7e BIJEENKOMST

WERKGROEP "MOLECULAIRE DIAGNOSTIEK IN DE

PATHOLOGIE 25 januari 2012

Martijn P. Lolkema

Department of Medical Oncology

The Netherlands

Oncology 1.0

Oncology 2.0

• http://nextarchitects.com/

A “thousand dollar genome”

Genetica voorspelt respons op therapie

Normal cell

Cancer cell with

mutation

Log cell

survival!

Log drug

concentration!

Genetica en targeted drugs in de oncologie gaan

samen

Target Disease Drug Success

Her2Neu Breast, stomach Herceptin,

Lapatinib

HR: +/- 0.50 for progression

free survival for Her2+

breast cancer patients

after surgery

c-KIT GIST Imatinib Majority of patients show

impressive responses

BCR-Abl CML Imatinib >50% response in BCR-

ABL positive CML

ALK NSCLC Specific ALK

inhibitor

Promising phase I/II data,

approved by FDA

PARP BRCA 1 and 2 associated Ovarian

carcinoma, Triple neg. breast

cancer

Multiple PARP

inhibitors

Promising phase I/II/III data

BRAF BRAF mutant melanoma Specific BRAF

inhibitor

Standard of care for BRAF

mutant melanoma in 7

years of clinical

development

Gerichte therapie heeft een betere effectiviteit

Oncologie registraties 2011 FDA

HR primary outcome % pts with

benefit

Biomarker

included

Cabazitaxel PFS: 0.70 Appr. 40% -

Ipilumimab OS: 0.72 Appr. 10% -

Denosumab SRE: 0.83 NR -

Vandetinib NR Appr. 73% - (RET)

Abiraterone PFS: 0.65 Appr. 29% -

Vemurafenib PFS: 0.26 Appr. 90% + (BRAFV600E)

Crizotinib NR Appr. 57% + (EML4-ALK)

•“Our mission is to provide more effective

cancer treatment by offering personalized

therapy and increasing the number of drugs

that reaches the market and becomes available

to patients”

Het “Center for Personalized Cancer Treatment” probeert

therapie voor oncologie patienten effectiever te maken

Increase the likelihood a drug shows

sufficient benefit in clinical trials to get

approved; contribute to drug-discovery

Increase the likelihood of a given treatment

being beneficial to patients; reduce the use

of ineffective treatment

Select

appropriate

cancer treatment

based on

patients’ tumor

DNA profile

Center for Personalized Cancer Treatment

2-4 Biopsies2-4 Biopsies

Pathological AnalysisPathological Analysis

DNA IsolationDNA Isolation

Patient StratificationPatient Stratification

10-50 ng 100-500 ng

IonTorrent PGM SOLiD 5500xl

Actionable Mutations>50-100 genes

Actionable Mutations>50-100 genes

Profiling Cancer Pathways and Processes

Profiling Cancer Pathways and Processes

Systems BiologySystems BiologyAllocation Fase1 Clinical Trial

Allocation Fase1 Clinical Trial

Targeted Resequencing± 2000 genes

Targeted Resequencing± 2000 genes

Response monitoringResponse monitoring

Resistance /Progression

Biomarker Discovery

Biomarker Discovery

Start Targeted Therapy

Start Targeted Therapy

Bioinformatic analysisBioinformatic analysis

DatabankingDatabanking

ResearchResearch

Mutations, INDELs,Copy Number Variations

Recurrence /Cure

+

in vitro / in vivo Modeling of Hypotheses

in vitro / in vivo Modeling of Hypotheses

On

e W

ee

k

Thre

e W

ee

ks

Patient with Metastatic Disease

Center for Personalized Cancer Treatment

2-4 Biopsies2-4 Biopsies

Pathological AnalysisPathological Analysis

DNA IsolationDNA Isolation

Patient StratificationPatient Stratification

10-50 ng 100-500 ng

IonTorrent PGM SOLiD 5500xl

Actionable Mutations>50-100 genes

Actionable Mutations>50-100 genes

Profiling Cancer Pathways and Processes

Profiling Cancer Pathways and Processes

Systems BiologySystems BiologyAllocation Fase1 Clinical Trial

Allocation Fase1 Clinical Trial

Targeted Resequencing± 2000 genes

Targeted Resequencing± 2000 genes

Response monitoringResponse monitoring

Resistance /Progression

Biomarker Discovery

Biomarker Discovery

Start Targeted Therapy

Start Targeted Therapy

Bioinformatic analysisBioinformatic analysis

DatabankingDatabanking

ResearchResearch

Mutations, INDELs,Copy Number Variations

Recurrence /Cure

+

in vitro / in vivo Modeling of Hypotheses

in vitro / in vivo Modeling of Hypotheses

On

e W

ee

k

Thre

e W

ee

ks

Patient with Metastatic Disease

Het CPCT wil de toekomst van persoonlijke behandeling

in Nederland vormgeven

De huidige opzet van de CPCT activiteiten

Fase I studie

patienten

Patienten met

standaard therapie

Patienten in CPCT

studies

NGS met 2000 genen set:

ontdekken van

genetische afwijkingen

die correleren met

therapie respons

Ion Torrent 100-200

“actionable” genen

set die direct

relevant zijn voor

therapie

Discovery Implementatie

aromatase inhibitors, tamoxifen,

imatinib, EGFR inhibition,

sunitinib, vemurafenib,

Hoe zit dat nou met tumor heterogeniteit?

Hoe zit dat nou met tumor heterogeniteit?

PJ Campbell et al. Nature 467, 1109-1113 (2010)

doi:10.1038/nature09460

Hoe zit dat nou met tumor heterogeniteit?

Vermaat J, et al. Clin Cancer Res 2011

Dus moeten we de metastase biopteren!

Biopsie pipeline CPCT

Breast

Liver

3 specimens CPCT-02

(+ 1 for regular diagnostics)

Tumor percentage: 80%

DNA isolation: 10400 ng

Biopten naar tumor types en orgaan

Site of Biopsy

Liver

other

Lymphnode

Ski

n / Subcu

taneo

us

Lung

0

5

10

15

20

25

% o

f sam

ple

s

0 2 4 6 8

CRC

RCC

Vulva

Head/Neck

Breast

Endometrial

CRC

CRC

Pancreatic

Breast

CRC

CRC

Ovarian

Head/Neck

Gallbladder

Melanoma

Myoepithelial 

Cervix

Cystic adenoid

HCC

Head/Neck

Upper GI

Carcinoid

Melanoma eye

NET

Sarcoma

RCC

CRC

No treatment

Integrin antagonist

Anti hormonal

CDK 4/6 inhibitor

Smoothened inhibitor

Non platinum based

Platinum based

BRAF inhibitor

TKI

Biopten succes percentage

0

5000

10000

15000

500ng

DN

A y

ield

(n

g)

N=65

0

25

50

75

100

no DNA

<250ng

>250ng but <500ng

>500ng

% o

f sam

ple

s

% of usefull biopsies Distribution of DNA yield

Klinische protocollen

Protocol Short Description Tumor type Status

M10PKS Sunitinib PK All comers Accrual completed

CPCT-01 Irinotecan mCRC Colorectal carcinoma

Open

CPCT-02 Bioptenprotocol All comers Open

CPCT-03 Everolimus solide tumoren

All comers Ethics approval, in process of activation

N03LAM

T-cel immuniteit melanoom

(CPCT side study)

Melanoma Open

Within CPCT-02 we will focus on obtaining paired biopsies for patients treated with standard of care

systemic treatments such as aromatase inhibitors, tamoxifen, imatinib, EGFR inhibition, sunitinib,

vemurafenib, to improve the efficacy of treatment with these targeted agents

Samenwerken is essentieel

Conclusies

• De komende tijd gaan we de komst van echte therapie op maat

zien

• Nederland heeft met het CPCT een van de consortia die in staat is

om dit te implementeren

• De eerste noodzakelijke stappen zijn gezet

• De rol van de patient is heel belangrijk en we zijn op zoek naar een

manier om effectief patienten te benaderen en te activeren om aan

dit onderzoek deel te nemen. Daarnaast is het belangrijk om dit

soort initiatieven te toetsen aan patienten meningen.

EMC/Daniel

den Hoed

Rotterdam

Stefan Sleijfer

Ron Mathijsen

John Martens

Jacqueline Kloth

NKI/AvL

Amsterdam

Rene Bernards

Lodewyk Wessels

Jan Schellens

Neeltje Steeghs

Nienke Lankheet

Acknowledgments

UMC Utrecht and

Hubrecht laboratory,

Utrecht

Cuppen group

Ies Nijman

Wigard Kloosterman

UMC Utrecht:

Emile Voest

Paul van Diest

Maurice van den Bosch

Marco Koudijs

Sjoerd Elias

Geert Cirkel

Christa Gadellaa

Marlous Hoogstraat

Nicolle Besselink

Stef van Lieshout

Team science: andere academische centra gaan binnenkort aansluiten

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