Cancers du sein, Gènes facteurs prédictifs et facteurs pronostics ?

Cancers du sein, Gènes facteurs prédictifs et facteurs pronostics ?

From bio-guided to personalized
oncology
Rafii A
Département de chirurgie Gynécologique,
université de montpellier
Department of Genetic Medicine, WCMC
• NO CONFLICT OF INTEREST
Personalized genomic based medicine
Diagnostic
• Breast and ovarian cancer: BRCA
• Colon Cancer: HNPCC
• Endometrial Cancer: Lynch
•
•
•
THERAPEUTIQUE
•
•
•
Hormone receptor: SERM, anti-aromatase
Her2 amplification and herceptin,
KRAS in colorecta cancer: cetumximab,
pamitumumab
EGFR mutation or amplification in NSCLC: EGFR
inhibitor
BRAF in melanoma
Bcr-abl: Glivec
Predictive Factors:
Improving
treatment choice
Pronostic factors:
Treating
less patients
What informations do we
obtain ?
Chromosome
abnormalities of
the specimen
biopsied
The mutational
profile of the tumor
biopsied
BIOLOGY
Gene expressed
by the tumor at a
specific
timepoint
Principle 1: The signaling pathways implicated in survival and
progression are regulated by genomic, genetic and epigenetic
alterations
Direct target
Herceptin
Driver vs passenger mutation
Indirect target
From Garraway L. JCO
PARP Inhibitor
Colon
Melanoma
Pancreas
Ras
CDKN2A
PI3K
CDK inhibitor
PI3K targeted
From L Garraway
Principle 2: Agents targeting the common pathway
disrupted in cancers are available
• In 2004: 11 targeted therapies from 4
categoriesenter clinical trials
• IN2012: 15 FDA approval, 150 are in trials
For the first time
biology matches
therapeutics
From L Garraway
Principle 3 : technology matches clinical
timeframe
FAST RUN
In house computational biologists
Ovary
70% of N- patients and 40 to 50% of N+ are
cured by chemotherapy and radiation therapy.
Most of them will recieve hormonal therapy or
chemotherapy.
Breast cancer and genomic
Selected genes
Estrogen
ER
PR
Bcl2
SCUBE2
-BCL2 : antiapoptotique /
induite par ER+
-Scube 2 :
angiogénèse
?invasion ?
Proliferation
HER2
Invasion
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
GRB7
HER2
Stromelysin 3
Cathepsin L2
-STK15 = Aurora A
kinase, ser/thr K
phase G2-> M
-Survivin : anti
apoptotique
-Cyclin B: cycle
-MYBL2 : FT
interagit Rb, en
amont cyclin A
Others
CD68
GSTM1
BAG1
-GRB7 :
prot
adaptatrice
domaine
SH2
-Stromelysin
MMProtéinase
-Cathepsin L2 :
protéinase
Refernce
Beta-actin
GAPDH
RPLPO
GUS
TFRC
-CD68 : fixation
sélectine / Scavenger
receptors
-BAG1: proteosomal
protein, apoptose ?
-Gluthathione-Stransferase Mu1 :
métab/ détox
housekeeping
Etude d’impact décisionnel SWITCH
• Multicentric prospective trial
• Objectives: mesure the impact of Oncotype Dx on therapeutic decision sin
patinents ER+, HER2-
Gligorov et al, ASCO 2012.
Genetic profiling
• 46 years old women
• Past medical history of sarcoma at 24 Years
• Breast IDC, 2 CM,
Classical approach
• Lumpectomy, sentinel node
Personalized approach
• Emergency sequencing
• Germline p53 mutation
• Bilateral mastectomy, sentinel node and
Immediate reconstruction
When should we evaluate the familal risk?
•3 or more breast cancers
•1 breast cancer associated to
I ovarian cancer
1 breast cancer ine a man
Bilateral breast cancer or under 40
• 1 breast cancer< 35 ans or triple neg <50 or
medullaire, 1 ovarian adenocarcinoma< 60
RPC St-Paul 2011
When should we evaluate the familail risk?
Weird cases?
100+
Risque
Cumulé (%)
BRCA1+
80+
60+
40+
Cancer ovarien
20+
Sporadique+
0+
20+
30+ 40+ 50+ 60+ 70+
Age
MC King ASCO 2008
Breast cancer and genomic
Situations Cliniques
Présent
Risk/ early diagnostics
BRCA 1, 2….
Localized cancer
Expression
Prediciting response
to therapy (Chemo)
Futur
GWAS*
Epigénomix
Profiling Cell Free
DNA
NGS
Advanced Cancer
CTCs
ctDNA
(*) Genome-wide association study : Etudes pan-génomique
NGS
characterization of
tumor
Circos Plot
P1, Difference Data
Lymph node-Ovary
Lymph node-Peritoneum
Why should I be interested by this?
A"
Genome"Targeted"A,"B,"C","
D…."Z"
A"Vs"B"
A’"
B’"
C’"
Phase"1"
Randomised"to"…………personalized"
Integration of
clinical context
Genomic analysis
based on the
clinical context
Biology based contextualized treatment
ICARE
Feedback system
DYNACT