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Abstract
Objective The 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.
Methods All 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.
Results In 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, showed KRAS mutations, BRCA wild-type status, and mismatch repair proficiency in all cases, but did not reveal genetic alterations potentially associated with a pro-immunogenic tumor environment.
Conclusions A 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.
- cystadenocarcinoma, mucinous
Data availability statement
Data are available upon reasonable request. Raw data were generated at the Medical University of Vienna. Derived data supporting the findings of this study are available from the corresponding author on request.
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Data availability statement
Data are available upon reasonable request. Raw data were generated at the Medical University of Vienna. Derived data supporting the findings of this study are available from the corresponding author on request.
Footnotes
Contributors TB developed the theoretical formalism, processed the experimental data, performed the analysis and took the lead in writing the manuscript. AA, AW and S-CP carried out the experiments, processed the experimental data and contributed to designing the figures. LM and GH contributed to sample preparation, performing the experiments and interpretation of results. CG contributed to the interpretation and presentation of results and supervised the conceptualization. DCC-T contributed to supervision of the experiments, interpretation of findings, led the project supervision and is responsible for the overall content as guarantor. All authors provided critical feedback and helped shape the research and analysis and approved the final version of the manuscript.
Funding The present project was supported by the Vienna Anniversary Foundation for Higher Education (Hochschuljubiläumsfonds der Stadt Wien).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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