Rarer Sarcoma Subtypes Andrew J. Wagner, MD, PhD Center for Sarcoma and Bone Oncology Dana-Farber Cancer Institute Boston, 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 – Demicco Benign 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 SFT IHC 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?), 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?

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. 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– Stacchiotti Primary and Secondary AS – Kasper CINSARC/Genomic Complexity in SynSarc - Chibon Oncogenes in SFT – Demicco Benign vs. malignant SFT- DeVito ALDH1 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 1 st, 2 nd, and 3 rd 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– Stacchiotti Primary and Secondary AS – Kasper CINSARC/Genomic Complexity in SynSarc - Chibon Oncogenes in SFT – Demicco Benign vs. malignant SFT- DeVito ALDH1 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– Stacchiotti Primary and Secondary AS – Kasper Gender Specific Age of MPNST Onset – Shurell CINSARC/Genomic Complexity in SynSarc - Chibon Oncogenes in SFT – Demicco Benign vs. malignant SFT- DeVito ALDH1 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– Stacchiotti Primary and Secondary AS – Kasper Gender Specific Age of MPNST Onset – Shurell CINSARC/Genomic Complexity in SynSarc - Chibon Oncogenes in SFT – Demicco Benign vs. malignant SFT- DeVito ALDH1 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?