Rarer Sarcoma Subtypes

1. Rarer Sarcoma Subtypes Andrew J. Wagner, MD, PhD Center for Sarcoma and Bone Oncology Dana-Farber Cancer Institute Boston, MA

2. 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

3. Genetic and Biologic Susceptibility Apoptosis in Synovial Sarcoma – Jones Preclinical Studies Clinical Responses and Outcomes CINSARC/Genomic Complexity in SynSarc - Chibon Predictive Markers Prospective Studies

4. 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?

5. 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?

6. Genetic and Biologic Characteristics ALDH1 in SFT – Bouvier Benign vs. malignant SFT- DeVito Oncogenes in SFT – Demicco Apoptosis in Synovial Sarcoma – Jones Preclinical Studies Dacarbazine in SFT – Stacchiotti Clinical Responses and Outcomes CINSARC/Genomic Complexity in SynSarc - Chibon Predictive Markers Prospective Studies

7. Solitary Fibrous Tumor • Diagnosis: Bouvier et al. • ALDH1 expression

8. ALDH1 in SFT – Bouvier et al. RNA expression profile of 16 SFT IHC on 899 Soft Tissue Tumors 84.9% of SFT, 12.9% of benign soft tissue tumours and 1.6%of sarcomaswere ALDH1+ Spindlecell/pleomorphiclipomaswere theonlytumoursthatshowedfrequent 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% NegativePredictive Value= 98.4%

9. 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

10. 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.

11. Search for SFT Oncogenes – Demicco et al. • Targeted analysis for 175 mutations in 41 genes in 122 tumors (malignant or benign?), twice No high frequency recurrent mutations identified Highlights 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?

12. 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.

13. Dacarbazine, etc, in dediff SFT – Stacchiotti et al. Mouse Clinical Trial (Frequentist Approach) Tumor model Clinical Responses Human Clinical Trial Underway

14. Novel Sarcoma Cancer Genes – Thomas Genetic and Biologic Susceptibility ALDH1 in SFT – Bouvier Benign vs. malignant SFT- DeVito Oncogenes in SFT – Demicco Apoptosis in Synovial Sarcoma – Jones Preclinical Studies New Treatment Strategies for AS - Young Dacarbazine in SFT – Stacchiotti Epithelioid AS– Stacchiotti Clinical Responses and Outcomes Primary and Secondary AS – Kasper CINSARC/Genomic Complexity in SynSarc - Chibon Predictive Markers Prospective Studies

15. 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

16. 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?

17. 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.

18. Genetic and Biologic Susceptibility ALDH1 in SFT – Bouvier Benign vs. malignant SFT- DeVito Oncogenes in SFT – Demicco Apoptosis in Synovial Sarcoma – Jones Preclinical Studies New Treatment Strategies for AS - Young Dacarbazine in SFT – Stacchiotti Epithelioid AS– Stacchiotti Clinical Responses and Outcomes Primary and Secondary AS – Kasper Prognostic Factors in Epithelioid Sarcoma – Donati CINSARC/Genomic Complexity in SynSarc - Chibon Predictive Markers Prospective Studies

19. 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!

20. Genetic and Biologic Susceptibility ALDH1 in SFT – Bouvier Benign vs. malignant SFT- DeVito Oncogenes in SFT – Demicco Gender Specific Age of MPNST Onset – Shurell Apoptosis in Synovial Sarcoma – Jones Preclinical Studies New Treatment Strategies for AS - Young PARP inhibitors in MPNST – Kivlin Dacarbazine in SFT – Stacchiotti Epithelioid AS– Stacchiotti Clinical Responses and Outcomes Primary and Secondary AS – Kasper Neoadjuvant therapy for MPNST - Shurell Prognostic Factors in Epithelioid Sarcoma – Donati CINSARC/Genomic Complexity in SynSarc - Chibon Predictive Markers Prospective Studies

21. Malignant Peripheral Nerve Sheath Tumor • Age of onset/Gender – Shurell et al.

22. 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?

23. 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?

24. Novel Sarcoma Cancer Genes – Thomas Genetic and Biologic Susceptibility ALDH1 in SFT – Bouvier Benign vs. malignant SFT- DeVito Oncogenes in SFT – Demicco Gender Specific Age of MPNST Onset – Shurell Apoptosis in Synovial Sarcoma – Jones Preclinical Studies New Treatment Strategies for AS - Young PARP inhibitors in MPNST – Kivlin Dacarbazine in SFT – Stacchiotti Epithelioid AS– Stacchiotti Clinical Responses and Outcomes Primary and Secondary AS – Kasper Neoadjuvant therapy for MPNST - Shurell Prognostic Factors in Epithelioid Sarcoma – Donati CINSARC/Genomic Complexity in SynSarc - Chibon Predictive Markers Prospective Studies

25. 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?

26. Genetic and Biologic Susceptibility Preclinical Studies Clinical Responses and Outcomes Predictive Markers Prospective Studies

27. 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?