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Biology

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  • Subset A: Stage I group I or Iia, Stage II group I and Stage III orbit Subset B: Stage I group IIB/Iic, Stage I group III non orbit, Stage II group II, andd stage III group I or II Subset C: remaining stage II or III group III

Biology Presentation Transcript

  • 1. Rhabdomyosarcoma
  • 2. Rhabdomyosarcoma
    • Most common soft-tissue sarcoma of childhood
    • Incidence: four to seven cases per million
    • Approximately 250 newly diagnosed cases a year in U.S.
  • 3. Pathology
    • Small blue round cell tumor
    • Myogenic lineage
      • MyoD
    • Two major histologic subtypes
      • Embryonal (LOH 11p15)
        • Botryoid, leiomyomatous
      • Alveolar t(2;13)(q35;q14) t(1;13) (p36;q14)
        • Solid
  • 4. Rhabdomyosarcoma Subtypes
  • 5. Alveolar RMS
  • 6. Embryonal RMS
  • 7. Histological Variants
  • 8. Clinical features
  • 9. Diagnostic Evaluation
    • Determine extent of primary and presence or absence of metastases
    • Staging system - evolved from surgical to nonsurgical staging
    • Biopsy-adequate tissue for routine path, cytogenetics, and molecular studies
  • 10. Diagnostic Evaluation (cont.)
    • Radiologic studies
      • CT/MR of primary lungs
      • Bone scan
      • Role of PET??
        • Several recent published studies suggest it depicts additional important information when combined with CT/MR
    • Other studies
      • Bone marrow exam (evolving 12/901 isolated + in IRS IV)
      • CSF evaluation for parameningeal
  • 11. RMS Staging System Made Simple Raney RB et al. Sarcoma 2001
  • 12. RMS Grouping Stystem Raney RB et al. Sarcoma 2001
  • 13. Prognostic Stratification for Rhabdomyosarcoma
  • 14. Orbital tumor
  • 15. Pelvic tumor
  • 16. Extremity with skip lesions
  • 17. Biology
    • Multiple Genetic Abnormalities
    • Ubiquitous overexpression of IGFII in both ARMS and ERMS
    • LOH at 11p15 in ERMS, LOI IGFII in ARMS
    • Other described alterations
      • Ras mutations
      • p53 mutations
      • p16-CDK4-Rb pathway alterations
      • Overexpression of Met (HGF receptor)
      • 13q31 amplification in 20%
      • IGFIR amplicfication
      • Loss at 9q22-PTH locus
  • 18. Biology (cont)
    • t(2;13)(q35;q14) fuses Pax-3 with FKHR
    • Variant t(1;13) fuses Pax-7 with FKHR
    • Allows for RT-PCR diagnosis
    • A target for therapy?
    • Prognostic significance
  • 19. Mouse Models
    • Heterozygous PTC KO
    • INK4a KO/HGF transgenic
    • p53KO/Her2 transgenic
    • P53/FOS KO
    • All develop embryonaly type histology
    • Most recently alveolar RMS model (conditional knock-in (Pax-3-FKHR and knock-out p53 or Ink4a)
  • 20. Cytogenetics: t(2;13)
  • 21. Identification of Pax-3-FKHR Positive Alveolar RMS Pax3 Probe GAPDH Pax3-FKHR Pax3-FKHR Pax3/7-FKHR Pax3/7-FKHR GAPDH Pax3-FKHR Pax3/7-FKHR M M Tumor 1 (+) Control
  • 22. Pax3 vs. Pax-7 Translocations
  • 23. Evolution of biology of fusions
    • Most recent analysis of all RMS showed increasing number of fusion negative tumors (from 20% to over 40%)
    • Recently found that solid alveolar variant frequently lacked fusion
    • For ARMS, best outcome in those with <50% alveolar histology, intermediate outcome for P7-FKHR or fusion negative and > 50% alveolar histology, worst outcome for P3-FKHR
  • 24. Age is a risk factor
    • For IRS 1-4, 5-yr FFS 72% for 1-10 yo, 51% for adolescents, and 53% for infants
    • While adolescents have tumors with known negative prognostic features (i.e. alveolar histology), infants do not
  • 25. Log Rank Test: p<0.001 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Failure-free survival, years 0 1 2 3 4 5 6 Probability <1 year 1-9 years 10+ years Impact of Age on Survival
  • 26. Epidemiology
    • Approximately 250 new cases diagnosed yearly
    • Among extracranial solid tumors, third most common after NB and WT
    • In US, incidence in African-American females half that for Caucasian females; incidence in males similar for both groups
    • Incidence appears to be lower in Asian populations
  • 27. Epidemiology (cont.)
    • Risk of genetic predisposition 7-33%
    • Index case in Li-Fraumeni (LFS)
      • Clustering of RMS and other STS, adrenocortical carcinoma, early onset breast cancer, neurofibromatosis
      • Associated with germline mutation of p53
      • Study of 33 cases “sporadic” RMS
      • 3/13 cases in children <3 had germline p53 mutations
      • 0/20 >3 had germline p53 mutations
  • 28. Epidemiology (cont.)
    • Associated with BWS-paternal disomy of 11p15
    • Should all patients <3 with RMS be screened for germllne p53 mutations?
    • Should those patients be treated differently?
    • How should patents with germline mutations be followed?
  • 29. Treatment
    • Local Therapy
      • Surgery
      • XRT
    • Chemotherapy
      • Vincristine
      • ActinoD
      • Adriamycin
      • Cytoxan
      • Ifosfamide
      • Etoposide
      • Topotecan/Irinotecan
      • Melphalan?
      • CDDP?
  • 30. Treatment (cont.)
    • Surgery
      • Major conclusion of IRSI-complete resection had major influence on overall survival
      • Probably due to inadequate (pre- CT guided XRT)
      • Currently recommend complete surgical resection if not mutilating or cosmetically damaging
        • Should re-excise for a whoops surgical resection
  • 31. Second-Look Surgery
    • Document pathologic evidence of CR after induction therapy-NO
      • 50% recurrence after documented CR (SIOP)
        • Biopsy only
    • Resect residual viable tumor after local therapy-maybe
      • CGIII patients in IRS III
        • 64% in PR found to be in CR
        • 52% with less that PR converted to CR
  • 32. Treatment
    • XRT
      • General principles to evolve
        • 4000-4500cGy for microscopic disease
          • Contrast to European approach
        • 4500-5000cGy for gross residual disease and >5cm tumor
        • Parameningeal tumors 4500-5500cGy to well-defined field
          • Whole brain or craniospinal XRT and IT therapy not indicated n absence of overt disease
  • 33. Treatment (cont.)
    • XRT in IRS IV
      • Defined by clinical group
      • Group I- No XRT
      • Group II- 4140cGy conventional two months into Rx to original tumor volume
      • Group II- 5040cGy conventional over five-six weeks vs 5940cGy hyperfractionated
  • 34.  
  • 35. IRS IV Results
    • Local/regional embryonal tumors-some improvement compared to IRS-III
      • 3-yr FFS 83% vs 74% IRS-III
      • CTX 2.2 gm vs 1.0 gm
    • Alveolar-no difference in FFS
      • 3-yr FFS 64% vs. 70% IRS-III for non-metastatic
  • 36. IRS IV Results Chemo
    • No difference between VAC vs VAI vs VIE
    • VAC “gold standard”
  • 37. IRS IV Results (XRT)
    • No apparent benefit of hyperfractionated XRT
    • CWS Study Group (Germany) reported the same finding
  • 38. Log Rank Test: p<0.001 Survival, IRS-I through IV Patients 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 2 4 6 8 10 Percent Alive IRS-I IRS-II IRS-III/IVP IRS-IV by Study
  • 39. Log Rank Test: p<0.001 Survival, IRS-I through IV Patients by Group 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 2 4 6 8 10 Percent Alive Group I Group II Group III Group IV
  • 40. Meza, J. L. et al. J Clin Oncol; 24:3844-3851 2006 Fig 3. Failure-free survival for 370 patients with nonmetastatic alveolar rhabdomyosarcoma or undifferentiated sarcoma enrolled onto Intergroup Rhabdomyosarcoma Study-III and -IV
  • 41. Meza, J. L. et al. J Clin Oncol; 24:3844-3851 2006 Fig 4. Failure-free survival for 88 patients with nonmetastatic embryonal rhabdomyosarcoma enrolled onto Intergroup Rhabdomyosarcoma Study-III and -IV
  • 42. Log Rank Test: p<0.001 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Failure-free survival, years 0 1 2 3 4 5 6 Probability Sarcoma-NOS Alveolar Emb/Spind/Botr Undifferentiated Survival by Histology
  • 43. Chemotherapy in IRS V
    • High Risk Stage IV patients-Irinotecan (Daily x5 x2 20 mg/M 2 ) + Vincristine window , followed by VCPT/VAC in responders vs. VAC alone in non-responders
    • Intermediate Risk Stage III patients-VAC vs. VAC/VTC
    • Low Risk Stage I patients and Stage II group I patients-VA for embryonal and VAC for alveolar + XRT for group II and III
  • 44. Treatment of Recurrent Disease
    • Localized Recurrence
      • Complete surgical resection offers best hope
      • Potentially followed by adjuvant XRT and chemotherapy
        • Long-term survival well described (vaginal, paratesticular)
    • Disseminated Recurrence
      • Chemotherapy is primary therapeutic modality
  • 45. Survival after relapse in RMS-IRSG
  • 46. Late Effects
    • Bladder, Prostate and Paratesticular Tumors
      • Bowel obstruction (surgical), enteritis (XRT), poor bladder function or hemorrhagic cystitis, sex hormone deficiency
      • Ifosfamide based Rx
        • Renal damage
      • Adriamycin-based Rx
        • Cardiomyopathy
  • 47. Late Effects (cont.)
    • Second malignancies
    • 22 SMNs out of 1770 patients on IRS-I/II
      • Eleven bone sarcomas (XRT fields), five ANLL median seven months off therapy
      • Etoposide induced leukemias
  • 48. Outcome Summary
    • 60%-70% of newly diagnosed patients with nonmetastatic disease can be cured with combined modality Rx
    • Less than 30% of metastatic disease currently cured-Cy/Topo alternating with VAC does not improve OS or EFS in this group of patients
  • 49. Challenges
    • Detection of MRD by RT-PCR
      • What is its significance?
      • What can we do?
    • Identification of “higher risk” and “lower risk” in localized patients
    • Identification of factors that contribute to metastases
  • 50. Challenges (cont.)
    • Development of less toxic therapy for “good risk”localized patients
      • Decrease long-term morbidity
      • Decrease incidence of second tumors
    • New therapeutic approaches for metastatic patients
  • 51. In situ bright field IGF-II
  • 52. In situ dark field IGF-II
  • 53. IRS-1 PI3K PIP2 PIP3 PTEN PDK1 PKB/Akt T308 S473 TSC1 TSC2 Rheb mTOR Raptor mLST8 mTOR Rictor mLST8 LKB1 AMPK Rapamycin FKBP12 Nutrents GF(insulin/IGF) S6K1 4E-BP1 elF4B elF4E rpS6 Top-dependent translation (e.g. IGF-II) Cap-dependent translation (e.g. Cyclin D1, c-MYC, HIF-1  , VEGF) Actin cytoskeleton RTK
  • 54. Variable levels of IGFIR in RMS tumors and cell lines
  • 55. Correlation between IGFIR levels and antiproliferative effect of IGFIR Ab
  • 56.  
  • 57. IGF-1R/InR IRS-1 PI3K Akt TSC1/2 mTORC1 S6K1 4E-BP1 Rheb Rapalogs mTORC2 LY294002 Akt inhibitors mTORC1and mTORC2inhibtion with kinase inhibitors ? IGF-1R Ab TK inhibitors PI3K/mTOR inhibitors
  • 58. Must Study Biology
    • Clinical studies should be designed to test a hypothesis related to biology
    • How can we set up clinical studies so outcome is not the only endpoint?