ctDNA-Guided Adjuvant Therapy in Colorectal Cancer: BESPOKE CRC and the Promise of Next-Generation Drugs
核心洞察
Nicholas Hornstein, MD, PhD, highlights that positive ctDNA after colorectal cancer (搜索) surgery signals an overwhelming likelihood of recurrence despite clean imaging and normal CEA.
The BESPOKE CRC study is reshaping clinical practice by examining ctDNA-guided adjuvant therapy decision-making for patients with stage II colorectal cancer (搜索).
Hornstein argues that current approved agents are insufficient to change disease trajectory, and the real clinical transformation will come from next-generation drugs now in phase 2 and 3 trials.
Liquid biopsy technology has given oncologists what Nicholas Hornstein, MD, PhD, describes as "X-ray vision" for residual cancer cells that no scan can detect. A positive ctDNA result after colorectal cancer (搜索) surgery — in a patient with clean imaging and normal CEA — now represents an overwhelming likelihood of recurrence if nothing changes. Yet Hornstein, a hematologist-oncologist and assistant professor at Northwell Health's Zucker School of Medicine, argues that the clinical tools available to act on that signal have not kept pace with the technology producing it.
The BESPOKE CRC study (NCT04264702) stands at the center of this evolving landscape, examining ctDNA-guided adjuvant therapy decision-making in colorectal cancer (搜索) and how liquid biopsy is beginning to reshape clinical practice for patients with stage II disease. Hornstein ranked this among the most impactful GI oncology trials of the past year, underscoring its role in moving ctDNA from a prognostic curiosity toward a actionable clinical tool.
The INTERCEPT-TT Program and the Honest Reckoning
Hornstein discussed the INTERCEPT-TT program, a series of trials at The University of Texas MD Anderson Cancer Center designed to intercept colorectal cancer (搜索) recurrence in patients with ctDNA-defined minimal residual disease before it becomes visible on imaging. He referenced updated data from the ALTAIR trial, a large Japanese ctDNA initiative, which showed that while disease-free survival was extended by approximately three months, the intervention did not change the fundamental course of the disease.
The conclusion Hornstein draws is consistent with what he has stated publicly: "The next generation of drugs, currently in phase 2 and 3 trials, is where the real clinical transformation will come from — not the agents currently approved in this setting."
Emerging Signals Across GI Malignancies
Asked what caught his attention at the 2026 ASCO Annual Meeting beyond the widely-discussed plenary presentation of daraxonrasib in pancreatic cancer, Hornstein pointed to several early-phase signals. A c-MET (搜索) inhibitor demonstrated a 23% overall response rate in heavily pretreated metastatic colorectal cancer (搜索). Additionally, a phase 1 combination of a RAS (搜索) inhibitor with an MTAP-deletion PRMT5 inhibitor showed a disease control rate exceeding 90% in pancreatic cancer.
Hornstein argues that these early signals, alongside the continuing maturation of antibody-drug conjugates and molecular glues, suggest the next several years will see meaningful new options reaching the clinic across GI malignancies.
Landmark Trials Reshaping the Treatment Landscape
Among the trials Hornstein ranked as most impactful, the phase 3 BREAKWATER trial (NCT04607421) moved BRAF (搜索)-targeted therapy into the first-line metastatic colorectal cancer (搜索) setting and doubled overall survival for a patient population where prognosis had long been poor. The phase 3 RASolute 302 trial (NCT06625320), evaluating daraxonrasib in second-line metastatic pancreatic ductal adenocarcinoma (搜索), was described by Hornstein as the most exciting development on his list, given that it targets a previously undruggable pathway and has pushed survival from months to nearly two years.
The phase 3 MATTERHORN trial (NCT04592913), evaluating the addition of durvalumab to FLOT chemotherapy in upper GI adenocarcinomas, and the phase 3 MOUNTAINEER-03 trial (NCT05253651), exploring dual HER2 (搜索)-targeted therapy in the front-line colorectal cancer (搜索) setting, round out the studies Hornstein identified as practice-changing.
Building Infrastructure for System-Level Impact
Since joining Northwell Health, Hornstein has built a GI oncology research program that now includes a half-dozen investigator-initiated studies in colorectal cancer (搜索), a robust sponsored trial portfolio, and — by his account — a clinical trial available for every patient with colorectal cancer regardless of where they are in their treatment journey. Northwell diagnoses approximately 26,000 new patients with cancer annually across its system, a scale he describes as both the challenge and the opportunity of the role.
Drawing on his PhD background in computational systems biology from Columbia University, Hornstein is leading an initiative using large language models and natural language processing to extract structured, actionable data from pathology reports and clinical notes. The goal is to use data that already exists within the electronic medical record to identify trial-eligible patients earlier and ensure molecular sequencing is ordered at the right point in each patient's care.