(P 048) IMMUNE INFILTRATION AS PROGNOSTIC FACTORS IN METASTATIC LEIOMYOSARCOMA

Objective: leiomyosacoma (LMS) is a tumor with genomic complexity and associated with poor prognosis when metastatic. Lymphocytic infiltration at diagnosis is prognostic in different tumors; however, the impact of tumor infiltrating lymphocytes and macrophages (TILMs) in LMS remains poorly described. The aims of this study were to investigate relationships between tumor-infiltrating immune cells, p53 expression and patient/tumor-related factors, and assess their predictive value for clinical benefit, overall survival (OS) and for progression-free survival (PFS) in metastatic LMS.

Methods: This is an explorative study conducted in a representative subgroup of patients enrolled in the LMS-04 trial, a randomised phase III comparing doxorubicin alone to doxorubicin + trabectedin in first line therapy in advanced/metastatic LMS; Cliniclatrials.gov, NCT02131480. One formalin fixed paraffin embedded (FFPE) block was mandatory at the inclusion in the study for translatiobal research. We report the first determination in a cohort of 49 patients as a representative population of the study (uterine and soft tissue LMS, arms A and B).
CD3, CD20, CD68 and CD57 expression using multiplex IHC and P53 expression were evaluated using immunohistochemistry. Units are expressed in number of immune cells positive/mm2 or % positive surface of tumor area and for P53 wa determined depending on staining intensity (1+ to 3+). TILMs were scored for each specimen on conventional slide (HES), in the stroma (% of TIMs compared to the stromal surface). Correlation to tumor primary (uterine (U-LMS) versus soft tissue (ST-LMS) was assessed using Chi-Squared test or Mann-Whitney test. Univariate Cox-regression models and logistic regression models were performed to investigate prognostic variables respectively for the survival outcomes (OS and PFS) and clinical benefit (complete/partial response or stable disease according to best recist criteria).

Results: 49 LMS out of 150 from the original trial population were included, 96% of which were metastatic and 53% were U-LMS. the median age was 59 years and 82% (n=40) were female patients. Thirty patients (61%) were in the experimental arm B (doxorubicin+trabectedin), while 39% were traited with doxorubicin alone. After 6 cycles only 7 patients (14%) were classified in progression. Comparison of biomarkers in relation to tumor location demonstrated that ST-LMS had higher CD20+ infiltration than U-LMS (68,8% vs 8,3%; p< 0,001) and lower p53 intensity (69,6% vs 30,8%; p=0,01); other immune cells were not associated with tumor location.
High TILMs values (>10%) were related with both increased risk of progression (Hazard Ratio (HR) = 1,97, 95% CI (1.00-3,88), p=0,049) and death (HR = 2,27 (1.07-4.81), p=0,031), with poorer disease control rate (83% of patients in progression vs 39% of patients who were responding or with stable disease for tumors with TILMs< 10 (p=0,07), and associated with a higher rate of progression in doxorubin alone arm (55.5% vs 0% in the combinaison arm, p=0,02). otherwise, TILMs< 10% seemed to be associated to a better prognosis independently of arm of treatment, with a median PFS of 1.4 months vs 7.9 months with doxorubicin alone and 8.5 months with doxorubicin + trabectedin for patients with respectively TIMs>10% and TILMs< 10%. other markers had no significant impact on outcome parameters.

Conclusion: TILMs seems to be a prognosis factor and possibly a predictive factor of sensitivite to trabectedin+doxorubicin. We have to confirm this prognosis/predictive role in the whole population.