Dr. Nicholas Hornstein on ctDNA, Colorectal Cancer and Why Better Drugs Are Coming

In this episode of The Moonlight Shift, Nicholas Hornstein, MD, PhD, a hematologist-oncologist and assistant professor at Northwell Health's Zucker School of Medicine, joins host Gina Mauro for a conversation spanning liquid biopsy science, clinical trial design, computational biology, and what it actually takes to build a research program from the ground up.

Hornstein — who trained in computational systems biology at Columbia University before a fellowship at The University of Texas MD Anderson Cancer Center — describes himself as "pluripotent": a clinician-scientist who chose the longer path specifically because he believed research could help more patients than a clinic schedule alone ever could.

What ctDNA Can and Cannot Do

Hornstein opens with a clear-eyed account of where liquid biopsy stands in colorectal cancer today. A positive ctDNA result after surgery — in a patient with clean imaging and normal CEA — is no longer a curiosity. With newer generation assays, he explains, it represents an overwhelming likelihood of recurrence if nothing changes. The technology has effectively given oncologists X-ray vision for residual cancer cells that no scan can see. The problem, he argues, is that the clinical tools available to act on that signal have not kept pace with the technology producing it.

The INTERCEPT-TT Trial and the Honest Reckoning

Hornstein discusses the INTERCEPT-TT program — a series of trials at The University of Texas MD Anderson Cancer Center designed to intercept colorectal cancer recurrence in patients with ctDNA-defined minimal residual disease before it becomes visible on imaging. He references 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 he draws is consistent with what he has said publicly before: 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.

Building Northwell's GI Oncology Research Program

A significant portion of the conversation concerns what it looks like to build a clinical research program at an institution where one did not previously exist in a mature form. When Hornstein joined Northwell Health, the GI oncology research infrastructure was limited. Two years later, the program has grown to include a half-dozen investigator-initiated studies in colorectal cancer, 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.

Computational Biology at the Bedside

Hornstein's PhD background in computational systems biology is not incidental to his clinical work — it is central to it. He describes an ongoing initiative at Northwell using large language models and natural language processing to extract structured, actionable data from pathology reports and clinical notes, enabling the health system to identify trial-eligible patients earlier and ensure that molecular sequencing is ordered at the right point in each patient's care. He is direct about the ambition: the goal is to use data that already exists within the electronic medical record to improve care delivery at a system level, not just for the patients he personally treats.

What He's Watching Beyond Daraxonrasib

Asked what caught his attention at the 2026 ASCO Annual Meeting beyond the already widely-discussed plenary presentation of daraxonrasib in pancreatic cancer, Hornstein points to a c-MET inhibitor showing a 23% overall response rate in heavily pretreated metastatic colorectal cancer, and a phase 1 combination of a RAS inhibitor with an MTAP-deletion PRMT5 inhibitor demonstrating a disease control rate exceeding 90% in pancreatic cancer. He 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.

The Moonlight Shift is available on YouTube and across MJH Life Sciences’ oncology platforms. New episodes, released bi-weekly, feature leading and early-career oncologists from the Tri-State corridor in peer-level conversations about where the field is going — and what it still has to work out.