Prognostic and clinical heterogeneity of PD1 and PD-L1- immunohistochemical scores in endometrial cancers.

introductionPD1/PD-L1 inhibition (ICi) has recently become a new standard of care for patients with advanced MMR-deficient (MMRd) endometrial cancers. Nevertheless, response to immunotherapy is more complex than the presence of a single biomarker and therefore it remains challenging to predict patients response to ICi beyond MMRd tumors. Elevated PD-L1 expression (CPS ≥ 1) is often used as a prognostic marker as well as a predictive biomarker of response to ICi in different tumor types. In a retrospective, patient derived study, we analyzed PD1- and PD-L1 staining and correlated the results of different scores to clinical data to evaluate the prognostic impact of these scores. MATERIALS AND

methodsImmunohistochemical analysis of the receptor PD1 and the receptor ligand PD-L1 were performed on TMAs of primary paraffin‑embedded tumor samples. All patients were treated for primary endometrial cancer in the Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus-Lübeck, Germany between the years 2006-2018. The evaluation and determination of the tumor proportion scoring (TPS), the combined positive score (CPS) and the immune cell scoring (IC) was automatically assessed semi-quantitatively, and results were correlated with clinicopathological characteristics and survival.

results130 samples were evaluable and 64% showed a positivity (IC > 0) for the receptor PD1 and 56% for the receptor ligand PD-L1. Patients with a PD1 IC Score ≥ 1 showed a significant longer disease-free survival of 140 months (95% confidence interval (CI): 124-158) compared to patients with a lower IC < 1 for PD1 of 89 months (95% confidence interval (CI): 69-110); p = 0.017). Furthermore, the disease-free survival for patients with a CPS ≥ 5 for PD1 was longer (153.7 months (95% confidence interval (CI): 134-173.6) vs. 98.6 months (95% confidence interval (CI): 83-114); p = 0.036). Additionally, a PD1 CPS ≥ 5 showed a better overall survival but the result was not statistically significant. No difference in survival was found between patients with PD-L1 higher or lower than CPS 5.

conclusionIn this study we pointed out that there are significant clinical differences among several immunohistochemical scoring systems. In our trial, a PD1-positivity with CPS ≥ 5 and IC ≥ 1 were significantly associated to a better disease-free survival while there was no association with TPS. The PD1-IC scoring was associated with MMRd while the TPS scoring was not. Therefore, PD1-IC could be more appropriate for endometrial carcinomas compared to TPS and could also add prognostic information beside the more established PD-L1-staining. Further prospective studies are needed for a validation of these scores in combination with other biomarkers.