(P 250) SYSTEMIC INFLAMMATORY INDICES IN SECOND LINE SOFT TISSUE SARCOMAS PATIENTS: FOCUS ON LYMPHOCYTE/MONOCYTE RATIO AND TRABECTEDIN ACTIVITY

Objective: A second-line standard of treatment has not yet been identified in patients with soft tissue sarcomas, therefore the identification of predictive markers could be a useful tool of choice. Recent studies have shown that the inflammatory system, both intratumoral and systemic, significantly influences tumor aggressiveness. The objective of the present study was to investigate prognostic values of pre-therapy neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and systemic inflammatory index (SII) for progression-free survival (PFS) and overall survival (OS) in soft tissue sarcoma patients treated in second line.

Methods: Ninety nine patients with soft tissue sarcomas, who received at least one line of therapy following the first one from 2008 to 2020 at the IRST Istituto Romagnolo per lo Studio dei Tumori (Meldola, Italy), were included . Patients were selected on the basis of first-line treatment including only patients treated with anthracycline-based therapy schedules in monotherapy or in combination. NLR was computed as the ratio of the absolute neutrophil count to the absolute lymphocyte count, PLR was obtained by dividing the absolute platelet count by the absolute lymphocyte count, SII was calculated as platelet count × neutrophil count/lymphocyte count while lymphocyte-to-monocyte ratio (LMR) was calculated as the ratio lymphocyte/monocyte. Information on blood counts were collected within a week before starting treatment. Curves of PFS and OS were calculated using the Kaplan-Meier method.
An RNAsequencing and subsequent analysis by CIBERSORT was performed to assess the share of tumor-induced immune cells.

Results: Patients’ characteristics are summarized in Table1. There was no significant difference in PFS according to gender, age, grading at diagnosis, type of first-line chemotherapy or type of response to 1st line. Patients with PS ECOG 0, metacronous metastatic onset and low tumor burden showed a better PFS (p=0.004, p=0.041, p=0.0086). None of these features showed a statistical significance in OS. Patients with pre-therapy NLR < 2.5 had a median PFS of 4.1 mo VS 2.7 mo of patients with pre-therapy NLR ≥ 2.5; p= 0.019. Patients with pre-therapy PLR < 190 had a median PFS of 5.7 mo VS 2.5 mo in patients with PLR ≥ 190; p = 0.004. Patients with pre-therapy SII < 991 had a median PFS of 4.7 mo VS 2.5 mo in patients with SSI ≥ 991; p = 0.006. Even if a difference trend was found also in overall survival, none of these indices reached a statistical significance. Patients with pre-therapy LMR < 2.4 showed no statistically significant difference in PFS compared to patients with values ≥ 2.4. In OS, patients with LMR before therapy < 2.4 had a median of 10.7 mo VS 17.1 mo in patients with LMR ≥ 2.4 (P = 0.006). Given the different trend of LMR compared to the other indices, and considering the peculiar mechanism of action of trabectedin , we tested it in patients treated with trabectedin VS all other treatments in the second and third line, reaching a sample population of 144 patients. PFS was: 5.83 mo in patients treated with Trabectedin and with LMR < 2.4 VS 3.37 mo in patients treated with Trabectedin but LMR ≥ 2.4; 2.5 mo in patients treated with other treatments and LMR < 2.4 VS 3.63 mo in patients treated with other treatments and with LMR ≥ 2.4; (p=0.0154)[Figure1]. Analysis of inflammatory infiltrate in 6 liposarcoma samples showed a correspondence between intratumoral levels of M2 macrophages and circulating monocytes. In particular, the lower the presurgical MRL, the higher the intratumoral M2 levels [Table2].

Conclusion: Our results confirm the prognostic role of systemic inflammatory markers in patients with soft tissue sarcoma.
Our study also demonstrated that LMR is a specific predictor of trabectedin efficacy and could be an easy index to be used in daily clinical practice. We also highlighted a possible correlation between LMR levels and the percentage of intratumoral macrophages. RNAseq analysis on a larger sample to validate our results is ongoing.

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