Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study

Abstract

Background In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study. Methods and findings We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient’s tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients’ tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/− adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing. Conclusions We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM. Trial registration ACTRN12612000345886.

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

“…In patients with resectable colorectal liver metastases (CRLMs), ctDNA was detectable in 46/54 (85%) patients prior to any treatment. In this group a median 40.93-fold decrease in ctDNA MAF with neoadjuvant chemotherapy was observed, although ctDNA clearance during neoadjuvant chemotherapy was not associated with a better RFS [ 97 ]. Notably, those with postoperative ctDNA-positivity had a significantly lower RFS (HR 6.3, 95% confidence interval or CI 2.58–15.2, p < 0.001) and OS (HR 4.2, 95% CI 1.5–11.8, p < 0.001) compared to patients with undetectable postoperative ctDNA, suggesting a role in guiding adjuvant therapy decisions in this arena.…”

Current Status of Next-Generation Sequencing-Based Cancer Genome Profiling Tests in Japan and Prospects for Liquid Biopsy

“…In such cases, noninvasive liquid biopsy can be a potent option for treatment. It has been reported that the recurrence rate after surgery is higher when mutations are detected in ctDNA after surgery [ 12 ]. For example, the presence of minimal residual disease (MRD) may be a factor for determining the need for more intensive anticancer drug treatment after surgery.…”

ctDNA: An emerging neoadjuvant biomarker in resectable solid tumors

“…Both Yaqi Wang and Pradeep Chauhan and their respective colleagues evaluate ctDNA as a tool capable of predicting complete pathological response (pCR) in locally advanced rectal cancer (LARC) and muscle invasive bladder cancer (MIBC), respectively [ 1 , 2 ]. Jeanne Tie and colleagues focus on ctDNA evaluation in high-risk metastatic colorectal cancer with liver metastases (CRLM), both during neoadjuvant therapy and following surgery and adjuvant therapy [ 3 ]. In this brief perspective we evaluate these advances within the wider context of recently published work.…”