Circulating tumor DNA for prognosis assessment and postoperative management after curative-intent resection of colorectal liver metastases

Abstract

The recurrence rate of colorectal liver metastases (CRLM) patients treated with curative intent is above 50%. Standard of care surveillance includes intensive computed tomographic (CT) imaging as well as carcinoembryonic antigen (CEA) measurements. Nonetheless, relapse detection often happens too late to resume curative treatment. This longitudinal cohort study enrolled 115 patients with plasma samples (N = 439) prospectively collected before surgery, postoperatively at day 30 and every third month for up to 3 years. Droplet digital PCR (ddPCR) was used to monitor serial plasma samples for somatic mutations. Assessment of ctDNA status either immediately after surgery, or serially during surveillance, stratified the patients into groups of high and low recurrence risk (hazard ratio [HR], 7.6; 95% CI, 3.0-19.7; P < .0001; and HR, 4.3; 95% CI, 2.3-8.1; P < .0001, respectively). The positive predictive value (PPV) of ctDNA was 100% in all postoperative analyses. In multivariable analyses, postoperative ctDNA status was the only consistently significant risk marker associated with relapse (P < .0001). Indeterminate CT findings were observed for 30.8% (21/68) of patients. All patients (9/21) that were ctDNA positive at the time of the indeterminate CT scan later relapsed, contrasting 42.6% (5/12) of those ctDNA negative (P = .0046). Recurrence diagnoses in patients with indeterminate CT findings were delayed (median 2.8 months, P < .0001). ctDNA status is strongly associated with detection of minimal residual disease and early detection of relapse. Furthermore, ctDNA status can potentially contribute to clinical decision-making in case of indeterminate CT findings, reducing time-to-intervention.

Keywords: circulating tumor DNA; colorectal cancer liver metastases; droplet digital PCR; minimal residual disease; recurrence surveillance.

FIGURE 1

Patient enrollment, sample collection and definition of the patient subgroups used to address the defined clinical questions. N = 29: No post‐OP blood (The patients did not provide any blood samples after CRLM resection), N = 7: Primary tumor not resected (the scheduled resection of the primary cancer was canceled), N = 6: Synchronous other cancer, N = 5: No assay for analysis. ACT, adjuvant chemotherapy; ctDNA, circulating tumor DNA; CT, computed tomography; post‐op, postoperative; RFS, recurrence free survival

FIGURE 2

ctDNA monitoring in patients with colorectal cancer liver metastases (CRLM). (A) Kaplan‐Meier estimates (CI = 95%) of recurrence free survival for 40 CRLM patients stratified by postoperative day 30 ctDNA status. (B) Kaplan‐Meier estimates (CI = 95%) of recurrence free survival for 67 patients with longitudinal samples, stratified by longitudinal postdefinitive treatment ctDNA status before the first recurrence. (C) Kaplan‐Meier estimates (CI = 95%) of recurrence free survival for 68 patients with longitudinal samples, stratified by longitudinal postdefinitive treatment ctDNA status, all samples. A patient was called positive if one or more plasma samples within the given timeframe were ctDNA positive

FIGURE 3

Associations between ctDNA relapse and clinical relapse and between ctDNA status and recurrence location at time of relapse. (A) Patients are sorted by time to recurrence. Only patients with blood drawn prior to or at the day of CT imaging are included (N = 39). Patient ID 55 was excluded because the first longitudinal blood sample was drawn 2.8 months subsequent to the relapse. (B) ctDNA positivity of matched blood samples from patients with liver or lung metastases were unevenly distributed (Fisher's exact test, P = .0016)

FIGURE 4

ctDNA stratified relapse rates of patients with indeterminate CT findings. (A) Kaplan‐Meier estimates (CI = 95%) of recurrence free survival for 21 CRLM patients with indeterminate findings stratified by concomitant ctDNA status before first relapse. (B) Kaplan‐Meier estimates (CI = 95%) of recurrence free survival for all patients with indeterminate findings stratified by concomitant ctDNA status. A patient was called positive if a concomitant plasma sample was ctDNA positive