Genomics, Morphoproteomics, and Treatment Patterns of Patients with Alveolar Soft Part Sarcoma and Response to Multiple Experimental Therapies

Abstract

Overexpression of transcription factor 3 in alveolar soft part sarcoma(ASPS) results in upregulation of cell proliferation pathways. No standard treatment algorithm exists for ASPS; multikinase inhibitors[tyrosine kinase inhibitor (TKI)] and immune checkpoint inhibitors (ICI) have shown clinical benefit. To date, no studies have reported on management strategies or sequencing of therapy. We evaluated ASPS treatment patterns and responses in an experimental therapeutics clinic. Genomic and morphoproteomic analysis was performed to further elucidate novel targets. We retrospectively reviewed patients with ASPS treated on clinical trials. Demographic and clinical next-generation sequencing (NGS) profiles were collected. AACR GENIE database was queried to further evaluate aberrations in ASPS. Morphoproteomic analysis was carried out to better define the biology of ASPS with integration of genomic and proteomic findings. Eleven patients with ASPS were identified; 7 received NGS testing and mutations in CDKN2A (n ¼ 1) and hepatocyte growth factor (n ¼ 1) were present. Ten patients were treated with TKIs with stable disease as best response and 4 patients with ICI (three partial responses). Within GENIE, 20 patients were identified harboring 3 called pathogenic mutations. Tumor mutation burden was low in all samples. Morphoproteomic analysis confirmed the expression of phosphorylated c-Met. In addition, fatty acid synthase and phosphorylated-STAT3 were detected in tumor cell cytoplasm and nuclei. Patients with ASPS have a quiescent genome and derive clinical benefit from VEGFtargeting TKIs. Morphoproteomic analysis has provided both additional correlative pathways and angiogenic mechanisms that are targetable for patients with ASPS. Our study suggests that sequential therapy with TKIs and immune checkpoint inhibitors is a reasonable management strategy.

Soft Tissue Sarcoma: An Insight on Biomarkers at Molecular, Metabolic and Cellular Level

“…In Ewing’s sarcoma, one study demonstrated TMB values of fewer than two mutations/Mb, with a 2–3-fold increase in relapsing cases [ 54 , 55 ]. Low values of TMB have also been found in alveolar STS [ 56 ].…”

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

“…Sarcoma studies consistently show TMB is low [13,71,72] and microsatellites are stable [73,74] across subtypes. Low TMB has been observed in subtype-specific cohorts of alveolar soft-part [75], Ewing [76,77], synovial [78], and osteosarcoma [76]. Tumor mutational burden was not associated with immune biomarkers in pleomorphic dermal sarcoma [78,79] or survival in synovial sarcoma [78], but negatively correlated with survival in pediatric Ewing sarcoma [80].…”

Emerging mechanisms of immunotherapy resistance in sarcomas

“…It has been widely recognized that a high tumor mutational burden (TMB), which can be detected by whole-genome sequencing (WGS), can lead to increased neoantigen expression and can correlate with immunotherapy responses [22,23] . Although TMB is not a perfect biomarker, most sarcomas do have a lower TMB than the currently approved tissue agnostic threshold (10 mutations/Mb) that has been shown to predict responses to checkpoint inhibitors [24] . However, 13.7% of angiosarcomas, 8.1% of UPS, and 8.2% of malignant peripheral nerve sheath tumors (MPNSTs) were found to have more than 20 mutations/Mb in an analysis of 100,000 different cancers [24] , potentially explaining the differential activity of immune checkpoint inhibitors (ICIs) in these subtypes.…”