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UPDATE ON SARCOMAS
Rare bone sarcomas
Silvia [email protected]
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DISCLOSURES
Personal financial interests (honoraria, consultancy or advisory role): Adaptimmune, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Immunedesign, Karyopharm, Maxivax, Pharmamar, Takeda
Institutional financial interests: Amgen Dompè, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Novartis, Pfizer, Pharmamar
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Cartilage tumours
• Chondrosarcoma
• Dedifferentiated chondrosarcoma
• Mesenchymal chondrosarcoma
• Clear cell chondrosarcoma
Fibrogenic tumours
Fibrohistiocitic tumours
Giant cell tumours
• Giant cell tumor
• Malignancy in giant cell tumours
Notochordal tumours
• Chordoma
Vascular tumours
• Haemangioma and related lesion
• Angiosarcoma
Myogenic, lipogenic, neural and epithelial
tumours
• Leiomyosarcoma of bone
• Liposarcoma of bone
• ...
Congenital snd inherited syndromes
• Enchondromatosis (Ollier/Maffucci
Syndrome)
• ...
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ion from author a
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Cartilage tumours
• Chondrosarcoma
• Dedifferentiated chondrosarcoma
• Mesenchymal chondrosarcoma
• Clear cell chondrosarcoma
Fibrogenic tumours
Fibrohistiocitic tumours
Giant cell tumours
• Giant cell tumor
• Malignancy in giant cell tumours
Notochordal tumours
• Chordoma
Vascular tumours
• Haemangioma and related lesion
• Angiosarcoma
Myogenic, lipogenic, neural and epithelial
tumours
• Leiomyosarcoma of bone
• Liposarcoma of bone
• ...
Congenital snd inherited syndromes
• Enchondromatosis (Ollier/Maffucci
Syndrome)
• ...
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ion from author a
nd ESO
Sbaraglia M et al, CTOS 2018
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Sbaraglia M et al, CTOS 2018
427 primary vascular tumors diagnosed at IOR (Bologna)
since 1937 (90 yrs!)
289 hemangiomas
183 sarcomas (32%)
52 (12%) angiosarcomas (45 epithelioid)
38 (8.9%) epithelioid hemangiomas
24 (5.6%) pseudomyogenic hemangioendotheliomas
21 (5.2%) epithelioid hemangioendotheliomas
2 retiform hemangioendotheliomas
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Sbaraglia M et al, CTOS 2018
Primary tumors
Recurrence free survival
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Sbaraglia M et al, CTOS 2018
Primary tumors
Overall survival
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SFT
leio
…
CHEMOSENSITIVITY: THE SAME AS THE
SOFT TISSUE COUNTERPART
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Chordoma
bone tumor
mesenchymal/epithelial differentiation
0.8/1.000.000
(benign lesion 20%)
600-750 pts/yr in EU
indolent clinical behaviourDo not duplicate or d
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Age ▪ Median age 60 yrs
A Trama, Sept 2017
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Pathology
▪ Conventional chordoma (>95%)
nuclear staining for brachyury
▪ Dedifferentiated chordoma (<5%)
▪ Poorly differentiated chordoma (<5%)Do not duplica
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INI1 loss and negative nuclear staining of
brachyury
DEDIFFERENTIATEDCHORDOMA
H&E
MIB
1
BRY
INI1
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Images courtesy of Dr. Mrinal Gounder
H&E Brachyury INI1
POORLY DIFFERENTIATED CHORDOMA
CHILDREN (0-21 YRS)Do not duplica
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wide excision +/- HD-RT
or
- unresected cases -
definitive HD-RT
Primary tumor
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ion from author a
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Relapsed chordoma
Ann Oncol 2017
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Ann Oncol 2017
Relapsed chordoma
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Ann Oncol 2017
“Medical therapy is an appropriate palliative option for patients whose disease is actively progressing or who are symptomatic
A brief observation period may be warranted before starting medical therapy to determine whether, and at
what rate, progressing “
Relapsed chordoma
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No active drug formally approved
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No active drug formally approved
the compassionate and off-label use
of new drugs
is widespread in chordoma
with
a very discordant access
to potentially active treatments
among different European countriesDo not duplica
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Overall <10% RECIST PRreported in literature
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Medical Treatment, chemo
cytotoxic
chemotherapy
“However, anecdotal reports of responses to anthracyclines,
cisplatin, alkylating agents, etoposide
in high-grade dedifferentiated and pediatric cases”
Stacchiotti S et al, Lancet Oncol 2015Ann Oncol 2017
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S David et al, CTOS 2018
Medical Treatment, chemo
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+3 mosbaseline
CDDPDo not duplicate or d
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” At present,
imatinib and sorafenib
are the medical therapies with the greatest evidence of antitumor
activity in chordoma and represent reasonable palliative treatment
options to slow disease progression or alleviate symptoms”
Ann Oncol 2017
Medical Treatment, TKI
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RECIST
PR = 1 pt (2%)minor response 9 (18%)
SD = 35 pts (70%)
PD = 14 pts (28%)
mPFS = 9 mos
Stacchiotti S et al, JCO 2012
Imatinib
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Baseline
2 mos
6 mos
18 mos+
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Bompas E et al, Ann Oncol 2015
RECIST
PR = 1/27
9-mo PFS 73.0%
12-mo OS 86.5%
Sorafenib
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Stacchiotti S et al, Eur J Cancer 2018
Imatinib + everolimus
40 evaluable pts, all progressive
imatinib 400 mg + everolimus 2.5 mg
Choi
PR 9/40 (ORR 20.9%)
RECIST
1 PR
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Stacchiotti S et al, Eur J Cancer 2018
Imatinib + everolimus
40 evaluable pts, all progressive
imatinib 400 mg + everolimus 2.5 mg
Choi
PR 9/40 (ORR 20.9%)
RECIST
1 PR
m-PFS (Choi) 11.5 mos
m-PFS (RECIST) 14 mos
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Stacchiotti S et al, Eur J Cancer 2018
Imatinib + everolimus
40 evaluable pts, all progressive
imatinib 400 mg + everolimus 2.5 mg
Choi
PR 9/40 (ORR 20.9%)
RECIST
1 PR
m-PFS (Choi) 11.5 mos
m-PFS (RECIST) 14 mos
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Stacchiotti S et al, Eur J Cancer 2018
Imatinib + everolimus
40 evaluable pts, all progressive
imatinib 400 mg + everolimus 2.5 mg
Choi
PR 9/40 (ORR 20.9%)
RECIST
1 PR
m-PFS (Choi) 11.5 mos
m-PFS (RECIST) 14 mos
30% definitive interruption for toxicity
S6/4EBP1 phosphorylated in a high and
moderate/low proportion of tumor cells in
responsive and nonresponsive patientsDo not duplica
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Sunitinib/ Pazopanib
Lipplaa A et al, Clin Sarc Res 2017
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Launay SG, BMC Cancer 2011
… erlotinibcetuximab
gefitinib
EGFR inhibitors
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Open trials
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Magnaghi P et al, Mol Cancer Ther 2018
IC50 (uM)
Compound UCH-1UCH-2
(Ch. F.)
UCH-2
(ATCC)Chor-IN-1
MUG-
Chor1JHC7
A2780
ctrl
EGFR1
Biochemical1
Afatinib 0.010 0.208 0.257 0.586 0.260 1.726 2.114 0.001
Neratinib 0.021 1.894 3.756 1.903 2.152 2.944 0.491 0.008
Erlotinib 0.137 6.297 6.885 1.917 2.615 1.712 3.447 0.005
Ibrutinib 0.388 5.600 4.770 9.319 > 10 3.655 3.463 0.021
Lapatinib 0.554 > 10 > 10 > 10 > 10 > 10 3.076 0.030
Gefitinib 0.608 3.418 5.133 8.650 6.787 7.133 4.990 0.004
Vandetanib 1.195 1.948 4.618 4.460 3.654 7.207 1.502 0.039
Rociletinib/CO-1686 2.115 2.650 3.176 0.897 4.615 2.670 0.915 0.535
Open trial, afatinib
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Advanced, progressing
chordoma
Afatinib
40 mg/day
Continue
up to progression
and/or toxicity
Open trials, afatinib
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Images courtesy of Dr. Mrinal Gounder
H&E Brachyury INI1
POORLY DIFFERENTIATED CHORDOMA
CHILDREN (0-21 YRS)
Open trials, tazemetostat
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Open trials, tazemetostat
TAZEMETOSTAT
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Open trials, tazemetostat
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CHILDREN (0-23 YRS)
Open trials, tazemetostat
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REGOBONE
Open trials, regorafenib
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ion from author a
nd ESO
Von Witlzleben et al, Cancer Res 2015
Open trials, palbociclib
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Migliorini D et al, Oncoimmunology 2017
Open trials, vaccine
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Chondrosarcoma
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▪ Conventional (85%)
▪ Dedifferentiated
H3K27me3 deficiency
▪Mesenchymal
HEY1-NCOA2
▪ Clear Cell
▪ Extraskeletal Myxoid Chondrosarcoma
Pathology
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wide excision +/- HD-RT
or
- unresected cases -
definitive HD-RT
Primary tumor
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Relapsed bone chondrosarcoma
limited chemosensitivity
to cytotoxicsDo not duplicate or d
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baseline
+ 4 mos
doxo
doxo, conventional/ dediff/ mesenchymal chondro
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- 3 mos
baseline
+ 4 mos
gemcitabine
PD
gemcitabine,
conventional chondro
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trabectedin,mesenchymal chondro
Morioka H et al, BMC Cancer 2016
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antiangiogenics
Jones et al., Mod Oncol 2017
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REGOBONE
Open trial, regorafenib
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ion from author a
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ion from author a
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Tawbi et al, Lancet Oncol 2017
Pembrolizumab
RECIST
PR = 1/5 ptminor response (<30%) 0
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Martin Broto J et al, ASCO 2018
Sunitinib + nivolumab
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bone tumor
mesenchymal/epithelial differentiation
synonym: osteoclastoma
4-5% of all primary bone tumor
Paget-related cases
>20-45 yrs
F>M
benign, locally aggressive
malignant transformation
Giant Cell Tumor of Bone
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Behjati S et al, Nature Genetics 2013
point mutations of
H3F3A gene
- coding for a histone H3.3
protein -
Pathology
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Behjati S et al, Nature Genetics 2013Righi A, Human Path 2017
Pathology
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Cartilage tumours
• Chondrosarcoma
• Dedifferentiated chondrosarcoma
• Mesenchymal chondrosarcoma
• Clear cell chondrosarcoma
Fibrogenic tumours
Fibrohistiocitic tumours
Giant cell tumours
• Giant cell tumour
• Malignancy in giant cell tumour
Notochordal tumours
• Chordoma
Vascular tumours
• Haemangioma and related lesion
• Angiosarcoma
Myogenic, lipogenic, neural and epithelial
tumours
• Leiomyosarcoma of bone
• Liposarcoma of bone
• ...
Congenital snd inherited syndromes
• Enchondromatosis (Ollier/Maffucci
Syndrome)
Fletcher C et al, WHO 2013
Pathology
Do not duplicate or d
istribute without
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ion from author a
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“benign but locally aggressive primary bone neoplasm”
Fletcher C et al, WHO 2013
Pathology
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ion from author a
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mononuclear stromal spindle cells
macrophage osteoclast-like giant round multinuclear cell
RANKL is expressed by stromal tumor cell
RANK is expressed by giant osteoclast-like cells
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Metastases can have
benign path aspects
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“A high-grade malignant neoplasm arising in GCT may be
identified at initial diagnosis (ie primary malignancy in
GCT) or at relapse (secondary malignancy in GCT)”
Fletcher C et al, WHO 2013
Pathology
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“Primary malignancy in GCT refers to cases where an area or nodule of
highly pleomorphic mononuclear cells is present in an otherwise
conventional GCT. The transition between the two components varies.
The high-grade sarcoma has no specific morphology; it may or may not
produce osteoid. In secondary malignancy in GTC, the pre-existing GCT
may or may not be evident”
Pathology
Fletcher C et al, WHO 2013
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Folpe AL et al. Mod Pathol 1999
Pathology
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surgery
recurrence rate:complete resection: 10-20%
curretage: > 60%
2-5% metastases (>lung)
Primary tumor
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Malignancy in GTC incidence
▪ 1-3% high-grade sarcoma dedifferentiation
Saada et al, JCO 2011
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Critical sites requiring demolitive surgery
(benign GCT)
Medical therapy, when?
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Critical sites requiring demolitive surgery
(benign GCT)
Metastatic cases
«Benign»
Malignant GCT
Medical therapy, when?
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Denosumab
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Bransletter et al, Clin Cancer Res 2012
Denosumab, path response
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282 pts
9/2008-3/2011
Chawla et al, Lancet Oncol 2013
PD: 8/282 pts (3%)
RECIST ORR: 41%
Denosumab
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ADVERSE EVENTS OF INTEREST N=526 (%)
Osteonecrosis of the jaw 28 (5%)
Palmerini E et al, ESMO 2017, 2740067
Denosumab
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ADVERSE EVENTS OF INTEREST N=526 (%)
Osteonecrosis of the jaw 28 (5%)
Atypical femur fracture 4 (1%)
New malignancy in GCTB
•Primary malignant
•Secondary malignant
•Sarcomatous transformation
10 (2%)
5 (1%)
1
4
Palmerini E et al, ESMO 2017, 2740067
Denosumab
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ADVERSE EVENTS OF INTEREST N=526 (%)
Osteonecrosis of the jaw 28 (5%)
Atypical femur fracture 4 (1%)
New malignancy in GCTB
•Primary malignant
•Secondary malignant
•Sarcomatous transformation
10 (2%)
5 (1%)
1
4
≥ Grade 3 hypercalcemia (following
discontinuation)
4 (1%)
Palmerini E et al, ESMO 2017, 2740067
Denosumab
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0
+ 6 months
+ 24 months
Denosumab
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ion from author a
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0 + 6 months
Denosumab
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ion from author a
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0
+ 1 month
+ 6 months
Denosumab
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ion from author a
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0 + 3 months
Denosumab
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Treatment duration?
Which is the best surgical approach after d’mab?
Relapse-free survival after d’mab + surgery?
Denosumab, open issues
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Which medical therapy in
sarcoma in GCTB?
0
+ 5 cycles
Epi-Ifx
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Silvia Stacchiotti
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Bone SFT
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COHORT 1 – unresectable GCTB
COHORT 2 – resectable GCTB
• 5-yr PFS 88%
• 67% surgery
• 5-yr EFS 88%
• 44% less extensive surgery
• 27% relapses
Palmerini E et al, ESMO 2017, 2740067
CURRETTAGE vs RESECTION
34% vs 12%
Palmerini E et al, ESMO 2017, 2740067
Denosumab
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CTOS 2013, ChicagoDo not duplica
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