Use of circulating tumor DNA (ctDNA) to monitor patients undergoing total neoadjuvant treatment (TNT) for locally advanced rectal adenocarcinoma (LARC).
Abstract
30 Background: While many patients with LARC experience durable responses after TNT, relapse risk remains a concern and is not reliably predicted by standard clinicopathologic measures. ctDNA is a promising biomarker for minimal residual disease (MRD) that could improve post-TNT risk-stratification and guide postoperative surveillance; however, reduced sensitivity demonstrated in previous studies has limited its clinical utility in this setting. Methods: In an ongoing prospective study of patients with LARC receiving TNT, plasma was collected pre-treatment, after TNT but before surgery, post-surgery (“landmark”), and every 3 months for 1 year. ctDNA analysis was performed using a tumor-informed MRD assay interrogating up to 50 personalized variants (Haystack MRD), and results were evaluated alongside clinical outcomes. Results: Forty patients treated with TNT followed by surgery were included in this analysis. Pre-treatment ctDNA was detected in 13/13 (100%) patients. Among 34 patients with ctDNA results post-TNT, 32/34 (94%) had residual disease and 2/34 (6%) achieved pathologic complete response (pCR). ctDNA was detected post-TNT in 22/32 (69%) patients with residual disease, while both patients with pCR were ctDNA negative. Post-TNT sensitivity was higher in patients with pathologic stage III/IV versus I/II disease (15/18 [83%] vs 7/14 [50%]). Out of 20 patients with ctDNA results at the landmark post-surgical time point, all 5 (100%) patients with positive ctDNA relapsed, while 1/15 (7%) ctDNA-negative patients relapsed (this patient had detectable ctDNA at 6-months post-surgery), yielding 83% sensitivity and 93% negative predictive value for disease relapse at the landmark timepoint, and 100% sensitivity within 6 months of surgery. Testing of additional patients and time points is ongoing. Conclusions: A next-generation tumor-informed MRD assay shows excellent sensitivity for ctDNA detection in LARC patients pre-treatment (100%) and post-surgery (83% at landmark, 100% at 6 months). Post-TNT sensitivity was 69% overall and 83% in stage III/IV disease, representing an improvement over previous reports. These initial findings support integrating ctDNA into post-TNT risk stratification and postoperative surveillance in LARC; testing of additional patients/time points and further follow up is ongoing to validate these results.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (20)
Harrison David Winters
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
Thanh J. Nguyen
Sidney Kimmel Comprehensive Cancer, Johns Hopkins University, Baltimore, MD
Reena Suresh
Department of Surgery, Johns Hopkins University, Baltimore, MD
Ervin J. Griffin
Sidney Kimmel Comprehensive Cancer, Johns Hopkins University, Baltimore, MD
Shannon Radomski
Department of Surgery, Johns Hopkins University, Baltimore, MD
Kareem Adams
Sidney Kimmel Comprehensive Cancer, Johns Hopkins University, Baltimore, MD
Charles Pierce
Sidney Kimmel Comprehensive Cancer, Johns Hopkins University, Baltimore, MD
Valerie Lee
Dan Laheru
Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
Nilo Azad
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD
Dung T. Le
Andrea Bafford
Department of Surgery, Johns Hopkins University, Baltimore, MD
Alodia Gabre-Kidan
Department of Surgery, Johns Hopkins University, Baltimore, MD
Hillary S. Sloane
Haystack Oncology, Baltimore, MD
Daniel L. Edelstein
Haystack Oncology, Baltimore, MD
Kneshay Harper
Haystack Oncology, Inc, Baltimore, MD
Emily Gramiccioni
Haystack Oncology, Inc, Baltimore, MD
Hannah Quinn
Haystack Oncology, Baltimore, MD
John Migaly
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
Eric Scott Christenson
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD