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• W2921347530 abstract "In this issue of Annals of Oncology, Trédan et al. [1.Trédan O. Wang Q. Pissaloux D. et al.Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial.Ann Oncol. 2019; 30: 757-765Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar] describe the results of the ProfiLER trial, in which 2579 adult and paediatric patients with previously treated metastatic cancer underwent molecular profiling. Next-generation sequencing (NGS) with two panels was used to sequence 59 or 69 genes, as well as microarray-based comparative genomic hybridization, to define genetic changes that might be targeted for effective therapy. Oncologists in four academic institutions in and around Lyon, France, managed the patients; the authors are to be congratulated on overcoming the logistics of undertaking such a large multi-institution trial. The primary aim of the study was to define the nature and incidence of genetic mutations in the tumour samples and their results, showing that mutations were observed frequently in CDKN2A, KRAS, PIKC3A, and CCND1 genes, have added to the work of others reporting the prevalence of these and other mutations. A secondary goal of the trial was to review each molecular profile at a Molecular Tumour Board, and where possible to treat with an appropriate targeted agent and record the response to treatment. Here, the outcome of their study is sobering. A molecular-based treatment was recommended for 27% of the participants, but only 6% of the participants actually received such treatment. Among 180 individual trials of matched treatment the partial response rate was 13%, but for the whole-sample molecular profiling led to response in only 0.9% of the population. This compares unfavourably with patients entered directly in phase I clinical trials, without selection of the agent(s) based on molecular properties, where reported response rates are in the range of 4% to 11% [2.Roberts Jr, T.G. Goulart B.H. Squitieri L. et al.Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials.JAMA. 2004; 292: 2130-2140Crossref PubMed Scopus (258) Google Scholar, 3.Horstmann E. McCabe M.S. Grochow L. et al.Risks and benefits of phase 1 oncology trials, 1991 through 2002.N Engl J Med. 2005; 352: 895-904Crossref PubMed Scopus (378) Google Scholar, 4.Gupta S. Hunsberger S. Boerner S.A. et al.Meta-analysis of the relationship between dose and benefit in phase I targeted agent trials.J Natl Cancer Inst. 2012; 104: 1860-1866Crossref PubMed Scopus (35) Google Scholar]. Experience from the ProfiLER trial parallels that from other groups that have described similar attempts to target cancer treatment to mutations in cancer genes, using panels that evaluate a variable number of cancer-related genes [5.André F. Bachelot T. Commo F. et al.Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER).Lancet Oncol. 2014; 15: 267-274Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, 6.Kris M.G. Johnson B.E. Berry L.D. et al.Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.JAMA. 2014; 311: 1998-2006Crossref PubMed Scopus (1221) Google Scholar, 7.Le Tourneau C. Delord J.-P. Gonçalves A. et al.Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.Lancet Oncol. 2015; 16: 1324-1334Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 8.Meric-Bernstam F. Brusco L. Shaw K. et al.Feasibility of large-scale genomic testing to facilitate enrollment onto genomically matched clinical trials.JCO. 2015; 33: 2753-2762Crossref PubMed Scopus (310) Google Scholar, 9.Sohal D.P.S. Rini B.I. Khorana A.A. et al.Prospective clinical study of precision oncology in solid tumors.J Natl Cancer Inst. 2016; 108Crossref Scopus (68) Google Scholar, 10.Aisner D. Sholl L.M. Berry L.D. et al.Effect of expanded genomic testing in lung adenocarcinoma on survival benefit: the Lung Cancer Mutation Consortium II experience.JCO. 2016; (Abstract 11510)Crossref Google Scholar, 11.Stockley T.L. Oza A.M. Berman H.K. et al.Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret IMPACT/COMPACT trial.Genome Med. 2016; 8: 109.Crossref PubMed Scopus (156) Google Scholar, 12.Wheler J.J. Janku F. Naing A. et al.Cancer therapy directed by comprehensive genomic profiling: a Single Center Study.Cancer Res. 2016; 76: 3690-3701Crossref PubMed Scopus (170) Google Scholar, 13.Massard C. Michiels S. Ferté C. et al.High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 Trial.Cancer Discov. 2017; 7: 586-595Crossref PubMed Scopus (425) Google Scholar, 14.Tsimberidou A.M. Hong D.S. Ye Y. et al.Initiative for molecular profiling and advanced cancer therapy (IMPACT): an MD Anderson Precision Medicine Study.JCO Precis Oncol. 2017; : 1Google Scholar]. More than 13 000 patients have been included in reported studies, and the experience is consistent: for every 1000 patients where biopsies from their tumours are used to provide a DNA sequence, about 400 will have a targetable mutation, about 120 will receive a matched drug and 8–30 of them will respond (Figure 1). Some studies have reported a higher response rate or longer survival for patients treated with drugs chosen by molecular profiling than those treated with non-matched drugs, but the overall impact is small and should take into account the delay in initiating treatment while awaiting genetic characterization. The United States National Cancer Institute is sponsoring large on-going trials (MATCH and MPACT) testing a similar strategy, but reports of the initial experience where three targeted agents were matched to patients bearing tumours with specific mutations showed disappointing rates of response of 0% to 9.5% [15.Coyne G.O. Takebe N. Chen A.P. Defining precision: the precision medicine initiative trials NCI-MPACT and NCI-MATCH.Curr Probl Cancer. 2017; 41: 182-193Crossref PubMed Scopus (65) Google Scholar, 16.Eckhardt S.G. Lieu S. Is precision medicine an oxymoron?.JAMA Oncol. 2019; 5: 142-143Crossref PubMed Scopus (13) Google Scholar]. The causes of this rather disappointing experience are multiple but include:During the time taken for molecular profiling and selection of a matching drug, patients with advanced cancer may progress and no longer be suitable for treatment; many need urgent therapy.Lack of availability of a matched targeted agent.Poor response to a targeted agent despite matching. Potential causes are incomplete pathway inhibition, biochemical plasticity in response to drugs, the presence of other driver mutations, and the effectiveness of targeted therapy being dependent on tumour type [17.Prahallad A. Sun C. Huang S. et al.Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR.Nature. 2012; 483: 100-103Crossref PubMed Scopus (1497) Google Scholar, 18.Hyman D.M. Puzanov I. Subbiah V. et al.Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations.N Engl J Med. 2015; 373: 726-736Crossref PubMed Scopus (1275) Google Scholar]. Also the matched drug must target the encoded proteins rather than the primary DNA sequence, and the structure and function of these proteins are regulated by multiple molecular factors that remain poorly understood.Inability to combine most targeted agents because of toxicity [19.Park S.R. Davis M. Doroshow J.H. Kummar S. Safety and feasibility of targeted agent combinations in solid tumours.Nat Rev Clin Oncol. 2013; 10: 154-168Crossref PubMed Scopus (48) Google Scholar].Intra-tumour heterogeneity, such that the molecular profile represents only one part of the tumour and its metastatic sites; the analysis of a single biopsy is insufficient to capture genetic heterogeneity [e.g. 20.Gerlinger M. Rowan A.J. Horswell S. et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.N Engl J Med. 2012; 366: 883-892Crossref PubMed Scopus (5759) Google Scholar, 21.Swanton C. Intratumor heterogeneity: evolution through space and time.Cancer Res. 2012; 72: 4875-4882Crossref PubMed Scopus (653) Google Scholar, 22.Jamal-Hanjani M. Wilson G.A. McGranahan N. et al.Tracking the evolution of non-small-cell lung cancer.N Engl J Med. 2017; 376: 2109-2121Crossref PubMed Scopus (1329) Google Scholar].In some cancers, changes in common cancer genes are observed in normal non-malignant tissue and may not be ‘drivers’ of subsequent malignancy but are passengers: targeting them is futile [23.Ciccarelli F.D. Mutations differ in normal and cancer cells.Nature. 2019; 565: 301-303Crossref PubMed Scopus (9) Google Scholar]. Several recommendations can be made based on the ProfiLER trial and similar studies. First, we do not need more studies of this type. While the initial hypothesis was perhaps reasonable, the concept has been adequately tested and has not led to meaningful gains in patient benefit [24.Marquart J. Chen E.Y. Prasad V. Estimation of the percentage of US patients with cancer who benefit from genome-driven oncology.JAMA Oncol. 2018; 4: 1093-1098Crossref PubMed Scopus (182) Google Scholar, 25.Joyner M.J. P N. Promises, promises and precision medicine.J Clin Invest. 2019; 129: 946-948Crossref PubMed Scopus (66) Google Scholar]. Unfortunately, genetic sequencing of tumours is now offered by several companies to patients and is funded by Medicare and many insurance companies in the United States [26.https://www.patientpower.info/medicare-to-cover-genetic-sequencing-in-cancer-patients (13 March 2019, date last accessed).Google Scholar]. While molecular characterisation of known markers (e.g. HER2, BRAF, ALK, KRAS, and perhaps DNA repair genes) can aid in choice of treatment for groups of patients with given types of malignancy, more widespread NGS sequencing outside of a well-designed research setting is not useful and is a waste of resources. Patients should be informed that this knowledge will not allow rational choice of treatment nor benefit them by increasing the duration or quality of their survival. Second, we need high-quality research into the factors described above, and others that emerge, that limit the therapeutic benefit of molecular profiling. While availability and quality of molecular-targeted agents will improve, the limits imposed by intra-tumour heterogeneity, which occurs both between different parts of the tumour at a given time and changes as the tumour progresses [20.Gerlinger M. Rowan A.J. Horswell S. et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.N Engl J Med. 2012; 366: 883-892Crossref PubMed Scopus (5759) Google Scholar, 21.Swanton C. Intratumor heterogeneity: evolution through space and time.Cancer Res. 2012; 72: 4875-4882Crossref PubMed Scopus (653) Google Scholar, 22.Jamal-Hanjani M. Wilson G.A. McGranahan N. et al.Tracking the evolution of non-small-cell lung cancer.N Engl J Med. 2017; 376: 2109-2121Crossref PubMed Scopus (1329) Google Scholar], may be the most important limit to personalised medicine. Deserving approaches that might overcome this are not only the immune targeting of clonal mutations [27.McGranahan N. Furness A.J. Rosenthal R. et al.Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.Science. 2016; 351: 1463-1469Crossref PubMed Scopus (1966) Google Scholar] but also personalised therapies with targeted agents used early in tumour evolution, or in an adjuvant setting, when heterogeneity may be more limited. This requires improved tools for the early detection of the changes driving malignancy and for the analysis of minimal residual disease. The final sentence of the abstract of the Trédan article states: ‘Molecular screening should not be used at present to guide decision-making in routine clinical practice outside clinical trials’ [1.Trédan O. Wang Q. Pissaloux D. et al.Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial.Ann Oncol. 2019; 30: 757-765Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. While we agree with this statement, we would add that new clinical trials of molecular profiling should only be performed if they evaluate new concepts that address and try to overcome the causes of failure of current strategies to provide therapeutic benefit. Clinicaltrials.gov lists an ongoing ProfiLER 02 study (NCT03163732) that compares the use of NGS to identify a wider panel of 324 cancer-related genes with a smaller panel of 87 genes similar to those evaluated in ProfiLER 01. The primary outcome is to compare the proportion of patients for whom a genomically identified recommended therapy could be initiated using the large NGS panel from FoundationOne versus the limited CONTROL panel. Sadly, neither this follow-up study nor the NCI MATCH and MPACT trials address the more important problems that limit therapeutic benefit in the ProfiLER 01 and other completed studies and have potential to add only a minimal increase in response for patients recruited to them. More imaginative approaches will be required to advance the field of personalized medicine. None declared." @default.
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• W2921347530 title "Molecular screening to select therapy for advanced cancer?" @default.
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