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![Page 1: Precision Medicine: From stratified therapies to personalized therapies Fabrice ANDRE Institut Gustave Roussy Villejuif, France.](https://reader035.fdocuments.in/reader035/viewer/2022062216/56649da25503460f94a8e7f9/html5/thumbnails/1.jpg)
Precision Medicine:From stratified therapies to
personalized therapies
Fabrice ANDREInstitut Gustave Roussy
Villejuif, France
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Frequent cancers include high number of very rare genomic segments
Stephens, Nature, 2012
(whole genome sequencing breast cancers)
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Working hypothesis
• Targeting mechanisms that lead to cancer progression can improve patient’s outcome
• These mechanisms are individual
• Goal: to identify the mechanism of cancer progression at the individual level, in order to target it
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Precision Medicine
Concept: Identify the targets to be treated in each patient
Molecular analysis
Therapy matched to genomic alteration
Andre, ESMO, 2012
Target identification
What is the optimal Biotechnology ?
What is the optimal Algorithm ?
Clinical evidence
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Outline
• Stratified medicine
• Personalized medicine
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Stratified medicine• Drug development or implementation in a strate
defined by a molecular alteration
FGFR1 amplification: 10% of breast cancer
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Translational research to feed stratified medicine
FGFR1 inhibitors present higher sensitivity
on FGFR1-amplified CC
FGFR1: amplification in 10% BC
Set-up genomic test(FISH)
Run phase II trialTesting the FGFR1 Inh in patients withFGFR1 amp BC
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Research and medical questions related to stratified medicine
• How to facilitate translation of discoveries ?• Develop translational research units
• How to set-up a molecular assay for stratified medicine ?• Develop genomic units for clinical use
• How to optimally run trials of stratified medicine ?• Set-up molecular screening programs
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Molecular screening with
High Throughput Genomics
Molecular screening with
High Throughput Genomics
IF Progressi
vedisease
IF Progressi
vedisease
Targetidentification
Targetidentification
Trial A
Trial F
Trial E
Trial D
Trial C
Trial B
Andre, Delaloge, Soria, J Clin Oncol, 2011
Molecular screening programs: to identify patients eligible for phase I/II trials
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SAFIR02 lung
Ongoing molecular screening or personalized medicine programs in France
SAFIR01
MOSCATO(Hollebecque,
ASCO 2013)
SAFIR02breast
MOST
preSAFIR(Arnedos, EJC, 2012)
Overall : >2 000 planned patients (all tumor types), >800 already includedBreast Cancer: > 1 000 planned, >70 already treated
Goal: To generate optimal algorithm for individualized therapy
SHIVA(LetourneauAACR 2013)
Pilot study 1st generation trialsNo NGS NGS
Randomized trialsSponsor
Gustave Roussy
Unicancer
L BerardLyon
Curie Institute
UnifiedDatabase:Pick-up
the winnertargets
2nd generationAlgorithm forPersonnalized
medicine
WINTHER
Profiler
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Molecular screening: Challenges
• No research in stratified medicine without molecular screening programs
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Evolution:GENOMIC DISEASES ARE BECOMING TO RARE OR COMPLEX TO ALLOW DRUG DEVELOPMENT IN GENOMIC SEGMENTS
How to move forward ?
Stephens, Nature, 2012
Are we going to make a drug developmentfor this AKT1 mut / FGFR1 amp segment ?
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Solution to improve outcome with targeted therapies in the genomic era:
test the algorithm not the drug
How to move there ???
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Her2-negative metastatic breast
cancerno more than 1 line
chemotherapy
Biopsy metastatic site:Next generation
sequencingArray CGH
Chemotherapy6-8 cycles
No alteration
Target defined by 1st generationVirtual cell (CCLE)
Followed up but not included
R
10 Targeted therapyAccording to
51 Molecular alterations
SOC
No PD
metastatic NSCLC no more than 1 line chemotherapy
EGFRwt / ALKwt
SAFIR02: Study Design
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SAFIR02 lung
Ongoing molecular screening or personalized medicine programs in France
SAFIR01
MOSCATO(Hollebecque,
ASCO 2013)
SAFIR02breast
MOST
preSAFIR(Arnedos, EJC, 2012)
Overall : >2 000 planned patients (all tumor types), >800 already includedBreast Cancer: > 1 000 planned, >70 already treated
Goal: To generate optimal algorithm for individualized therapy
SHIVA(LetourneauAACR 2013)
Pilot study 1st generation trialsNo NGS NGS
Randomized trialsSponsor
Gustave Roussy
Unicancer
L BerardLyon
Curie Institute
UnifiedDatabase:Pick-up
the winnertargets
2nd generationAlgorithm forPersonnalized
medicine
WINTHER
Profiler
![Page 16: Precision Medicine: From stratified therapies to personalized therapies Fabrice ANDRE Institut Gustave Roussy Villejuif, France.](https://reader035.fdocuments.in/reader035/viewer/2022062216/56649da25503460f94a8e7f9/html5/thumbnails/16.jpg)
Long term perspective
1st generationtrials database
2nd generation
algorithm
2nd generation
trials
Targeting oncogenic
drivers
Integration ofother systems:
DNA repairImmunologymetabolism
database
2013 20152018-2020
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Challenges / Research questions
• Bioinformatic algorithm for treatment decision, that integrates all biological systems
• Technologies: – whole exome sequencing – RNA seq– Protein-based assays
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Conclusion: genomic medicine for cancer patients
• bioinformatic algorithm for treatment decision
• Integration of DNA repair, immunology, metabolism in personalized medicine
• large scale screening and implementation new technologies
• Target identification for stratified medicine
• understanding mechanisms of resistance