Serial Post-Operative ctDNA Analysis Could Inform Treatment Decision Making in Stage III Colorectal Cancer

Serial postoperative ctDNA appeared to successfully assess tumor growth rate and have notable prognostic value for patients with stage III colorectal cancer, according to a study published in Clinical Cancer Research.

Presence of circulating tumor DNA (ctDNA) was reported to be a notable predictor of postoperatively recurrence (Hazard ratio [HR], 7.0; 95% CI, 3.7-13.5; P <.001) and recurrence immediately after adjuvant chemotherapy (HR, 50.76; 95% CI, 15.4-167; P <.001). Patients who were ctDNA positive had a recurrence rate of 80% following treatment with adjuvant chemotherapy vs 18% for patients who were ctDNA negative.

A total of 160 patients were eligible for the study, including 1204 plasma samples with a median of 7 per patient. Recurrence was reported in 25% of patients, with a median time to recurrence of 35 months. Prior to surgery, ctDNA was detected in 91% of plasma samples.

Postoperative plasma samples were collected from 140 patients prior to adjuvant chemotherapy. Investigators reported a median sampling point of 2 weeks following surgery. ctDNA was observed in 14% of samples. In postoperative samples, 22 patients who recurred and were ctDNA negative had higher circulating free DNA (cfDNA) compared with 20 patients who were ctDNA positive (P = .015).

Of those who were ctDNA positive following surgery, adjuvant chemotherapy was given to 90% of patients, with 13 samples being collected during and after adjuvant chemotherapy and up to 3 years. A total of 23% (95% CI, 8.2%-50.0%) of patients demonstrated complete and permanent clearance of plasma ctDNA during the end of treatment and during follow-up. At 36 months, the 3 patients did not relapse, although 100% of those who did lacked a clearance of plasm ctDNA or had a transient clearence.

After treatment ended, 114 patients had surveillance samples collected, 88% of which were ctDNA positive and 24 patients had relapsed. During surveillance, 22 patients were ctDNA positive with a recurrence rate of 96% vs 3% among patients who were ctDNA negative (P <.001). Of 602 samples collected from 92 patients who did not have a recurrence, 0.3% were ctDNA positive, which came from the same patient twice; this was followed by 6 ctDNA-negative samples. Presence of ctDNA was associated with a significantly shorter recurrence-free survival (RFS; HR, 50.80; 95% CI, 14.9-172; P <.001), according to a Cox regression analysis with serial ctDNA as a time-dependent variable. The multivariable adjustment for longitudinal ctDNA was found to be the only significant predictor of RFS (HR, 40.7; 95% CI, 11.6-143; P <.001).

In 43% of patients, ctDNA was detected prior to completion of adjuvant chemotherapy, with the samples increasing the median lead time to 10 months. Investigators conducted an additional lead-time analysis in 18 of the 21 patients who recurred, wherein ctDNA was assessed at the time of CT imagine. Investigators reported that ctDNA was present in 33% of patients prior to recurrence with a median lead time of 10 months.

In 17 patients who had relapsed with 2 or more ctDNA-positive samples collected during follow-up and before clinical recurrence, investigators assessed change in ctDNA as a proxy for tumor growth. Using a Cox proportional hazard model, investigators reported that increased ctDNA was associated with poorer overall survival (OS; HR, 3.95; 95% CI, 1.1-7.0; P = .039).

Reference

Henriksen TV, Tarazona N, Frydendahl A, et al. Circulating tumor DNA in stage III colorectal cancer, beyond minimal residual disease detection, toward assessment of adjuvant therapy efficacy and clinical behavior of recurrences. Clin Cancer Res. 2022;28(3):507-517. doi:10.1158/1078-0432.CCR-21-2404