Systemic Inflammatory Indices in Second-Line Soft Tissue Sarcoma Patients: Focus on Lymphocyte/Monocyte Ratio and Trabectedin

Abstract

A second-line standard of treatment has not yet been identified in patients with soft tissue sarcomas (STS), so identifying predictive markers could be a valuable tool. Recent studies have shown that the intratumoral and inflammatory systems significantly influence tumor aggressiveness. We aimed to investigate prognostic values of pre-therapy neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory index (SII), progression-free survival (PFS), and overall survival (OS) of STS patients receiving second-line treatment. In this single-center retrospective analysis, ninety-nine patients with STS were enrolled. All patients received second-line treatment after progressing to anthracycline. PFS and OS curves were calculated using the Kaplan–Meier method of RNA sequencing, and CIBERSORT analysis was performed on six surgical specimens of liposarcoma patients. A high NLR, PLR, and SII were significantly associated with worse PFS (p = 0.019; p = 0.004; p = 0.006). Low LMR was significantly associated with worse OS (p = 0.006). Patients treated with Trabectedin showed a better PFS when the LMR was low, while patients treated with other regimens showed a worse PFS when the LMR was low (p = 0.0154). The intratumoral immune infiltrates analysis seems to show a correlation between intratumoral macrophages and LMR. PS ECOG. The metastatic onset and tumor burden showed prognostic significance for PFS (p = 0.004; p = 0.041; p = 0.0086). According to the histologies, PFS was: 5.7 mo in liposarcoma patients vs. 3.8 mo in leiomyosarcoma patients vs. 3.1 months in patients with other histologies (p = 0.053). Our results confirm the prognostic role of systemic inflammatory markers in patients with STS. Moreover, we demonstrated that LMR is a specific predictor of Trabectedin efficacy and could be useful in daily clinical practice. We also highlighted a possible correlation between LMR levels and the percentage of intratumoral macrophages.

Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need

“…Interestingly, we identified the down-regulation of several immunoglobulin genes as well as down-regulation of neutrophil-mediated immunity and activation pathways in LR patients compared to LNR ones. These results are particularly interesting in light of recently published results, which showed that an increased neutrophils-to-lymphocyte ratio was significantly associated with worse PFS in a case series of 99 STS patients [ 6 ]. Indeed, it is known from the literature that neutrophils can remodel the extracellular matrix and promote angiogenesis, thereby stimulating tumor cell migration and metastasis.…”

“…UPS is characterized by a transition from storiform to pleomorphic areas representing a highly variable morphology. Since no specific diagnostic biomarkers are currently available, the diagnosis is mainly based on the exclusion of other cancer histotypes e.g., dedifferentiated and pleomorphic liposarcoma, pleomorphic leiomyosarcoma, pleomorphic rhabdomyosarcoma, MFS, poorly differentiated carcinoma, and melanoma [ 6 ]. The standard of care for localized STS including MFS and UPS is represented by surgery combined with (neo)adjuvant radio and chemotherapy in selected cases.…”

New therapeutics for soft tissue sarcomas: Overview of current immunotherapy and future directions of soft tissue sarcomas

“…A low lymphocyte-to-monocyte ratio (LMR) was associated with worse OS (p = 0.006). Interestingly, low lymphocyte-to-monocyte ratio (LMR) was an indicator of trabectedin efficacy, which could be applied in clinical practice ( 9 ). In a previous study in 2021, 3D-cultured cells from leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS) surgical specimens were treated with trabectedin and demonstrated the involvement of ECM-associated genes such as mmps and their inhibitor timp1 , emphasizing the potential role of ECM in the activity of trabectedin ( 10 ).…”

Factors predictive of second‐line chemotherapy in soft tissue sarcoma: An analysis of the National Genomic Profiling Database

“…7 Moreover, although there are reports that biomarkers, such as the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and systemic inflammatory index, which can be used as predictors of the prognosis in patients with STS, the information about the relationship between genetic mutations and overall survival is still insufficient. 26 Information about genetic mutations in tumor tissue is increasingly being used to help choose treatments for advanced STS. Memorial Sloan Kettering Cancer Center reported that clinical genomic profiling of bone and STS helped provide information crucial for targeted therapy for genetic mutations detected in 29% of patients.…”

“…However, it remains unclear which regimen is optimal for patients with non‐L‐sarcoma STS on an individual basis 7 . Moreover, although there are reports that biomarkers, such as the neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio, lymphocyte‐to‐monocyte ratio, and systemic inflammatory index, which can be used as predictors of the prognosis in patients with STS, the information about the relationship between genetic mutations and overall survival is still insufficient 26 …”