Harnessing extracellular vesicles using liquid biopsy for cancer diagnosis and monitoring: highlights from AACR Annual Meeting 2024

Abstract

Liquid biopsy, an advanced technology for analyzing body fluid samples, is gaining traction in cancer diagnostics and monitoring. Blood-based liquid biopsy, particularly focusing on cell-free DNAs (cf-DNAs), circulating tumor cells (CTCs), and extracellular vesicles (EVs), has garnered significant attention. EVs stand out for their potential in tumor diagnosis, prognosis prediction, and treatment response assessment, owing to their stable molecular cargo and clear extraction process. At the recent American Association for Cancer Research (AACR) Annual Meeting 2024, groundbreaking EVs-based liquid biopsy studies showcased promising strides in early detection and diagnosis of various cancers, including breast cancer (BC), high-grade serous ovarian cancer (HGSOC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), colon adenocarcinoma (COAD), head and neck cancer (HNC), neuroblastoma, and retinoblastoma (RB). Despite these advancements, challenges persist in translating EVs biomarkers into clinical practice. Overcoming these challenges promises to propel EVs-based liquid biopsy into a new era of personalized precision medicine, revolutionizing cancer detection, monitoring, and treatment.

To the Editor,

Currently, blood-based liquid biopsy dominates research efforts, primarily detecting free blood components, including cell-free DNAs (cf-DNAs), circulating tumor cells (CTCs), and extracellular vesicles (EVs). EVs are vesicles released by cells into the extracellular environment. They have shown high accuracy and sensitivity in early cancer detection, classification, and treatment evaluation, making them valuable as a source of biomarkers. They carry stable and representative molecular components, including proteins, nucleic acids, and lipids, enhancing their clinical utility. Excitingly, The American Association for Cancer Research (AACR) Annual Meeting 2024 highlighted several EVs-based liquid biopsies, heralding significant progress in early detection and diagnosis of common malignancies like breast cancer (BC), high-grade serous ovarian cancer (HGSOC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), colon adenocarcinoma (COAD), head and neck cancer (HNC), neuroblastoma, and retinoblastoma (RB) (Tables 1 and 2).

Table 1 Sample types and EV biomarker extraction methods used for liquid biopsy

Table 2 Specific targets, assay cohort, and assay performance of liquid biopsy

BC is one of the most prevalent and lethal cancers affecting women worldwide. Jee Ye Kim et al. used BC-derived EVs from blood samples, identifying 5 EV-miRNAs as potential biomarkers, with AUC values exceeding 0.8 [1]. In another case-control study, Barbara Cardinali et al. used cyst fluid from patients and extracted 7 EV-miRNAs with clinical variables into a risk model, yielded an AUC of 0.8 [2]. Additionally, they integrated machine learning to analyze the EV proteomic data, discovered that 3 proteins can be combined to effectively distinguish TNBC patients from healthy individuals, achieving 93.3% sensitivity and 93% specificity [3].

Ovarian cancer (OC) is a prevalent gynecological malignancy, with HGSOC being its most aggressive subtype. Michelle Lightfoot et al. verified 4 EV-contained proteins serving as potent biomarkers for late-stage HGSOC detection, with AUC values of 0.94 (CFH), 0.83 (CCNE1), 0.42 (MUC16), and 0.91 (PCP) [4]. Multi-target biomarkers showed superior predictive efficacy, achieving a true positive rate (TPR) of 0.943 and a false positive rate (FPR) of 0.000 in 70 patients [4]. It is worth noting that another team determined the co-localization of tumor markers BST2, MUC1, and sTn on EVs, demonstrating their effectiveness in the early detection of HGSOC [5]. Additionally, Ryosuke Uekusa et al. innovatively revealed that copy number variation (CNV) status of RAD51, BRCA1, AKT2, CCNE1, and MSH6 in malignant tumor tissues were significantly higher than those in benign tissues [6].

CRC is a leading malignant tumor of the digestive system globally. Guo et al. conducted bioinformatics analyses using public databases along with qPCR results from clinical samples, founded that the EV protein RNF208 is a novel diagnostic tool for CRC [7]. Another team enhanced the accuracy of the standard soluble carcinoembryonic antigen (CEA) by incorporating specific EVs, achieving an AUC of 0.975 [8]. Colorectal adenocarcinoma (COAD) is a significant component of the global cancer disease spectrum. Yura Seo et al. identified 7 EV proteins as combined biomarkers. The AUC values for COAD stages I to IV were 0.913, 1.000, 0.985, and 0.984, respectively [9].

Pancreatic cancer (PC) is a highly malignant tumor of the digestive tract, with PDAC comprises about 90% of all PCs. Xu et al. developed a diagnostic model using a combination of biomarkers (including 3 types of miRNAs and CA19-9), with an AUC of 0.97, sensitivity of 0.95, and specificity of 0.96 [10]. Meanwhile, Shivani Bansal et al. introduced a classification algorithm based on 12 multi-omics analytes within EVs, demonstrated high accuracy, sensitivity and specificity in PC identification and stratification [11]. In addition, related study found that the concentrations of ALPPL2⁺ and THBS2⁺ EVs in PDAC patients were significantly increased and closely correlated with changes in tumor size [12].

Furthermore, in certain rare cancers, including HNC, neuroblastoma, and RB, EV-based liquid biopsy demonstrates significant potential. This approach enhances diagnostic and monitoring accuracy and offers innovative sample types and methods (see Supplementary Material).

In summary, EV-based liquid biopsy methods show great potential for the early diagnosis of cancer, allowing for the differentiation between benign and malignant tumors and between tumor grades. Additionally, these methods are effective in monitoring cancer progression and evaluating patients’ responses to treatment. It is imperative to continuously promote relevant basic and clinical research on liquid biopsy based on EV biomarkers while concurrently establishing industrialization and commercialization systems along with corresponding policies.