Leiomyosarcoma undifferentited pleomorphic sarcoma
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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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Leiomyosarcoma undifferentited pleomorphic sarcoma

Leiomyosarcoma– UndifferentitedPleomorphic Sarcoma.

Dr Philippe CASSIER, MD

Centre Léon Bérard

Lyon, France


Outline

Outline

  • Local therapy

  • Prognosis

  • Molecular markers

  • Therapeuticintervension


Local therapy surgery

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


Leiomyosarcoma undifferentited pleomorphic sarcoma

LRFS


Leiomyosarcoma undifferentited pleomorphic sarcoma

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


Prognosis

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


Prognosis1

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….


Survival of lms patients

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


Prognosis2

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….


Molecular markers

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


Gene expression signatures

Gene expression signatures

Hierarchicalclustering identifies differentssubtypes

Great!

So what?

Nielsen TO et al. Lancet 2002


Tumor initiating cells in sts

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


Gene expression signatures1

Gene expression signatures

PrMet – Skubitz et al Cancer 2012

Skubitz et al. CTOS

CINSARC – Chibon et al. Nat Med 2010


T x 17 mbtd1 cxorf67 in ess

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


Therapeutic intervension

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


Endocrine therapy for ulms

Endocrine therapy for uLMS

Median PFS = 9.1 weeks (90% CI, 6.1-12.4)

N=26

George et al. CTOS 2012


Endocrine therapy for ulms1

Endocrine therapy for uLMS

N=34

Median 2.9 months

O’Cearbhaill et al. GynecolOncol 2010


Chemotherapy for ulms

Chemotherapy for uLMS

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


Chemotherapy for ulms1

Chemotherapy for uLMS

Overallresponse-rate


Targeted therapy for ulms

Targetedtherapy for uLMS

  • Plk1 inhibitors and rapamycin


Ups and lms conclusions

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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