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The NCI-MATCH (Molecular Analysis for Therapy Choice) trial ( NCT02465060 ) was launched in 2015 as a genomically driven, signal-seeking precision medicine platform trial-largely for patients with treatment-refractory, malignant solid tumors. Having completed in 2023, it remains one of the largest tumor-agnostic, precision oncology trials undertaken to date. Nearly 6,000 patients underwent screening and molecular testing, with a total of 1,593 patients (inclusive of continued accrual from standard next-generation sequencing) being assigned to one of 38 substudies. Each substudy was a phase 2 trial of a therapy matched to a genomic alteration, with a primary endpoint of objective tumor response by RECIST criteria. In this Perspective, we summarize the outcomes of the initial 27 substudies in NCI-MATCH, which met its signal-seeking objective with 7/27 positive substudies (25.9%). We discuss key aspects of the design and operational conduct of the trial, highlighting important lessons for future precision medicine studies., (© 2023. Springer Nature America, Inc.)

Purpose: An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors., Clinical Context: An increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers. However, there is a lack of clarity as to when tumor genomic sequencing should be ordered, what type of assays should be performed, and how to interpret the results for treatment selection., Provisional Clinical Opinion: Patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel-based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumor mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase ( NTRK ) fusions provide a rationale for genomic testing for all solid tumors. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and expected efficacy of genomic biomarker-linked options relative to other approved or investigational treatments.Additional information is available at www.asco.org/assays-and-predictive-markers-guidelines., Competing Interests: Debyani ChakravartyConsulting or Advisory Role: Medendi Medical Travel Jeffrey SklarStock and Other Ownership Interests: PrecipioResearch Funding: Jilin Zixin (Inst) Kathleen MooreHonoraria: Research To Practice, Prime Oncology, Physicans' Education Resource, Great Debates and UpdatesConsulting or Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, TESARO (Inst), VBL Therapeutics, Merck, Aravive, Eisai, Vavotar Life Sciences, Mersana (Inst), Myriad Genetics, Alkemeres (Inst), Blueprint Pharmacetuicals (Inst), GlaxoSmithKline/Tesaro (Inst), I-Mab (Inst), InxMed (Inst), Mereo BioPharma (Inst)Research Funding: PTC Therapeutics (Inst), Lilly (Inst), Merck (Inst), Tesaro (Inst), Genentech (Inst), Clovis Oncology (Inst), Lilly Foundation (Inst), Regeneron (Inst), Advaxis (Inst), Bristol Myers Squibb (Inst), Verastem (Inst), Novartis Pharmaceuticals UK Ltd (Inst), AstraZeneca (Inst), Agenus (Inst), Takeda (Inst), Forty Seven (Inst), Stem CentRx (Inst), Immunogen (Inst), Bayer (Inst), Novogen (Inst), AbbVie/Stemcentrx (Inst)Other Relationship: GOG Partners (Inst) Shridar GanesanEmployment: Merck (I)Stock and Other Ownership Interests: Ibris, Inspirata, Merck (I), SilageneConsulting or Advisory Role: Inspirata, Novartis, Roche, Foghorn Therapeutics, Foundation Medicine, Merck Sharp & Dohme, Silagene, EQRx, EMD Serono, KayoTheraResearch Funding: M2Gen (Inst)Patents, Royalties, Other Intellectual Property: I hold 2 patents for digital imaging that may be licensed to Ibris Inc and Inspirata IncOther Relationship: NIH/NCI Christine M. LovlyHonoraria: Takeda, Pfizer, Cepheid, Foundation Medicine, AstraZeneca, Blueprint Medicines, Lilly, Genentech, Syros Pharmaceuticals, Amgen, Roche, EMD Serono, Daiichi Sankyo/AstraZeneca, Puma BiotechnologyConsulting or Advisory Role: Novartis, Foundation Medicine, Pfizer, Takeda, Cepheid, AstraZeneca, Blueprint Medicines, Syros Pharmaceuticals, Genentech, Lilly, Amgen, EMD Serono, Daiichi Sankyo/AstraZeneca, Puma BiotechnologyResearch Funding: Novartis, Xcovery, AstraZeneca (Inst)Travel, Accommodations, Expenses: Pfizer, Takeda, Foundation Medicine, Novartis, Cepheid, Genentech Stacy W. GrayStock and Other Ownership Interests: Magenta Therapeutics (I)Honoraria: Triptych Health PartnersConsulting or Advisory Role: Magenta Therapeutics (I) Jimmy HwangConsulting or Advisory Role: Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Caris Centers of Excellence, Pfizer, QED Therapeutics, Deciphera, IncyteSpeakers' Bureau: Bristol Myers Squibb, Deciphera, IncyteResearch Funding: Caris Centers of Excellence (Inst), Boehringer Ingelheim (Inst) Christopher LieuConsulting or Advisory Role: Ipsen (Inst), HalioDx (Inst), Pfizer (Inst)Research Funding: Merck (Inst) Fabrice AndréStock and Other Ownership Interests: PegacsyResearch Funding: AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst), Lilly (Inst), Roche (Inst), Daiichi (Inst)Travel, Accommodations, Expenses: Novartis, Roche, GlaxoSmithKline, AstraZeneca Nilofer AzadConsulting or Advisory Role: AMAG Pharmaceuticals, Taiho Pharmaceutical, QED Therapeutics, Merck, Incyte, Helsinn Therapeutics/QED TherapeuticsResearch Funding: Celgene (Inst), Genentech (Inst), Astex Pharmaceuticals (Inst), Agios (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Syndax (Inst), Array BioPharma (Inst), Intensity Therapeutics (Inst), Bayer (Inst), EMD Serono, Debiopharm Group (Inst), Incyte (Inst), Loxo/Lilly (Inst), AtlasMedx (Inst) Mitesh BoradStock and Other Ownership Interests: Gilead Sciences, AVEO, Intercept Pharmaceuticals, Spectrum PharmaceuticalsConsulting or Advisory Role: G1 Therapeutics, Fujifilm (Inst), Agios (Inst), Insys Therapeutics (Inst), Novartis (Inst), ArQule (Inst), Celgene (Inst), Inspyr Therapeutics, Halozyme (Inst), Pieris Pharmaceuticals (Inst), Taiho Pharmaceutical (Inst), Immunovative Therapies, Exelixis, Lynx Group, Genentech, Western Oncolytics, Klus Pharma, De Novo Pharmaceuticals, Merck, ImvaxResearch Funding: Boston Biomedical (Inst), miRNA Therapeutics (Inst), Senhwa Biosciences (Inst), MedImmune (Inst), BiolineRx (Inst), Agios (Inst), Halozyme (Inst), Celgene (Inst), Threshold Pharmaceuticals (Inst), Toray Industries (Inst), Dicerna (Inst), Sillajen (Inst), Eisai (Inst), Taiho Pharmaceutical (Inst), EMD Serono (Inst), Isis Pharmaceuticals (Inst), Incyte (Inst), Sun Biopharma (Inst), ARIAD (Inst), ImClone Systems (Inst), QED Therapeutics (Inst), Incyte (Inst), Puma Biotechnology (Inst), Adaptimmune (Inst), Merck Serono (Inst), RedHill Biopharma (Inst), Basilea (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: ArQule, Celgene, AstraZeneca Laura TafeStock and Other Ownership Interests: Exact Sciences, GlaxoSmithKlineResearch Funding: Biocartis (Inst)Other Relationship: College of American Pathologists, Association for Molecular Pathology Mark RobsonConsulting or Advisory Role: Change HealthCareResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Merck (Inst)Other Relationship: Research to Practice, Clinical Care Options, Physicans' Education Resource, Pfizer, MyMedEd, Clinical Education AllianceUncompensated Relationships: Merck, Pfizer, Daiichi Sankyo, Epic Sciences, Artios, Tempus, Zenith PharmaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/612669/summary Funda Meric-BernstamEmployment: MD Anderson Cancer CenterHonoraria: Rutgers Cancer Institute of New JerseyConsulting or Advisory Role: Samsung Bioepis, Xencor, Debiopharm Group, Silverback Therapeutics, IBM Watson Health, Roche, PACT Pharma, eFFECTOR Therapeutics, Kolon Life Sciences, Tyra Biosciences, Zymeworks, Puma Biotechnology, Zentalis, Alkermes, Infinity Pharmaceuticals, AbbVie, Black Diamond Therapeutics, Eisai, OnCusp Therapeutics, Lengo Therapeutics, Tallac Therapeutics, Karyopharm Therapeutics, BiovicaSpeakers' Bureau: Chugai PharmaResearch Funding: Novartis (Inst), AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Genentech (Inst), Calithera Biosciences (Inst), Debiopharm Group (Inst), Bayer (Inst), Aileron Therapeutics (Inst), PUMA Biotechnology (Inst), CytomX Therapeutics (Inst), Jounce Therapeutics (Inst), Zymeworks (Inst), Curis (Inst), Pfizer (Inst), eFFECTOR Therapeutics (Inst), AbbVie (Inst), Boehringer Ingelheim (I), Guardant Health (Inst), Daiichi Sankyo (Inst), GlaxoSmithKline (Inst), Seattle Genetics (Inst), Taiho Pharmaceutical (Inst), Klus Pharma (Inst), Takeda (Inst)Travel, Accommodations, Expenses: Beth Israel Deaconess Medical CenterNo other potential conflicts of interest were reported.

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapy in cancers with homologous recombination repair deficiency. However, efficacy is limited by both intrinsic and acquired resistance. The Olaparib Combinations basket trial explored olaparib alone and in combination with other homologous recombination-directed targeted therapies. Here, we report the results of the arm in which olaparib was combined with the orally bioavailable ataxia telangiectasia and RAD3-related inhibitor ceralasertib in patients with relapsed or refractory cancers harboring DNA damage response and repair alterations, including patients with BRCA -mutated PARP inhibitor-resistant high-grade serous ovarian cancer (HGSOC)., Patients and Methods: Germline and somatic mutations had to be deleterious by COSMIC or ClinVar for eligibility. Olaparib was administered at 300 mg twice daily and ceralasertib at 160 mg daily on days 1-7 in 28-day cycles until progression or unacceptable toxicities. Primary end points were confirmed complete response (CR) or partial response (PR) rates and clinical benefit rate (CBR; CR + PR + stable disease [SD] at 16 weeks)., Results: Twenty-five patients were enrolled, with median four prior therapies. Five patients required dose reductions for myelosuppression. Overall response rate was 8.3% and CBR was 62.5% among the entire cohort. Two of five patients with tumor harboring ATM mutation achieved CR or SD ongoing at 24+ months, respectively (CBR 40%). Of seven patients with PARP inhibitor-resistant HGSOC, one achieved PR (-90%) and five had SD ranging 16-72 weeks (CBR 86%)., Conclusion: Olaparib with ceralasertib demonstrated preliminary activity in ATM -mutated tumors and in PARP inhibitor-resistant BRCA1/2 -mutated HGSOC. These data warrant additional studies to further confirm activity in these settings., Competing Interests: Joseph Eder Honoraria: Roche Molecular Diagnostics Consulting or Advisory Role: Roche/Genentech No other potential conflicts of interest were reported. Joseph Eder Honoraria: Roche Molecular Diagnostics Consulting or Advisory Role: Roche/Genentech No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols., Patients and Methods: Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared., Results: Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, > 35% for urothelial cancers and < 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so., Conclusion: We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens.

Background: The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology., Methods: Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA-targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial., Results: At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround)., Conclusions: The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients., (© The Author(s) 2019. Published by Oxford University Press.)

Personalized medicine in the treatment of cancer is based on the recognition that molecularly targeted therapies are most effective in patients whose tumors carry specific genetic or genomic alterations. These alterations, which often activate oncogenes that encode the components of signal transduction pathways, serve as predictive markers for sensitivity or resistance of individual tumors to drugs that target such pathways. In the recent past, individual mutations and other changes within tumors have been assayed to determine the likelihood of response or nonresponse to specific targeted therapies. However, with the development of increasing numbers of molecularly targeted drugs, attention has shifted to high-throughput testing of tumors for dozens of predictive markers. This approach to predictive testing has been termed molecular tumor profiling. This review describes the background to this field, the principal markers analyzed, and the methodologies that are being utilized or are under development for tumor profiling.

Chimeric gene products, most often resulting from chromosome translocations, have been considered unique features of cancer, or at least of cells at high risk for becoming cancerous. Chimeric JAZF1-JJAZ1 mRNA transcribed from DNA spanning the site of recombination in the (7;17)(p15;q21) chromosomal translocation found in half of endometrial stromal sarcomas and most cases of benign stromal nodules is one such example. The recent finding that chimeric JAZF1-JJAZ1 mRNA can also be detected in normal endometrial stromal cells suggests that chimeric gene products are not limited to cancer or pre-cancerous cells. The JAZF1-JJAZ1 mRNA and the protein encoded by it appear to be identical to that synthesized from the gene fusion in neoplastic cells. In cultured cells, the chimeric protein has anti-apoptotic properties and is pro-proliferative when unrearranged JJAZ1 alleles are silenced, as they are in endometrial stromal sarcomas but not in the stromal nodules. These observations are consistent with the conclusion that chromosomal rearrangements and gene fusions in neoplastic cells may represent mechanisms for the deregulated expression of chimeric gene products that are generated at specific stages in cell development and have physiologic functions in normal cells. Furthermore, it may be possible that other means for abnormal production of chimeric gene products, such as hyperactive transsplicing of RNA, may be another mechanism underlying the neoplastic properties of tumor cells.

Revolutionary advances in technology have enhanced our understanding of the genetic changes that occur in cancer cells. This article summarizes some of the basic features of these techniques and describes their application to the identification of specific types of genetic alterations in cells. The emphasis is on their use in obtaining information that is of diagnostic and prognostic importance. The techniques fall into two broad categories; the first is the direct analysis of the chromosome pattern in metaphase cells or the indirect assessment of chromosome abnormalities in interphase nuclei. The second general category involves the isolation of DNA, RNA, or protein from the tumor cells and the analysis of these components for abnormalities related to the presence, absence, or amplification of a specific gene or its products or other alterations, eg, those due to chromosome translocations. The techniques described in this article have broad applicability to medicine in general and some familiarity with these techniques is critical for the practice of modern medicine.

Analysis of clonality by X chromosome inactivation has proven to be a powerful strategy in the study of neoplastic and preneoplastic disorders (P. J. Fialkow, Biochim. Biophys. Acta, 458: 283-321, 1976; B. Vogelstein et al., Cancer Res., 47: 4806-4813, 1987). Recently, the gene for the androgen receptor has been shown to be a highly polymorphic locus in which methylation of DNA correlates with inactivation of one or the other X homologue (R. C. Allen et al., Am. J. Hum. Genet., 51: 1229-1239, 1992). Unlike other loci used for analysis of X inactivation, the methylation sites within the androgen receptor gene lie close to the region of DNA containing the polymorphism. Consequently, it should be possible to use methylation-sensitive restriction enzymes and polymerase chain reaction to study differential methylation among alleles of this gene in formalin-fixed and paraffin-embedded archival tissue specimens. To investigate this question, we performed clonal analysis on a variety of randomly selected, formalin-fixed, paraffin-embedded tumor tissues from 15 women. Thirteen of the women were found to be heterozygous for polymorphisms at the androgen receptor locus. Among these women, 11 tumors were clearly clonal in assays of methylation of the androgen receptor gene. Interpretation of results for the remaining two cases was complicated because of a skewed pattern of X chromosome inactivation found in normal control tissues. We conclude that analysis of methylation in the androgen receptor gene should allow study of clonality in most formalin-fixed, paraffin-embedded tissue specimens from women, including small preneoplastic lesions or rare conditions for which sufficient material is not available for analysis by other techniques.

Studies of DNA rearrangements in antigen receptor genes and at sites of chromosomal translocations are having an increasing impact on the diagnostic evaluation of lymphoid tissue biopsy specimens. Such rearrangements represent clonal molecular markers that can be very easily detected by Southern blot hybridization or polymerase chain reaction amplification. Detection of these markers can be useful in the diagnosis or subclassification of lymphoid neoplasms, particularly when morphologic or immunophenotypic findings alone are ambiguous. At the same time, application of DNA rearrangement to the evaluation of tissue specimens also has certain shortcomings and limitations, some of which may be overcome by current research methods or advances expected in the near future.

DNA hybridization is becoming an important new adjunct to conventional methods for the diagnosis of infectious diseases, inherited conditions, and neoplasia. Applications of this technology require very small quantities of tissue or body fluids because the DNA probes used in the hybridization assays detect minute amounts of homologous DNA sequence in the test material. Under the proper conditions, these DNA probes are absolutely specific for the pathogen or gene being examined, and hybridization with them usually yields objective answers that require little interpretation. The relatively minor inconveniences currently associated with DNA hybridization are related to the use of radioactivity as a detection signal and the time and labor required to obtain diagnostic data. In the future, technical improvements currently being developed and the preparation of new probes for additional human and microbial genes are likely to create an increasingly larger role for DNA hybridization in diagnostic pathology.