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

Abstract

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. 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. Precision Oncology is the form of medicine which uses cancer treatments that are targeted to individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given cancer patient from other patients with similar clinical presentations [[1]Jameson J.L. Longo D.L Precision medicine–personalized, problematic, and promising.N Engl J Med. 2015 Jun 4; 372: 2229-2234Crossref PubMed Scopus (600) Google Scholar]. While this is not an entirely new approach in oncology, it takes advantage of recent advances in genome sequencing and the growing availability of clinical data, and also offers an unprecedented opportunity to make personalized precision patient care a clinical reality [[2]Hodson R Precision medicine.Nature. 2016 Sep 8; 537: S49Crossref PubMed Scopus (105) Google Scholar]. The Cancer Genome Atlas (TCGA) project was undertaken in 2005 to map the human cancer genome [[3]Wheeler D.A. Wang L From human genome to cancer genome: the first decade.Genome Res. 2013 Jul; 23: 1054-1062Crossref PubMed Scopus (98) Google Scholar,[4]Green E.D. Watson J.D. Collins F.S Human Genome Project: twenty-five years of big biology.Nature. 2015 Oct 1; 526: 29-31Crossref PubMed Scopus (117) Google Scholar], The TCGA project, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), has identified new oncogenic point mutations, fusions and variants that have therapeutic impact, and impact the clinical course cancer patients. This growing data about cancer opened up the first steps towards precision oncology with the aim of ensuring that cancer patients get the right treatment at the right dose at the right time, with minimum ill consequences and maximum efficacy [[5]Mirnezami R. Nicholson J. Darzi A Preparing for precision medicine.N Engl J Med. 2012 Feb 9; 366: 489-491Crossref PubMed Scopus (480) Google Scholar]. While an early precedent of precision oncology was the use of tamoxifen in estrogen receptor-positive breast cancer [[6]Jordan V.C Fourteenth Gaddum Memorial LectureA current view of tamoxifen for the treatment and prevention of breast cancer.Br J Pharmacol. 1993 Oct; 110: 507-517Crossref PubMed Scopus (269) Google Scholar], the first precision cancer medicines approved specifically against a molecular target were trastuzumab (for HER2+ breast cancer in 1998) and imatinib (for Bcr/abl-positive chronic myelogenous leukemia in 2001). In the ensuing 20 years, the number of actionable alterations that have a corresponding targeted therapy has been growing steadily, and these include both single genes (such as BRAF or ALK), or composite genetic signatures (such as mismatch repair or homologous recombination deficiency). A timeline of the most remarkable precision oncology highlights is shown in Fig. 1. Molecular testing has become useful in clinical practice to detect actionable genomic alterations for both diagnostic and therapeutic purposes. As a general rule, molecular testing (like most medical testing) should be ordered when results may impact clinical management. At the end of 2019, the number of anticancer therapies targeted against a molecular alteration was 64, and the number of targetable molecular alterations was 24. It is very relevant that in 19 of these, the detection of the alteration was required in order to effectively indicate a particular prescription (Table 1).Table 1FDA approved targeted therapies in solid malignancies.†in 2019(modified from[63])..GENE TARGETGENOMIC ALTERATIONMALIGNANCYTHERAPEUTIC AGENTSEML4-ALK*Required for prescription.RearrangementLung CancerCrizotinib, Alectinib, Ceritinib, Brigatinib, LorlatinibBRAF*Required for prescription.MutationMelanomaVemurafenib, Dabrafenib, Trametinib, Cobimetinib, Encorafenib, BinimetinibMutationAnaplastic thyroid cancer, lung cancerDabrafenib, trametinibBRCA1/2*MutationOvarian Cancer, Prostate CancerOlaparib, Niraparib, Talazoparib, RucaparibMutationTriple negative breast cancerOlaparibCKIT*Required for prescription.MutationGIST, MastocytosisImatinib, Sunitinib, RegorafenibEGFR*Required for prescription.MutationLung CancerErlotinib, Gefitinib, Afatinib, Osimertinib, DacomitinibEGFR*Required for prescription.ExpressionColonCetuximab, PanitumumabLung CancersNecitumumabHER2*Required for prescription.Amplification, overexpressionBreast CancerTrastuzumab, Lapatinib, Pertuzumab, Ado-trastuzumab emtansine, NeratinibAmplification, overexpressionGastric CancerTrastuzumabFGFR3, FGFR2*Required for prescription.MutationBladder cancerErdafitinibHomologous Recombination Deficiency (HRD)*Required for prescription.CompositeOvarian cancerNiraparibC-KIT*Required for prescription.Mutation, expressionGISTImatinib, sunitinib, regorafenibMismatch Repair (MMR)*Required for prescription.Expression, mutationTumor-agnostic, MSI-H CancersPembrolizumabExpression, mutationColorectal MSI-H CancersNivolumabNTRK*Required for prescription.FusionTumor-agnostic, NTRK+ cancersEntrectinib, larotrectinibPDGFRA*Required for prescription.MutationGIST, SarcomaImatinib, Sunitinib, OlaratumabCOL1A1-PDGFΒRearrangementDermatofibrosarcoma protuberansImatinibPDL-1*Required for prescription.ExpressionLung, triple negative breast, urothelial, cervical cancerPembrolizumab, atezolizumabPI3K*Required for prescription.MutationBreast CancerAlpelisibSMO and PTCH1MutationBasal Cell CarcinomaVismodegib, SonidegibK-RAS*Required for prescription.MutationColon cancerCetuximab, panitumumab (in RAS-non mutated)RET*Required for prescription.MutationThyroid CancerVandetanib, Cabozantinib, LenvatinibROS-1*Required for prescription.RearrangementLung cancerCrizotinib, EntrectinibVEGF/VEGFRExpressionKidney, Colon, Lung, Gastric, Cervix, Ovarian CancersBevacizumab, Ramucirumab, Regorafenib, Ziv-aflibercept, Axitinib, Pazopanib, Sunitinib, SorafenibCDK4/6AmplificationBreast CancerPalbociclib, Ribociclib, AbemaciclibmTORMutationBreast, Renal, Brain CancersEverolimus, TemsirolimusEstrogen Receptor*Required for prescription.ExpressionBreast CancerTamoxifen, fulvestrant, anastrozole, letrozole, exemestane, everolimus, palbociclib, ribociclib, abemaciclibAndrogen ReceptorExpressionProstate CancerAbiraterone, Enzalutamide, Apalutamide, Darolutamide† in 2019(modified from[[63]Chen H.Z. Bonneville R. Roychowdhury S Implementing precision cancer medicine in the genomic era.Semin Cancer Biol. 2019; 55: 16‐27Crossref PubMed Scopus (17) Google Scholar]). Required for prescription. Open table in a new tab Furthermore, TRK fusions and microsatellite instability have both been validated as histology-agnostic biomarkers for FDA approval of larotrectinib and entrectinib, and pembrolizumab, respectively. These markers are detected in some but not all NGS platforms, emphasizing the need for clinicians to know the differences between platforms and to keep in mind what is likely to be detected in different tumor types when initiating NGS testing. The European Society for Medical Oncology (ESMO) has developed a Scale of Clinical Actionability for molecular Targets (ESCAT) that defines six levels of clinical evidence for molecular targets according to the implications for patient management [[7]Mateo J. Chakravarty D. 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