(P 397) MTOR ACTIVITY: A BIOMARKER FOR CHEMO- AND IMMUNOTHERAPY RESPONSE AND OUTCOMES IN SARCOMAS

Objective: mTOR signaling is vital to multiple malignancy-associated processes including cell survival, metastasis, and angiogenesis. High mTOR activity (mTOR-act) is associated with tumor aggressiveness and poorer outcomes across solid and hematologic cancers. Although treatment with an mTOR inhibitor (mTORi) in the SUCCEED trial did not meaningfully benefit a pan-sarcoma population, patients were not stratified by mTOR-act. Our recent work detailed patterns of mTOR-act across sarcomas, identifying subtypes with high mTOR-act. We now report how a biomarker of mTOR-act may predict responses to chemotherapy (chemo) and immunotherapy (IO) in soft tissue sarcoma (STS) patients.

Methods: RNAseq data for 87 samples from subjects with STS were downloaded from the Gene Expression Omnibus (GSE213065). Correlating clinical data were downloaded from published files (Subramanian, 2024). Gene set variation analysis (GSVA) was performed using the gsva and msigdb packages in R version 4.3.2, generating GSVA scores (“scores”) based on the HALLMARK_MTORC1_SIGNALING gene set. For the whole and sub-populations, descriptive statistics were generated. Median scores were compared using Mann-Whitney U tests. Relationships between continuous variables were assessed using Spearman’s rank correlations. Relationships between dichotomous variables were assessed using Fisher’s exact tests. A Cox proportional hazard model was used to compare progression-free survival (PFS) of groups with positive vs. negative (mTOR-high vs. -low) scores, and Kaplan-Meier analysis was performed.

Results: In patients who received chemo (n=37), responders (partial + complete responses) displayed a non-significant, lower median GSVA mTOR score than non-responders (stable + progressive disease) (p=0.44). No significant differences in median scores were seen in responders vs. non-responders in undifferentiated pleomorphic sarcoma (UPS, n=16) or leiomyosarcoma (LMS, n=12) subgroups. A non-significant, weak positive correlation was found between score and change in tumor size (%change, rho=0.21, p=0.235). mTOR-high was significantly associated with shorter PFS (HR 2.40, 1.11-5.19, p=0.026), which was also true for the UPS subgroup (HR 3.52, 1.06-11.7, p=0.041) but not LMS (HR 0.76, 0.09-6.17, p=0.800). In patients who received IO (n=38), median score was higher in responders than in non-responders (p< 0.001). The relationship between scores (high/low) and response (yes/no) was significant (p=0.021). Median scores were also higher for responders in the UPS subgroup (n=15, p=0.048). No patients with LMS (n=14) had a response to IO. A weak negative correlation between score and %change was found to approach significance in these patients (rho=-0.29, p=0.081). mTOR-high trended towards longer PFS in the whole sample (HR 0.54, 0.26-1.13, p=0.100) and the UPS subgroup (HR 0.62, 0.18-2.12, p=0.400); in LMS, no significant association was found (HR 1.68, 0.34-7.90, p=0.500). Comparable results were seen in patients who received IO but no chemotherapy. There were no differences in pre- and post-treatment scores for patients with paired samples (n=24).

Conclusion: High mTOR-act is associated with shorter PFS in patients with STS receiving chemo. Conversely, it is associated with greater tumor shrinkage and clinical response to IO, which is primarily driven by UPS. Thus, the otherwise poor prognostic implication (PFS) of high mTOR-act is reversed in these patients who undergo IO treatment. This suggests mTOR-act as a biomarker for choosing appropriate therapies in clinic. mTOR-act does not change significantly despite treatment with chemo and/or IO, indicating a potential role for mTORi in combination with, or following, these therapies. The small sample size limits the power of this analysis, and further investigation is needed.