Abstract
BackgroundDespite the consistency of patient age, disease stage and treatment options, the prognosis of different high-grade serous ovarian carcinoma (HGSOC) patients is different. Here, we sought to measure predictive biomarkers for distinct responses to platinum-based chemotherapy and immunotherapy benefits.MethodsSixteen HGSOC patients receiving debulking surgery and adjuvant first-line combination chemotherapy at Peking Union Medical College Hospital (PUMCH) were enrolled. Whole exome sequencing (WES) and RNA-seq were performed on tumor and normal tissues of these patients.ResultsThe tumor mutational burden (TMB) and intratumoral heterogeneity (ITH) of the platinum-resistant group were significantly higher than those of the platinum-sensitive group (P=0.0321 and P=0.0452, respectively). TMB, neoantigen and ITH had certain predictive value according to the area under the receiver operating characteristic (ROC) curve (AUC 0.7778 for TMB, 0.7619 for neoantigen, 0.7778 for ITH). The infiltration of other immune cells in tumor tissues was different between the two groups, but the difference was not significant. Univariate Cox proportional hazard analysis revealed poorer progression-free survival (PFS) for those patients who carried a higher number of neoantigens (P =0.0069), higher TMB (P =0.0083), and higher ITH (P =0.0249). Further Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis indicated the Differentially expressed genes (DEGs) in platinum-resistant and platinum-sensitive patients were mainly enriched in the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) signaling pathway and focal adhesion pathway, which are associated with platinum resistance.ConclusionsHigher TMB, neoantigen and ITH may account for the worse prognosis of patients with platinum-based chemotherapy and higher TMB was observed in the platinum-resistant group, which could make the patients in the platinum-resistant group to be the better candidates for immunotherapy.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, for which the standard treatment is cytoreductive surgery followed by platinum-taxane combination chemotherapy
Univariate Cox regression analysis was performed with the immunotherapy-related variables, and the results showed significant associations between progression-free survival (PFS) and the number of neoantigens (P=0.0069), between PFS and tumor mutational burden (TMB) (P =0.0073), and between PFS and intratumoral heterogeneity (ITH) (P=0.0249), whereas age, serum CA125 value and each kind of immune cell were not significantly related to PFS (Table 4)
The results of this study showed that TMB, neoantigen and ITH are significantly correlated with PFS in platinum-sensitive and platinum-resistant groups
Summary
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, for which the standard treatment is cytoreductive surgery followed by platinum-taxane combination chemotherapy. High-grade serous carcinoma (HGSC) is the most common histological subtype of ovarian cancer and is highly aggressive and grows rapidly. Sensitivity to firstline chemotherapy is associated with the prognosis of patients. Different responses to platinum-based chemotherapy are observed even among patients with similar clinical characteristics and disease stages. The presence of intratumoral heterogeneity (ITH) and mutation is likely associated with the responsiveness of HGSC to platinum-based chemotherapy, which has inspired efforts to explore predictive biomarkers for the response rate to platinum-based chemotherapy. Despite the consistency of patient age, disease stage and treatment options, the prognosis of different high-grade serous ovarian carcinoma (HGSOC) patients is different. We sought to measure predictive biomarkers for distinct responses to platinum-based chemotherapy and immunotherapy benefits
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