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

• Published in: Clinical cancer research Vol. 26; no. 8; pp. 1877 - 1885
• Main Authors: Parikh, Aparna R, Mojtahed, Amikasra, Schneider, Jaime L, Kanter, Katie, Van Seventer, Emily E, Fetter, Isobel J, Thabet, Ashraf, Fish, Madeleine G, Teshome, Bezaye, Fosbenner, Kathryn, Nadres, Brandon, Shahzade, Heather A, Allen, Jill N, Blaszkowsky, Lawrence S, Ryan, David P, Giantonio, Bruce, Goyal, Lipika, Nipp, Ryan D, Roeland, Eric, Weekes, Colin D, Wo, Jennifer Y, Zhu, Andrew X, Dias-Santagata, Dora, Iafrate, A John, Lennerz, Jochen K, Hong, Theodore S, Siravegna, Giulia, Horick, Nora, Clark, Jeffrey W, Corcoran, Ryan B
• Format: Journal Article
• Language: English
• Published: United States 15-04-2020
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - genetics; Circulating Tumor DNA - blood; Disease Progression; Female; Gastrointestinal Neoplasms - blood; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - pathology; High-Throughput Nucleotide Sequencing - methods; Humans; Longitudinal Studies; Male; Middle Aged; Mutation; Neoplasm Metastasis; Prospective Studies; Survival Rate; Treatment Outcome; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-19-3467

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.
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.
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,
< 0.0001) and clinical benefit [CB: PR and stable disease (SD),
< 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 (
< 0.0001). Four-week change in tumor markers also predicted response (
= 0.0026) and CB (
= 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 (
= 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;
< 0.0001).
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.