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

• DOI: 10.1016/j.esmoop.2022.100524
• Publication Date: 2022-08-12T23:37:31Z
• Authors: J. Thouvenin; C. Van Marcke; L. Decoster; G. Raicevic; K. Punie; M. Vandenbulcke; R. Salgado; E. Van Valckenborgh; B. Maes; S. Joris; D. Vander Steichel; K. Vranken; S. Jacobs; F. Dedeurwaerdere; G. Martens; H. Devos; F.P. Duhoux; M. Rasschaert; P. Pauwels; K. Geboes; J. Collignon; S. Tejpar; J.-L. Canon; M. Peeters; A. Rutten; T. Van de Mooter; J. Vermeij; D. Schrijvers; W. Demey; W. Lybaert; J. Van Huysse; J. Mebis; A. Awada; K.B.M. Claes; A. Hebrant; J. Van der Meulen; B. Delafontaine; I. Vanden Bempt; J. Maetens; M. de Hemptinne; S. Rottey; P. Aftimos; J. De Grève
• Keywords: Reimbursement; Precision oncology; Targeted Therapy; Profiling (computer programming); Cancer drugs

•PRECISION is a national program involving academia, regulatory authorities, and the pharmaceutical industry.•It promotes molecular testing, data storage sharing, treatment access via trials tumor board.•The multistakeholder collaboration stepping stone to broader next-generation sequencing reimbursement for targeted therapies. PRECISION an initiative from Belgian Society of Medical Oncology (BSMO) in with several stakeholders, encompassing four programs that aim boost genomic clinical knowledge ultimate goal offer patients metastatic solid tumors molecularly guided treatments. The 1 study has led creation clinico-genomic database. Approach Local Laboratory Extensive Tumor Testing (BALLETT) GeNeo studies will increase number advanced cancer have comprehensive genotyping their cancer. 2 project consists investigator-initiated phase II aiming provide drug whose harbor actionable mutations case matched not available through or Belgium. IntroductionUnderstanding mechanisms sensitivity anticancer therapies may improve patient selection, response therapy, rational designs. In last years, much progress been made toward improving overall prognosis identification activated pathways involved pathophysiology carcinogenesis, metastasis, resistance, as well emergence technologies enabling analysis continuous development stimulated research focusing on optimal use agents.1Zehir A. Benayed R. Shah R.H. et al.Mutational landscape revealed prospective 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. 168: 584-599Abstract Full Text PDF (287) 3Bedard P.L. Hyman Davids M.S. Siu L.L. Small molecules, big impact: 20 years therapy oncology.Lancet. 2020; 395: 1078-1088Abstract (143) Scholar administration specifically targeting activating alteration confer more benefit than conventional systemic therapy.4Massard C. Michiels S. Ferté al.High-throughput genomics outcome hard-to-treat cancers: results MOSCATO 01 trial.Cancer Discov. 7: 586-595Crossref (401) This approach found be relevant I trials, where refractory, treated had higher rates longer time failure survival without matching treatment.5Mackley M.P. Fernandez N.R. Fletcher B. Woolcott C.G. C.V. Revisiting risk early oncology era precision medicine: systematic review meta-analysis single-agent therapies.JCO Precis Oncol. 2021; 5: 17-26Crossref (4) Scholar,6Schwaederle M. Zhao Lee J.J. al.Impact medicine diverse trials.J Clin 2015; 33: 3817-3825Crossref (291) Most alterations are rare7Chang M.T. Bhattarai T.S. Schram A.M. al.Accelerating discovery functional mutant alleles cancer.Cancer 2018; 8: 174-183Crossref (163) consequence escape pharma-driven validation treatments.8Chakravarty D. Gao Phillips S.M. al.OncoKB: base.JCO 2017Google Given heterogeneity cancer-driving events encountered given type, profiling (CGP) identify single multiple offers possibility capture variety presents with. strategy ultimately allows design genotype-driven different present specific type (umbrella trial) types (basket trials). Currently, there increasing enrolling based [e.g. NTRK fusion, microsatellite instability (MSI), mutational burden (TMB), DNA mismatch repair deficiency9Adashek Subbiah V. Kurzrock From Tissue-Agnostic N-of-One therapies: (R)Evolution paradigm.Trends Cancer. 15-28Abstract (34) Scholar], agencies approved tumor-agnostic indications (MSI, TMB, NTRK). Furthermore, recent randomized breast field proven against validated targets [ESMO Scale Clinical Actionability Targets (ESCAT) levels II].10André F. utility profiling: trial SAFIR02-BREAST.https://www.abstractsonline.com/pp8/#!/10462/presentation/2168Date accessed: June 14, 2022Google bottleneck this remains such alterations. Indeed, country-specific criteria still frequently lead small gene panels (Table 1) hamper implementation broad routine diagnostics. lack CGP also threatens competitiveness Belgium, currently leading force Europe,11Carneiro Amaral T.M.S. Brandao al.Disparities Europe period 2009-2019.Ann 31: S1142-S1215Google biomarker-specific could disadvantage countries smaller populations.Table 1List used Belgium analysis31Antoniou Ghislain Dekairelle A.-F. al.Expertise ET Prestations De Services Qualite Des Laboratoires Comite Experts AD HOC.https://www.wiv-isp.be/qml/activities/NGS/_fr/Rapport%20global%20d%C3%A9finitif%20NGS%20EEQ%202021-1%20FR.pdfDate ScholarCustom TSCA panel (Illumina, Mechelen, Belgium) hotspots 24 genes total 8.1-kb regionIon AmpliSeq Cancer Hotspot v2 (CHP2; Thermofisher Scientific, Merelbeke, Belgium)Ion Colon Lung Research Panel (CLPv2; Scientific)Ion Gyneco (Custom panel; Scientific)Lung-colorectal designed module Designer (Thermofisher Scientific) TruSight 26 (Illumina)TruSight 15 (Illumina)TruSeq Amplicon (48 genes) (Illumina)Tumor MASTR Plus (Illumina)Illumina TruSeq Custom INCa (INCa.bed; Agilent Technologies, Machelen, kit 'Human Actionable Mutations Panel' (Qiagen; Technologies) Genes: BRaf, cKit, EGFR, IDH1, IDH2, KRas, NRas, PDGFRA Open table new tab Precision InitiativeThe already acknowledged ago three main issues personalized centers. First, isolated initiatives launched at individual laboratories sequence significantly efficient by being part large, prospective, collaborative effort would allow harmonization methods options. they each only generate fragmented unknown significance long term, collection settings precludes documentation confident estimates activity variants. Second, expensive reimbursed, limiting availability daily practice. roadmap includes evidence generation, reimbursement, decrease price consumables/tests. Finally, even if targetable detected, providing recommended issue. Of note, selection strongly dependent no financing off-label treatments, resulting fact besides medical need remain option situations lacking, which unfortunately current situation some treatments highest level regard variant interpretation (e.g. pembrolizumab TMB/MSI high tumors, alpelisib PIK3CA-altered cancer). programs, however, legal restrictions willingness companies these settings, often lacking absence programs. context, BSMO stakeholders (Figure Table 2) tackle issues. protocol provides setting collect both information who underwent circulating were subsequently drug, standard treatment, entered existing biomarker-driven trials. protocols tests detection single-nucleotide variants (SNVs), indels, copy variations (CNVs), rearrangements/fusions, RNA splice variants, signatures. master basket biomarker-matching drugs available.Table 2Components initiativeEligibility criteriaMolecular testingTreatmentPRECISION 1•Patients (age ≥18 years) candidates profiling•N/A•N/AGeNeo BALLETT•Patients therapy•Included program•FoundationOne CDx, FoundationOne Liquid Heme (rare tumors)•Illumina 500•Local hotspot (when reimbursed)Discussed MTB recommendations care, studies.PRECISION 2: Olaparib•Age years•Advanced cancer, either locally metastatic, harboring pathogenic genetic homologous recombination (with exception prostate BRCA1/2 mutation deficiency ovarian cancer)•No typeNo other genomic-driven I, II, III type•N/A•OlaparibPRECISION Afatinib•Age ≥ 18 years•Histologically confirmed HER2, HER3 mutation.•No eligible trial•Failure least one previous line treatment•N/A•Afatinib (+ paclitaxel disease progression)BALLETT, Testing; MTB, board. studyPRECISION (NCT03873103) multicenter, program. correlate across participating centers.The stored section Healthdata database (https://www.sciensano.be/en/about-sciensano/sciensanos-organogram/healthdatabe), platform developed store citizens' health secure uniform manner. Thus gone approval processes including government's privacy commission, embedding it legislative context. anonymized collected shared physicians researchers directly impact care system. Data sharing relies Healthdata.be managing omics projects, allowing investigators containing data, efficacy. They therefore able how centers same what was. overview prevalence all types, helpful future Irrespective choice (chemotherapy, immunotherapy, trial), followed collaborating clinician, follow-up every 6 months focus status endpoints (response rate, progression-free survival).GeNeo (NCT04641676) BALLETT (NCT05058937)The nomenclature (NGS) its limited amount funding supportive larger tissue-agnostic approach. Several weaknesses 'hotspot' can highlighted.12Van Valckenborgh E. Hébrant Antoniou al.Roadbook practice hemato-oncology Belgium.Arch Public Health. 76: 49Crossref (9) Scholar,13Hébrant Froyen G. Maes al.The next generation guidelines haematological tumours.Belg J Med 11: 56-67Google cover potentially regions. SNVs indel CNVs, fusions) rearrangements yet assessed NGS laboratories. Third, large disparities between methodologies. A demonstrated potential applying agnostic assessing alterations; Food Drug Administration (FDA)-approved 324 Foundation Medicine (Roche FMI) instead small-panel rate increased 28% 66%.14Rothwell D.G. Ayub Cook N. al.Utility ctDNA support trials: TARGET study.Nat 2019; 25: 738-743Crossref (140) Both investigate added value (centralized FMI testing GeNeo, decentralized Illumina TSO500 BALLETT) compared reimbursed advanced/metastatic molecular-guided and/or immunotherapy results. standardized CE-IVD (CE-IVD mark under In-Vitro Diagnostics Directive (IVDD 98/79/EC))- FDA-approved commercial facilitates exchange creates leverage aggregating multinational pharma companies.GeNeo (Genetic, Neo referring 'novel techniques') recruiting 1000 consecutive 13 academic nonacademic hospitals, centralized carried out FMI). Cases meeting local undergo CGP. Nonreimbursed tested using central Tissue biopsy required whenever received known induce resistance anti-epidermal growth factor receptor (anti-EGFR) non-small-cell lung liquid cohort capped 100 recruit accessible site. most frequent dedicated rare histologies.15Gatta van der Zwan J.M. Casali P.G. al.Rare cancers so rare: Europe.Eur 2011; 47: 2493-2511Abstract (433) ScholarThe aims examine consortium nine 936 recruited hospitals consent enter test, parallel panel. For studies, fully among consortium, respect wet laboratory execution dry analysis. common account two commercially available, tertiary software (OncoKDM: OncoDNA CGW: PierianDx) laboratories.Results cases (10 25 week) presented discussed weekly basis digital multi-institution board (MTB) composed experts sites. addition complete report, report summarizing alterations, biological interpretation, sent treating physician within 14 days receipt Publicly resources annotation used. Recommended consist drugs, on/off-label recommendations. gives provided OncoKB.8Chakravarty When OncoKB, we rationale evidence. Every recommendation back mention addition, deemed appropriate, referral counseling report. leveraging indications, uptake country. Reasons nonmatching final recorded endpoint study.PRECISION trialsSeveral identified very low frequencies insufficient develop satisfy Many Belgium.PRECISION respond unmet need. explorative open-label carrying prespecified These considered supporting biomarker predictive role another (phase Inclusion requires indication question absent. Patients 1, BALLETT, any test.Currently, ongoing first efficacy olaparib germline somatic implicated (NCT03967938), excluding indications. second afatinib ERBB2, ERBB3 mutation16Decoster L. Cappoen Aftimos al.An HER2 mutation: society oncology.J 36 (TPS2615-TPS2615)Crossref (NCT03810872), progression. Enrollment ongoing.16Decoster ScholarA illustrating deliveryHere 56-year-old female pancreatic adenocarcinoma.The duodenopancreatectomy August 2017 pT2N2M0 moderately differentiated ductal adenocarcinoma (PDAC), adjuvant chemotherapy capecitabine gemcitabine. September 2018, she subcutaneous metastases associated recurrence. Until March 2020, lines chemotherapy: gemcitabine nab-paclitaxel, FOLFIRINOX, cisplatin–5 fluorouracil. Targeted (Life Belgium), 19 genes, reported in-frame deletion exon EGFR (c.2237_2255delinsT, p.Glu746_Ser752delinsVal) alteration. Previous generated field, demonstrate tyrosine kinase inhibitors (TKIs) conferred located region.17Ning Wu Q. Liu Z. Wang Lin X. Mapping inhibitor deletions, insertions duplications epidermal (EGFR) non-small cell cancer.J Recept Signal Transduct Res. 2016; 36: 37-44Crossref (8) MSI PCR was negative. After informed consent, included trial, ERBB3. Afatinib second-generation TKI, irreversibly binds domain potently inhibits activation first-generation EGFR-TKI. dose 40 mg interruptions date. Adverse grade acneiform rash topic antibiotics intermittent diarrhea. Partial (decrease ∼40% hepatic target lesions according RECIST version 1.1) CA 19-9 normalization noted after cycles latest >12 (Figures 3). Here chemorefractory PDAC experienced durable deep partial afatinib. PDACs represent aggressive poor.18Bengtsson Andersson Ansari actual 5-year survivors real-world data.Sci Rep. 1016425Crossref (73) PDAC, <1% cases.19Cancer Genome Atlas NetworkElectronic address: [email protected], Network. Integrated Genomic Characterization Pancreatic Ductal Adenocarcinoma.Cancer Cell. 32: 185-203.e13Abstract (917) literature, few EGFR-targeted mainly erlotinib, PDAC.20Park Al-Jumayli Miller K. Saeed Exceptional erlotinib monotherapy 19-deleted, KRAS wild-type, chemo-refractory adenocarcinoma.Cancer Treat Res Commun. 27100342PubMed instance, combination despite difference median 10 days.21Moore M.J. Goldstein Hamm al.Erlotinib plus alone cancer: National Institute Canada Trials Group.J 2007; 1960-1966Crossref (3097) conducted biomarker-selected patients.Figure 2Serial computed tomography (CT) scan images EGFR-mutated receptor.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Evolution (PPT)DiscussionThe components challenges hindering clinic: many possible assay, establish benefits enlarge range therapeutic actionability patients, scale-up logistics establishment decisions. versus discussion regarding securing CGP, create eventually better decisions care.CGP classes (SNVs, rearrangements) signatures loss heterozygosity, dramatically enrollment trials.22Bailey M.H. Tokheim Porta-Pardo al.Comprehensive characterization driver mutations.Cell. 173: 371-385.e18Abstract (887) damage beyond BRCA1 BRCA2 example, enroll aberrant fusions driving oncogenesis spectrum types.23Radonic T. Geurts-Giele W.R.R. Samsom K.G. al.RET fluorescence situ hybridization sensitive but highly unspecific screening method RET Thorac 16: 798-806Abstract (18) Inhibitors rearrangement ev