Colorectal Cancer Observational Data and Risk Stratification

Dr. Weinberg discusses 2 major observational datasets informing colorectal cancer ctDNA practice.

The BESPOKE CRC study, conducted in the United States with Georgetown's participation, uniquely surveyed physicians and patients about result interpretation and reactions, finding that while "ctDNA anxiety" represents a real phenomenon with some patients preferring not to know, most patients want this information, and predominantly negative results help alleviate anxiety.

The GALAXY trial, a large Japanese observational study enrolling stage I to IV patients, included the ALTAIR interventional trial testing trifluridine/tipiracil versus placebo for patients remaining ctDNA-positive after completing adjuvant therapy; this escalation study was negative, suggesting that using later-line approved drugs earlier doesn't necessarily provide benefit.

These studies demonstrated that ctDNA positivity is prognostic regardless of stage and may be a stronger recurrence predictor than traditional staging.

Dr. Weinberg suggests the field needs to move beyond TNM staging, as pathology reports represent a single timepoint whereas ctDNA monitors ongoing disease status.

He illustrates this with the example that a traditionally low-risk T1N1 stage III patient who is ctDNA-negative likely has better prognosis than a traditionally high-risk T4N0 stage II patient who is ctDNA-positive.

GALAXY data showed that ctDNA-positive patients not receiving adjuvant chemotherapy recurred quickly regardless of stage, whereas ctDNA-positive patients receiving chemotherapy had substantially better outcomes.

In contrast, ctDNA-negative patients showed minimal outcome differences whether or not they received adjuvant chemotherapy, particularly in high-risk stage II and stage III populations, although Dr. Weinberg cautions against over-interpreting non-randomized observational data.

He notes increased comfort withholding adjuvant chemotherapy in ctDNA-negative stage II patients, while awaiting Circulate North America's prospective randomized data to definitively address stage III de-escalation and escalation strategies.