- Emerging liquid biopsy approaches—such as cfDNA methylation profiling, fragmentomics, and AI-driven analyses—are often described as game-changers for early cancer detection. Which of these innovations do you believe holds the most promise for improving cancer screening, and what challenges must be overcome to translate them into routine clinical practice?
RE: I believe that a combination of these liquid biopsy approaches holds most promise for improving cancer screening and would also include non-ctDNA biomarkers such as circulating extracellular vesicles, proteins, metabolites, RNAs and tumor cells. Such a composite biomarker panel is currently evaluated for early pancreatic cancer screening in the EU Horizon consortium PANCAID (https://pancaid-project.eu; Lead-PI: K. Pantel). Challenges that must be overcome include optimization of pre-analytical variables (e.g., each biomarker may have different optimal conditions for blood tubes), availability of biobanks from patients with pre-neoplastic or early-stage disease with long term follow up, cancer-associated aberration in non-cancer cells of ageing patients, andcost effectiveness as compared to existing screening modalities.
2. You have emphasized focusing on high-risk populations (e.g., genetically predisposed individuals or patients with chronic conditions) for liquid biopsy screening, rather than broad population-wide testing. Given the risks of overdiagnosis, how should researchers decide which cancers and patient groups to target first with early-detection liquid biopsy?
RE: Key is in my opinion the clinical need such as a tumor types that are notoriously detected at late stages and where no routine screening exists yet. For some tumor types such as pancreatic or ovarian cancer, it is obvious that most tumors are being diagnosed too late and there is at present no routinely used other modality able to detect earl-stage cancers, leading to a high mortality. Another example is lung cancer where low dose CT scans are being used in some countries for screening but the performance needs to be improved.
3. Your research suggests that liquid biopsy can detect minimal residual disease or recurrence months before traditional imaging. What implications does this early detection have for patient management—for example, could it enable low-toxicity “preventive” therapies to eliminate residual tumor cells—and what steps are needed to translate that vision into reality?
RE: Detection of minimal residual disease (MRD) has opened a new avenue for interventional clinical trials that assess which treatment is suitable to eliminate or control MRD (reviewed in Pantel & Alix-Panabieres, Nat. Rev. Clin. Oncol. 2025). These trials are needed to translate MRD diagnostic into reality. Promising data exist that de-escalation of toxic therapies such as chemotherapy in MRD-negative patients might become an option. In the EU/IHI project GUIDE.MRD (www.guidemrd-horizon.eu), we are currently assessing which ctDNA tests are best suitable for early detection of MRD and subsequent metastatic relapse in patients with colorectal, lung and pancreatic cancer. Additional assessment of the host response (e.g., tumor immunity) might be also important to predict the course of MRD towards overt metastasis.
