# Presentation: 196860

## Sarcomas

- Perspectives and Background

## Sarcomas:  Themes

- Sarcomas are a heterogeneous collection of diseases and families of diseases
- Individual diseases/families may be defined molecularly and a molecular derangement characterizes each tumor type (usually)
- Molecular derangement supersedes histomorphology in defining disease
- Unlikely that characteristic molecular derangement is the entire story
- Prototypic diseases which span the child/young adult age range

## Distribution of Common Pediatric Malignancies

## The Sarcomas

- Osteosarcoma
- Ewing family of tumors
- Ewing sarcoma of bone and soft tissue
- Peripheral Primitive neuroectodermal tumor
- Soft tissue sarcomas
- Non-rhabdomyosarcoma STS
- Rhabdomyosarcoma
- Embryonal rhabdomyosarcoma
- Alveolar rhabdomyosarcoma
- Other variants

## Five Year Survival Rates Among Children with Sarcomas:  Improvement Over Time

- From: Arndt C and Crist W.  N Engl J Med 341:342-352, 1999

## Osteosarcoma: Distribution by Site, Age, and Sex

- <date/time>

- From:  Dahlin DC, Unni KK. Bone Tumors: General Aspects and Data on 8542 Cases (ed 4). Springfield, IL: Charles C Thomas; 1986

## Molecular Derangements in Osteosarcoma

- Mutations in RB gene (inactivation)
- Mutations in p53 (inactivation)
- MDM2 amplification (and thus inactivation of p53)
- Over-expression of HER2/erbB-2
- No single molecular derangement defines osteosarcoma

## Multi-Institutional Osteosarcoma Study (1981-1986):  Outcome of All Patients Treated with Chemotherapy

- <date/time>

- Multi-Institutional Osteosarcoma Study (1981-1986):  Outcome of All Patients Treated with Chemotherapy

## Intergroup Osteosarcoma Study (1993-1997): Event-Free Survival for all Patients 

## Metastatic Osteosarcoma: Outcome

- <date/time>

- 100

- 60

- 40

- 20

- 0

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- Event-free survival

- Survival

- Probability (%)

- Years followed

- 80

## Ewing Sarcoma:  Distribution by Site, Age and Sex

- <date/time>

- From:  Dahlin DC, Unni KK. Bone Tumors: General Aspects and Data on 8542 Cases (ed 4). Springfield, IL: Charles C Thomas; 1986

## Molecular Pathogenetic Mechanisms in Rhabdomyosarcoma and Ewing’s Sarcoma

- From: Arndt C and Crist W.  N Engl J Med 341:342-352, 1999

## The 11;22 Translocation And The Family of Ewing’s Sarcomas 

- Reciprocal translocation t(11;22)(q24;q12)
- Found consistently in bone and soft tissue Ewings,  PNET, Askin tumors
- Unifying diagnostic criterion for Ewing’s family of tumors
*EWS* (RNA binding protein) fused to *FLI-1 *or *ERG* (transcription factors of the ETS family)
- Translocation results in a tumor-associated fusion gene
- Fusion transcript present in > 95% of tumors of Ewings family

## Effect of Presence of Metastases on EFS

- <date/time>

- Effect of Presence of Metastases on EFS

## EFS for All Non-Metastatic Patients by Location

- <date/time>

## EFS for Non-Metastatic Patients by Age

- <date/time>

- EFS for Non-Metastatic Patients by Age

## Rhabdomyosarcoma

## Age

- <date/time>

## Common Histiotypes of Rhabdomyosarcoma

## Survival by Histology

## Gene Fusions with Novel Chimeric Protein Products

**t(2;13)(q35;q14)**

**PAX3**

**FKHR**

**Chromosome 2**

**Chromosome 13**

**Activation of aberrant gene program**

**Malignant transformation**

## Genetic Features of Rhabdomyosarcoma

- Embryonal rhabdomyosarcoma
- Associated with inactivation of tumor suppressor gene located at 11p15.5
- Cases with hyperdiploid DNA content associated with better outcome
- Alveolar rhabdomyosarcoma
- Cases with tetraploid DNA content  fare poorly
- Characteristic reciprocal translocation t(2;13)(q35;q14)
- Results in fusion of *PAX3* (transcriptional regulatory protein expressed during embryogenesis) to *FKHR *(member of the forkhead family of transcription factors)
- Infrequently, t(1;13)(p36;q14) involving* PAX7 *and *FKHR *

## Overall Survival: Metastatic Patients Only

- <date/time>

-              **Global : p = 0.0026**
**PAX3 vs PAX7: p = 0.0015**

- Proportion

- 0.0

- 0.1

- 0.2

- 0.3

- 0.4

- 0.5

- 0.6

- 0.7

- 0.8

- 0.9

- 1.0

- Overall survival (years)

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- 8

- 9

- 10

**PAX7**

- Negative

**PAX3**

## Failure-free Survival of Patients with Local/Regional Rhabdomyosarcoma on IRS-IV

**by Chemotherapy Regimen**

**Log Rank Test: p=0.52**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Years**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**VAC**

**VAI**

**VIE**

**Failure-free Survival**

- <date/time>

- 7%	Orbit
- 28%	Head & Neck
- 11%	Trunk
- 2%	Intrathoracic
- 2%	GI-Hepatic
- 6%	Retroperitoneum
- 18%	GU
- 2%	Perineum-Anus
- 24%	Extremities

- Sites

## Failure-free Survival, IRS-IV  for Patients with Local/Regional Tumors by Primary Site

** ****Extremity**

**    ****GU B/P**

**GU non-B/P**

**     ****H & N**

**     ****Orbit**

**     ****Other**

**        ****PM**

**Failure-free Survival, IRS-IV  for Patients with Local/Regional ****Tumors by Primary Site**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Years**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**Failure-free Survival**

## Tumor Histologic Subgroup Distribution by Age Group 

- <date/time>

- Tumor Histologic Subgroup Distribution by Age Group

**p<0.001**

## Disease Stage Distribution by Age Group 

- <date/time>

- Disease Stage Distribution by Age Group

**p<0.001**

## Results of Univariate Analysis

- <date/time>

**Adolescents (>10 years) more often have*********:**
**alveolar tumors (p<0.001)**
**tumors arising in extremity or paratestis sites (p=0.001)**
**large tumors (>5 cm, p<0.001)**
**invasive tumors (i.e. T****2****, p=0.007)**
**+ regional nodes (i.e. N****1****, p<0.001)**
**metastatic disease (p<0.001)**
**unfavorable tumor stage (p<0.001)**

***compared to children (1 to 9 yrs of age)**

## Estimated Relative Risk of Failure by Age Group(Cox Proportional Hazards Model)

- <date/time>

- Estimated Relative Risk of Failure by Age Group(Cox Proportional Hazards Model)

## The Common Soft Tissue Sarcomas in Children

- Rhabdomyosarcoma
- Soft tissue Ewing/PNET
- Synovial Sarcoma
- Malignant Peripheral Nerve Sheath Tumor
- Malignant Fibrous Histiocytoma
- Sarcoma NOS
- Leiomyosarcoma
- Fibrosarcoma
- Clear cell sarcoma
- Epithelioid sarcoma
- Liposarcoma

## Molecular Diagnosis of Sarcomas

| Tumor | Translocation | Fusion Gene |
| --- | --- | --- |
| Ewing/PNET | t(11;22)(q24;q12) | EWS/FLI1 |
| 
 | t(21;22)(q22;q12) | EWS/ERG |
| Alveolar Rhabdomyosarcoma | t(2;13)(q35;q14) | PAX3/FKHR |
|  | t(1;13)(p36;q14) | PAX7/FKHR |
| Desmoplastic small round cell tumor | t(11;22)(p13;q12) | EWS/WT1 |
| Synovial Sarcoma | t(X;18)(p11.2;q11.2) | SYT/SSX1+2 |
| Congenital Fibrosarcoma | t(12;15)(p13;q25) | ETV6/NTRK3 |
| Clear Cell Sarcoma | t(12;22)(q13;q12) | EWS/ATF1 |
|  |  |  |

## Outcome of Children with Localized Non-Rhabdomyosarcoma Soft Tissue Sarcomas

- From Pratt C et al J Clin Oncol 17:1219, 1999

## Considerations of Linking Studies of Sarcomas

- Diseases occur in children, adolescents and *young *adults (excluding non-rhabdo STS)
- Diseases in adults and children *may* be similar on a molecular level
- But, heterogeneity even within major subclasses of sarcomas
- Histopathological
- Biological
- Other significant molecular derangements and differences in gene expression likely
- Limited numbers of patients
- Relatively high cure rate with current therapy limits subjects available for experimental therapies
- Therefore:  Combine efforts among adult and pediatric patients where the disease appears to be a continuum encompassing pediatric and young adults

## Challenges in Linking Studies in Children and Adults 

- Older patients fare less well in all varieties of sarcoma
- ?True age-related biological differences
- Older age associated with higher risk features and more advanced disease
- Age remains independently prognostic
- ?Differences in host tolerance for therapy
- ?Difference in compliance with intensive therapies
- ?Differences in physician compliance with intensive therapies
- Mindset of medical v. pediatric oncologists

## Novel Targets for Biological Agents in Sarcomas

- Osteosarcoma
- Her2 via herceptin
- PDGF signal transduction pathway blockade via STI-571
- Agents which target p53 and Rb
- Rhabdomyosarcoma
- PAX/FKHR fusion gene products
- Ewing family
- EWS/FLI1 and EWS/ERG fusion gene products
- Stem cell factor/*c-kit *signal transduction pathway* *blockade via STI-571
- Desmoplastic Small Round Cell tumor
- PDGF signal transduction pathway blockade via STI-571
- Other Soft Tissue Sarcomas
- Products of associated fusion genes

## Slide 37