Abstract
Thus far immunotherapy has had limited impact on ovarian cancer. Vigil (a novel DNA-based multifunctional immune-therapeutic) has shown clinical benefit to prolong relapse-free survival (RFS) and overall survival (OS) in the BRCA wild type and HRP populations. We further analyzed molecular signals related to sensitivity of Vigil treatment. Tissue from patients enrolled in the randomized double-blind trial of Vigil vs. placebo as maintenance in frontline management of advanced resectable ovarian cancer underwent DNA polymorphism analysis. Data was generated from a 981 gene panel to determine the tumor mutation burden and classify variants using Ingenuity Variant Analysis software (Qiagen) or NIH ClinVar. Only variants classified as pathogenic or likely pathogenic were included. STRING application (version 1.5.1) was used to create a protein-protein interaction network. Topological distance and probability of co-mutation were used to calculated the C-score and cumulative C-score (cumC-score). Kaplan–Meier analysis was used to determine the relationship between gene pairs with a high cumC-score and clinical parameters. Improved relapse free survival in Vigil treated patients was found for the TP53m-BRCAwt-HRP group compared to placebo (21.1 months versus 5.6 months p = 0.0013). Analysis of tumor mutation burden did not reveal statistical benefit in patients receiving Vigil versus placebo. Results suggest a subset of ovarian cancer patients with enhanced susceptibility to Vigil immunotherapy. The hypothesis-generating data presented invites a validation study of Vigil in target identified populations, and supports clinical consideration of STRING-generated network application to biomarker characterization with other cancer patients targeted with Vigil.
Highlights
Ovarian cancer is the third most common gynecologic cancer, and it carries the worst prognosis and highest mortality rate of gynecologic cancers [1,2,3]
Within Vigil treated patients there was no impact of tumor mutational burden (TMB) on relapse-free survival (RFS) (HR = 1.289 90% CI 0.639–2.602) or overall survival (OS) (HR = 1.266 90% CI 0.448–3.578)
Comparison of high TMB effect involved in Vigil compared to placebo related to RFS (HR = 0.598 90% CI 0.354–1.011 p = 0.052) and OS (HR = 0.514 90% CI 0.252–1.051 p = 0.06) was not significant, but a trend to the benefit of Vigil was interaction (PPI) network was constructed using 83 genes that were identified as having pathogenic mutations in the study population [42]
Summary
Ovarian cancer is the third most common gynecologic cancer, and it carries the worst prognosis and highest mortality rate of gynecologic cancers [1,2,3]. Mortality from ovarian cancer is three times that of breast cancer [3, 4]. Standard treatment of resectable newly diagnosed stage III/IV ovarian cancer involves surgical resection and adjuvant or neoadjuvant chemotherapy [7, 8]. Nearly 75% of this patient population who undergo standard treatment will experience recurrence following frontline therapy [7, 9]. The establishment of more effective therapies for ovarian cancer is essential
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