Circulating Tumor DNA Analysis May Indicate Adjuvant Therapy Efficacy for Stage III CRC

A JAMA Oncology investigation suggests that circulating tumor (ct)DNA analysis after surgery may be a promising prognostic marker in stage III colon cancer.¹

Results also indicated that postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. According to researchers, this high-risk population presents a unique opportunity to explore additional therapeutic approaches.

In this multicenter cohort study of 96 patients with newly diagnosed stage III colon cancer, a significant difference in 3-year recurrence-free interval (RFI) was found in patients with detectable levels of ctDNA, compared with undetectable levels, after surgery (47% vs 76%, respectively) and after completion of chemotherapy (30% vs 77%).

“These observations open new opportunities for enriching recruitment to studies of novel therapies in high risk patients with detectable ctDNA,” the researchers wrote.

ctDNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior RFI (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P <.001); and was also detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P <.001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P <.001).

Tumor-specific DNA mutations can be detected in the cell-free component of peripheral blood samples in almost all patients with advanced colorectal cancer and many other advanced solid tumors. Several studies, including in colorectal cancer, have shown that detectable ctDNA after surgery for early-stage cancers is associated with a very high risk of recurrence.

“Unfortunately, because of the limitations of our current standard of surveillance, we can never be sure that all the tumor cells have been eradicated and therefore can never be sure of a cure,” Harry B. Burke, MD, PhD, department of medicine, Uniformed Services University of the Health Sciences, and Scott Kopetz, MD, PhD, department of gastrointestinal medical oncology, the University of Texas MD Anderson Cancer Center, wrote in an accompanying editorial.²

In this study, blood samples for ctDNA and carcinoembryonic antigen (CEA) analysis were collected 4 to 10 weeks after surgery (before commencing any adjuvant chemotherapy) and at the completion of treatment (within 6 weeks of the final cycle of chemotherapy). All patients had a surveillance CT scan 4 to 8 weeks after completion of adjuvant chemotherapy. Pathology reports from resection specimens were reviewed to assess pathologic prognostic factors. 

“The stratification by treatment and by factor allows us to observe a treatment-associated change in a factor that may indicate that the patient responded to the therapy,” Burke and Kopetz wrote.

Numerous clinical studies have suggested that the treatment of patients with low burdens of metastatic disease is far more efficacious than the treatment of patients with radiologically detectable disease. Therefore, the treatment of patients with detectable ctDNA levels but without radiological evidence of disease after adjuvant chemotherapy could, in theory, eradicate residual disease and increase the chance of a cure. This possibility is being further explored in a series of randomized studies that are currently recruiting.

The University of Pittsburgh in collaboration with the National Cancer Institute is also currently recruiting for a clinical trial evaluating ctDNA as a prognostic marker and as a monitor of disease recurrence in stage III colorectal cancer.

References:

1. Tie J, Cohen JD, Wang T, et al. Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer. JAMA Oncol. doi:10.1001/jamaoncol.2019.3616.

2. Burke HB, Kopetz S. Is the Patient Cured? JAMA Oncol. doi:10.1001/jamaoncol.2019.3612.