The Clinical Importance of Circulating Tumor DNA

Introduction
Choice of therapy
Risk of recurrence
Response to therapy
Targeted and personalized therapies
Conclusion
References
Further research 


Cancer remains a leading killer among medical causes of death worldwide. Scientists have been working for a long time on methods to identify and monitor the presence and spread of tumors in the body. One such is the detection of circulating tumor DNA (ctDNA).

Image Credit: crystal light/Shutterstock.com

Introduction

Along with circulating tumor cells (CTCs) and exosomes secreted from cancer cells, ctDNA is obtained as part of a liquid biopsy. It was expected to help unravel the cancer cell genetic makeup without having to resort to invasive sampling methods.

Its relevance is due to the availability of very sensitive next-generation sequencing (NGS) tools, the ability to display a full range of cancer cell genes and the dynamic changes in the tumor's genotype with time and treatment.

CtDNA originates from cell-free DNA released by dying cancer cells, though the fraction varies with the patient and the tumor over time and with treatment.

It is rapidly cleared from the blood within a short period, from 15 minutes to several hours, thus making it suitable as a real-time biomarker to monitor the type of tumor and the tumor burden, as well as the response to treatment and the emergence of tumor resistance.

Choice of therapy

Using ctDNA could help measure the cancer risk of different types of surgery and thus help optimize the management of tumors. Also, the kind of ctDNA in the blood can be distinguished to help establish the origin of a given tumor and thus help to select the right treatment.

Patients with advanced cancer are more likely to have ctDNA due to increased tumor burden. The ctDNA comes from the primary and multiple metastatic sites, allowing a more complete assessment of tumor cell clones and the type of mutations.

In addition, examining genetic biomarkers provides a more accurate estimate of the risk of recurrence compared to epigenetic markers.

Risk of recurrence

Similarly, residual disease is linked to the persistence of ctDNA, which is otherwise more likely to drop after surgery, thus helping to evaluate whether curative surgery was successful.

Currently, the need for adjuvant therapy is determined by the TNM staging system, which helps estimate the risk of recurrent tumor.

However, even with this system, many patients do receive unnecessary adjuvant therapy, while others with early-stage tumors fail to receive it and develop recurrent tumors.

"The clinical use of ctDNA for assessing for risk of microscopic residual disease has the potential to have a large impact on determining which patients may require adjuvant therapy and in the early detection of recurrence, thereby improving disease-free survival and overall survival." Reece et al. 2019

The use of ctDNA as a biomarker could help direct such therapy to those who need it to improve their odds of survival. A negative post-operative ctDNA result in patients is associated with a low risk for relapse.

Response to therapy

The use of ctDNA also shows significant potential for early stratification of responses to therapy. Whereas it may take a few months for changes in tumor size to show up radiographically, a much earlier indicator, within a month or less, may come from falling plasma ctDNA levels.

This could help pick up patients who need more intensive therapy early in treatment rather than offer the same intensive course to all patients.

Targeted and personalized therapies

Genomic profiling is meant to identify alterations in specific genes that affect tumor sensitivity to targeted therapies. The origin of the tumor tissue in conventional tissue-based genomic profiling is from surgical resection or biopsy. These use NGS to evaluate hundreds of genes at the same time, with the potential for better fusion detection.

Both somatic and epigenetic markers are examined. While the latter help to personalize cancer therapy, epigenetic markers are more relevant across the board and help monitor any change in tumor bulk.

With solid tumors, sampling may miss subclones of the tumor, primary or metastatic, while ctDNA shows the complete genetic picture. Here again, the completeness of the genetic picture helps determine the right treatment while also picking up drug resistance over time. This could help avoid potentially ineffective treatments and limit drug toxicity.

Some selected ctDNA molecules may help pick the right drug. For instance, genes in the RAS cellular pathway may be mutated to confer resistance to drugs like cetuximab and panitumumab, both antagonists of a common growth factor called EGFR. These are often used to treat small cell lung cancer.

Similarly, in prostate cancer, the ability to detect genetic and epigenetic alterations could identify patients with neuroendocrine markers, thus averting the unnecessary use of androgen receptor antagonists.

In metastatic colorectal cancer, the use of liquid biopsy to understand how resistance to systemic therapy emerges, such as EGFR-escaping KRAS pathway mutations.

Conversely, the low ctDNA concentration in plasma samples vs tumor tissue means a higher risk of missing some mutations, either because the sample is insufficient or because the NGS panel targets a few dozen genes, rather than the hundreds in tissue-based genomic profiling panels.

The former also does not match their results with white blood cell sequencing, so germline variants or somatic mutations in blood cells from the bone marrow may contribute to false-positive results.

However, the advantage of avoiding invasive or high-risk biopsies is significant, especially when combined with the reduced risk of missing different clones in the tumor and the short turnaround time. There is the presence of artefacts in both due to tumor tissue acquisition and processing.

Plasma ctDNA can be sampled more regularly and more often than tumor biopsies can be taken, allowing dynamic changes in the tumor to be picked up. Measurements can be taken from the baseline to after treatment, and either the absolute values or the fold-change compared. The latter gives a more accurate prediction of the tumor response.

Circulating Tumor DNA: Enhanced Cancer Detection | Stanford Cancer Institute

Conclusion

ctDNA can be personalized to some extent, in that it can predict and monitor treatment of one type if the right biomarker is used, such as detecting RAS mutations during treatment with EGFR antagonists. It can also be used to follow tumors for recurrence at a very sensitive scale when epigenetic biomarkers are used, without the need for such selectivity.

Moreover, ctDNA is useful in picking up markers of resistance early, so as to change the treatment protocol accordingly. Regular ctDNA sampling will be necessary for this purpose, using quantitative thresholds or the slope of observed change for higher sensitivity.

It can also help select patients for neoadjuvant treatment and monitor them, either for future surgical resection or to underpin a watchful waiting policy. Not only does ctDNA allow sequential sampling in a non-invasive way, but it reduces the chances of missing a region within the tumor or a metastasis. Treatment effectiveness can be visualized by watching the tumor response.

The presence of ctDNA could also indicate the presence of micrometastases that are not visible on imaging as yet, but more studies will indicate if this ability is connected to improved outcomes or survival. The use of molecular stratification techniques could help exploit the array of cancer therapies available to optimize the utility while reducing the risk for the patient, by selecting the best treatment approach.

"The result is the potential for ctDNA to be utilized for guiding treatment decisions—initiating, altering, and ceasing treatments, or prompting investigation into the potential for residual disease." Reece et al. 2019

Much more research is required to build on early progress in understanding the response to therapy and monitoring the emergence of resistance. This could help develop nimble diagnostic and monitoring tests and reduce the uncertainty around ambiguous radiographic results.

References

Further reading

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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