1093\/annonc\/mdu145","article-title":"Second ESMO consensus conference on lung cancer: Pathology and molecular biomarkers for non-small-cell lung cancer","volume":"25","author":"Kerr","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/modpathol.2013.192","article-title":"Immunohistochemical detection of ROS1 is useful for identifying ROS1 rearrangements in lung cancers","volume":"27","author":"Yoshida","year":"2014","journal-title":"Mod. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1111\/his.13076","article-title":"Screening forROS1gene rearrangements in non-small-cell lung cancers using immunohistochemistry with FISH confirmation is an effective method to identify this rare target","volume":"70","author":"Selinger","year":"2017","journal-title":"Histopathology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1093\/annonc\/mdv208","article-title":"Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer","volume":"26","author":"Lim","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"523","DOI":"10.3390\/curroncol28010053","article-title":"Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults","volume":"28","author":"Bebb","year":"2021","journal-title":"Curr. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Russo, A., Franchina, T., Ricciardi, G., Battaglia, A., Picciotto, M., and Adamo, V. (2019). Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061431"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"24172","DOI":"10.18632\/oncotarget.8138","article-title":"Genomic profiling of lung adenocarcinoma patients reveals therapeutic targets and confers clinical benefit when standard molecular testing is negative","volume":"7","author":"Lim","year":"2016","journal-title":"Oncotarget"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1158\/1078-0432.CCR-14-2683","article-title":"Broad, Hybrid Capture-Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches","volume":"21","author":"Drilon","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.lungcan.2019.11.022","article-title":"Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis","volume":"139","author":"Tan","year":"2020","journal-title":"Lung Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.18.00356","article-title":"Economic Impact of Next-Generation Sequencing Versus Single-Gene Testing to Detect Genomic Alterations in Metastatic Non\u2013Small-Cell Lung Cancer Using a Decision Analytic Model","volume":"2019","author":"Pennell","year":"2019","journal-title":"JCO Precis. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.18.00211","article-title":"Real-World Utility of an Amplicon-Based Next-Generation Sequencing Liquid Biopsy for Broad Molecular Profiling in Patients with Advanced Non\u2013Small-Cell Lung Cancer","volume":"3","author":"Remon","year":"2019","journal-title":"JCO Precis. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1093\/annonc\/mdy512","article-title":"Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping","volume":"30","author":"Zugazagoitia","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Rolfo, C., Mack, P., Scagliotti, G.V., Aggarwal, C., Arcila, M.E., Barlesi, F., Bivona, T., Diehn, M., Dive, C., and Dziadziuszko, R. (2021). Liquid Biopsy for Advanced Non-Small Cell Lung Cancer: A Consensus Statement from The International Association for the Study of Lung Cancer (IASLC). J. Thorac. Oncol.","DOI":"10.1016\/j.jtho.2021.06.017"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1200\/PO.19.00335","article-title":"Multicenter Validation Study to Implement Plasma Epidermal Growth Factor Receptor T790M Testing in Clinical Laboratories","volume":"2020","author":"Leighl","year":"2020","journal-title":"JCO Precis. Oncol."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/28\/5\/284\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:51:58Z","timestamp":1760165518000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/28\/5\/284"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,25]]},"references-count":50,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["curroncol28050284"],"URL":"https:\/\/doi.org\/10.3390\/curroncol28050284","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,25]]}}}