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Clara MontagutServicio de Oncología Médica & Programa de Investigación en Cáncer
Hospital del Mar, Barcelona
Valor clínico de la biopsia líquida en cáncer de colon
Hospital del Mar, Barcelona
SEAP-IAP / SEOM, 27 Mayo 2016
Aplicaciones Clínicas de los Test de ADN tumoral
circulante (Cáncer Colorrectal)
Aplicaciones Clínicas de la biopsia líquidaen cáncer colorrectal
1. Determinación de RAS al diagnóstico
2. Monitorizar respuesta / resistencia al tratamiento antiEGFR
3. Monitorizar “tumor load”
Aplicaciones Clínicas de los Test de ADN tumoral
circulante (Cáncer Colorrectal)
Aplicaciones Clínicas de la biopsia líquidaen cáncer colorrectal
1. Determinación de RAS al diagnóstico
2. Monitorizar respuesta / resistencia al tratamiento antiEGFR
3. Monitorizar “tumor load”
Greater patient selection with RAS testing increases the survival benefit with cetuximab + FOLFIRI
HR 0.69 (0.54–0.88)p=0.0024
∆ = 8.2 months
HR=0.796 (0.67–0.95)p=0.0093
HR=0.878 (0.77–1.00)p=0.0419
∆ = 3.5 months∆ = 1.3 months
1.01.01.0
RAS wtKRAS exon 2 wtUnselected
Cetuximab + FOLFIRI (n=178)
FOLFIRI (n=189)
0.0
0.2
0.4
0.6
0.8
Months5442 48186 12 24 30 36
28.4
20.2
0Time (months)
5442 48
23.520.0
0.0
0.2
0.4
0.6
0.8
180 6 12 24 30 36Months
5442 480.0
0.2
0.4
0.6
0.8
180 6 12 24 30 36
OS
est
imat
e
19.9
18.6
Cetuximab + FOLFIRI (n=599)
FOLFIRI (n=599)
Cetuximab + FOLFIRI (n=316)
FOLFIRI (n=350)
Tissue RAS Result
Plasma Ras
Result
Positive Negative Total
Positive 25* 2 27
Negative 1 22 23
Total 26 24 50
Plasma/Tissue Correlation - H. del Mar Experience
Total 26 24 50
* 1 positive in tissue and plasma but in different codon
Positive Agreement: 25/26: 96.15%
Negative Agreement: 22/24: 91.66%
Overall Agreement: 47/50: 94%
Aplicaciones Clínicas de los Test de ADN tumoral
circulante (Cáncer Colorrectal)
Aplicaciones Clínicas de la biopsia líquidaen cáncer colorrectal
1. Determinación de RAS al diagnóstico
2. Monitorizar respuesta / resistencia al tratamiento antiEGFR
3. Monitorizar “tumor load”
Emergence of mutations of resistance
KRASKRAS
wtKRAS wt
Clonal dynamics during antiEGFR treatment in mCRC
wt
Response to anti-EGFR treatment
Progression to anti-EGFRtreatment
Basal tumor
wtKRAS wt
EGFR
Anti-EGFR treatment
KRAS
LIGANDS overexpressionAREG, HRG, TGFα
Cell membrane
EGFR HER2 ampl MET ampl
NRAS
1. Mutations in extracellulardomain of EGFR
Resistencia adquirida a tratamiento anti-EGFR
KRAS
BRAF
MEK-1
ERK
PI3-K
AKT
NRAS
2. Downstream mutationsor activation of alternativereceptors that converge in MEK activation
Montagut, Nat Med 2012; Misale, Nature 2012; Diaz, Nature 2012; Bardelli, Cancer Discov 2013; Troiani, CCR 2013; Misale, STM 2014; Hobor, CCR 2014; Arena, CCR 2015; Siravegna, Nat Med 2015; Russo, Cancer Discov 2016
Monitoring mutations of resistance in the blood of patients
Misale, Nature 2012; Diaz, Nature 2012; Bettegowda, STM 2014 ; Morelli, Ann Oncol 2015
Biopsia líquida recoge la heterogeneidad de todas las clonas de resistencia
Aim: To assess the clinical relevance of monitoring mutations in serial plasma samples from RAS wt mCRC patients treated with cetuximab-based therapy in 1st line
Diagnosis During treatm ent Progression Post -progression
Cetuximab-based treatment in 1st line
Diagnosis During treatm ent Progression Post -progression
Plasma
sample
Tumor sample
MonthlyBaseline +3 / +6 monthsEndof treatment
Biopsia liquida para guiar decisión terapéutica después de cetuximab/panitumumab
• rechallenge• segunda generación antiEGFR
Mutations in KRAS emerge during anti-EGFR treatmentand decline when treatment is suspendend
KRASKRAS
wt wtKRAS wt
EGFR
Response to treatment Progression to treatmentBasal tumor
Off treatment
EGFR
Liquid biopsy for longitudinal monitoring of RAS mutations in blood of patientsRechallenge with cetuximab
Siravegna et al. Nat Med 2015
Rechallenge with anti-EGFR therapy
Cetuximab + FOLFIRI
R
FIRE-4 (Phase III, n=550)
Bevacizumab + FOLFOX/XELOX
Cetuximab + irinotecan/FOLFIRI
RegorafenibCetuximab + FOLFIRI
R
1st line 2nd line 3rd line
RAS wt
mCRCBevacizumab + FP maintenanceFOLFIRI
Liquid biopsy to track/identify resistance
• Primary endpoint: OS after randomization 2• Results expected: January 2022
FP maintenance
New generation anti-EGFR moAb
0.25
0.50
0.75
1.00
1.25CetuximabPanitumumabSym004
Det
ecte
d st
aine
d ce
lls(N
orm
aliz
ed to
EG
FR
WT
)
Sym004 is effective in colorectal cancer harbouring EGFR ECD mutations
Receptor binding
Sánchez-Martín et al. CCR 2016
0.00Empty EGFR WT S492R R451C K467T G465R
0
200
400
600
800
1000
1200
1400
1600
4 7
10
12
14
17
20
24
27
31
39
48
56
62
69
76
83
89
97
10
9
12
4
13
9
Tu
mo
r v
olu
me
(m
m3
)
Days
Control
Cetuximab
Sym004
S492R EGFR ECD mut
Liquid biopsyEGFR ECDRAS/RAF
mCRC patients withacquired resistance to
cetuximab/ panitumumab
Sym004EGFR ECD mut
MM-151 overcomes acquired resistance to cetuximab and panitumumab in CRC harbouring EGFR ECD mutations
Arena et al, STM 2015
Aplicaciones Clínicas de los Test de ADN tumoral circulante (Cáncer Colorrectal)
Aplicaciones Clínicas de la biopsia líquidaen cáncer colorrectal
1. Determinación de RAS al diagnóstico
2. Monitorizar respuesta / resistencia al tratamiento antiEGFRtratamiento antiEGFR
3. Rechallenge
4. Monitorizar “tumor load”
El ADN tumoral circulante predice la respuesta al tratamiento antes que las pruebas de
imagen
Evaluación precoz de respuesta a tratamiento con quimioterapia
8 semanas después
Tie et al. Ann Oncol 2015
1%
2%
3%
4%
5%
6%
7%
8%
Patient 1: NRAS 61
Patient 2: NRAS 61
Patient 3: KRAS 146
mut
ant
ctD
NA
frac
tion
Evaluación de respuesta a tratamiento con antiangiogénico
0%
Baseline CT scan: SD CT Scan: PDRA
S m
utan
t
BASELINE Stable Disease
Patient 1
Take-home message
• La detección de RAS en biopsia líquida ha demostrado altacorrelación con la determinación en tejido en pacientes con cáncer colorrectal metastásico
• La determinación de RAS en biopsias líquidas seriadas permitemonitorizar la dinámica clonal de los tumores, detectarprecozmente la aparición de resistencias y seleccionar el tratamiento adecuado en cada momento
• Ensayos clínicos con toma de decisiones basadas en biopsialíquida están en marcha
5
10
50
100
150
tumor load (%)
Tu
mo
r lo
ad
(%
of
ba
seli
ne
)
NRAS p.Q61L
% m
uta
nt
all
ele
s
Detección de adquisición de mutaciones de RAS en sangre periféricamediante BEAMing en paciente tratado con anti-EGFR
0 0
Tu
mo
r lo
ad
(%
of
%
Baseline 1st CT scan PD
27-FEB-2012 01-MAY-2012
Last administration of anti-EGFR
CT scan: PR
*
22-DEC-201401-AGO-2013
FOLFOX+CETUX
*
FOLFIRI+Aflibercept
***
tumor load (%)
Tu
mo
r lo
ad
(%
of
ba
seli
ne
)
EGFR p.S492R
KRAS p.Q61H
% m
uta
nt
all
ele
s
Clonal dynamics in a CRC patient treated with anti-EGFR therapy
Baseline 1st CT scan1st line
1st line PD 2nd line PD1st CT scan2nd line
PANIT
25-JUN-2009 21-AGO-2009 17-MAY-2010
Last administration of anti-EGFR(1st line)
CT scan: PR
Last administration of anti-EGFR(2nd line)
CT scan: PR
9-DEC-2010 13-APR-20111-NOV-2010
First administration ofanti-EGFR (2nd line)
FOLFOX+CETUX
Joana Vidal.Unpublished data
Global implementation of RAS liquid biopsy* testing: Goals for 2016
*Launch of a CE-marked in vitro diagnostic for RAS, using liquid biopsies, by Sysmex Inostics, in collaboration with Merck is expected in 2016 (a ‘research use only’ kit is already available). Launch of a CE-marked in vitro diagnostic for RAS, using liquid biopsies, by Biocartis, in collaboration with Merck is expected in 2017.
Tratamiento Anti-EGFR
TejidoWT
cáncer colorrectal metastásico
Estado de la mutación RAS
Anti-EGFR
Quimioterapia,antiangiogenico
MUT
Pre-Treatm
entP
ost-Treatment
Patient #
KRAS exon 2
KRAS exon 3
KRAS exon 4
NRAS exon 2
NRAS exon 3
NRAS exon 4
BRAF exon 15
PIK3CA exon 9
PIK3CA exon 20
EGFR exon 12
KRAS exon 2
KRAS exon 3
KRAS exon 4
NRAS exon 2
NRAS exon 3
NRAS exon 4
BRAF exon 15
PIK3CA exon 9
PIK3CA exon 20
EG
FR
exo
n1
2
R451C
S464L
G465R
K467T
I491M
S492R
45811
13
15
16
Em
ergence of mutations of resistance
during cetuximab
treatment in colorectal cancer
16
17
18
20
21
23
26
27
31
33
34
35
36
37
Montagut et al. N
atMed
2012A
rena&B
ellosilloet al. C
linC
ancerR
es 2015
Sym004Phase I clinical trial in patients progressing to cetuximab
EGFR G465R mutation EGFR S492R mutation
Dientsmann. Cancer Discov 2015 Sánchez-Martín et al. CCR 2016
Monitorización de recaída tras cirguía
Diehl et al. Nat Med 2008
Before surgery(mutant DNA 13%)
d+3 after surgery(mutant DNA 0.01%)
d+48 after surgery(mutant DNA 0.1%)
d+244 after surgery(mutant DNA 0.66%)
Monitorización de recaída tras cirugía
Diehl et al. Nat Med 2008
Coexistance of mutations of resistance
Patient TreatmentKRAS
mutationNRAS
mutationEGFR
mutationRespon
sePFS (w)
2 FOLFIRI cetuximab G465R SD 63
4 FOLFIRI cetuximab Q61H; V114I S464L; I491M SD 39
8 IRINO cetuximab G12S PR 55
9 FOLFIRI cetuximab G12V PR 41
10 IRINO cetuximab G60R SD 24
12 IRINO cetuximab G12V CR 48
13 IRINO cetuximab Q61H SD 20
16 FOLFOX cetuximab G12S SD 24
18 IRINO cetuximab G12A Q61H PR 25
19 FOLFIRI cetuximab G12V SD 23
20 IRINO cetuximab A146T SD 51
21 FOLFOX cetuximab S492R PR 42
Supplementary Table 1
22 FOLFOX cetuximab Q61L S492R PR 60
24 FOLFIRI cetuximab Q61L SD 26
25 FOLFOX cetuximab S492R PR 44
29 IRINO cetuximab K467T PR 52
32 IRINO cetuximab V114I Q61K SD 21
33 IRINO cetuximab G12D; G60D R451C SD 22
39 IRINO cetuximabG12C; G12D; G12A; G12V
S464L; G465E; G465R
PR 61
42 IRINO cetuximab G465R PR 45
43 IRINO cetuximab S464L PR 69
44 panitumumab G465R; G465E PR 39
45 IRINO panitumumab Q61H Q61H G465R; S464L SD 32
46 panitumumab Q61H SD 26
47 FOLFIRI cetuximab G12D G465R; S464L PR 17
53 FOLFIRI cetuxi Q61H S464L PR 67
59 panitumumab Q61H PR 37
EGFR ECD mut Clinical work Frequency % median
G465R / G465E Arena. STM 2016 3/11 3%
4%
Bertotti. Nature 2015 2/22 1%
Sanchez. CCR 2016 1/13 8%
Non-published data 3/20 3%
S464L Arena. STM 2016 1/11 9%5%
Non-published data 3/20 2%
EGFR ECD mutations. Prevalence in patients
Mutations of resistance. Clinical implications 1
Non-published data 3/20 2%
K467T Arena. CCR 2015 1/37 3% 3%
I491M Non-published data 1/20 <1% 1%
R451C Arena. CCR 2015 1/37 3%3%
Heracles study 1/?
S492R Montagut. Nat Med 2012 2/10 20%
11%
Morelli. Ann Oncol 2015 5/62 8%
Dienstmann. Can Discov 2015 1/26 1%
Newhall, WCGIC 2014 46/258 16%
27%Total frequency (median)