Characterizing patterns of mTORC1 activation across sarcoma subtypes using single-sample gene set enrichment analysis (ssGSEA) and a national biomarker database.
Authors: Lefler Daniel S. , Elliott Andrew , Blomain Erik , Maki Robert G. , Modiano Jaime , Seeber Andreas , Riedel Richard F. , Sarver Aaron , Espejo-Freire Andrea P. , Khushman Moh'd M. , Boikos Sosipatros Alexandros , Lagos Galina , Florou Vaia , von Mehren Margaret , Oberley Matthew James , D'Amato Gina Z. , Trent Jonathan C. , Basu Mallick Atrayee 
Published: June 2024

11544

Background: The mTOR pathway is a central signaling circuit that contributes to cancer cell proliferation, angiogenesis, metabolism, and other pivotal processes. The phase III SUCCEED trial showed marginal benefit of mTOR inhibition (mTORi) in chemo-responsive sarcomas, despite promising foundational phase II data. Since these trials did not account for mTOR-related physiology, we sought to identify sarcoma subgroups that display mTORC1 activated/activation phenotypes (mTORC1-act) that might derive more benefit from mTORi. Methods: DNA (592-gene or whole exome; N=7028) and RNA (whole transcriptome; N=3757) sequencing was performed from sarcoma patient samples, representing 49 histologic subtypes, submitted to Caris Life Sciences (Phoenix, AZ). A transcriptomic signature associated with up-regulation of mTORC1 complex activity (HALLMARK_MTORC1_SIGNALING, mSigDB) was analyzed by single-sample Gene Set Enrichment Analysis (ssGSEA). Real-world overall survival (OS) was obtained from insurance claims data and calculated from date of biopsy to last contact, with hazard ratio calculated using Cox proportional hazards model (p-values calculated by log-rank test). Results: Among the most mTORC1-act subtypes were PEComa (n=49, median ssGSEA score=0.114) and osteosarcoma (n=163, median score=0.084). Novel findings included high degrees of mTORC1-act in UPS (n=225, median score=0.132), IMT (n=36, median score=0.167), and epithelioid sarcoma (n=26, median score=0.155). Histologic subtype was a strong predictor of mTORC1-act (p<0.00001); other predictors were alterations in TSC2 (p<0.0001), TSC1 (p=0.0019), PTEN (p=0.0126), and PIK3R1 (p=0.0223). In PEComa, TSC2 alterations were associated with mTORC1-act (p=0.036), but TSC1 alterations were not (p=0.63). In a pan-sarcoma population, high ssGSEA mTORC1-act scores were associated with lower median OS of 15.4 months (m) compared to intermediate (24.2 m) and low (36.8 m) mTORC1-act scores (p<0.000001). Similar findings were observed for LMS (16.2 v 30.6 v 45.9 m, p<0.0001) and LPS (11.2 v 30.1 v 46.8 m, p<0.0001), but not all subtypes. Conclusions: The high levels of mTORC1-act in PEComa and osteosarcoma are consistent with prior reports. Increased mTORC1-act among TSC2-mutant, but not TSC1-mutant, PEComa aligns with lower responses to mTORi observed in non- TSC2-mutant patients in the AMPECT trial. Together, these findings support the use of ssGSEA to identify histologic subtypes (UPS, IMT, epithelioid) and genetic factors ( TSC2 variants > others) associated with increased mTORC1 activity that may predict for better responses to mTORi, and they suggest a clinical trial to further pursue this pathway in sarcomas. These data provide additional valuable prognostic information for patients with a wide range of sarcoma subtypes.