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%