UGCI Oncología Médica. Hospital Universitario Regional … · Aplicaciones de la biopsia líquida en Oncología Emilio Alba UGCI Oncología Médica. Hospital Universitario Regional

Aplicaciones de la biopsia líquida en Oncología

Emilio Alba

UGCI Oncología Médica. Hospital Universitario Regional y Virgen de la Victoria

Departamento de Medicina. Universidad de Málaga. IBIMA

Congreso Nacional del Laboratorio Clínico 2017

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


Ru Wang et al. Oncotarget 2017


I Dagogo-Jack. Nat Rev Clin Oncol. 2017

Capturing tumor heterogeneity Congreso Nacional del Laboratorio Clínico 2017

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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

TOPICS Congreso Nacional del Laboratorio Clínico 2017

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CONCLUSIONS


Selected Studies of ctDNA detection

Analytic Platform Molecular

Alteration Patients Tumor Stage Sensitivity

Digital PCR (Beaver 2014)

SNV (PIK3CA) 14 Breast I-II 93%

BEAMing (Bettegowda 2014)

SNV (structural

variants)

7 Bladder Localized 57%

19 Breast Localized 53%

40 CCR Localized 78%

14 Gastric-E Localized 57%

9 Ovarian Localized 89%

121 Pancreatic Localized 50%

SCODA (Kidess 2015)

SNV (Kras, BRAF,

PIK3CA, EGFR) 10 CCR I-II 60%

Beaver JA, Clin Cancer Res 2014

Bettegowda C, Sci Transl Med 2014

Kidess E, Oncotarget 2015


ctDNA as Diagnostic Tool

Correlation

Biopsy NGS: 10 gens more frecuently mutated (Illumina/BEAMING)

Blood ctDNA

Mx: BIRADS 4a - 5


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CONCLUSIONS


CTCs in Localized Disease

Tumor Patients Method Results

Prostate (Khurana 2013)

12 Cell Search Inconclusive

CRC (Tsai 2016)

95 CMx Platform > 5CTC = ↓ DFS

CRC (Bork 2015)

239 Cell Search ≥ 1 CTC = ↓ DFS, OS

Khurana KK, 2013

Tsai WS, Sci Rep 2016

Bork U, Br J Caancer 2015


Presence of CTCs and clinical outcome in early breast cancer

Banys-Paluchowski M. Front Oncol 2016


Presence of persistent CTCs and outcome in early breast cancer

Banys-Paluchowski M. Front Oncol 2016


Detection of Residual Disease after Surgery (ctDNA)

Method Tumor Patients Results

Chromosomal

Rearrangement (Olsson 2015)

Breast 20 ctDNA : Recurrence 0 / 6

ctDNA + : Recurrence 13/14

NGS (Tie 2016)

CRC 178 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


Monitoring ctDNA

Olsson E EMBO Mol Med 2015


Estudio Prospectivo

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.

Chemotherapy treatment

(NAC)

Expansion

Solid biopsy Pre-

Chemotherapy

Solid biopsy Post-

Chemotherapy

Solid biopsy Primary

Metastasis

Liquid Biopsy: CTCs

cfDNA

Pre-treatment samples

Metastatic

samples

Post-treatment samples

&

Diseño experimental (Incluyendo todos los subtipos de cáncer de

mama)

Estudio Retrospectivo


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.

KRAS-2, cd12 MAF: 1,71%

BEAMing-1: 01/06/2016 pre-Cx

WT MAF: 0,006%

BEAMing-3: 22/08/2016

En curso de ¨Xelox adyuvante” BEAMing-2: 20/06/2016 post-Cx

KRAS-2, cd12

MAF: 0,198%

Cx primario y hepática: 02/06/2016 Tumor primario: KRAS-2, cd12

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.


Ciriello G Nat Genetics 2014

Most frequent mutated and methylated genes Congreso Nacional del Laboratorio Clínico 2017

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PROFILE



CONCLUSIONS


Lanman et al. 2015 PLOS One

Tissue NGS vs. Plasma Cell-Free NGS on 165 Paired Samples from Five Centers

SENSITIVITY

SPECIFICITY

DIAGNOSTIC ACCURACY

Cell-free DNA vs. Tissue NGS

85.0% (78.9%-89.7%)

99.6% (99.4%-99.7%)

99.3% (99.1%-99.4%)

Tissue vs. Cell-free DNA NGS SENSITIVITY

SPECIFICITY

DIAGNOSTIC ACCURACY

80.7% (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 2500.

0 25 50 75 100 I I I I I

0 25 50 75 100 I I I I I


Hofman P. Cancers 2017

Genomic alterations in lung cancer Congreso Nacional del Laboratorio Clínico 2017

Concordancia tejido/plasma en CCR diseminado

Concordancia global 25/28 89,2%

Concordancia nativos 9/12 75%

Concordancia mutados 16/16 100%


Lebofsky R Mol Oncol 2014

Concordance tissue/blood in a clinical trial Congreso Nacional del Laboratorio Clínico 2017

Baselga J, et al. SABCS 2015. Abstract S6-01.

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)

Buparlisib + Fulvestrant

Placebo + Fulvestrant

HR (95% CI)

P Value

ctDNA PIK3CA mutant (n = 200)*

7.0 (5.0-10.0) 3.2 (2.0-5.1) 0.56 (0.39-0.80) < .001

ctDNA PIK3CA non-mutant (n = 387)† 6.8 (4.7-8.5) 6.8 (4.7-8.6) 1.05 (0.82-1.34) .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%)


Karachaliou et al. 2015 EURTAC trial JAMA Oncology

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 (8.4 – 12.9) Chemotx arm 5.1 mos (4.5 – 5.8)

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 (8.4 – 14.7) Chemotx arm 5.5 mos (4.5 – 6.7)

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.


Kim et al. 2016 ASCO Abstract J Clinical Oncology 34;15_suppl

Gastric Cancer (N = 78)

NSCLC (N = 72)

ctDNA matched Therapies (n) 10 17

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%


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CONCLUSIONS


Kim et al. 2016 ASCO Abstract J Clinical Oncology 34;15_suppl

EGFR T790M Mutations Respond to Osimertinib When Measured in Plasma (ddPCR)

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.


Hofman P. Cancers 2017

ctDNA and immunotherapy Congreso Nacional del Laboratorio Clínico 2017

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

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

CONCLUSIONS Congreso Nacional del Laboratorio Clínico 2017

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UGCI Oncología Médica. Hospital Universitario Regional … · Aplicaciones de la biopsia líquida en Oncología Emilio Alba UGCI Oncología Médica. Hospital Universitario Regional