cáncer colorrectal: nueva clasificación molecular. ¿qué ... · cáncer colorrectal: nueva...

Cáncer colorrectal: Nueva clasificación molecular.

¿Qué hacemos ahora? Implicaciones en la práctica asistencial

Dr. Ramon Salazar

Institut Català d’Oncologia

L’Hospitalet de Llobregat, Barcelona

2

– CIN, MSI (dMMR) – Individual mutations/amplifications/fusions….

• (RAS/BRAF…)

– Supervised signatures • (Oncotype/Coloprint…)

– CRCSC Consensus Classification • (Intrinsec subtypes)

PROGNOSIS & PREDICTION

Clinical setting

Molecular criteria (tumor)

MSI (stage II/III) – ACCENT DBase

MMR data available in 7803 patients (IHC and/or MSI testing)

Sargent et al., ASCO Annual Meeting 2014

Stage II: MSI Good Prognosis 5FU no benefit in MSI & marginal benefit in MSS

Stage III: MSI Good Prognosis 5FU benefits both MSI and MSS

• MSI & BRAF: poor prognostic after relapse • Oxaliplatin: benefits stage III both MSS & MSI,

no benefit in stage II

C07 (FULV+/-Ox) and C08 (Ffox+/-Bev):

Stage II and III Colon Cancer

Gavin P G et al. Clin Cancer Res 2012;18:6531-6541 *Pogue-Geile K et al, JNCI 2013: 105 , 989-992

Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in

patients with BRAFV600E-mutated advanced cancers and metastatic colorectal cancer

David S. Hong1, Van Morris2, Badi El-Osta1, Siqing Fu1, Michael Overman2, Sarina Piha-Paul1, Vivek Subbiah1, Bryan Kee2, Apostolia Tsimberidou1, Ralph Zinner1, David Fogelman2, Jorge Bellido1, Imad Shureiqi2, Funda

Meric-Bernstam1, Scott Kopetz2

ASCO 2015

Responses by HER2 IHC Score

Presented By Salvatore Siena at 2015 ASCO Annual Meeting

35% RR 78% Dis. control

HERACLES TRIAL A: Lapatinib + Herceptin in HER ++/+++ Fish >50%

8

– CIN, MSI (MMR)/CIMP/hypermutated – Individual mutations

• (RAS/BRAF…)

– Prognostic Signatures (stage II) • (Supervised trainning e.g. Oncotype/Coloprint…)

– CRCSC Consensus Classification • (Intrinsec subtypes)

PROGNOSIS & PREDICTION

Molecular criteria (tumor)

Multivariable Analysis: Relationship of RS, T Stage, and MMR with Risk of Recurrence

Venook et al., J Clin Oncol 2013

ONCOTYPE DX® IN CALGB 9581

The 12-gene RS was calculated by using the prespecified genes and algorithm previously validated in QUASAR

Recurrence risk groups

% patients 5-year RR

Low RS 44% 13% (10% - 16%)

Int RS 34% 16% (13% - 19%)

High RS 22% 21% (16% - 26%)

Subgroup analysis in T3-MSS patients



Low RS NR 12% (10% - 15%)

Int RS NR 15% (12% - 17%)

High RS NR 18% (14% - 22%)

Recurrence risk in the overall population. NR = not reported

CALGB 9581 trial: edrecolomab vs observation – stage II colon cancer

ONCOTYPE DX® IN NSABP C07 (FULV+/-Ox) st II & III

Algorithm for chemotherapy decision

Stage III Stage II

FOLFOX

NO MSI Determination

needed

Colon Cancer

MSS

CT may be discussed Other Markers: T3/T4, Other Factors: age, patient wish...

Prognostic signatures?*

MSI

NO CT Good prognosis, resistance to FU


Stage III Stage II

FOLFOX


needed

Colon Cancer

MSS

CT may be discussed Other Markers: T3/T4, Other Factors: age, patient wish...

Prognostic signatures?*

MSI


Oncotype Dx®/ColoPrint®/Veridex/GeneF® Colon

(others run-ups: ColoStage, microRNA, CDX2)

recommended if uncertain decision:

• T3 MSS if chemo considered only if high risk signature

• T4 MSS if follow-up w/o chemo considered only if low risk signature

CRCSC – Original Individual Group Classifiers

Guinney, Dienstmann et al, Nat Med 2015

Dissecting Colorectal Cancer in multiple subtypes

Proposed taxonomy of colorectal cancer

Prognosis

Liver Surgery

outcome? ?


Relapse-free survival


A BC

Salazar et al, J Clin Oncol 2011: 29:17-24


Survival after relapse



?

Prognosis

Drug response

prediction

? ? ?

Supervised immune and stromal infiltration analysis

Becht et al, Clin Car Res 2016

CMS1 CMS2 CMS3 CMS4


Supervised immune infiltration analysis

Becht et al, Clin Car Res 2016

CMS1 CMS2 CMS3 CMS4


6 cells

Unpublished

Broad Institute Pharmacogenomic collection



Inmune checkpoints

blockade

TGF-

inhibition + Inmune

checkpoint blockade

Prognosis

Drug response

prediction

Metabolism &

DNA damage

Oncogene drivers

Amplifications

Summary

• Prognostic Clinically Relevant Molecular Variables – MSI in Stage II – BRAF and MSI in stage IV – Supervised & Intrinsec Signatures?

• Predictive Clinically Relevant Molecular Variables – MSI in stage II (5FU) and IV (PD1) – RAS and BRAF in stage IV – CMS 1-4 (Clinical Trials) – Still unknown what combination of genomic features

(mutation + MSI + gene expression + immune + stromal) will provide will provide the best prediction of drug response.

Acknowledgements & Collaborations Agendia

Iris Simon

Paul Roepman

Annuska Glas

Sun Tian

Laura V´Veer

IDIBELL CRC Group, HUB & ICO CRTeam

Víctor Moreno

Adriana López-Doriga

Rebeca Sanz-Pamplona

Susanna Aussó,

UMC Leiden

Rob Tollenaar

Wilma Mesker

H. Del Mar BCN

Clara Montagut

NKI R. Bernards Lab

Anirudh Prahallad

Begoña Diosdado

Magali Michaut Slotervaart Hospital

Johan Westerga

Sjoerd Bruin

Rechts der Isar Munich Robert Rosenberg Ulricht Nitsche

Hospital Gasthuisberg Leuven Sabine Tejpar

Swiss Inst Bioinformat

Vlad Popovici Mauro Delorenzi

VHIO BCN

Josep Tabernero

Rodrigo Dienstmann

E.Élez, Fiorella Ruiz, Ariadna Garcia, Marta Vilaro,

Gabriel Capellà

Alberto Villanueva

Dani Azuara

M. Nadal, M. Martínez

E. Kreisler, S.Biondo

Xavier Sanjuan

Antonio Soriano

Cristina Santos

Gemma Soler

Merche Martínez V.

Alex Teulé

Julieta Grasselli

Xavi Pérez

JL Manzano

UBB

LRT UGR

HUB UFCCR

ICO CRT

SOM UIC

IRB

E Batlle E.Sancho

Idibell M Esteller G.Thomas

MDACC S. Kopetz

BACK up slides….

Other RAS mutations: CRYSTAL & OPUS

Ciardiello F et al. Ann Oncol 2014; Tejpar S et al. Ann Oncol 2014

Study N Method Sensitivity Other RAS

mt, %

CRYSTAL 430 BEAMing† 0.01% 14.7

OPUS 118 BEAMing† 0.01% 26.3

FIRE-3 407 Pyrosequencing 1-5% 16.0

PRIME 620 Dideoxy sequencing/WAVE 5% 17.4

PEAK 221 Dideoxy sequencing/WAVE 5% 23.1

RAS mutations: Which is the right

sensitivity cut-off?

Ciardiello F et al. Ann Oncol 2014

?

?

Cobas 4800 (ROCHE) – Cobas Kits Sensitivity 1-5%

PyroMark (QIAGEN) – TherascreenPyro Kits Sensitivity 1%

BioMark Digital PCR Arrays (Fluidigm) Sensitivity 0.1%

LightCycler 480 Sensitivity 1-5 %

Sensitivity 5-10%

The puzzle of RAS testing

Slide provided by R. Salazar

BEAMing Sysmex Inostics Sensitivity 0.01%

Response to anti-EGFR according to fraction of mutant

alleles by quantitative digital PCR

CR n=1

PR n=29

SD n=26

PD n=37

% o

f m

uta

ted

alle

les

p<0.005

D.Azuara, C. Santos, et al. Nanofluidic digital PCR and extended genotyping of RAS and BRAF for improved selection of metastatic colorectal cancer patients to anti-EGFR therapies

MOLECULAR CANCER THERAPEUTICS. In Press

D.Azuara, C. Santos, et al. Nanofluidic digital PCR and extended genotyping of RAS and BRAF for improved selection of metastatic colorectal cancer patients to anti-EGFR therapies

MOLECULAR CANCER THERAPEUTICS. In Press

Improvement in response prediction by assessing mutation status of each gene

Vilar E & Tabernero J, Nature 2012

“Under pressure” clonal selection vs evolution

35

Treatment of Resistance (primary or secondary)

in present or future clinical trials

RAS mutants:

Cetuximab + Irinotecan in KRAS G13D mutant CRC….

MEK inhibitors + pan HER inhibitors

BRAF mutants:

BRAF + EGFR + PIK3Ca or WNT inhibitors

S492R mutants:

Panitumumab

C-MET amplifications

C-MET inhibitors ?

Tumor debulking in unresectable metastasic disease

proof of principle cfDNA load as surrogate endpoint of

effective debulking of clones with resistance potential

QUASAR col. group, Lancet 2007

Adjuvant chemotherapy - benefit

QUASAR

Risk stratification in stage II colon cancer

• Clinicopathological features

• Microsatellite instability, KRAS and BRAF

• Supervised Prognostic signatures – Do gene signatures currently add information to the decision making

progress?

• Intrinsic molecular subtypes

ACCENT – MSI (stage II)

MMR data available in 7803 patients (IHC and/or MSI testing)

Sargent et al., ASCO Annual Meeting 2014

dMMR patients had better outcome without adjuvant treatment 5FU resistance should not be considered for chemo

ACCENT – MSI (stage III)

Treated dMMR stage III retained favourable prognosisMMR should not guide decission in stage III

MOSAIC and NSABP-C07

Sargent et al., ASCO Annual Meeting 2014 *Gavin PG et al., Clin Cancer Res 2012; Fléjou JF et al., ASCO Annual Meeting 2013

Oxaliplatin seem to benefit equally both MSS and MSI patients*

both MSI and MSS should be considered for chemo (OXL based)

• MSI: prognostic factor with HR 0.48 for RFS (and OS) • MSI: oxaliplatin similar benefit in pMMR and dMMR • BRAF (& MSI): poor prognostic after relapse • MSI: predictive of BEV benefit OS HR 0.52 p:0.02 favours BEV *

C07 (FULV+/-Ox) and C08 (Ffox+/-Bev):

Stage II and III Colon Cancer

Gavin P G et al. Clin Cancer Res 2012;18:6531-6541 *Pogue-Geile K et al, JNCI 2013: 105 , 989-992

Stage II and III dMMR MOSAIC study

Fléjou JF, ASCO 2013

100

80

20

40

60

0

RFSprobability(%)

109876543210Time(years)

LV5FU2FOLFOX4

LV5FU2FOLFOX4

5144

4440

4039

4038

3738

3737

3636

3235

2934

2732

2026

Nbatrisk

100

80

20

40

60

0

DFSprobability(%)

109876543210Time(years)

LV5FU2FOLFOX4

5144

4440

4039

4038

3738

3737

3636

3235

2934

2732

2026

109876543210Time(years)

LV5FU2FOLFOX4

5144

4741

4540

4339

4239

4139

3938

3437

3136

2924

2228

100

80

20

40

60

0

0Sprobability(%)

109876543210Time(years)

LV5FU2FOLFOX4

2918

2315

2015

2014

1814

1814

1813

1612

1511

1411

119

100

80

20

40

60

0DFSprobability(%)

109876543210Time(years)

LV5FU2FOLFOX4

2226

2125

2024

2024

1924

1923

1823

1623

1423

1321

917

100

80

20

40

60

0

DFSprobability(%)

STADESII&III

DFSRFS OS

STADEIIISTADEIIDFS DFS

LV5FU2FOLFOX4

Nbatrisk

LV5FU2FOLFOX4

Nbatrisk


Stage III Stage II

FOLFOX


needed

Colon Cancer

MSS

CT may be discussed Other Markers: T3/T4, BRAF, KRAS?

Other Factors: age, patient wish... Prognostic signatures?*

MSI



Stage III Stage II

FOLFOX


needed

Colon Cancer

MSS



MSI


*Are gene signatures ready for use in the selection of patients

for adjuvant treatment?

Kerr et al., ASCO Annual Meeting 2009 Gray et al., J Clin Oncol 2011

ONCOTYPE DX® IN QUASAR



Low RS 43.7% 12% (0% - 16%)

Int RS 30.7% 18% (13% - 24%)

High RS 25.6% 22% (16% - 29%)

Multivariable Analysis: Relationship of RS, T Stage, and MMR with Risk of Recurrence

Venook et al., J Clin Oncol 2013

ONCOTYPE DX® IN CALGB 9581

The 12-gene RS was calculated by using the prespecified genes and algorithm previously validated in QUASAR



Low RS 44% 13% (10% - 16%)

Int RS 34% 16% (13% - 19%)

High RS 22% 21% (16% - 26%)

Subgroup analysis in T3-MSS patients



Low RS NR 12% (10% - 15%)

Int RS NR 15% (12% - 17%)

High RS NR 18% (14% - 22%)

Recurrence risk in the overall population. NR = not reported

CALGB 9581 trial: edrecolomab vs observation – stage II colon cancer

ONCOTYPE DX® IN NSABP C07 (FULV+/-Ox) st II & III

ColoPrint®

HR = 3.41 (P> 0.0001) 5-year DMFS 82%(95CI, 76-89%) low-risk 50%(95CI, 38-66%) high-risk

30%

DM

FS

Whole Genome analysis on 44K Agilent microarrays

70% N = 188 (SI:24; SII:100; SIII:56; SIV:8) RC: 92; LC:74; Rectum: 17)

No Chemo: 145; Chemo: 31

18 gene signature

18 genes identified that correlate Distant Metastasis-free Survival, 18 most stable genes selected

Salazar et al., J Clin Oncol 2011


Stage III Stage II

FOLFOX


needed

Colon Cancer

MSS



MSI



Stage III Stage II

FOLFOX


needed

Colon Cancer

MSS



MSI


Oncotype Dx®/ColoPrint®/Veridex/GeneF® Colon

(others run-ups: microRNA)

recommended if uncertain decision:

• T3 MSS if chemo considered only if high risk signature

• T4 MSS if follow-up w/o chemo considered only if low risk signature

cáncer colorrectal: nueva clasificación molecular. ¿qué ... · cáncer colorrectal: nueva...

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