PRECISION: the Belgian molecular profiling program of metastatic cancer for clinical decision and treatment assignment

Abstract

•PRECISION is a national program involving academia, regulatory authorities, and the pharmaceutical industry.•It promotes molecular testing, data storage and sharing, and treatment access via trials and a national molecular tumor board.•The multistakeholder collaboration is the stepping stone to broader next-generation sequencing reimbursement and for access to targeted therapies. PRECISION is an initiative from the Belgian Society of Medical Oncology (BSMO) in collaboration with several stakeholders, encompassing four programs that aim to boost genomic and clinical knowledge with the ultimate goal to offer patients with metastatic solid tumors molecularly guided treatments. The PRECISION 1 study has led to the creation of a clinico-genomic database. The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) and GeNeo studies will increase the number of patients with advanced cancer that have comprehensive genotyping of their cancer. The PRECISION 2 project consists of investigator-initiated phase II studies aiming to provide access to a targeted drug for patients whose tumors harbor actionable mutations in case the matched drug is not available through reimbursement or clinical trials in Belgium. PRECISION is an initiative from the Belgian Society of Medical Oncology (BSMO) in collaboration with several stakeholders, encompassing four programs that aim to boost genomic and clinical knowledge with the ultimate goal to offer patients with metastatic solid tumors molecularly guided treatments. The PRECISION 1 study has led to the creation of a clinico-genomic database. The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) and GeNeo studies will increase the number of patients with advanced cancer that have comprehensive genotyping of their cancer. The PRECISION 2 project consists of investigator-initiated phase II studies aiming to provide access to a targeted drug for patients whose tumors harbor actionable mutations in case the matched drug is not available through reimbursement or clinical trials in Belgium. IntroductionUnderstanding the genomic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. In the last years, much progress has been made toward improving the overall prognosis of patients with metastatic cancer. The identification of activated pathways involved in the pathophysiology of carcinogenesis, metastasis, and drug resistance, as well as the emergence of technologies enabling tumor molecular analysis and the continuous development of targeted therapies have stimulated research focusing on the optimal use of targeted agents.1Zehir A. Benayed R. Shah R.H. et al.Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.Nat Med. 2017; 23: 703-713Crossref PubMed Scopus (1712) Google Scholar, 2Hyman D.M. Taylor B.S. Baselga J. Implementing genome-driven oncology.Cell. 2017; 168: 584-599Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 3Bedard P.L. Hyman D.M. Davids M.S. Siu L.L. Small molecules, big impact: 20 years of targeted therapy in oncology.Lancet. 2020; 395: 1078-1088Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar The administration of a therapy specifically targeting an activating genomic alteration may confer more benefit to the patient than a conventional systemic therapy.4Massard 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 (401) Google Scholar This approach has been found to be relevant in phase I clinical trials, where patients with refractory, advanced cancer treated with molecularly matched targeted therapy had higher rates of response and longer time to treatment failure and survival than patients treated without matching targeted treatment.5Mackley M.P. Fernandez N.R. Fletcher B. Woolcott C.G. Fernandez C.V. Revisiting risk and benefit in early oncology trials in the era of precision medicine: a systematic review and meta-analysis of phase I trials of targeted single-agent anticancer therapies.JCO Precis Oncol. 2021; 5: 17-26Crossref PubMed Scopus (4) Google Scholar,6Schwaederle M. Zhao M. Lee J.J. et al.Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials.J Clin Oncol. 2015; 33: 3817-3825Crossref PubMed Scopus (291) Google Scholar Most of the genomic alterations are rare7Chang M.T. Bhattarai T.S. Schram A.M. et al.Accelerating discovery of functional mutant alleles in cancer.Cancer Discov. 2018; 8: 174-183Crossref PubMed Scopus (163) Google Scholar and as a consequence escape the pharma-driven validation of matched drug treatments.8Chakravarty D. Gao J. Phillips S.M. et al.OncoKB: a precision oncology knowledge base.JCO Precis Oncol. 2017; 2017Google Scholar Given the heterogeneity of cancer-driving events encountered in a given tumor type, comprehensive genomic profiling (CGP) aiming to identify single or multiple genomic alterations offers the possibility to capture the variety of genomic alterations the tumor presents with. This strategy ultimately allows the design of genotype-driven clinical trials focusing on different alterations present in a specific cancer type (umbrella trial) or on a specific alteration present in several cancer types (basket trials). Currently, there is an increasing number of studies enrolling patients based on molecular alterations of tumors [e.g. NTRK fusion, microsatellite instability (MSI), tumor mutational burden (TMB), DNA mismatch repair deficiency9Adashek J.J. Subbiah V. Kurzrock R. From Tissue-Agnostic to N-of-One therapies: (R)Evolution of the precision paradigm.Trends Cancer. 2021; 7: 15-28Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar], and regulatory agencies have approved tumor-agnostic indications (MSI, TMB, NTRK). Furthermore, recent data from a randomized study in the breast cancer field have proven the clinical benefit of molecularly guided therapies against validated targets [ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) levels I and II].10André F. Clinical utility of molecular tumor profiling: results from the randomized trial SAFIR02-BREAST.https://www.abstractsonline.com/pp8/#!/10462/presentation/2168Date accessed: June 14, 2022Google Scholar The bottleneck of this approach remains the identification of such patients with molecular alterations. Indeed, country-specific reimbursement criteria still frequently lead to the use of small targeted gene panels (Table 1) and hamper the implementation of broad genomic profiling in the routine molecular oncology diagnostics. The lack of tumor-agnostic CGP also threatens the competitiveness of Belgium, currently a leading force in Europe,11Carneiro A. Amaral T.M.S. Brandao M. et al.Disparities in access to oncology clinical trials in Europe in the period 2009-2019.Ann Oncol. 2020; 31: S1142-S1215Google Scholar in the clinical research field with the increase of biomarker-specific clinical trials that could disadvantage countries with smaller populations.Table 1List of gene panels used in clinical routine in Belgium for solid tumor analysis31Antoniou A. Ghislain V. Dekairelle A.-F. et al.Expertise ET Prestations De Services Qualite Des Laboratoires Comite Des Experts AD HOC.https://www.wiv-isp.be/qml/activities/NGS/_fr/Rapport%20global%20d%C3%A9finitif%20NGS%20EEQ%202021-1%20FR.pdfDate accessed: June 14, 2022Google ScholarCustom TSCA panel (Illumina, Mechelen, Belgium) with hotspots from 24 genes for a total of 8.1-kb targeted regionIon AmpliSeq Cancer Hotspot panel v2 (CHP2; Thermofisher Scientific, Merelbeke, Belgium)Ion AmpliSeq Colon and Lung Research Panel v2 (CLPv2; Thermofisher Scientific)Ion AmpliSeq Panel Gyneco (Custom panel; Thermofisher Scientific)Lung-colorectal panel designed with the module AmpliSeq Designer (Thermofisher Scientific) TruSight Tumor 26 (Illumina)TruSight tumor 15 (Illumina)TruSeq Amplicon Cancer Panel (48 genes) (Illumina)Tumor Hotspot MASTR Plus (Illumina)Illumina TruSeq Custom Amplicon INCa panel (INCa.bed; Agilent Technologies, Machelen, Belgium) kit ‘Human Tumor Actionable Mutations Panel’ (Qiagen; Agilent Technologies) Genes: BRaf, cKit, EGFR, IDH1, IDH2, KRas, NRas, and PDGFRA Open table in a new tab The Precision InitiativeThe Belgian Society of Medical Oncology (BSMO) already acknowledged several years ago three main issues in personalized oncology programs of cancer centers. First, isolated initiatives launched at individual laboratories to sequence tumor DNA from patients with metastatic solid tumors could be significantly more efficient by being part of a large, prospective, collaborative effort that would allow the harmonization of methods and ultimately treatment options. Indeed, they each only generate results of or small in the and of data in isolated the of of targeted drug to specific broad genomic profiling panels are and not their in The to an increase in and a in the of the alterations are a drug to the patients remains an treatment in Belgium is on reimbursement and there is for in the that clinical trials only programs as an for treatment access in where reimbursement is is the in Belgium for matched with the of with to clinical for solid for breast Medical are on and of the pharmaceutical to provide the drug in and access to matched treatment frequently is in the of clinical trials, or In this the launched four programs in collaboration with several 1 and to The PRECISION 1 a to genomic and clinical of patients with metastatic cancer sequencing of their tumor DNA or tumor DNA and treated with a matched or clinical The GeNeo and Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) provide access to broad genomic profiling enabling the of small number gene and mutational PRECISION 2 is a for trials to patients with metastatic cancer in where clinical trials are not of the PRECISION with metastatic solid tumors that are for systemic therapy that have had tumor genomic and with metastatic solid tumors that are for systemic in the PRECISION 1 TruSight Oncology panels at the with for genomic of clinical trials, or PRECISION 2 advanced or a specific alteration involved in the of patients with breast or cancer a and approved targeted therapy for the specific alteration in the specific tumor phase or trial available for the specific genomic alteration in the specific tumor advanced advanced or an EGFR, an or an phase or trial available for the specific tumor type or patient not for such of at of at Belgian Approach for Local Laboratory Extensive Tumor molecular tumor Open table in a new tab The PRECISION 1 1 is a national collaborative molecular profiling The aim is to genomic and clinical data of patients with metastatic solid tumors that are for systemic therapy the Belgian oncology clinical and molecular data are in the Precision Belgium of the a national to and the data in a and this has through different the Belgian in a national The data may be with and with the aim to the Belgian on the designed for the to access a genomic clinical and anticancer and their will be to identify at different treated patients with the molecular alterations and the treatment outcome The data will also provide an of the of different alterations cancer a for the design of clinical of treatment molecularly guided of clinical the patient is by the with data with a on and survival and used for the reimbursement of next-generation sequencing in Belgium with indications and small of is not of panels and a of this approach be A. A. et for the implementation of next-generation sequencing in clinical in oncology and in 2018; PubMed Scopus Google A. B. et Belgian sequencing for and solid Oncol. 2017; Scholar First, panels a number of actionable genes and on of genomic alteration types than DNA or small and number alterations is not by there are the different recent study the of a broad gene panel several types of by the and panel of genes of of testing, the of actionable mutations from to M. et of to patient for early phase clinical the Med. PubMed Scopus Google Scholar GeNeo and will the of comprehensive and genomic profiling in in as with in patients with solid tumors access to a therapy based on genomic The use of the panels also data and a for data in studies with to is currently patients with solid metastatic for a systemic therapy, at Belgian and access to a CGP by Belgian criteria for reimbursement of targeted also indications are only from a new is a patient therapy to genomic mechanisms of such as with therapy in cancer. to patients will patients with The tumor types will also be and a will be to tumors and tumors with et are not the cancer burden in Cancer. Full Text Full Text PDF PubMed Scopus Google Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) initiative to the clinical of CGP by a of Belgian total of patients with metastatic solid tumors that are for a systemic therapy are currently at in Belgium. The patients that to the a in to CGP the CGP the clinical and molecular data are in the Precision Belgium of the through the PRECISION 1 The CGP analysis is laboratories of the with to the CGP and the on data analysis and is being used by the from patient in GeNeo and to patients a are and on a at a national molecular tumor of from the In to the genomic a the and clinical and genotype-driven treatment is to the of the of the available for and treatment matching are of genotype-driven clinical trials with matched or treatment The national based on the levels of by D. Gao J. Phillips S.M. et al.OncoKB: a precision oncology knowledge base.JCO Precis Oncol. 2017; 2017Google Scholar the of is not in use the to provide a of is given to with the of the of In for also be in the This collaborative effort is patient to with clinical trials enrolling improving the of precision medicine in the for the and the treatment are and are an of the 2 clinical alterations in the programs are present at in a cancer type, and are to prospective clinical studies that the regulatory genotype-driven clinical trials are also not available in 2 trials designed to to this are phase II each a specific drug in the treatment of advanced cancer genomic alterations. genomic alterations are based on the development as a or of their in drug sensitivity in cancer type or trials). that the is not for this cancer type and that a more specific trial for the cancer type in is may be through PRECISION or through genomic PRECISION 2 studies are in Belgium. The is the of in patients with advanced cancer and a or in a gene in regulatory approved The is the of in the treatment of advanced cancer a EGFR, or et phase 2 study of for advanced an EGFR, a or a a precision trial of the Belgian of Clin Oncol. 2018; Google Scholar by the of to at in studies is et phase 2 study of for advanced an EGFR, a or a a precision trial of the Belgian of Clin Oncol. 2018; Google case precision medicine the case of a patient treated in a PRECISION 2 clinical trial for an advanced patient in for a by with and In and with a three of and and gene sequencing AmpliSeq Technologies, Merelbeke, a panel of an in of the gene as the only genomic in the cancer the clinical sensitivity to by alterations in this genomic J. J. response to the and of in PubMed Scopus Google Scholar by in the PRECISION 2 an phase II study of for advanced with a in EGFR, or is a to the and more than The patient has been treated with at the of without to events 2 treated with and 1 response of of the and to and and still at the 2 and the case of a patient with a an a and response on Indeed, metastatic a and the prognosis A. R. D. The of based on 2020; Scopus Google Scholar In mutations are found in of the Research Cancer Research of 2017; Full Text Full Text PDF PubMed Scopus Google Scholar In the only the use of therapy, in the treatment of metastatic R. M. A. A. response to in advanced 2021; Google Scholar an in with is an treatment of metastatic the in overall survival of only D. J. et with in patients with advanced a phase trial of the Cancer of Clinical Clin Oncol. PubMed Scopus Google Scholar this trial not in the response on in a patient with metastatic cancer. EGFR, of on for a patient with metastatic cancer. EGFR, four of the PRECISION initiative aim to the main the routine implementation of precision oncology in the to identify as actionable mutations as comprehensive genomic to of genotype-driven to the of for and to the through the of a clinico-genomic to optimal treatment This could ultimately allow to generate data and the of CGP of to generate the of reimbursement of and to a clinico-genomic enabling data and treatment in routine the of the four of molecular alterations and genomic in to and such as of and TMB, could increase the of patients in genotype-driven clinical C. et of cancer genes and 2018; Full Text Full Text PDF PubMed Scopus Google Scholar DNA response genes and are and of the Belgian cancer would not be to patients in the PRECISION 2 trial through their in gene are also genomic events the of cancer et in analysis is a for in Oncol. 2021; Full Text Full Text PDF PubMed Scopus Google Scholar of specific events have regulatory clinical being of the tumor type in indications such as F. Clinical utility of molecular tumor profiling: results from the randomized trial SAFIR02-BREAST.https://www.abstractsonline.com/pp8/#!/10462/presentation/2168Date accessed: June 14, 2022Google Scholar and in genomic and for tumor panel in Precis Oncol. 2020; Scopus Google Scholar events are by is et in analysis is a for in Oncol. 2021; Full Text Full Text PDF PubMed Scopus Google Scholar as a and specific gene in the also be by of as this allows to identify the gene at the of not knowledge of the involved The of national regulatory as allow more and reimbursement of molecular this initiative that a of patients to access molecularly guided in the of personalized cancer is a for oncology The of genomic in to an increasing of data and also an in genomic and for tumor panel in Precis Oncol. 2020; Scopus Google Scholar Indeed, recent studies the lack of in the use of tumor genomic to lack of genomic in genomic and for tumor panel in Precis Oncol. 2020; Scopus Google Scholar The Society of Clinical Oncology oncology this and the specific and knowledge in this C. M. S. et for a in oncology Full Text Full Text PDF Scopus Google Scholar Furthermore, results from molecular profiling are by each their for V. A. et study to of molecular in cancer precision Precis Oncol. 2018; Google Scholar The allows the and of data by tumor genomic profiling and to a treatment to the Furthermore, the to improve the prognosis of through the analysis of as well as clinical and genomic data of S. et data from a molecular tumor with a precision 2020; PubMed Scopus Google Scholar this could lead to an in the molecularly guided clinical et molecular tumor to improve and of precision oncology to and their PubMed Scopus Google Scholar The national is the of with the access not available in Belgium) to molecularly guided data in oncology cancer academia, and is multiple to improve the of trials and to increase the to the in and Furthermore, this could the number of trials, a to of treatment in small and could allow of and trial is the of Cancer Research project an on a for in precision cancer medicine by cancer genomic data with clinical outcome data for of of patients with cancer treated at multiple This project already data from and is to to in the precision medicine through an Discov. 2017; 7: PubMed Scopus Google Scholar Furthermore, there are more initiatives aiming to clinical criteria to patients genomic for targeted therapies. provide a the of the genomic a for D. Gao J. Phillips S.M. et al.OncoKB: a precision oncology knowledge base.JCO Precis Oncol. 2017; 2017Google J. D. R. et to genomic alterations as targets for cancer precision medicine: the Scale for Clinical Actionability of molecular Targets Oncol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar In the PRECISION the and harmonization of sequencing the cancer of the and the of the of genomic data are to patients to clinical trials, the Belgian on the of clinical the results of the GeNeo and trials an of CGP the currently the the PRECISION program lead to reimbursement of molecular profiling and access to by from the 1 study and from the Belgian against Cancer and to the PRECISION 1 and 2 studies and the GeNeo is by a from is by from and and are of and are of is an of Belgian against Cancer. from and the and from from and the and from from from the and is also the of the Belgian Society for Medical from the is the of the and from the of the from and the from the of the and also from the from the of the from the from and the from have of IntroductionUnderstanding the genomic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. In the last years, much progress has been made toward improving the overall prognosis of patients with metastatic cancer. The identification of activated pathways involved in the pathophysiology of carcinogenesis, metastasis, and drug resistance, as well as the emergence of technologies enabling tumor molecular analysis and the continuous development of targeted therapies have stimulated research focusing on the optimal use of targeted agents.1Zehir A. Benayed R. Shah R.H. et al.Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.Nat Med. 2017; 23: 703-713Crossref PubMed Scopus (1712) Google Scholar, 2Hyman D.M. Taylor B.S. Baselga J. Implementing genome-driven oncology.Cell. 2017; 168: 584-599Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 3Bedard P.L. Hyman D.M. Davids M.S. Siu L.L. Small molecules, big impact: 20 years of targeted therapy in oncology.Lancet. 2020; 395: 1078-1088Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar The administration of a therapy specifically targeting an activating genomic alteration may confer more benefit to the patient than a conventional systemic therapy.4Massard 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 (401) Google Scholar This approach has been found to be relevant in phase I clinical trials, where patients with refractory, advanced cancer treated with molecularly matched targeted therapy had higher rates of response and longer time to treatment failure and survival than patients treated without matching targeted treatment.5Mackley M.P. Fernandez N.R. Fletcher B. Woolcott C.G. Fernandez C.V. Revisiting risk and benefit in early oncology trials in the era of precision medicine: a systematic review and meta-analysis of phase I trials of targeted single-agent anticancer therapies.JCO Precis Oncol. 2021; 5: 17-26Crossref PubMed Scopus (4) Google Scholar,6Schwaederle M. Zhao M. Lee J.J. et al.Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials.J Clin Oncol. 2015; 33: 3817-3825Crossref PubMed Scopus (291) Google Scholar Most of the genomic alterations are rare7Chang M.T. Bhattarai T.S. Schram A.M. et al.Accelerating discovery of functional mutant alleles in cancer.Cancer Discov. 2018; 8: 174-183Crossref PubMed Scopus (163) Google Scholar and as a consequence escape the pharma-driven validation of matched drug treatments.8Chakravarty D. Gao J. Phillips S.M. et al.OncoKB: a precision oncology knowledge base.JCO Precis Oncol. 2017; 2017Google Scholar Given the heterogeneity of cancer-driving events encountered in a given tumor type, comprehensive genomic profiling (CGP) aiming to identify single or multiple genomic alterations offers the possibility to capture the variety of genomic alterations the tumor presents with. This strategy ultimately allows the design of genotype-driven clinical trials focusing on different alterations present in a specific cancer type (umbrella trial) or on a specific alteration present in several cancer types (basket trials). Currently, there is an increasing number of studies enrolling patients based on molecular alterations of tumors [e.g. NTRK fusion, microsatellite instability (MSI), tumor mutational burden (TMB), DNA mismatch repair deficiency9Adashek J.J. Subbiah V. Kurzrock R. From Tissue-Agnostic to N-of-One therapies: (R)Evolution of the precision paradigm.Trends Cancer. 2021; 7: 15-28Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar], and regulatory agencies have approved tumor-agnostic indications (MSI, TMB, NTRK). Furthermore, recent data from a randomized study in the breast cancer field have proven the clinical benefit of molecularly guided therapies against validated targets [ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) levels I and II].10André F. Clinical utility of molecular tumor profiling: results from the randomized trial SAFIR02-BREAST.https://www.abstractsonline.com/pp8/#!/10462/presentation/2168Date accessed: June 14, 2022Google Scholar The bottleneck of this approach remains the identification of such patients with molecular alterations. Indeed, country-specific reimbursement criteria still frequently lead to the use of small targeted gene panels (Table 1) and hamper the implementation of broad genomic profiling in the routine molecular oncology diagnostics. The lack of tumor-agnostic CGP also threatens the competitiveness of Belgium, currently a leading force in Europe,11Carneiro A. Amaral T.M.S. Brandao M. et al.Disparities in access to oncology clinical trials in Europe in the period 2009-2019.Ann Oncol. 2020; 31: S1142-S1215Google Scholar in the clinical research field with the increase of biomarker-specific clinical trials that could disadvantage countries with smaller populations.Table 1List of gene panels used in clinical routine in Belgium for solid tumor analysis31Antoniou A. Ghislain V. Dekairelle A.-F. et al.Expertise ET Prestations De Services Qualite Des Laboratoires Comite Des Experts AD HOC.https://www.wiv-isp.be/qml/activities/NGS/_fr/Rapport%20global%20d%C3%A9finitif%20NGS%20EEQ%202021-1%20FR.pdfDate accessed: June 14, 2022Google ScholarCustom TSCA panel (Illumina, Mechelen, Belgium) with hotspots from 24 genes for a total of 8.1-kb targeted regionIon AmpliSeq Cancer Hotspot panel v2 (CHP2; Thermofisher Scientific, Merelbeke, Belgium)Ion AmpliSeq Colon and Lung Research Panel v2 (CLPv2; Thermofisher Scientific)Ion AmpliSeq Panel Gyneco (Custom panel; Thermofisher Scientific)Lung-colorectal panel designed with the module AmpliSeq Designer (Thermofisher Scientific) TruSight Tumor 26 (Illumina)TruSight tumor 15 (Illumina)TruSeq Amplicon Cancer Panel (48 genes) (Illumina)Tumor Hotspot MASTR Plus (Illumina)Illumina TruSeq Custom Amplicon INCa panel (INCa.bed; Agilent Technologies, Machelen, Belgium) kit ‘Human Tumor Actionable Mutations Panel’ (Qiagen; Agilent Technologies) Genes: BRaf, cKit, EGFR, IDH1, IDH2, KRas, NRas, and PDGFRA Open table in a new tab