Potential clinical utility of liquid biopsies in ovarian cancer

Abstract

Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide. One of the main challenges in the management of OC is the late clinical presentation of disease that results in poor survival. Conventional tissue biopsy methods and serological biomarkers such as CA-125 have limited clinical applications. Liquid biopsy is a novel sampling method that analyzes distinctive tumour components released into the peripheral circulation, including circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), cell-free RNA (cfRNA), tumour-educated platelets (TEPs) and exosomes. Increasing evidence suggests that liquid biopsy could enhance the clinical management of OC by improving early diagnosis, predicting prognosis, detecting recurrence, and monitoring response to treatment. Capturing the unique tumour genetic landscape can also guide treatment decisions and the selection of appropriate targeted therapies. Key advantages of liquid biopsy include its non-invasive nature and feasibility, which allow for serial sampling and longitudinal monitoring of dynamic tumour changes over time. In this review, we outline the evidence for the clinical utility of each liquid biopsy component and review the advantages and current limitations of applying liquid biopsy in managing ovarian cancer. We also highlight future directions considering the current challenges and explore areas where more studies are warranted to elucidate its emerging clinical potential.

Fig. 1

Schematic representation of ovarian cancer classification into Type I and Type II tumours based on histology, clinical features, and molecular profile with commonly associated mutations. Type I tumours tend to be slow growing, less aggressive, and more likely to be diagnosed at earlier stages of disease associated with genetic stability. Type II tumours usually present with more aggressive, rapid growing disease that is diagnosed in more advanced stages, and are associated with a higher degree of genetic instability

Fig. 2

Overview of the liquid biopsy process, from hypothesized mechanisms of tumour release of liquid biopsy components, to laboratory analysis techniques. Tumour biomarkers are first released and enter the circulation via one of three main mechanisms: apoptosis, necrosis, or secretion. Liquid biopsy involves the collection and analysis of five distinctive tumour components from peripheral blood samples: cell-free nucleic acids (cfDNA/ctDNA, cfRNA), CTCs, exosomes and tumour educated platelets. Tumour components in peripheral blood samples are then captured and analyzed using their corresponding laboratory assays. cfDNA: circulating free DNA, ctDNA: circulating tumour DNA, cfRNA: cell-free RNA, CTCs: circulating tumour cells, TEPs: tumour educated platelets, NGS: next generation sequencing, qPCR: quantitative polymerase chain reaction

Fig. 3

Overview of the five major clinical applications of liquid biopsy in ovarian cancer. Earlier in the disease course, sample analysis for ovarian cancer biomarkers can allow earlier diagnosis. Following primary debulking surgery, liquid biopsy can detect minimal residual disease as a prognostic indicator and allow for earlier detection of recurrent disease. During treatment, liquid biopsy may enhance longitudinal monitoring with its non-invasive approach that enables serial sampling. Additionally, liquid biopsy offers the advantage of capturing the entire tumour genome, which can help identify novel genetic markers for targeted therapies and detect treatment resistance. ctDNA: circulating tumour DNA, MRD: minimal residual disease; AAF: alternative allele frequency

Fig. 4

Comparison of five liquid biopsy components and the main advantages, disadvantages, and future directions of their clinical application in ovarian cancer management

Fig. 5

The utility of liquid biopsy during different stages of tumour progression. The molecular profile of the primary tumour changes as cancer progresses. New mutations and treatments can lead to intra-tumour heterogeneity. Furthermore, heterogeneity causes drug resistance and treatment failure. Liquid biopsy can aid in the detection of primary ovarian tumours (A). The prognosis of EOC patients can potentially be determined by liquid biopsy (B). Likewise, this technique can help with the detection of residual disease after primary debulking surgery and contribute to the detection of EOC recurrence (C). Physicians can potentially use liquid biopsy to uncover the molecular profile of the tumor and select the correct therapy for each patient (D). Liquid biopsy can also reflect tumour heterogeneity and predict resistance to platinum-based chemotherapy in addition to both primary and acquired resistance to PARPi (E)