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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 offour presentations onSarcomas 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

Translocations

Complex

genomics

SyS

DFSP

Ewing

Mutations

APC/bCat

Desmoids

LMS, UPS


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%)


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

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


Barretina et al Nat Gen 2010


We need

  • To betterpredict relapse

  • To identifybetter the « driver » mutations

  • Biomarkers to predict for primary and secondaryresistance


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. 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

  • Predictive value in other cancers

  • Commercial tools imperfect for sarcoma cells

  • Novel technology

  • - detects telomerase + cells


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?

  • To be expanded and confirmed

  • Biological significance of CTC?

  • To guide adjuvant treatment?

  • Help to monitor response or relapse?


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


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 miRNAs, assessed in STS subtypes

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


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 need

  • To betterpredict relapse

  • To identifybetter the « driver » mutations

  • Biomarkers to predict for primary and secondaryresistance


What is a good target?

Expression

Possible target

Expression + activation

Promising target

Expression + activation + mechanism

A major target

Expression + activation + mechanism + drug

Clinical trial


Dual PTEN/P53 suppression promotes high grade sarcomas

by activating Notch

Eva Hernando, Ph.D.


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


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

  • N=57 patients,

  • Druggable alterations

  • Documented responses

  • Documented SD


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

  • 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

  • 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


A World Sarcoma Network is needed

Join us!

11/14/2014

28


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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