Biomarkers for checkpoint inhibitor therapy in mucinous epithelial ovarian cancer

Abstract

ObjectiveThe prognosis of patients with advanced stage mucinous epithelial ovarian cancer remains poor due to a modest response to platinum-based chemotherapy and the absence of therapeutic alternatives. As targeted approaches may help to overcome these limitations, the present study evaluates biomarkers indicative of potential immune-checkpoint inhibitor therapy response.MethodsAll patients who underwent primary cytoreductive surgery from January 2001 to December 2020 and for whom formalin-fixed paraffin-embedded tissue samples were available were included (n=35; 12 International Federation of Gynecology and Obstetrics (FIGO) stage ≥IIb). To define sub-groups potentially suitable for checkpoint inhibition, expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (CD3+, CD8+, CD20+, CD45+, CD68+, FoxP3+), and AT-rich interactive domain-containing protein 1A (ARID1A) immunostaining were evaluated in whole tissue sections and compared with clinicopathologic parameters and next-generation sequencing results, where available (n=11). Survival analyses were performed to assess whether identified sub-groups were associated with specific clinical outcomes.ResultsIn total, 34.3% (n=12/35) of tumors were PD-L1 positive. PD-L1 expression was associated with infiltrative histotype (p=0.027) and correlated with higher CD8+ (r=0.577, p<0.001) and CD45+ (r=0.424, p=0.011), but reduced ARID1A expression (r=−4.39, p=0.008). CD8+ expression was associated with longer progression-free survival (hazard ratio (HR) 0.85 (95% CI 0.72 to 0.99), p=0.047) and disease-specific survival (HR 0.85 (95% CI 0.73 to 1.00), p=0.044) in the sub-group with FIGO stage ≥IIb. Three (8.6%) samples demonstrated high PD-L1 expression at a combined positive score of >10, which was associated with increased CD8+ expression (p=0.010) and loss of ARID1A expression (p=0.034). Next-generation sequencing, which was available for all samples with a combined positive score of >10, showedKRASmutations,BRCAwild-type status, and mismatch repair proficiency in all cases, but did not reveal genetic alterations potentially associated with a pro-immunogenic tumor environment.ConclusionsA sub-group of mucinous ovarian cancers appear to demonstrate a pro-immunogenic tumor environment with high PD-L1 expression, decreased ARID1A expression, and characteristic tumor-infiltrating lymphocyte infiltration patterns. Further clinical validation of anti-PD-L1/PD-1 targeting in selected mucinous ovarian cancers appears promising.