rarer sarcoma subtypes

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 SarcomaJones 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


Predictive Markers

Prospective Studies


Oncogenes in SFT – DemiccoBenign vs. malignant SFT- DeVito

Dacarbazine in SFT – Stacchiotti

ALDH1 in SFT – Bouvier


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



• 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?




• Genetics: Demicco et al. • Treatment: Stacchiotti et al.

Dacarbazine, etc, in dediff SFT – Stacchiotti et al.

Days after inoculum

Tum

or v

olum

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


Preclinical Studies


Predictive Markers

Prospective Studies

Novel Sarcoma Cancer Genes – Thomas



Epithelioid AS– StacchiottiPrimary and Secondary AS – Kasper


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 diseaseChemoresponsive 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.


Preclinical Studies


Predictive Markers

Prospective Studies







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!


Preclinical Studies


Predictive Markers

Prospective Studies




PARP inhibitors in MPNST – Kivlin

Neoadjuvant therapy for MPNST - Shurell


Gender Specific Age of MPNST Onset – Shurell




Malignant Peripheral Nerve Sheath Tumor

• Age of onset/Gender – Shurell et al.


• 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?


• 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?


Preclinical Studies


Predictive Markers

Prospective Studies

Novel Sarcoma Cancer Genes – Thomas



PARP inhibitors in MPNST – Kivlin

Neoadjuvant therapy for MPNST - Shurell


Gender Specific Age of MPNST Onset – Shurell





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?


Preclinical Studies


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?

rarer sarcoma subtypes

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