circulante en cáncer de pulmón como biomarcador no invasivo - PDF

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Enfoque clínico del uso de ADN circulante en cáncer de pulmón como biomarcador no invasivo Luis Paz-Ares Hospital Universitario Doce de Octubre Madrid, Spain NSCLC - Genotype NTRK fusions 2015 Lung Cancer

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Enfoque clínico del uso de ADN circulante en cáncer de pulmón como biomarcador no invasivo Luis Paz-Ares Hospital Universitario Doce de Octubre Madrid, Spain NSCLC - Genotype NTRK fusions 2015 Lung Cancer Oncogenic Drivers & Targeted Therapy Kris et al., JAMA 2015. ctdna Analysis Clinical applications Harber et al. Cancer Discov 2014 ctdna - Technologies Harber et al. Cancer Discov 2014 Guiding Treatments in Clinical Practice Mission Trial - Biomarker analysis 357 of 703 (51%) patients consented to biomarker analysis Paz-Ares et al., JTO 2015 (in press) 107 (15%) Tumor samples available for EGFR/KRAS mutation analysis 346 (49%) Plasma samples available for EGFR/KRAS mutation analysis 90 (13%) Tumor samples analyzed for EGFR mutations 71 (10%) Tumor samples analyzed for KRAS mutations 346 (49%) Plasma samples analyzed for EGFR mutations 346 (49%) Plasma samples analyzed for KRAS mutations Concordance of tumor and plasma mutations EGFR Tumor Wild-type Mutant Plasma Wild-type 75 2 Mutant 4 8 Total number 89 Concordance (%) 93.3* KRAS Tumor Wild-type Mutant Plasma Wild-type 45 5 Mut 6 14 Total number 70 Concordance (%) 84.3* * P 0.001 by chi-square test Paz-Ares et al., JTO 2015 Concordance 94.3% Sensitivity 66% Specifity 100% Douillard J et al. JTO 2014 IRESSA receives CHMP positive opinion to include blood based diagnostic testing in European label On 26 th Sep, 2014 Diagnostic Value of ctdna for the Detection of EGFR Mutations in NSCLC Sensitivity Specificity Luo J, et al. Sci Rep. Prognostic Implications For patients with the L858R mutation in tissue, median OS was 13.7 months for patients with the L858R mutation in cfdnaand 27.7 months for those in whom the mutation was not detected in cfdna KarachaliouN et al. JAMA Oncol2015 Monitorizing the benefit FASTAC-2 Translational Relevance Concordance between tumor and blood: 88% Sensitivity: 75% Specificity: 96% ctdna produces similar results to tissue-based assays for predicting PFS and OS outcomes. Those with EGFR mutation negative assessment at cycle 3 had better efficacy outcomes in terms of PFS and OS than those whose samples were still EGFR mutation positive at cycle 3 MokT et al. CCR 2015 Resistance Mechanisms and Subsequent Treatments Implications Knowledge of clinical resistant mechanisms is limited Camidgeet al. NatRevCancer2014 PFS according to treatment group and T790M mutation status (A) and treatment group and BCL2L11 (BIM) mrna expression levels (low/intermediate vs. high; B). Carlota Costa et al. Clin Cancer Res 2014;20: Gefitinib/Chemotherapy vs Chemotherapy in EGFR Mutation- Positive NSCLC Resistant to First-Line Gefitinib: IMPRESS T790M Subgroup Analysis Progression-free survival in T790M mutation-negative patients Probability of PFS Gefitinib (n=46) Placebo (n=59) T790M mutationnegative (n=105) Median PFS, months Time of randomization (months) Patients at risk: Gefitinib Placebo Gefitinib (n=46) Placebo (n=59) HR a (95% CI) = 0.67 (0.43, 1.03); p=0.07 a PrimaryCox analysis with covariates A HR 1 implies a lower risk of progression with gefitinib MokT et al. WLCC 2015 Resistance Emergence Monitoring Slide 31 Thresset al. LungCancer2015 Assessment of T790M in ctdna vs Tissue Thresset al. LungCancer2015 T790M in ctdna Cobas vs Beaming Disagreed arose in cases where the T790M was very low below the detection limit of the cobas EGFR mutation test These data suggest that tumor heterogeneity, and not technological limitations alone, may explain the tissue-plasma discordance These data suggest that plasma ctdna may be more precise and informative than tissue as a blood mirrors the entire tumor burden Z Piotrowska et al., Cancer Discovery 2015 Rociletinib Resistance fsdna Plasma Monitoring PFS by tumor and plasma T790M Osimertinib Oxnard GR, et al. ELCC 2016 Oxnard GR, et al. ELCC 2016 EGFR Mut+ NSCLC Clonal Evolution Under TKI Preassure to AZD9291 DS Costa & Kobayashiet al. Nature Medicine 2016 Mechanisms of Resistance to AZD9291 in EGFR T790M Positive Lung Cancer 15 (22%) out of 67 patients, had detectable C797S, all with detectable T790M C797S was more common with EGFR exon 19 del (13/43, 30%) vs those with L858R (2/24, 8%, p=0.06) 32 of 67 (48%) had no detectable T790M in plasma despite presence of the EGFR-TKI-sensitizing mutation, suggesting overgrowth of an alternate resistance mechanism, such as MET or HER2 amplification or BRAF V600E Thress KS et al. Nature Medicine 2015 Oxnard G et al. MINI 17.07 Results: MET amplification 69-year-old female with EGFR-mutant NSCLC metastatic to liver, adrenal, bones who had progression after first-line chemotherapy and subsequent erlotinib Resistance biopsy was inadequate for genotyping, but plasma genotyping positive for L858R (26%) and T790M (4%) Initiated AZD9291 and responded on the first scan (-40%) but progressed after 24 weeks Resistance biopsy undergone for targeted NGS: o o Positive for L858R, negative for T790M, positive for MET amplification MET protein overexpression also seen on IHC Pre-AZD9291 plasma genotype: L858R (26%) T790M (4%) Progression tumor genotype: L858R T790M negative MET amplified Baseline 4 months 6 months WLCC 2015 Oral GR Oxnard Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may be able to predict and monitor outcome to crizotinib and early detect acquired resistance Nilsson J et al. Oncotarget 2015 Screening of Druggable Aberrations Molecular profiling and drug development NGS clinical research utilities Siuet al. ClinCancerRes 2015 Molecular profiling and drug development Timing for molecular prescreening Rodonet al. NatRevClinOncol2012 Molecular profiling and drug development NGS clinical research utilities Siuet al. ClinCancerRes 2015 Some Ongoing Umbrella Trials Histology-Specific Genotyping Study: Umbrella Trials Siuet al. ClinCancerRes 2015 NGS in circulating DNA cfdnangs in themoscato trial NGS clinical research utilities Joveletet al. ClinCan Res 2016 NGS in circulating DNA cfdnangs in themoscato trial NGS clinical research utilities Mutation level Patient level Sensitivity: 49.9 % Especificity: 99.8 % Sensitivity: 55 % Joveletet al. ClinCan Res 2016 cfdnangs in themoscato trial Predictive score for the success of cfdna NGS Joveletet al. ClinCan Res 2016 SPECTA PLATFORMS SPECTAcolor SPECTAlung SPECTAbrain SPECTAmel SPECTA rare SPECTA prostate Protocol developme nt Regulatory submission Study Activation First Patient In First Sample Received First NGS results First downstream trial SPECTAlung Screening Patients with thoracic tumors for Efficient Clinical Trial Access EORTC ETOP collaboration Study Coordinator: Benjamin Besse (Gustave Roussy Cancer Campus Grand Paris, FR) Objectives To screen per year after the first year of operation To offer downstream biomarker-driven clinical trials Population Lung cancer, malignant pleural mesothelioma, thymoma or thymic carcinoma Any stage; Availability of HBM: FFPE tissue sample from the primary tumor, recurrent tumor, metastasis, the progressive site and at regular timing during follow-up; At least three months life-expectancy. SPECTAlung SAMPLES Type Storage Amount Collection timepoints Mandatory FFPE tumor tissue Optional FFPE tumor tissue Frozentumor tissue Room T Room T At least 1 FFPE block or 15 slides At least 1 FFPE block or 15 slides -80C At least one tissue core At baseline At recurrence, at PD At recurrence Blood -80C Up to 50 ml At baseline,at FU (once a year), at each PD Scope Central confirmation of adequacy Centralscreening and future research Centralscreening and future research Future research Future research Pleural fluid -80C Up to 50 ml Anytime available Future research Plataforma de Biomarcadores en Cáncer SEAP-SEOM 40 CONCLUSIONS fsdna is a valuable source to study genomic aberrations in lung cancer (and other tumors) and inform clinical practice Current applications include initial diagnosis, prognosis, efficacy monitoring and resistance emergence and treatment guiadance Oncogenic Drivers &Targeted Therapy Kris et al., JAMA 2015. Some Challenges Clinical implementation of precision oncology Dealing with tumor heterogeneity and resistance Prioritizing targets Low frequency aberrations - innovative trials Predictive biomarkers for immune-based therapies Drug combinations: emerging and limiting toxicities Clinical Implementation Expert teams Tumor matherial Technology Bioinformatics Adequate time-frame Quality assurance programs Link to a innovative clinical trials program Slide 17 Presented By Sameek Roychowdhury at 2015 ASCO Annual Meeting ORAL Q Zhang 46 Cancer Research UK Stratified Medicine Program ORAL Q Zhang 47 Research Ins tutes/groups Groups: 1, 4, 5, 6, 7, 10, 12 WP1: Coordina on, Ge enomics and Bioinforma cs WP3: Biomarkers in exosomes WP4: Valida on in clinical cohorts WP5: Implementa on of new technologies WP6: Na onal pla orm Groups: 7, 1, 3, 4, 9, 12, 13 Groups: 10, 1, 11, 12, 13 Groups: 2, 1, 5, 6, 7, 8, 10, 11, 12, 13 Groups: 5, 1, 2, 4, 6, 7, 8, 9, 10, 11, 12 Groups: 6, 1, 2, 4, 5, 7, 8, 10, 11, 12, 13 PIE 2015 L Paz-Ares (IP) Gracias Other Applications in Clinical Reserach Exceptional responders NGS clinical research utilities Everolimus responsive urotelial carcinoma NGS and coclinical trials with PDX models NGS clinical research utilities Hidalgo et al. Cancer Discov 2014 Generación de plataforma PDX de tumores de pulmón para su posterior uso como modelo preclínico de evaluación terapéutica Fase con pacientes Fase de establecimiento de injerto Fase de expansión X 2-3 P0 P1 P2 Fase experimental X tto + control Unraveling acquired resistant mechanisms Complex picture of acquired resistance NGS clinical research utilities Wilson et al. CancerCell2015
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