Aplicaciones de la biopsia líquida en Oncología

Transcription

1 Aplicaciones de la biopsia líquida en Oncología Congreso Nacional del Laboratorio Clínico 2017 Emilio Alba UGCI Oncología Médica. Hospital Universitario Regional y Virgen de la Victoria Departamento de Medicina. Universidad de Málaga. IBIMA

2 Bettegowda, C., et al Sci. Trans. Med., (2014) vol 6

3 Ru Wang et al. Oncotarget 2017

4 Capturing tumor heterogeneity I Dagogo-Jack. Nat Rev Clin Oncol. 2017

5 TOPICS Congreso Nacional del Laboratorio Clínico 2017 LOAD Detection of cancers in high-risk population/early diagnosis Monitoring for minimal residual disease PROFILE Detection of response/resistance to therapy Choice of targeted agent CONCLUSIONS

6 TOPICS Congreso Nacional del Laboratorio Clínico 2017 LOAD Detection of cancers in high-risk population/early diagnosis Monitoring for minimal residual disease PROFILE Detection of response/resistance to therapy Choice of targeted agent CONCLUSIONS

7 Selected Studies of ctdna detection Analytic Platform Digital PCR (Beaver 2014) Molecular Alteration Patients Tumor Stage Sensitivity SNV (PIK3CA) 14 Breast I-II 93% BEAMing (Bettegowda 2014) SCODA (Kidess 2015) SNV (structural variants) SNV (Kras, BRAF, PIK3CA, EGFR) Congreso Nacional del Laboratorio Clínico Bladder Localized 57% 19 Breast Localized 53% 40 CCR Localized 78% 14 Gastric-E Localized 57% 9 Ovarian Localized 89% 121 Pancreatic Localized 50% 10 CCR I-II 60% Beaver JA, Clin Cancer Res 2014 Bettegowda C, Sci Transl Med 2014 Kidess E, Oncotarget 2015

8 ctdna as Diagnostic Tool Mx: BIRADS 4a - 5 Biopsy NGS: 10 gens more frecuently mutated (Illumina/BEAMING) Blood ctdna Correlation

9 TOPICS Congreso Nacional del Laboratorio Clínico 2017 LOAD Detection of cancers in high-risk population/early diagnosis Monitoring for minimal residual disease PROFILE Detection of response/resistance to therapy Choice of targeted agent CONCLUSIONS

10 CTCs in Localized Disease Tumor Patients Method Results Prostate (Khurana 2013) CRC (Tsai 2016) CRC (Bork 2015) Congreso Nacional del Laboratorio Clínico Cell Search Inconclusive 95 CMx Platform > 5CTC = DFS 239 Cell Search 1 CTC = DFS, OS Khurana KK, 2013 Tsai WS, Sci Rep 2016 Bork U, Br J Caancer 2015

11 Presence of CTCs and clinical outcome in early breast cancer Banys-Paluchowski M. Front Oncol 2016

12 Presence of persistent CTCs and outcome in early breast cancer Banys-Paluchowski M. Front Oncol 2016

13 Detection of Residual Disease after Surgery (ctdna) Method Tumor Patients Results Chromosomal Rearrangement (Olsson 2015) NGS (Tie 2016) Breast 20 CRC 178 ctdna : Recurrence 0 / 6 ctdna + : Recurrence 13/14 ctdna + : Recurrence 11 / 14 ctdna : Recurrence 16/164 Digital PCR (Garcia Murillas 2015) Breast 37 ctdna + v : HR: 25.1 Olsson E, EMBO Mol Med 2015 Tie J, Sci Transl Med 2016 García Murillas J, Sci Transl Med 2015

14 Monitoring ctdna Olsson E EMBO Mol Med 2015

15 Correlación del perfil mutacional y de expresión de la enfermedad residual y de la primera metástasis del tumor primario en mujeres con cáncer de mama tratadas en neoadyuvancia. Diseño experimental (Incluyendo todos los subtipos de cáncer de mama) Estudio Retrospectivo Solid biopsy Post- Chemotherapy Pretreatment samples Posttreatment samples Estudio Prospectivo Metastati c samples Chemotherap y treatment (NAC) Expansio n Solid biopsy Pre- Chemotherapy Solid biopsy Primary Metastasis & Liquid Biopsy: CTCs cfdna

16 Analizando los resultados de un paciente con mutación en KRAS, exón 2, Cd12 en diferentes procesos clínicos, podemos observar en las gráficas que en la intervención del primario hay una disminución del % del MAF presente antes de ella. Cuando comienza el tratamiento, baja el % de MAF hasta el límite donde la técnica determina como wildtype. BEAMing-1: 01/06/2016 pre-cx BEAMing-2: 20/06/2016 post-cx Cx primario y hepática: 02/06/2016 Tumor primario: KRAS-2, cd12 BEAMing-3: 22/08/2016 En curso de Xelox adyuvante KRAS-2, cd12 MAF: 1,71% KRAS-2, cd12 MAF: 0,198% WT MAF: 0,006% El BEAMing podría ser una excelente técnica para monitorizar la enfermedad, ya que a través de la sangre obtendríamos una representación de lo que ocurre en ese momento concreto de la evolución tumoral o de la respuesta del paciente al tratamiento.

17 Most frequent mutated and methylated genes Ciriello G Nat Genetics 2014

18 TOPICS Congreso Nacional del Laboratorio Clínico 2017 LOAD Detection of cancers in high-risk population/early diagnosis Monitoring for minimal residual disease PROFILE Detection of response/resistance to therapy Choice of targeted agent CONCLUSIONS

19 Tissue NGS vs. Plasma Cell-Free NGS on 165 Paired Samples from Five Centers Cell-free DNA vs. Tissue NGS SENSITIVITY SPECIFICITY DIAGNOSTIC ACCURACY I I I I I % (78.9%-89.7%) 99.6% (99.4%-99.7%) 99.3% (99.1%-99.4%) Congreso Nacional del Laboratorio Clínico 2017 Tissue vs. Cell-free DNA NGS SENSITIVITY SPECIFICITY DIAGNOSTIC ACCURACY I I I I I % (74.4%-85.8%) 99.7% (99.5%-99.8%) 99.3% (99.1%-99.4%) Cell-free DNA sensitivity may be limited when tumor DNA is not shed into circulation. Tissue DNA sensitivity may be limited because samples fail to capture tumor heterogeneity. All sequencing (both tissue and cfdna) on Illumina HiSeq Lanman et al PLOS One

20 Genomic alterations in lung cancer Hofman P. Cancers 2017

21 Concordancia tejido/plasma en CCR diseminado Congreso Nacional del Laboratorio Clínico 2017 Concordancia global 25/28 89,2% Concordancia nativos 9/12 75% Concordancia mutados 16/16 100%

22 Concordance tissue/blood in a clinical trial Lebofsky R Mol Oncol 2014

23 BELLE-2: Efficacy by PIK3CA Mutation in ctdna PIK3CA mutation analysis in ctdna by BEAMing method (N = 587 pts) Buparlisib + fulvestrant extended PFS in pts with PIK3CA mutations vs fulvestrant alone Median PFS, Mos (95% CI) ctdna PIK3CA mutant (n = 200)* Buparlisib + Fulvestrant Placebo + Fulvestrant HR (95% CI) P Value 7.0 ( ) 3.2 ( ) 0.56 ( ) <.001 Congreso Nacional del Laboratorio Clínico 2017 ctdna PIK3CA non-mutant (n = 387) 6.8 ( ) 6.8 ( ) 1.05 ( ).642 *n = 87 buparlisib + fulvestrant; n = 113 placebo + fulvestrant. n = 199 buparlisib + fulvestrant; n = 188 placebo + fulvestrant. ORR higher with buparlisib + fulvestrant in pts with PIK3CA mutations vs fulvestrant alone (18.4 % vs 3.5%) but similar in pts with non-mutant PIK3CA (11.6% vs 10.6%) Baselga J, et al. SABCS Abstract S6-01.

24 Erlotinib Carboplatin with docetaxel or gemcitabine A - EGFR L858R or exon 19 Del Measured in Tissue (N = 86) Median PFS (95% CI): Erlotinib arm 10.4 mos ( ) Chemotx arm 5.1 mos ( ) B - EGFR L858R or exon 19 Del Measured in Plasma (N = 49) Median PFS 995% CI) by qpcr or TaqMan: Erlotinib arm 12.3 mos ( ) Chemotx arm 5.5 mos ( ) Whether measured in tissue or blood, EGFR L858R and ex19 deletions responded to erlotinib. This is intuitive since the mutations in the blood come from the tissue. Karachaliou et al EURTAC trial JAMA Oncology

25 Gastric Cancer (N = 78) NSCLC (N = 72) ctdna matched Therapies (n) Therapeutic Targets ERBB2 amplification (6) PIK3CA mutation (2) FGFR2 amplification (1) MET amplification (1) EGFR mutation (8) EGFR T790M mutation (8) EML4-ALK fusion (1) Results 1 PD, 1 CR, 5 PR, 3 SD 1 PD, 1 SD, 15 PR Response Rate (PR+CR) 60% 88% Disease Control Rate (PR+CR+SD) 90% 94% Kim et al ASCO Abstract J Clinical Oncology 34;15_suppl

26 TOPICS Congreso Nacional del Laboratorio Clínico 2017 LOAD Detection of cancers in high-risk population/early diagnosis Monitoring for minimal residual disease PROFILE Detection of response/resistance to therapy Choice of targeted agent CONCLUSIONS

27 EGFR T790M Mutations Respond to Osimertinib When Measured in Plasma (ddpcr) Congreso Nacional del Laboratorio Clínico 2017 There was no difference in PFS between plasma-detected and tissue-detected EGFR T790M, the median response duration was 9.7 months (95% CI, 8.3 to 11.6) in the osimertinib group and 4.1 months (95% CI, 3.0 to 5.6) in the platinum pemetrexed group. Kim et al ASCO Abstract J Clinical Oncology 34;15_suppl

28 ctdna and immunotherapy Hofman P. Cancers 2017

29 CONCLUSIONS FACTS CTCs ARE PROGNOSTIC MARKERS IN EARLY AND METASTATIC DISEASE CTCs AND ctdna DETECT MRD HIGH CONCORDANCE TISSUE/BLOOD PREDICTIVE FACTORS FOR SOME ANTITARGET THERAPY Congreso Nacional del Laboratorio Clínico 2017 PROMISES ctdna AS SCREENING TOOL CTCs AND ctdna AS SURROGATE MARKERS OF ALL TUMOR POPULATIONS (heterogeneity) CLINICAL UTILITY OF EARLY DIAGNOSIS OF MRD CLINICAL UTILITY AS PREDICTIVE FACTORS