ctDNA Continues to Emerge As A Potentially Useful Disease Monitoring Tool in CRC

ctDNA Continues to Emerge As A Potentially Useful Disease Monitoring Tool in CRC

Circulating tumor DNA (ctDNA) analysis is playing an increasingly important role in colorectal cancer (CRC) treatment decision-making, according to Holly Chitwood, DNP, FNP-C, AGACNP-BC; and Adria Myers, DNP, AOCNP, APRN. As such, oncology nurses and advanced practice registered nurses (APRNs) can be vital in improving patient education in this space, as well as advocating for better insurance coverage for ctDNA.¹

“Studies now support the use of ctDNA testing to measure MRD [minimal residual disease], in addition to standardized testing and data, to determine the personalized benefit of adjuvant therapy for stage I and II CRC,” Chitwood, who is assistant professor, and Myers, who is anurse practitioner, both in the Markey Cancer Center at the University of Kentucky, wrote in an article published in the Clinical Journal of Oncology Nursing. “Alongside traditional means such as CEA [carcinoembryonic antigen] and response to treatment in metastatic disease, ctDNA analysis may provide insight into identifying patients at higher risk for early recurrence of CRC.”

Historically, providers have used whole-exome sequencing molecular analysis to identify pathogenic variants in tumor specimens. These findings have been used to guide therapy selection for solid tumors. However, liquid biopsies that use cell-free DNA extracted from plasma have become popular for molecular analysis in patients when tumor tissue is not available. The process of apoptosis or necrosis results in cell-free DNA (also known as ctDNA) being released into the bloodstream.²

In 2019, the first ctDNA assay designed to measure MRD became commercially available.³ Although this first technology was tumor-informed—meaning that an existing tissue sample was used to compare and identify the ctDNA—tumor-agnostic assays have since been developed. These newer tests do not require matching tumor sequencing.

The nurses explained that there are benefits associated with ctDNA. For example, compared with an open biopsy, ctDNA analysis is less invasive.⁴ It can also be conducted on a serial basis, and it is believed that it may better represent the whole tumor, as well as provide a picture of potential metastases. ctDNA can now be used as a biomarker across all solid tumors, but the authors noted that it is being extensively used to guide CRC treatment decisions.^1,3

As Chitwood and Myers pointed out, clinicopathologic and demographic characteristics are typically used to determine a patient with CRC’s risk of recurrence.⁵ These factors may include patient age at diagnosis, disease stage, tumor grade, and the presence of perineural and perivascular invasion. However, numerous clinical trials have assessed the accuracy of ctDNA as a tool for predicting and monitoring recurrence—as well as measuring treatment response and resistance to therapy. For example, a study conducted by Tie et al demonstrated that among 100 patients with newly diagnosed, stage III disease, those with high ctDNA levels following surgery had worse outcomes compared with those who had undetectable levels of ctDNA postsurgery. Specifically, the estimated 3-year recurrence-free interval was 30% among patients with detected ctDNA postsurgery and 77% among patients with no detectable ctDNA postsurgery (HR, 68; 95% CI, 11.0-157.0; P < .001).

They went on to note that, in addition to standard-of-care testing and surveillance imaging, ctDNA testing can help patients with stage I or II disease understand the potential benefit of adjuvant therapy following surgery.⁶ ctDNA may also be associated with overall survival benefit, as it may be used to identify patients with early or synchronous metastasis, and these patients can potentially be cured by locoregional therapy.⁷

“MRD assays using ctDNA can guide adjuvant therapy, serve as a prognostic biomarker, assist in early detection of recurrence or progression, and be used in surveillance for patients with CRC,” the authors wrote.

Of note, ctDNA has limitations; ctDNA assays, whether they are performed on whole blood or plasma, require a matching tissue specimen. Companies can assist with obtaining the tissue specimen; however, the turnaround time can be as long as 3 weeks for the initial test, and subsequent serial testing can take an additional 7 to 14 days. Moreover, sites with low tumor shedding, or insufficient samples of blood or plasma, can result in false negatives for MRD detection; errors in sequencing the ctDNA can also lead to false positives.⁸

Lastly, the cost-effectiveness of ctDNA analysis remains to be determined, the nurses pointed out, and only a few states require biomarker analyses to be covered by insurance.

“The associated costs are unclear and vary with insurance coverage, with patients reporting insurance denials and high co-pays,” the authors wrote. “Many companies offer patient assistance programs to cover the cost of biomarker molecular analysis.”

The nurses concluded by noting that the emerging role of ctDNA has implications for oncology nurses and advanced practice RNs. Because these individuals are a trusted source of information for many patients with cancer, they can play a key role in helping them and their families understand the science behind ctDNA, as well as obtain informed consent, assist in the collection of specimens, and help with monitoring tests and their results. APRNs may also play a key role in identifying patients for whom ctDNA analysis would be appropriate, as well as ordering the required diagnostics, helping patients understand their tests results, and incorporating these results into the treatment plan.

Moreover, they assert that nurses are in a unique role to advocate for expanded access to emerging ctDNA technology, as well as expanded insurance coverage with ctDNA.

“Nurses can help educate the patient and family about ctDNA testing in cancer management, assist in collecting blood, monitor test results, participate in interprofessional collaboration of care, and advocate for coverage of testing,” they concluded.

References

1. Chitwood H, Myers A. Use of circulating tumor DNA to monitor minimal residual disease among patients with colorectal cancer. Clin J Oncol Nurs. 2023;27(4):369-374. doi:10.1188/23.CJON.369-374
2. Corcoran RB, Chabner BA. Application of Cell-free DNA Analysis to Cancer Treatment. N Engl J Med. 2018;379(18):1754-1765. doi:10.1056/NEJMra1706174
3. Tie J, Cohen JD, Wang Y, et al. Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol. 2019;5(12):1710–1717. doi:10.1001/jamaoncol.2019.3616.
4. De Mattos-Arruda L, Siravegna G. How to use liquid biopsies to treat patients with cancer. ESMO Open. 2021;6(2):100060. doi:10.1016/j.esmoop.2021.100060
5. Luo D, Yang Y, Shan Z, et al. Clinicopathological features of stage I-III colorectal cancer recurrence over 5 years after radical surgery without receiving neoadjuvant therapy: evidence from a large sample study. Front Surg. 2021; 8:666400. doi:10.3389/fsurg.2021.666400
6. Reinert T, Henriksen TV, Christensen E, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124-1131. doi:10.1001/jamaoncol.2019.0528
7. Dhiman A, Vining CC, Witmer HDD, et al. Phase II prospective, open-label randomized controlled trial comparing standard of care chemotherapy with and without sequential cytoreductive interventions for patients with oligometastatic foregut adenocarcinoma and undetectable circulating tumor deoxyribose nucleic acid (ctDNA) levels. Ann Surg Oncol. 2022;29(7):4583-4592. doi:10.1245/s10434-021-11249-7
8. Cheng ML, Pectasides E, Hanna GJ, Parsons HA, Choudhury AD, Oxnard GR. Circulating tumor DNA in advanced solid tumors: clinical relevance and future directions. CA: Cancer J Clin. 2021;71(2):176–190: doi:10.3322/caac.21650