Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers

Abstract

Purpose: ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer.

Experimental design: A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response.

Results: A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P < 0.0001). Four-week change in tumor markers also predicted response (P = 0.0026) and CB (P = 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (P = 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00; P < 0.0001).

Conclusions: Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.

©2020 American Association for Cancer Research.

Figures

Figure 1.

Draw Schedule (a) and Consort Diagram (b)

Figure 2.

Change in ctDNA (panels a, b) and tumor markers (panels c, d) at 4 weeks are shown for patients grouped by radiographic response by RECIST1.1 criteria. Each data point represents the percent change in ctDNA or tumor markers at 4 weeks relative to baseline for a single patient. Horizontal bars represent the median and error bars indicate 95% Confidence Interval. PR: partial response; SD: stable disease; PD: progressive disease; CB: clinical benefit.

Figure 3.

Kaplan Meier curves showing progression-free survival by percent change in ctDNA for all patients at 4 weeks (panel a), 8 weeks (panel b) from treatment initiation, or for patients with CRC only (panel c) or non-CRC at 4 weeks (panel d). mPFS: median progression free survival.

Figure 4.

Panels a-d: Changes in ctDNA at 2 weeks (panels a, b) or 8 weeks (panels c, d) of treatment by RECIST1.1 criteria in patients achieving partial response (PR), stable disease (SD) and progressive disease (PD) (panels a, c) or clinical benefit (CB) and PD (panels b, d). Panel e: Longitudinal ctDNA changes during the first 100 days of therapy in patients with PR (upper panel, purple lines), SD (middle panel, blue and orange lines) and PD cases (lower panel, red lines). For SD patients, blue lines represent patients with PFS 6 months. Horizontal bars represent the median and error bars indicate 95% Confidence Interval.