Circulating Tumor DNA: Revolutionizing Cancer Diagnosis

Authored by: Andy Lin

Art by: Caitlin Sweeney

In the war on cancer, information is power. Survival chances skyrocket when malignancies are detected early and treated accordingly. But cancer is a moving target. Tumors develop resistance and spread to other parts of the body before symptoms appear. Although imaging and tissue biopsy help establish a diagnosis and guide treatment, they provide only limited information about a constantly changing disease.

Tissue biopsy remains the gold standard in clinical settings, but it has significant shortcomings. The procedure is invasive, at times risky, and uncomfortable for patients. More importantly, a single biopsy taken from one area of a tumor at a specific time does not capture intratumoral heterogeneity, or genetic diversity within and between tumor lesions [1]. As under the influence of treatment cancers evolve, tissue resampling becomes impossible leading to the need for safer and more accurate surveillance strategies. 

CtDNA, a major component of liquid biopsy, is one of the most promising tools for addressing this challenge. Instead of removing the tumor tissue, liquid biopsy looks for tumor-derived material in the circulating bodily fluids such as blood. This genetic material consists of tumor-generated fragments of DNA in the blood resulting from cancer cell apoptosis and necrosis [2]. While these are part of the circulating cell-free DNA (cfDNA), ctDNA differs from the normal cfDNA in having tumor-specific mutations, copy number changes, and methylation patterns linked to the respective malignancy [2, 3]. Although ctDNA often constitutes only a small fraction of circulating DNA, especially in early stage disease, advances in molecular detection have made its identification increasingly sensitive.

Highly sensitive methods, such as digital PCR and next-generation sequencing (NGS) enable the detection of mutant alleles at variant frequencies well below 1% [4]. The analysis of ctDNA following a blood draw provides genomic information, similar to tumor genetics in a variety of metastatic locations. 

The clinical applications of ctDNA go far beyond detection. In fact, the assessment of disease burden is superior to tumor biopsy at a single site. The ctDNA levels formed at different stages of treatment also reflect the tumor burden and therapeutic effect [5]. For instance, in colorectal cancer, ctDNA detection following curative-intent surgery has been demonstrated to predict minimal residual disease and recurrence faster than radiographic evidence [6]. Similar findings have been reported in breast and lung cancers, where rising ctDNA levels can precede relapse before clinical symptoms appear [7]. 

Aside from being a monitoring tool, ctDNA also plays a role in precision oncology. Genomic profiling through the analysis of ctDNA can identify actionable mutations that can be used to select targeted therapies, particularly in situations where tissue samples are not available or insufficient [8]. In addition to this, resistance mutations can also be detected using longitudinal ctDNA, which gives the clinician an opportunity to make changes in the treatment strategy against cancer in real time. The proportion of tumor-derived DNA has been shown to correlate strongly with overall survival and progression-free survival in advanced prostate cancer [9]. 

Moreover, researchers are also exploring ctDNA for early detection of cancers. Multi-cancer early detection (MCED) approaches have been developed to identify cancer signals from a single blood sample by analyzing methylation and mutation patterns in ctDNA [10]. Early validation studies have been able to detect many cancer types and predict the origin of tissue with high accuracy [10]. 

Clearly, the ctDNA testing procedure is not foolproof. In early-stage cancers, the sensitivity levels of mutated ctDNA are too low to detect DNA and hence, generate false-negative results [2]. Also, clonal hematopoiesis due to age can cause somatic mutations in cfDNA that have nothing to do with cancer [11]. Assay standardization, as well as cost issues, are also still challenges for mass adoption. For this reason, ctDNA complements traditional tissue biopsy instead of replacing it. 

Nonetheless, as sequencing techniques become more sensitive and computational tools more sophisticated, ctDNA analysis is likely to become more integrated within routine oncology care. Previously invasive sampling may become avoidable with routine blood testing, thereby “never losing sight” of tumor evolution. 

Cancer care is shifting slowly from cause-and-effect intervention to cause and surveillance. Circulating tumor DNA reflects this transition by giving clinicians the opportunity to intervene earlier, tailor treatment plans more effectively, and monitor treatment response in real time. 

References:

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