Genome-wide Copy-number Alterations in Circulating Tumor DNA as a Novel Biomarker for Patients with High-grade Serous Ovarian Cancer

Abstract

Purpose: High-grade serous epithelial ovarian cancer (HGS-EOC) is defined by high levels of somatic copy-number alterations (SCNA) with marked spatial and temporal tumor heterogeneity. Biomarkers serving to monitor drug response and detect disease recurrence are lacking, a fact which reflects an unmet clinical need. Experimental Design: A total of 185 plasma samples and 109 matched tumor biopsies were collected from 46 patients with HGS-EOC, and analyzed by shallow whole-genome sequencing (sWGS). The percentage of tumor fraction (TF) in the plasma was used to study the biological features of the disease at the time of diagnosis (T0) and correlated with patients' survival. Longitudinal analysis of TF was correlated with CA-125 levels and radiological images to monitor disease recurrence. Results: Gain in the clonal regions, 3q26.2 and 8q24.3, was observed in the 87.8% and 78.05% of plasma samples, suggesting that plasma sWGS mirrors solid biopsies. At T0, multivariate analysis revealed that plasma TF levels were an independent prognostic marker of relapse (P < 0.022). After platinum (Pt)-based treatment, circulating tumor DNA (ctDNA) analysis showed a change in the heterogeneous pattern of genomic amplification, including an increased frequency of amplification, compared with before Pt-based treatment in the 19p31.11 and 19q13.42 regions. TF in serially collected ctDNA samples outperformed CA-125 in anticipating clinical and radiological progression by 240 days (range, 37–491). Conclusions: Our results support the notion that sWGS is an inexpensive and useful tool for the genomic analysis of ctDNA in patients with HGS-EOC to monitor disease evolution and to anticipate relapse better than serum CA-125, the routinely used clinical biomarker. See related commentary by Dhani, p. 2372

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

“…In agreement, we more recently showed that FOXM1 copy number correlates with FOXM1 mRNA and protein expression in pan-cancer [ 27 ]. The 12p13.33 amplifications were reported to be common in an independent cohort of HGSC patients before and after front-line chemotherapy (and detectable in plasma), further supporting this mechanism [ 128 ]. Despite the high frequency of FOXM1 SCNA observed in HGSC, an even greater proportion of tumors show FOXM1 overexpression or pathway activation (reaching ~90% of HGSC cases) [ 30 , 127 ], indicating that additional mechanisms contribute to FOXM1 overexpression and pathway activation in HGSC.…”

“…In HGSC patients, shallow whole genome sequencing (sWGS) of circulating tumor DNA (ctDNA) from plasma revealed a 16% increase in chromosome 12p13.33 amplification (location of FOXM1 ) after the acquisition of chemotherapy resistance [ 128 ]. In agreement, we observed that almost half of HGSC patients have increased FOXM1 expression in recurrent chemoresistant tumors [ 256 ].…”

Association of 17q22 Amplicon Via Cell-Free DNA With Platinum Chemotherapy Response in Metastatic Triple-Negative Breast Cancer

“…36,37 Lowcoverage WGS of cfDNA has been used to characterize CNAs in many cancers including TNBC, and the burden of CNAs may be prognostic. 7,[38][39][40][41][42][43][44][45] In some cancers, CNA burden may be predictive of response to checkpoint inhibitors. 46,47 But, to our knowledge, no previous study has associated a focal CNA detected by ctDNA ULP-WGS with response to a particular therapy for any cancer.…”

Liquid Biopsy in the Clinical Management of High-Grade Serous Epithelial Ovarian Cancer—Current Use and Future Opportunities

“…The genomic heterogeneity of relapse disease was reduced after pt treatment, with the emergence of newly frequent cytobands that could be involved in t resistance. While this represents a proof-of-principle study performed in a small cohort of patients (n = 46) and lack of an independent clinical validation set, it provides evidence that the low-pass shallow whole-genome sequencing in cfDNA is an inexpensive and useful tool to monitor disease evolution and to anticipate relapse better than the routine clinical biomarkers [ 61 ].…”