Patients with metastatic
soft tissue sarcoma (STS) have a poor prognosis and few available systemic treatment options.
Trabectedin is currently being investigated as a potential adjunct to
immunotherapy as it has been previously shown to kill tumor-associated macrophages. In this retrospective study, we sought to identify
biomarkers that would be relevant to trials combining
trabectedin with
immunotherapy. We performed a single-center retrospective study of
sarcoma patients treated with
trabectedin with long-term follow-up. Multiplex gene expression analysis using the NanoString platform was assessed, and an exploratory analysis using the lasso-penalized Cox regression and kernel association test for survival (MiRKAT-S) methods investigated
tumor-associated immune cells and correlated their gene signatures to patient survival. In total, 147
sarcoma patients treated with
trabectedin were analyzed, with a mean follow-up time of 5 years. Patients with fewer prior
chemotherapy regimens were more likely to stay on
trabectedin longer (pairwise correlation = -0.17, p = 0.04). At 5 years, increased PD-L1 expression corresponded to worse outcomes (HR = 1.87, p = 0.04, q = 0.199). Additionally, six immunologic gene signatures were associated with up to 7-year survival by MiRKAT-S, notably myeloid-derived suppressor cells (p = 0.023, q = 0.058) and M2 macrophages (p = 0.03, q = 0.058). We found that the number of
chemotherapy regimens prior to
trabectedin negatively correlated with the number of
trabectedin cycles received, suggesting that patients may benefit from receiving
trabectedin earlier in their
therapy course. The correlation of
trabectedin outcomes with immune cell infiltrates supports the hypothesis that
trabectedin may function as an immune modulator and supports ongoing efforts to study
trabectedin in combination with
immunotherapy. Furthermore,
tumors with an immunosuppressive microenvironment characterized by macrophage infiltration and high PD-L1 expression were less likely to benefit from
trabectedin, which could guide clinicians in future treatment decisions.