by Tesam Ahmed
Graphic design by Josip Petrusa
Ovarian cancer, the most fatal female reproductive cancer in the world, is responsible for over 240,000 new cases, and 150,000 deaths in women every year.1,2 There are various risk factors associated with its development, including obesity, diet, physical inactivity, and advanced age (>65 years).3
High mortality rates in ovarian cancer are, in part, a result of its frequent late-stage detection. Decreased efficacy of surgical or pharmacological therapies result from approximately 75% of cases being diagnosed when the disease is in its advanced stages.4,5 The presentation of ovarian cancer often includes vague, nonspecific symptoms that are late in onset. In addition, surveillance is generally only reserved for populations at high-risk, such as those with known genetic mutations or a strong family history.6 The five-year survival rate for women with advanced ovarian cancer is alarmingly low, hovering around 20%.5 These statistics highlight the urgent need for improved early detection strategies.
Current ovarian cancer diagnostic tools, including serum markers like CA-125, imaging, and tissue biopsy approaches, present with limitations. CA-125 lacks adequate sensitivity and specificity in detecting early-stage disease.7 Tissue biopsies are physically invasive, presents with limitations for longitudinal monitoring, and is spatially limited. Ovarian cancer treatment and diagnostics are in urgent need of tools that are minimally invasive, sensitive, and capable of detecting early or minimal residual disease (MRD), a small number of cancer cells that remain post-treatment and may lead to relapse.8,9
In this context, liquid biopsies have emerged over the past decade as a promising, non-invasive molecular screening and monitoring tool. Unlike traditional tissue biopsy, liquid biopsy serves to measure various tumour-derived components in peripheral blood: cell-free RNA (cfRNA), circulating tumour cells (CTCs), tumour DNA (ctDNA), tumour-educated platelets (TEPs), and exosomes. Tumours are hypothesized to release these components into the bloodstream via one of three primary mechanisms: secretion, apoptosis (regulated cell death), or necrosis (unregulated cell death).9
Decoding Tumour Biology Through the Blood
Circulating Tumour Cells (CTCs) are cells deriving from the primary tumour site that have entered the circulatory or lymphatic system.10 CTCs have properties distinct from cells of the primary tumour, and can be isolated from blood using various methods, based on their biological surface markers or underlying physical properties, including size, density, and electric charge.9,11
Cell-free RNA (cfRNA), consisting of mRNA and microRNA (miRNA) are produced as a result of high levels of gene transcription caused by quick tumour turnover. cfRNA in the plasma provides information about the body’s response to tumour growth, and about the tissue of tumour origin.12 miRNA specifically has also been implicated in tumour metastasis, genesis, and apoptosis.9
Tumour-Educated Platelets (TEPs) play an important role in the progression of tumour growth.13 The “education” component of their name refers to the process of sequestration of tumour cell biomolecules into platelets, leading to changes in their RNA and profiles of protein expression. TEPs are involved in the systemic and local response of the body to cancer, changes in their profile make them a useful diagnostic biomarker, providing information about tumour bioactivity, and cancer progression.14
Exosomes are small extracellular vesicles (EVs) released from both healthy and cancerous cells.9 Exosomes are released in higher levels from cancerous cells than normal ovarian epithelial cells, providing utility in ovarian cancer detection.15 In addition, exosomes are involved in cancer progression, drug resistance, and tumour metastasis.16
Clinical Utility and Future Potential
Liquid biopsy, compared to standard techniques, offers several clinical advantages. It is noninvasive, allows for earlier detection and temporal surveillance of ovarian cancer, and for a more precise prognosis.17 By analyzing various tumour components within collected samples of plasma, treatment resistance, and molecular therapy targets can be identified. The ability of liquid biopsy to carry out non-invasive routine screening in the general population is also beneficial.9
Despite its promise, liquid biopsy is not without limitations. In my view, while these challenges are significant, they are not insurmountable. Technical challenges include variability in isolation methods, and low abundance and instability of molecules of interest. Research also suggests that liquid biopsy may be more effective when used as a complementary tool rather than singularly when determining clinical approach. I believe this emphasizes the importance of integrating tools including liquid biopsy into a broader diagnostic strategy. Ongoing research is focused on improving methods of detection for specific cell types and establishing standardized protocols for implementation.9
It appears the future of ovarian cancer may lie in the bloodstream. In my opinion, liquid biopsy has the potential to become a crucial component of the diagnostic toolbox, as research advances its techniques and broadens its uses.
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6. Golia D’Augè T, Giannini A, Bogani G, et al. Prevention, Screening, Treatment and Follow-Up of Gynecological Cancers: State of Art and Future Perspectives. Clin Exp Obstet Gynecol. 2023 Aug 2;50(8):160.
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9. Zhu JW, Charkhchi P, Akbari MR. Potential clinical utility of liquid biopsies in ovarian cancer. Mol Cancer. 2022 Dec;21(1):114.
10. Lin D, Shen L, Luo M, et al. Circulating tumor cells: biology and clinical significance. Sig Transduct Target Ther. 2021 Nov 22;6(1):404.
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12. Roskams-Hieter B, Kim HJ, Anur P, et al. Plasma cell-free RNA profiling distinguishes cancers from pre-malignant conditions in solid and hematologic malignancies. NPJ Precis Onc. 2022 Apr 25;6(1):28.
13. Haemmerle M, Stone RL, Menter DG, et al. The Platelet Lifeline to Cancer: Challenges and Opportunities. Cancer Cell. 2018 Jun;33(6):965–83.
14. Ding S, Dong X, Song X. Tumor educated platelet: the novel BioSource for cancer detection. Cancer Cell Int. 2023 May 11;23(1):91.
15. Taylor DD, Homesley HD, Doellgast GJ. “Membrane‐Associated” Immunoglobulins in Cyst and Ascites Fluids of Ovarian Cancer Patients*. American Journal of Reproductive Immunology. 1983 Jan;3(1):7–11.
16. Tian W, Lei N, Zhou J, et al. Extracellular vesicles in ovarian cancer chemoresistance, metastasis, and immune evasion. Cell Death Dis. 2022 Jan 18;13(1):64.
17. Feng W, Dean DC, Hornicek FJ, et al. Exosomes promote pre-metastatic niche formation in ovarian cancer. Mol Cancer. 2019 Dec;18(1):124.
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