ctos 2013 discussion of four presentations on sarcomas with complex karyotypes medical oncology,...
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CTOS 2013
Discussion offour presentations on
Sarcomas with complex karyotypes
Medical Oncology, Lyon
UCBL1- CLB
JY Blay
CTOS 2013
GIST
Sarcomas and locally Sarcomas and locally aggressive connective aggressive connective
tissue tumorstissue tumors
KinaseKinaseMutations Mutations
TranslocationsTranslocations
SySSySDFSP DFSP EwingEwing
Mutations Mutations APC/bCatAPC/bCat
DesmoidsDesmoids
WD/DDLPSWD/DDLPSAmplification Amplification
12q13-1512q13-15MDM2/CDK4MDM2/CDK4
MPNSTMPNST
PEComasPEComas
TSGTSGNF1, TSC1/2NF1, TSC1/2
ComplexComplexgenomicsgenomics
LMS, UPSLMS, UPS
CTOS 2013
Sarcoma subtypes
Other very rare subtypes (8%)Other very rare subtypes (8%)
Endometrial stromal sarcoma (2%)Endometrial stromal sarcoma (2%)
Synovial sarcoma (2%)Synovial sarcoma (2%)
Myxofibrosarcoma (2%)Myxofibrosarcoma (2%)
Angiosarcoma (3%)Angiosarcoma (3%)
Rhabdomyosarcoma (3%)Rhabdomyosarcoma (3%)
Leiomyosarcoma (11%)Leiomyosarcoma (11%)
Unclassified sarcoma (16%)Unclassified sarcoma (16%)
Dermatofibrosarcoma (5%)Dermatofibrosarcoma (5%)
Kaposi sarcoma (3%)Kaposi sarcoma (3%)
Soft-tissue Ewing sarcoma/pNET (4%)Soft-tissue Ewing sarcoma/pNET (4%)
Liposarcoma (15%)Liposarcoma (15%)
GIST (18%)GIST (18%)
Bone primary (osteosarcoma/Bone primary (osteosarcoma/chondrosarcoma) (8%)chondrosarcoma) (8%)
8%8%
18%18%
15%15%
4%4%3%3%5%5%
16%16%
11%11%
3%3%3%3%
2%2%2%2%
2%2% 8%8%
CTOS 2013Sarcomas with complex karyotypes
0 0.2 0.4 0.6 0.8 1 1.2 1.4
GISTLipo_s
Sarcoma NOSLeiomyo_s
Kaposi_sDermatofibro_s
Uterine leiomyo_sOtherMFH
Myxofibro_sRhabdomyo_s
Synovial_sEwing_sAngio_s
Fibromyxoid_sMPNSTFibro_s
Solitary_Osteo_s
Rate per 100,000
CTOS 2013
Systemic treatments
• Doxorubicin
• Doxorubicin ifosfamide
• Trabectedine
• Pazopanib
• Gemcitabine Docetaxel
• Gemcitable DTIC
Localized phase- Adjuvant CT controversial
Advanced phase- Median PFS
= 4-6 mos in 1st line
= 2-4 mos in 2+ lines
CTOS 2013
Barretina et al Nat Gen 2010Barretina et al Nat Gen 2010
CTOS 2013
We need
• To better predict relapse
• To identify better the « driver » mutations
• Biomarkers to predict for primary and secondary resistance
CTOS 2013
4 presentations• Preclinical model
– p53-/+ PTEN-/+ mice developping LMS
• Theranostics– Guiding treatment of patients with NGS results
• Biomarker for response– For new generation of cytotoxic treatments
• CTC in sarcoma– Monitoring micrometastatic disease
A DETECTION SYSTEM FOR CIRCULATING TUMOR CELLS USING GFP EXPRESSING TELOMERASE-SPECIFIC
REPLICATION-COMPETENT ADENOVIRUS IN BONE AND SOFT TISSUE SARCOMA
T. Kunisada1 J. Hasei1 K. Takeda1
Y. Urata3 T. Fujiwara2 T. Ozaki1
1 Dept. of Orthopaedic Surgery2 Dept. of Gastroenterological SurgeryOkayama University, Okayama, Japan
3 Oncolys BioPharma, Inc., Tokyo, Japan
CTOS 2013
CTC in sarcoma
• Predictive value in other cancers
• Commercial tools imperfect for sarcoma cells
• Novel technology
• - detects telomerase + cells
CTOS 2013
CTC in sarcoma
• 11/22 patients with detectable sarcoma cells
• All histotypes (even DFSP)
• Fewer CTC vs other cancer?
• Predictive value?– 4/11 relapse CTC+– 1/11 relapses CTC-
CTOS 2013
CTC in sarcoma : questions?
• To be expanded and confirmed
• Biological significance of CTC?
• To guide adjuvant treatment?
• Help to monitor response or relapse?
Identification of potential molecular biomarkers Identification of potential molecular biomarkers for response for response
of soft tissue sarcoma to eribulinof soft tissue sarcoma to eribulin..TTranslational results of EORTC trial 62052ranslational results of EORTC trial 62052
A. Wozniak*, E.A.C. Wiemer*, H. Burger, J. Allemeersch, R. van Eijsden, R.H.J. Mathijssen,
S. Sleijfer, M. Smid, G.Floris, S. Marreaud,A. Nzokirantevye, R.Sciot, P. Schöffski
(*equal contribution)
18th CTOS Meeting, 30/10-2/11/2013, New York, USA
ALS2CR11
•amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 11 protein (locus 2q33.1)•Overexpressed in Leydig cells, germ cells, adipocytes•Role not known•Single reports on genomic status in cancer (mainly LOH)
•In our experiment higher expression in non-responders (p=0.000102)
18th CTOS Meeting, 30/10-2/11/2013, New York, USA
Differentially expressed mRNAs (responders vs. non-responders)
Non-responders
Responders
CTOS 2013
Differentially expressed mRNAs and miRNAs, assessed in STS subtypes
mRNAs miRNAs
STS subtype
Down-regulated*
Up-regulated
*
Potential biomarker
s
Down-regulated*
Up-regulated*
Potential biomarker
s
ADI 58 500 MYLK3 8 0 miR-106b
LMS 11 13 SLC8A1 6 2 miR-146a; 1271;
590-3p; 29b-2#
OTH 66 93 IGF2, COL1A2
1 0 miR-186
ADI – adipocADI – adipocyytic sarcomas, LMS - leiomytic sarcomas, LMS - leiomyoosarcomas, OTH – other sarcoma subtypes;sarcomas, OTH – other sarcoma subtypes; *in responders*in responders
CTOS 2013
• mRNAs and miRNAs are differentially expressed in STS from eribulin responders and non-responders
• Significance of biological pathways?
• Possible predictive biomarker?
• Why differences across histotypes?
• Further validation studies are required
• A research tool
Eribulin : questions?
CTOS 2013
We need
• To better predict relapse
• To identify better the « driver » mutations
• Biomarkers to predict for primary and secondary resistance
CTOS 2013
What is a good target?
ExpressionExpression Possible targetPossible target
Expression + activationExpression + activation Promising targetPromising target
Expression + activation + mechanismExpression + activation + mechanism A major targetA major target
Expression + activation + mechanism + drugExpression + activation + mechanism + drug Clinical trialClinical trial
Dual PTEN/P53 suppression promotes high grade
sarcomas by activating Notch
Eva Hernando, Ph.D.
CTOS 2013
Dual PTEN/TP53 suppression and sarcomagenesis
• Mutational profling of sarcoma patients
• Dual suppression in SMC
• P53-/+ & PTEN -/+
• HGUPS, LMS
• Activation of the Notch pathway, and sensitivity to GSI
Gamma-secretase inhibition suppresses the clonogenic and invasive potential of tumor cells
CTOS 2013
Sarcomagenesis: questions
• A relevant model for LMS/UPS subsets?
• Screen human tumors
• To reevaluate the role of GSI/Notch pathway modulators in vivo in the clinics?
CTOS 2013
CTOS 2013
• N=57 patients,
• Druggable alterations
• Documented responses
• Documented SD
NGS analysis
CTOS 2013
• N=57 patients, • Documented responses• Documented SD• Value of GMI?
– PFS2/PFS1
• Denominator?• From N of 1 to
prospective series with homogenous molecular diagnosis
NGS analysis
CTOS 2013
• Valuable strategy
• N of 1 trials methodology
• Guide research programs in larger patients sets
• Negative results also should be informative
• Difficult analysis when combinations are used
Theranostics : questions
CTOS 2013
Conclusions
• Four important reports
• Biomarkers and predictive factors for relapse and resistance are needed.
• Preclinical models to guide us for drug development.
• Translational research : biopsy and rebiopsy
CTOS 2013
A World Sarcoma Network is neededA World Sarcoma Network is needed
04/11/23 28
Join us!Join us!
CTOS 2013
Connective tissue tumours5 types of sarcomas
• Specific translocations generating fusion genes 15%• Kinase mutations (KIT…) 15%• Gene inactivation (NF1…) 10% (?)• Amplifications chromosome 12 (MDM2+CDK4) 15%• Complex genetic alterations (MFH, LMS, ...) 50%