Richie Soong, BSc (Hons), PhD FRCPath

Pascific Pte Ltd National University of Singapore Singapore


Liquid biopsies include samples of blood, urine, stool, sputum or other bodily fluids that can be a source of relevant information on health status. Previously consigned to systemic measurements in clinical biochemistry, liquid biopsies are now increasingly entering clinical practice as counterparts to tissue biopsies, particularly for molecular testing. These tests can encompass the analysis of circulating tumour cells, cell-free DNA and extracellular vesicles, and include interrogation of many types of DNA sequence variants (e.g. mutations, deletions, amplifications, fusions), and epigenetic features (e.g. DNA methylation, histone modifications). Compared to tissue biopsies, the less-invasive nature of sampling liquid biopsies promise a reduction in the health risks of sampling, new information from difficult to biopsy anatomical sites, and an enhanced patient willingness for testing. The reduced skill requirement for sampling liquid biopsies also makes for easier collection and logistics, opening up test access for remote geographies. The properties of liquid biopsies also present a new frontier in longitudinal testing and monitoring previously unachievable by tissue sampling.

Nonetheless, it is important to recognize that the upsurge in applications for liquid biopsies have only been achieved because of recent and complex technological advancements. Molecular analysis of liquid biopsies relies on detection at levels well below those in clinical biochemistry, obliging new collection, processing and logistics workflows, as well as high-level domain expertise, facilities, and data processing for reliable results and responsible execution. However, with the demand for liquid biopsies outstripping reasonable timelines for the generation of appropriate evidence, many are currently forgoing usual clinical rigour for the

promise of the technology. This has led to the current scenario of having a multitude of offerings and claims from both genuine and non-genuine providers, with many practitioners uninformed enough to differentiate them. This is also compounded by fact that quality control systems and regulatory frameworks for liquid biopsies are still being established. The goal of this lecture will be to educate on principles and latest developments in this emerging field that is shaping up to significantly impact the future practice of Pathology.


The introduction of molecular pathology to lung cancer diagnosis in the 1990s has coincided with sharp improvements in treatment outcomes from the disease. Such has been the impact that molecular pathology is now part of the standard of care for lung cancer, and can no longer be dismissed as a fanciful luxury. From treatment with cytotoxics and histological typing, clinical practice has progressed to molecular targeted therapies and single gene PCR analysis (e.g. for EGFR mutations) and then next generation sequencing (NGS, for multiple gene mutations), then liquid biopsy and ultra-sensitive PCR analysis (e.g. for EGFR T790M resistance mutations in blood), then immune-checkpoint inhibitors and single protein immunohistochemistry (IHC, e.g. for PD-L1), to emerging evaluations of combination therapies and liquid biopsy NGS, tumour mutation burden (TMB) and digital pathology, as well as liquid biopsy treatment monitoring and even risk prediction in asymptomatic individuals.

Beyond the prominent tests mentioned above, evidence has also supported the performance of other tests (e.g. for ALK, ROS, RET, NTRK, FGFR1-3, KRAS, BRAF, MET, HER-2) that are each matched to response to different agents. This has prompted international medical

societies such as CAP, IASLC and AMP to include recommendations for multi-gene NGS tumour testing for the attainment of maximal information and sample, time and cost efficiency.

The accumulated evidence has also been a major driver for movements worldwide towards precision healthcare, comprising the tailoring of clinical management to each individual based on upfront testing. The rapid emergence of molecular pathology, and the need to upgrade skills, facilities and workflows for its implementation, is generating major challenges in Pathology, with slow adoption and resistance/dismissal being a common response. However, the march of improved outcomes to patients and evolving standards of care isn’t going away, meaning Pathology is best off educating itself and embracing the strategic opportunity to be a leader of future medicine. The goal of this lecture will be to provide a basic understanding of principles and developments in the recent molecular revolution in lung cancer pathology, and future directions and opportunities.

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