NCCN Updates ctDNA Stance in Colon, Rectal, and MCC Guidelines

The National Comprehensive Cancer Network (NCCN) has updated their Clinical Practice Guidelines in Oncology for colon and rectal cancer to include circulating tumor DNA (ctDNA) as a high-risk factor for recurrence in the adjuvant setting.1-3 Additionally, the NCCN Clinical Practice Guidelines in Oncology for Merkel cell carcinoma (MCC) have been updated to state that ctDNA can be used to evaluate disease burden in virus-positive and virus-negative disease; they noted that ctDNA typically becomes positive prior to or at the time of a clinically evident recurrence and that the test is often obtained every 3 months when used for surveillance.1,4

The updated colon cancer guidelines state that ctDNA is prognostic but not predictive in the adjuvant treatment of patients with microsatellite stable/mismatch repair–proficient disease and that there is currently insufficient evidence to recommend the routine use of ctDNA assays outside of clinical trials.2 Care de-escalation and treatment decision-making are not recommended based on ctDNA findings. ctDNA is not recommended for surveillance in patients with stage IV disease.

In the updated rectal cancer guidelines, the NCCN stated that ctDNA is a prognostic marker following transanal local excision but added that there is presently insufficient evidence to recommend routine use of ctDNA assays outside of a clinical trial.3 De-escalation of care and treatment decision-making are not recommended based on ctDNA data. For patients with stage II to IV disease, ctDNA is not recommended for surveillance.

“These guideline changes came faster than expected given the typical timelines to be included,” Alexey Aleshin, MD, corporate chief medical officer and general manager of oncology for Natera, stated in a news release.1 “The inclusion of ctDNA testing in NCCN guidelines for these histologies is another step toward more personalized care for patients with cancer.”

In the updated MCC guidelines, the NCCN referenced findings from a prospective study published in the Journal of Clinical Oncology which examined ctDNA as a biomarker for detecting MCC recurrence.5 In the multicenter, observational study, investigators collected plasma samples as well as clinical and imaging data from 319 patients and analyzed them using a tumor-informed ctDNA assay developed and provided by Signatera. Patients were divided into discovery (n = 167) and validation (n = 152) cohorts. The diagnostic performance of the assay was assessed in terms of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Findings from the study demonstrated that the assay sensitivity for detecting disease at enrollment in the discovery and validation cohorts was 95% (95% CI, 87%-99%) and 94% (95% CI, 85%-98%), respectively. The corresponding specificities were 90% (95% CI, 82%-95) and 86% (95% CI, 77%-93%), respectively.

Additionally, a positive ctDNA finding during surveillance was associated with an increased risk of disease recurrence in both the discovery (HR, 6.8; 95% CI, 2.9-16.0; P < .001) and validation (HR, 20.0; 95% CI, 8.3-50.0; P < .001) cohorts. The PPV for clinical recurrence at 1 year following a positive ctDNA test was 69% (95% CI, 32%-91%) and 94% (95% CI, 71%-100%) in the respective cohorts. The NPV at 135 days after a negative test was 94% (95% CI, 90%-97%) and 93% (95% CI, 89%-97%), respectively. Those with ctDNA positivity within 4 months following treatment experienced higher 1-year rates of disease recurrence compared with those who did not have ctDNA positivity at this time point, at 74% vs 21%, respectively (adjusted HR, 7.4; 95% CI, 2.7-20.0; P < .001).

“Signatera tumor-informed ctDNA testing is a highly accurate and prognostic biomarker for surveillance of high- and low-risk patients with MCC to help determine imaging frequency,” Lisa Zaba, MD, PhD, associate professor of dermatology, director of the MCC multi-disciplinary clinic, and member of the supportive oncodermatology group at the Stanford Cancer Center in Palo Alto, California, added in the news release.1

References

1. NCCN strengthens guidance on ctDNA in colon cancer, rectal cancer, and Merkel cell carcinoma. News release. Natera. February 10, 2025. Accessed February 12, 2025. https://www.natera.com/company/news/nccn-strengthens-guidance-on-ctdna-in-colon-cancer-rectal-cancer-and-merkel-cell-carcinoma/
2. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 1.2025. Accessed February 12, 2025. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
3. NCCN. Clinical Practice Guidelines in Oncology. Rectal cancer, version 1.2025. Accessed February 12, 2025. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
4. NCCN Clinical Practice Guidelines in Oncology. Merkel cell carcinoma, version 1.2025. Accessed February 12, 2025. https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf
5. Akaike T, Thakuria M, Silk AW, et al. Circulating tumor DNA assay detects Merkel cell carcinoma recurrence, disease progression, and minimal residual disease: surveillance and prognostic implications. J Clin Oncol. 2024;42(26):3151-3161. doi:10.1200/JCO.23.02054