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Leiomyosarcoma – Undifferentited Pleomorphic Sarcoma.

Leiomyosarcoma – Undifferentited Pleomorphic Sarcoma. Dr Philippe CASSIER, MD Centre Léon Bérard Lyon, France. Outline. Local therapy Prognosis Molecular markers Therapeutic intervension. Local therapy - Surgery.

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Leiomyosarcoma – Undifferentited Pleomorphic Sarcoma.

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  1. Leiomyosarcoma– UndifferentitedPleomorphic Sarcoma. Dr Philippe CASSIER, MD Centre Léon Bérard Lyon, France

  2. Outline • Local therapy • Prognosis • Molecular markers • Therapeuticintervension

  3. Local therapy - Surgery • ID 1403273, The effect of the setting of a positive margin on local recurrence for extremity soft tissue sarcoma. Dr O’Donnel how good a margin do we need? how can we further improve local control

  4. LRFS

  5. Metastasis-Free Survival, Negative vs. Positive Critical Structure Margin Negative Critical Structure Margin 72.7% (p = 0.005) Positive Critical Structure Margin 52.2% Depth, p=0.594 Grade, p=0.61 Size, p=0.89 Chi-square/ Fisher’s Exact for depth/grade t-test for size as it is continuous

  6. Prognosis • ID 1437122 Long-term outcomes of patients with leiomyosarcoma of uterine versus extra-uterine origin. S.N. Divi et al. • ID 1414211 Uterine leiomyosarcoma management, outcome and associated molecular biomarkers. K. Lusby et al • ID1436107 The outcome of patients with leiomyosarcoma: a retrospective single center analysis. H. Kosela et al

  7. Prognosis • uLMS vs eLMS: not reallydifferent, and overallpoor= lessthanhalf of patients survive 5 years… • uLMS have poorprognosiswhen M+ and overall, express markers similar to other LMS, molecularfeatures of agressive disease confer poorprognosis… • uLMS > eLMS > RP-LMS; large, high grade tumorsfareworse….

  8. Survival of LMS patients Divi et al. N=640 yrs 1982-present Lusby et al. N=349 yrs 1989-2011 Kosela et al. N=162 yrs 1998-2010

  9. Prognosis • uLMS vs eLMS: not reallydifferent, and overallpoor = lessthanhalf of patients survive 5 years… • uLMS have poorprognosiswhen M+ and overall. Express markers similar to other LMS, molecularfeatures of agressive disease confer poorprognosis… • uLMS > eLMS > RP-LMS • Large, high grade tumorsfareworse….

  10. Molecular markers • ID 1423580 Gene expression signature from tumor initiating population predicts clinical outcome in undifferentiated pleomorphic sarcoma. I. Han et al. • ID1424007 Gene expression identifies heterogeneity of metastatic behavior among high-grade pleomorphic soft tissue sarcomas. K.M. Skubitz et al • ID 1433743 Identification of a novel, recurrent MBTD1-CXorf67 fusion in low grade endometrial stromal sarcoma. B.M. Dewaele et al

  11. Gene expression signatures Hierarchicalclustering identifies differentssubtypes Great! So what? Nielsen TO et al. Lancet 2002

  12. Tumorinitiatingcells in STS 15 samples of UPS Separate TIC Gene profilling Apply to 114 STS samples Wu et al. Cancer Res 2007 Prognosis/metastasis-free survival

  13. Gene expression signatures PrMet – Skubitz et al Cancer 2012 Skubitz et al. CTOS CINSARC – Chibon et al. Nat Med 2010

  14. t(X;17) MBTD1-CXorf67 in ESS 70 genes CXorf67 MBTD1 cDNA 1 16 1 YWHAE-FAM22A JAZF1-SUZ12 JAZF1-SUZ12 YWHAE-FAM22A MBTD1-CXorf67 JAZF1-SUZ12 JAZF1-SUZ12 YWHAE-FAM22A MBTD1-CXorf67 ESS high ESS low UES

  15. Therapeuticintervension • 1436034 Targeting hormone receptors in uterine leiomyosarcoma (U-LMS): phase II clinical study of Letrozole in women with advanced U-LMS expressing estrogen and/or progesterone receptors. S. George et al • ID1417328 Systematic chemotherapy for inoperable, locally advanced, recurrent or metastatic uterine leiomyosarcoma: a systematic review. A. Gupta et al • ID 1437166 Small molecule inhibitors for Polo-Like Kinase-1 (Plk-1) sensitize uterine leiomyosarcoma to Rapamycin. W. Shan et al

  16. Endocrine therapy for uLMS Median PFS = 9.1 weeks (90% CI, 6.1-12.4) N=26 George et al. CTOS 2012

  17. Endocrine therapy for uLMS N=34 Median 2.9 months O’Cearbhaill et al. GynecolOncol 2010

  18. Chemotherapy for uLMS Systemic chemotherapy for inoperable, locally advanced, recurrent or metastatic uterine leiomyosarcoma: a systematic review. A. Gupta et al

  19. Chemotherapy for uLMS Overallresponse-rate

  20. Targetedtherapy for uLMS • Plk1 inhibitors and rapamycin

  21. UPS and LMS: Conclusions • Local therapy: not all positive margins are the same….but relapse is in most cases systemic. • Overallprognosisremainspoor • Molecularstudiesshouldaimatidentifyingpredictiveratherthanprognostic markers. • Obviouslyweneed more effective systemictherapies

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