Qué hemos aprendido hasta hoy? What have we learned so far? Luís Costa Hospital de Santa Maria & Instituto de Medicina Molecular Faculdade de Medicina de Lisboa
Disclosures Research Grants: Amgen; Novartis; Roche. Consultant: Novartis; Amgen. Speaker Honoraria: Amgen; Novartis; Bayer; Janssen.
Natural History of Cancer: time-points of intervention and interest of Liquid Biopsy in solid tumors Before Cancer Premalignant Lesions Early Stage Advanced Stage Prevention / Chemoprevention Carcinogens Risk Factors LifeStyle Host factors Genetic susceptibility Early Detection Early detection Curative strategy Adjuvant therapy Palliative Increase survival Symptoms control Curative (?) (a few) Clinical Research (new drugs) Metastatic de novo
Liquid Biopsies: A good chance to capture Dynamics / Heterogeneity / Clonal evolution / Resistance / Tumor-Host interaction Early Diagnosis
Liquid Biopsy in Metastatic Setting Detect emergent Resistance to target therapy: therapeutic guidance Detect new targets (clonal evolution) Prognostic Scan for heterogeneity /resistance Predict response to Immunotherapy Already applicable in daily clinical practice (Lung Cancer; Melanoma; Colorectal Cancer)
Guide to Utilization of ctdna Testing at Progression of Disease. TheOncologyJournal.com ONCOLOGY Kimberly M. Komatsubara et al ctdna = circulating tumor DNA; EGFR = epidermal growth factor receptor; NSCLC= non small-cell lung cancer; TKI = tyrosine kinase inhibitor.
2016 The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98) Rodrigo A. Toledo et al Red dots are cfdna mutation levels > 0,02% newly acquired during the FOLFIRIcetuximab therapy.
Mol Cancer Ther; June 2016 The amount of BRAF-mutant cfdna is a prognostic biomarker for Time to Treatment-Failure The Royal Marsden Hospital (RMH) prognostic score. The RMH score is a prospectively validated tool to predict OS in patients with advanced cancers referred for early phase clinical trials. LDH; Albumin; number of metastatic sites
Max Schreuer et al This graph shows the evolution of the BRAF V600E mutant cell-free tumor (ctdna) copy number (solid line) and fraction (dashed line) over time. The evolution of lactate dehydrogenase (LDH) is also presented (dotted line). Maximum intensity projections of 18F-FDG PET-CT images at baseline, and at first and second response evaluation are added above the graph. The use of dabrafenib (dabra) and trametinib (trame) is added below the time-line. Ipi indicates treatment with ipilimumab at a standard dose of 3mg/kg every 3 weeks. CT, computed tomography; 18F-FDG, fluorine-18 fluorodeoxyglucose.
Published at jco.org on December 22, 2017 The CTC0 and CTC conversion end points had the highest discriminatory power for overall survival. Validation of blood-based molecular biomarkers Howard I. Scher, Ryan Dittamore, and Jorge S. Reis- Filho AACR Education Book; 2014 http://educationbook.aacrjournals.org
Published at jco.org on April 6, 2017. Clinical outcomes in the overall cohort of men starting treatment with abiraterone or enzalutamide (N = 202), according to CTC status and AR-V7 status. CTC (AR-V7agnostic)
Oncodynamics Biobanking CTCs Total Epithelial CTCs Epithelial-to-Mesenchymal Transition CTCs (DAPI + /CD45 - /CK + /Vim - ) (DAPI + /CD45 - /CK + /Vim + ) Mesenchymal CTCs (DAPI + /CD45 - /CK - /Vim + ) 1ª collection 2821 1435 635 751 2ª collection 0* 1 0* 1 0* 1 0* 1 DAPI: nucleus; CD45: lymphocyte; CK: pan-citokeratin; Vim: vimentin. * 1 No CTCs events scored, because no event meets CTC established criteria. Prostate Cancer Case; #1
Tumor Progression Clonal progression Heterogeneity: CTCs; CtDNA; Tumor biopsies January 13th n: 28 (stage IV) Breast cancer Colon cancer Prostate Cancer 3 Immune 1 Response: Immune cell profile Oncodynamics 2 1 TME; Tumor-Host Interaction: Exosomes Sample collection: 1-Lança, T et al, (2012). Oncoimmunology, 1(5), 717-725 baseline (before starting systemic treatment) at each objective evaluation of tumor status (every 12-16 weeks if not requested before by the assistant physician) until two consecutive episodes of progression
69 patients with diverse malignancies who received checkpoint inhibitor based immunotherapy and blood-derived ctdna NGS testing (54 70 genes)* Statistically significant improvement in PFS was associated with high versus low alteration number in variants of unknown significance (VUS, >3 alterations versus VUS 3 alterations), SD 6 months/pr/cr 45% versus 15%, respectively; P = 0.014. Similar results were seen with high versus low total alteration number (characterized plus VUS, 6 vs. <6). * The Guardant360 (54 to 70 gene) test identifies characterized and VUS tumor-related genomic alterations within cancer-related genes.
Liquid Biopsy in early stage/after Adjuvant Setting Detect earlier the relapse Prognostic Scan for persistent minimal residual disease
Phylogenetic ctdna analysis depicts early stage lung cancer evolution Nature, April 2017 The TRACERx study monitors the clonal evolution of NSCLC from diagnosis through to death. Using multi-region exome sequencing (M-Seq) derived tumor phylogenetic trees developed through prospective analysis of a 100 patient TRACERx cohort, we conducted a phylogenetic approach to ctdna profiling in early-stage NSCLC
Phylogenetic ctdna analysis depicts early stage lung cancer evolution Nature, April 2017 At least 2 SNVs were detected in 13 of 14 (93%) patients with confirmed NSCLC relapse prior to, or at, clinical relapse. Within LUADs, driver events in KRAS, EGFR or TP53 were not associated with ctdna detection LUSCs, Lung squamous cell carcinomas ; LUADS, Lung adenocarcinomas ; SNVs, single nucleotide variants
N Engl J Med 2017;377:1836-46. Joseph A. Sparano CTC-positive patients had a recurrence rate per person-year of 24.7%, compared with 1.5% for CTC-negative patients. The positive predictive value of the CTC test for 2-year recurrence was 35%, and the negative predictive value was 98%, meaning a negative test meant a 2% or less chance of recurrence with the next 2 years
Liquid Biopsy to detect Genetic Susceptibility & Homologous Repair Deficiency (HRD) Host Factors Selection for clinical trials Treatment with PARP inhibitors Somatic vs germline mutation
TNBC; stage IV 42 years old
Liquid Biopsy to improve early detection of Cancer Golden Objective Medical need in Pancreatic Cancer The HOT TOPIC: CancerSEEK
May 4, 2017 The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient s primary tumor (100% concordance). Sensitivities of ctdna KRAS mutations alone, ctdnakras mutations plus CA19-9, and ctdnakras mutations with CA19-9 and other proteins (combination assay) with respect to tumor size. Unlike CA19-9, no predefined threshold exists for the use of CEA, HGF, or OPN as markers for pancreatic cancer.
CancerSEEK evaluates levels of 8 proteins and the presence of mutations in 2,001 genomic positions
Earlier detection The CancerSEEK story False Positive: 7 of 812 healthy controls scored positive Capture Dynamics Capture Tumor-Host Interaction
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