When should we order a next generation sequencing test in a patient with cancer?

Technical advances in genome sequencing and the implementation of next-generation sequencing (NGS) in clinical oncology have paved the way for individualizing cancer patient therapy based on molecular profiles. When and how to use NGS testing in the clinic is at present an unsolved issue, although new research results provide evidence favoring this approach in some types of advanced cancer. Clinical research is evolving rapidly, from basket and umbrella trials to adaptative design precision oncology clinical studies, and genomic and molecular data often displace the classical clinical validation procedures of biomarkers. In this context, physicians must be aware of the clinical evidence behind these new biomarkers and NGS tests available, in order to use them in the right moment, and with a critical point of view. This review will present the status of currently available targeted drugs that can be effective based on actionable molecular alterations, and the NGS tests that are currently available, offering a practical guide for the application of Clinical Precision Oncology in the real world routine practice.probability of identifying a targetable mutation is low[62], the canceris in early stages with recognized and effective forms of standardtreatment, or the patient has an irreversible disease with very shortlife-expectancy. As with any other laboratory test, doctors andpatients must be sure before ordering an NGS test that its result willhave an impact of the therapeutic plan. In any case, standard single-gene molecular testing must always be performed when indicated,since important therapeutic targets might be potentially missed if nomolecular analyses were performed.Clinical trials are showing that NGS testing can have an impact inthe response rate and progression-free survival of patients, and cantherefore be a very useful strategy leading to new molecularly-tar-geted treatment indications. Key factors responsible for improvedresults in precision-oriented clinical research, include refining themolecular pathways studied, developing molecular testing that inte-grates standarised genomic tests with transcriptomic analysis andimmunohistochemistry, selecting more active targeted agents,designing combinations of targeted agents -also with other forms oftherapy, and providing early treatment recommendations with avail-able Molecular Multidisciplinary Boards. Interdisciplinary discussionare very important to help with the interpretation of unclear molecu-lar results that are oftentimes seen with NGS testing.Important unsolved issues that will need to be addressed in thefuture include deciding which is the best tissue to perform NGS (pri-mary tumor vs metastasis, tumor DNA vs circulating tumor DNA),when is the right moment to test (atfirst diagnosis of advanced dis-ease or when the disease is refractory), and whether there are NGSclinical trial designs that allow for the use of control groups. Finally,using a complete informed consent before NGS testing and communi-cating NGS reports to patients are two very important aspects of theprocedure that have raised ethical concerns, and that must be alwaysaddressed by the practicing oncologists when ordering a NGS test.Search strategy and selection criteriaWe identified references through PubMed with the search terms“cancer AND NGS,”“cancer AND next generation sequencing,”“can-cer AND genomics,”for articles published to March 30, 2020. Thefinalreference list was generated on the basis of originality and relevanceto the broad scope of this Review.FundingThis Review was funded in part by research funds from projectsPIE15/00068andPI17/01865(Instituto de Salud Carlos III) awardedto RC, projectsJR17/00007andPI17/008(Instituto de Salud CarlosIII), awarded to NR-L,PI15/01491andPI19/00549(Instituto de SaludCarlos III) awarded to AA, projectsSAF2017 82886-R(Ministerio deEconomía y Competitividad), INDISNET-S2011/BMD-2332(Fundaci on Ram on Areces), andHR17-00016("La Caixa" Foundation)awarded to FS-M, and projectsPI16/00354(Instituto de Salud CarlosIII) andB2017/BMD-3733from the Consejería de Educaci on, Juventudy Deporte, Comunidad de Madrid, awarded to MQ-F. The manuscriptis part of the activities of the endowed Chair of Personalised PrecisionOncology, Universidad Aut onoma de Madrid (UAM-Fundaci on Insti-tuto Roche)S