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

Yuan Li; Xiaolan Zhang; Yan Gao; Chunliang Shang; Bo Yu; Tongxia Wang; Junyan Su; Cuiyu Huang; Yu Wu; Hongyan Guo; Chunfang Ha

doi:10.3389/fonc.2020.625866

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

Front Oncol. 2021 Mar 5:10:625866. doi: 10.3389/fonc.2020.625866. eCollection 2020.

Authors

Yuan Li¹, Xiaolan Zhang¹, Yan Gao¹, Chunliang Shang¹, Bo Yu¹, Tongxia Wang¹, Junyan Su², Cuiyu Huang¹, Yu Wu¹, Hongyan Guo¹, Chunfang Ha³

Affiliations

¹ Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
² Lifehealthcare Clinical Laboratories, Hangzhou, China.
³ Department of Gynecology and Obstetrics Department, General Hospital of Ningxia Medical University, Yinchuan, China.

Abstract

Background: High 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.

Methods: Ninety-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.

Results: A 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%.

Conclusions: A 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.

Keywords: BRCA; DNA damage repair; homologous recombination deficiency; initial platinum resistance; ovarian cancer.