Development of a Genomic Signatures-Based Predictor of Initial Platinum-Resistance in Advanced High-Grade Serous Ovarian Cancer Patients

Abstract

BackgroundHigh grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet.MethodsNinety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients.ResultsA high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1–100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%.ConclusionsA multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.

The role of the tumor primary chemosensitivity relative to the success of the medical-surgical management in patients with advanced ovarian carcinomas

“…Several gene signatures have been reported in patients with ovarian carcinomas [41][42][43][44]. The Cancer Genome Atlas (TCGA) signatures identified four subgroups of ovarian cancers (differentiated, immunereactive, mesenchymal, proliferative) associated with overall survival differences [42].…”

“…Other signatures were developed for predicting the risk of primary platinumresistance. For example, the University of Peking used whole exome sequencing and whole genome sequencing to build a DRD score that was able to predict the likelihood of platinum-resistance after first-line treatment in 99 patients (sensitivity, specificity, and accuracy of 90.91%, 96.77%, and 95.24%, respectively) [44]. Complex by essence, these gene signatures appear promising, and their reproducibility and potential impact on disease management will have to be assessed.…”

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer Part 2: Medical Perspectives

“…As such, this could be a useful biomarker with negative predictive value for sensitivity to PARPis [ 115 , 116 ]. Similarly, indirect assessment with molecular signatures (genetic or epigenetic signatures) associated with platinum resistance could help classify patients with inconclusive or conflicting results [ 117 ].…”

Leveraging Genomics, Transcriptomics, and Epigenomics to Understand the Biology and Chemoresistance of Ovarian Cancer

“…These mutations were associated with better survival and higher platinum sensitivity. Recently, a genomic signature was reported to predict platinum resistance in HG-SOC patients [35]. By WGS and WES, they identified mutations in TP53 and TTN, as well as defects in HR repair, as the most common genomic alterations in both platinum-sensitive and platinum-resistant patients.…”