Rarer Sarcoma Subtypes Andrew J. Wagner, MD, PhD Center for Sarcoma and Bone Oncology Dana-Farber...
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Transcript of Rarer Sarcoma Subtypes Andrew J. Wagner, MD, PhD Center for Sarcoma and Bone Oncology Dana-Farber...
Rarer Sarcoma Subtypes
Andrew J. Wagner, MD, PhDCenter for Sarcoma and Bone Oncology
Dana-Farber Cancer InstituteBoston, MA
Rarer Soft Tissue Sarcomas• Screening for Novel Sarcoma Cancer
Genes – Thomas• Apoptosis in Synovial Sarcoma – Jones• Negative Prognostic Factors in
Epithelioid Sarcoma – Donati• Oncogenes in Solitary Fibrous Tumor –
Demicco• Clinical characteristics of benign and
malignant SFT- DeVito• Dacarbazine in SFT – Stacchiotti• PARP inhibitors in Malignant
Peripheral Nerve Sheath Tumors – Kivlin
• Neoadjuvant therapy for MPNST - Shurell
• Chromosomal complexity in Synovial Sarcoma – Chibon
• Epithelioid Angiosarcoma – Stacchiotti
• New Treatment Strategies for Angiosarcoma – Young
• Primary and Secondary Angiosarcomas – Kasper
• ALDH1 in SFT – Bouvier• Gender Specific Age of
MPNST Onset – Shurell
Genetic and Biologic Susceptibility
Preclinical Studies
Clinical Responses and Outcomes
Predictive Markers
Prospective Studies
CINSARC/Genomic Complexity in SynSarc - Chibon
Apoptosis in Synovial Sarcoma – Jones
Synovial Sarcoma
Jones et al. • GEM model of synovial
sarcoma and human cell lines
• SS18-SSX2 suppresses MCL1 and BCL2A1 expression
• BCL2 is expressed• Sensitivity to BH3 mimetic
ABT-263 (navitoclax) – BCL2/BCLXL inhibitor
• Explore BCL2 inhibitors in Synovial Sarcoma?
Synovial Sarcoma
Chibon et al. • CINSARC and CGH profiling of Synovial
Sarcoma predict risk of metastases
Validate in larger series/Prognostic marker?Does this reflect response to therapy or behavior of tumors?Can these data help select who may need (or may not need) chemotherapy?Or help guide choice of regimen?
Genetic and Biologic Characteristics
Preclinical Studies
Clinical Responses and Outcomes
Predictive Markers
Prospective Studies
Apoptosis in Synovial Sarcoma – Jones
Oncogenes in SFT – DemiccoBenign vs. malignant SFT- DeVito
Dacarbazine in SFT – Stacchiotti
ALDH1 in SFT – Bouvier
CINSARC/Genomic Complexity in SynSarc - Chibon
Solitary Fibrous Tumor
• Diagnosis: Bouvier et al.– ALDH1 expression
84.9% of SFT, 12.9% of benign soft tissue tumours and 1.6%of sarcomas were ALDH1+
Spindle cell/pleomorphic lipomas were theonly tumours that showed frequent ALDH1 expression (18/31 cases, 58%)
ALDH1 is an accurate diagnostic marker
IS IT A THERAPEUTIC TARGET?Sensitivity= 84.9%,Specificity= 96.5%, Positive Predictive Value= 71.2% Negative Predictive Value= 98.4%
ALDH1 in SFT – Bouvier et al. RNA expression profile of 16 SFTIHC on 899 Soft Tissue Tumors
Solitary Fibrous Tumor
• Diagnosis: Bouvier et al.– ALDH1 expression
• Benign vs. Malignant: DeVito et al.– 82 patients, roughly 50/50 benign/malignant– No difference in location of primary– Survival worse with malignant disease
Solitary Fibrous Tumor
• Diagnosis: Bouvier et al.– ALDH1 expression
• Benign vs. Malignant: DeVito et al.– 82 patients, roughly 50/50 benign/malignant– No difference in location of primary– Survival worse with malignant disease
• Genetics: Demicco et al.
Search for SFT Oncogenes – Demicco et al. • Targeted analysis for 175 mutations in 41 genes in 122 tumors
(malignant or benign?), twiceRun 1 Run 2 Total
Number SNPs detected (% of all useable reads)
12 (0.23%) 21 (0.15%)
33 (0.17%)
SiteALK T3733G (p.F1245V) - 1 1BRAF T1799A* (p.V600E) 2 1 3KRAS G35A (p.G12D)** 1 10 11KRAS G34A (p.G12S)** - 1 1KRAS C181A (p.Q61K) - 1 1MET C2962T (p.R988C) 1 1 2MET C3029T (p.T1010I) - 3 3NRAS G35A (p.G12D)** 7 3 10NRAS G38A (p.G13D)** 1 - 1
No high frequency recurrent mutations identifiedHighlights the challenges of using primarily carcinoma-targeted reagents to study sarcomas
Frozen tumor panel provides ability for other testing: whole genome, whole exome, RNAseq, etc.
What are the drivers of this disease? What distinguishes benign from malignant disease?
Solitary Fibrous Tumor
• Diagnosis: Bouvier et al.– ALDH1 expression
• Benign vs. Malignant: DeVito et al.– 82 patients, roughly 50/50 benign/malignant– No difference in location of primary– Survival worse with malignant disease
• Genetics: Demicco et al. • Treatment: Stacchiotti et al.
Dacarbazine, etc, in dediff SFT – Stacchiotti et al.
Days after inoculum
Tu
mo
r vo
lum
e (m
m3 )
30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180
10
100
1000
CtrSunitinib (40 mg/kg qd x 5d/w x 4 w, p.o)Bevacizumab (4.3 mg/kg q3-4d x 8, i.p)Temozolomide (50 mg/kg qd x 5d/w x 4 w, p.o)
Tumor model Mouse Clinical Trial(Frequentist Approach) Clinical Responses
Human Clinical Trial Underway
Genetic and Biologic Susceptibility
Preclinical Studies
Clinical Responses and Outcomes
Predictive Markers
Prospective Studies
Novel Sarcoma Cancer Genes – Thomas
Apoptosis in Synovial Sarcoma – Jones
Dacarbazine in SFT – Stacchiotti
Epithelioid AS– StacchiottiPrimary and Secondary AS – Kasper
CINSARC/Genomic Complexity in SynSarc - Chibon
Oncogenes in SFT – DemiccoBenign vs. malignant SFT- DeVitoALDH1 in SFT – Bouvier
New Treatment Strategies for AS - Young
Angiosarcoma
• Epithelioid AS – Stacchiotti et al. – 58 patients; 56 received CT for advanced disease
(25 had had adjuvant chemo previously)– Approx 2/3 had benefit to 1st, 2nd, and 3rd line Rx– Median OS only 24 months; 33 months for locally
advanced disease
Chemoresponsive but not durable
Angiosarcoma
• Epithelioid AS – Stacchiotti et al. • Primary vs Secondary AS – Kasper et al.
– 18 primary (5F/13M)• 44% local recurrence; 2/3 metastatic• Median DFS 4 months; OS 13 months
– 10 secondary (8F/2M)• 70% local recurrence, 40% metastatic• Median DFS 9 months; OS 45 months
We need more durable therapies for this responsive disease
Can we “prove” a role for adjuvant therapy?
Angiosarcoma
• Epithelioid AS – Stacchiotti et al. • Primary vs Secondary AS - Kasper et al.• New strategies for AS Rx - Young et al.
– Cell line VEGF production in hypoxia>>normoxia– No effect of bevacizumab, axitinib, sirolimus– Modest effects of MEKi or VDA
Activity of anti-VEGFR drugs in patients with angiosarcoma.Cell line versus in vivo differences? Role of microenvironment? Culture conditions? Biologic and clinical importance of VEGFR
antagonism need to be elucidated.
Genetic and Biologic Susceptibility
Preclinical Studies
Clinical Responses and Outcomes
Predictive Markers
Prospective Studies
Apoptosis in Synovial Sarcoma – Jones
Dacarbazine in SFT – Stacchiotti
Epithelioid AS– StacchiottiPrimary and Secondary AS – Kasper
CINSARC/Genomic Complexity in SynSarc - Chibon
Oncogenes in SFT – DemiccoBenign vs. malignant SFT- DeVitoALDH1 in SFT – Bouvier
New Treatment Strategies for AS - Young
Prognostic Factors in Epithelioid Sarcoma – Donati
Epithelioid Sarcoma – Donati et al.
• Follow up on 44 patients in 29 years– Median 10 years of follow up– 34M/10F; median age 35, range 13-82!)– 31 normal, 9 proximal, 4 unknown
• OS 58%• 23% metastatic at presentation with median OS of 24
months• Proximal location worse than distal location
Only 4 patients received chemotherapy – need new targets and drugs for this disease!
Genetic and Biologic Susceptibility
Preclinical Studies
Clinical Responses and Outcomes
Predictive Markers
Prospective Studies
Apoptosis in Synovial Sarcoma – Jones
Prognostic Factors in Epithelioid Sarcoma – Donati
Dacarbazine in SFT – Stacchiotti
PARP inhibitors in MPNST – Kivlin
Neoadjuvant therapy for MPNST - Shurell
Epithelioid AS– StacchiottiPrimary and Secondary AS – Kasper
Gender Specific Age of MPNST Onset – Shurell
CINSARC/Genomic Complexity in SynSarc - Chibon
Oncogenes in SFT – DemiccoBenign vs. malignant SFT- DeVitoALDH1 in SFT – Bouvier
New Treatment Strategies for AS - Young
Malignant Peripheral Nerve Sheath Tumor
• Age of onset/Gender – Shurell et al.
Malignant Peripheral Nerve Sheath Tumor
• Age of onset/Gender – Shurell et al.• Neoadjuvant Rx – Shurell et al.
– 38 patients treated and with available pathology– 13 responders (>90% necrosis)/25 non-responders– Responders more likely to have had radiation; equally likely
to have had ifosfamide; had improved DFS and DSS What governs response? Need new agents.
Does Chemo/RT lead to Response lead to Improved Outcomes?
Or Does Response reflect different tumor biology that has lower propensity for recurrence/metastasis?
Malignant Peripheral Nerve Sheath Tumor
• Age of onset/Gender – Shurell et al.• Neoadjuvant Rx – Shurell et al. • PARPi - Kivlin et al.
– G2M arrest and apoptosis in MPNST cell lines
Does this suggest defective DNA repair in MPNST? How does it relate to the EWS laboratory results?
Clinical trial of PARP inhibitor in MPNST? Why not?
Genetic and Biologic Susceptibility
Preclinical Studies
Clinical Responses and Outcomes
Predictive Markers
Prospective Studies
Novel Sarcoma Cancer Genes – Thomas
Apoptosis in Synovial Sarcoma – Jones
Dacarbazine in SFT – Stacchiotti
PARP inhibitors in MPNST – Kivlin
Neoadjuvant therapy for MPNST - Shurell
Epithelioid AS– StacchiottiPrimary and Secondary AS – Kasper
Gender Specific Age of MPNST Onset – Shurell
CINSARC/Genomic Complexity in SynSarc - Chibon
Oncogenes in SFT – DemiccoBenign vs. malignant SFT- DeVitoALDH1 in SFT – Bouvier
New Treatment Strategies for AS - Young
Prognostic Factors in Epithelioid Sarcoma – Donati
Screening for Genes Posing Risk of Sarcoma – Thomas et al.
• Remarkable international effort• Will potentially identify novel (and known)
inherited genetic risk syndromes• 7 Probands with defects in DNA repair genes
– What do these cancer genomes look like?– Does this lead us to potential roles of PARP
inhibitors, etc?
Genetic and Biologic Susceptibility
Preclinical Studies
Clinical Responses and Outcomes
Predictive Markers
Prospective Studies
Biologic differences among subsets of rare sarcomas – Splitting Hairs?
• SynSarc with Complex vs Simple Genetics
• Benign vs Malignant SFT
• Primary vs Secondary Angiosarcoma
• NF1-associated vs sporadic MPNST
• Gender disparities in sarcoma subtypes – why?
• Inherited defects in DNA repair?