Sarcomi

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The antitumor effect of targeting myxoid
liposarcoma
Paolo G. Casali paolo.casali_at_istitutotumori.mi.it
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Trabectedin (ET-743)
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(No Transcript)
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RCT on two regimens of Trabectedin in
lipo/leiomyosa
Morgan JA, ASCO Ann meet 2007 10060
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L-sarcomas
leiomyosarcoma
liposarcoma
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Liposarcoma
Well diff ? dediff
Myxoid ? round cell
Pleomorphic
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Well diff ? dediff
Myxoid ? round cell
Pleomorphic
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• 60 yrs
• limbs
• other
• ..

Pleomorphic
Well/de differentiated
Myxoid /round cell
DD!

• 60 yrs
• thigh
• retroperitoneum
• paratesticular
• mediastinum
• subcutis
• ..

• 45 yrs
• thigh (!)
• popliteal
• groin
• buttocks
• ..

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(No Transcript)
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Cancer 19998585
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Cancer 20071092522
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Cariotype
Pleomorphic
Well/de differentiated
complex
Myxoid /round cell
amplification 12q 14-15 (MDM2)
t(1216) t(1222)
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t(1216)(q13p11)
q13
12 16
CHOP
FUS/CHOP
FUS
p11
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Chemosensitivity
WD MRC
Jones RL et al. EJC 2005 41 2853
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(No Transcript)
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(No Transcript)
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Trabectedin in myxoid lipo
2 c
0
5 c
8 c
11 c
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0 ET743 x 1
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Tumor response
RECIST
30
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Tumor response in GIST
Chois
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15
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0 1 c 4 c
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(No Transcript)
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• Istituto Nazionale Tumori, Milan, Italy
• Royal Marsden, Sutton, UK
• Dana-Farber Cancer Institute, Boston, USA
• Centre Léon Bérard, Lyon, France
• Institut Gustave Roussy, Villejuif, France

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Tumor response
PD 9
SD 25
Tumor control gt85
MR 18
OR 43
PR 41
CR 2
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PFS
PFR _at_6mos 80
Median PFS 17 mos
Median follow-up 14 mos
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Cytotoxic chemotherapyand hypodensity
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myxoid
round cell
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Round cell liposa
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Myxoid liposa
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Duration of response
0 TTP 36 mos
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Surgery of residual disease
ET743 x 13
TTP 24 mos
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Ongoing Phase II study
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simple karyotype with reciprocal translocations
complex unbalanced karyotype
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Synovial sa t(X18)(p11q11) SS18-SSX1 SS18-SSX2
SS18-SSX4 Myxoid liposa t(1216)(q13p11) FUS-C
HOP t(1222)(q13q12) EWS-CHOP Esk. myx.
chondrosa t(922)(q22q12) EWS-NR4A3 t(917)(q22
q11) RBP56-NR4A3 t(915)(q22q21) TCF12-NR4A3 Fib
romyxoid sa t(716)(q33p11) FUS-CREB3L2 t(1116)
(p11p11) FUS-CREB3L1 Clear cell
sa t(1222)(q13q12) EWS-ATF1 Dermatofibrosa t(17
22)(q22q13) COL1A1-PDGFB EFT t(1122)(q24q12) E
WS-FL1 t(2122)(q22q12) EWS-ERG t(722)(p22q12
) EWS-ETV1 t(1722)(q12q12) EWS-E1AF t(222)(q3
3q12) EWS-FEV Desmopl. SRCT t(1122)(p13q12) EWS
-WT1 Alv. rhabdomyosa t(213)(q35q14) PAX3-FOXO1A
t(113)(p36q14) PAX7-FOXO1A Alv. soft part
sa t(X17)(p11q25) TFE3-ASPL Angiomatoid f.
histiocytoma t(1216)(q13p11) FUS-ATF1 Cong
fibrosa t(1215)(p13q25) ETV6-NTRK3 Endometrial
stromal sa t(717)(p15q21) JAZF1-JJAZ1 Infl.
myofibro. t. t(12)(q22p23) TPM3-ALK t(219)(p23
p13) TPM4-ALK t(217)(p23q23) CLTC-ALK t(22)(
p23q13) RANBP2-ALK
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Synovial sarcoma
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Low gr. Endometrial Stromal Sa
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Alveolar soft part sa
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Ewings sarcoma
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Conclusions

• In the clinic, targeting a translocation means
  targeting a disease, and the outcome is the
  result of an interplay
• In myxoid liposarcoma, patterns of tumor response
  to Trabectedin are peculiar, and this may be the
  result of a selective mechanism of action
  vis-à-vis the specificity of the disease
• Tumor responses to Trabectedin have been seen in
  other translocation-related sarcomas, but the
  machanisms will be different, the diseases are
  different, and perspectives are therefore
  different
• While the drug has been finally approved in the
  EU for second-line therapy of advanced STS,
  studies are ongoing to investigate its clinical
  potential in myxoid liposarcomas, in parallel
  with translational studies
• Of current concern for clinical research are
  strategic issues, like duration of treatment, its
  combination with surgery of residual metastatic
  disease, its value in the localized disease

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paolo.casali_at_istitutotumori.mi.it federica.grosso_at_
istitutotumori.mi.it roberta.sanfilippo_at_istitutotu
mori.mi.it