Discussion of four presentations on sarcomas with complex karyotypes
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Discussion of four presentations on Sarcomas with complex karyotypes. JY Blay. Medical Oncology, Lyon UCBL1- CLB. GIST. Amplification 12q13-15 MDM2/CDK4. WD/DDLPS. Kinase Mutations. TSG NF1, TSC1/2. Sarcomas and locally aggressive connective tissue tumors. MPNST PEComas.

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Discussion of four presentations on Sarcomas with complex karyotypes

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Discussion of four presentations on sarcomas with complex karyotypes

Discussion offour presentations onSarcomas with complex karyotypes

JY Blay

Medical Oncology, Lyon

UCBL1- CLB


Discussion of four presentations on sarcomas with complex karyotypes

GIST

Amplification

12q13-15

MDM2/CDK4

WD/DDLPS

Kinase

Mutations

TSG

NF1, TSC1/2

Sarcomas and locally

aggressive connective

tissue tumors

MPNST

PEComas

Translocations

Complex

genomics

SyS

DFSP

Ewing

Mutations

APC/bCat

Desmoids

LMS, UPS


Sarcoma subtypes

Sarcoma subtypes

Bone primary (osteosarcoma/chondrosarcoma) (8%)

8%

8%

2%

GIST (18%)

2%

Liposarcoma (15%)

2%

3%

Soft-tissue Ewing sarcoma/pNET (4%)

3%

18%

Kaposi sarcoma (3%)

Dermatofibrosarcoma (5%)

Unclassified sarcoma (16%)

11%

Leiomyosarcoma (11%)

Rhabdomyosarcoma (3%)

Angiosarcoma (3%)

15%

Myxofibrosarcoma (2%)

16%

Synovial sarcoma (2%)

4%

Endometrial stromal sarcoma (2%)

5%

3%

Other very rare subtypes (8%)


Discussion of four presentations on sarcomas with complex karyotypes

Sarcomas with complex karyotypes

Osteo_s

Solitary_

Fibro_s

MPNST

Fibromyxoid_s

Angio_s

Ewing_s

Synovial_s

Rhabdomyo_s

Myxofibro_s

MFH

Other

Uterine leiomyo_s

Dermatofibro_s

Kaposi_s

Leiomyo_s

Sarcoma NOS

Lipo_s

GIST

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Rate per 100,000


Systemic treatments

Systemic treatments

Localized phase

- Adjuvant CT controversial

Advanced phase

- Median PFS

= 4-6 mos in 1st line

= 2-4 mos in 2+ lines

  • Doxorubicin

  • Doxorubicin ifosfamide

  • Trabectedine

  • Pazopanib

  • Gemcitabine Docetaxel

  • Gemcitable DTIC


Discussion of four presentations on sarcomas with complex karyotypes

Barretina et al Nat Gen 2010


We need

We need

  • To betterpredict relapse

  • To identifybetter the « driver » mutations

  • Biomarkers to predict for primary and secondaryresistance


4 presentations

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


Discussion of four presentations on sarcomas with complex karyotypes

A detection system for circulating tumor cells using GFP expressing telomerase-specific replication-competent adenovirus in bone and soft tissue sarcoma

T. Kunisada1J. Hasei1K. Takeda1

Y. Urata3T. Fujiwara2 T. Ozaki1

1 Dept. of Orthopaedic Surgery

2 Dept. of Gastroenterological Surgery

Okayama University, Okayama, Japan

3OncolysBioPharma, Inc., Tokyo, Japan


Ctc in sarcoma

CTC in sarcoma

  • Predictive value in other cancers

  • Commercial tools imperfect for sarcoma cells

  • Novel technology

  • - detects telomerase + cells


Ctc in sarcoma1

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-


Ctc in sarcoma questions

CTC in sarcoma : questions?

  • To be expanded and confirmed

  • Biological significance of CTC?

  • To guide adjuvant treatment?

  • Help to monitor response or relapse?


Discussion of four presentations on sarcomas with complex karyotypes

Identification of potential molecular biomarkers for response of soft tissue sarcoma to eribulin.Translationalresults 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


Differentially expressed mrnas responders vs non responders

Responders

Non-responders

Differentially expressed mRNAs (responders vs. non-responders)

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 and mirna s assessed in sts subtypes

Differentially expressed mRNAs and miRNAs, assessed in STS subtypes

ADI – adipocytic sarcomas, LMS - leiomyosarcomas, OTH – other sarcoma subtypes;*in responders


Eribulin questions

Eribulin : questions?

  • 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


We need1

We need

  • To betterpredict relapse

  • To identifybetter the « driver » mutations

  • Biomarkers to predict for primary and secondaryresistance


What is a good target

What is a good target?

Expression

Possible target

Expression + activation

Promising target

Expression + activation + mechanism

A major target

Expression + activation + mechanism + drug

Clinical trial


Discussion of four presentations on sarcomas with complex karyotypes

Dual PTEN/P53 suppression promotes high grade sarcomas

by activating Notch

Eva Hernando, Ph.D.


Dual pten tp53 suppression and sarcomagenesis

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


Discussion of four presentations on sarcomas with complex karyotypes

Gamma-secretase inhibition suppresses the

clonogenic and invasive potential of tumor cells


Sarcomagenesis questions

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?


Ngs analysis

NGS analysis

  • N=57 patients,

  • Druggable alterations

  • Documented responses

  • Documented SD


Ngs analysis1

NGS analysis

  • N=57 patients,

  • Documented responses

  • Documented SD

  • Value of GMI?

    • PFS2/PFS1

  • Denominator?

  • From N of 1 to prospective series with homogenous molecular diagnosis


Theranostics questions

Theranostics : questions

  • 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


Conclusions

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


Discussion of four presentations on sarcomas with complex karyotypes

A World Sarcoma Network is needed

Join us!

11/14/2014

28


Connective tissue tumours 5 types of sarcomas

Connective tissue tumours5 types of sarcomas

  • Specific translocations generating fusion genes15%

  • Kinase mutations (KIT…)15%

  • Gene inactivation (NF1…)10% (?)

  • Amplifications chromosome 12 (MDM2+CDK4)15%

  • Complex genetic alterations (MFH, LMS, ...)50%


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