Historically, discussing adjuvant therapy for Stage III colon cancer was quick and straightforward, while Stage II was complex. The advent of ctDNA testing has reversed this dynamic. Stage II decisions are now clearer (treat if positive), while Stage III discussions have become much longer and more nuanced as clinicians integrate ctDNA data with patient preferences.

While the DYNAMIC-2 trial confirmed a ctDNA-guided approach is non-inferior for Stage II colon cancer and reduces chemotherapy use, the DYNAMIC-3 trial in Stage III patients failed to prove non-inferiority for de-escalation or show benefit for escalation. This highlights a critical, stage-dependent limitation in using current MRD assays.

Circulating tumor DNA (ctDNA) testing is described as unequivocally the most prognostic tool available for colorectal cancer. Patients who remain serially negative have a minimal recurrence risk, while a positive result almost universally predicts a future clinical recurrence by 6-8 months.

Instead of basing adjuvant radiation decisions on a patient's initial, pre-treatment tumor stage, clinicians should use the post-neoadjuvant pathological stage (ypTNM). Patients with a major pathologic response (e.g., downstaging from T3 to T1) may be able to safely avoid additional adjuvant radiation therapy.

Oncologists are more comfortable using a positive ctDNA test to escalate care (e.g., recommend chemo for a low-risk Stage II patient). However, they are more hesitant to use a negative test to de-escalate or withhold standard chemo for higher-risk patients, pending more definitive trial data.

The Rampart study's use of the Leibovic score for risk stratification is a key strength. Unlike traditional TNM staging, this score more heavily weights tumor grade, which clinicians find to be a more granular and clinically relevant predictor of recurrence risk than just tumor size.

For every 10 Stage III patients receiving adjuvant chemo, 5 are already cured by surgery and 2-3 will recur regardless. This means therapy only benefits 2-3 patients, leading to significant overtreatment for the majority who endure toxicity without benefit.

The standard approach for first-line metastatic colorectal cancer is obsolete. Clinicians must test for and categorize patients into at least four, soon five, distinct biomarker-defined subgroups (MSI-high, BRAF V600E, RAS/RAF wild-type, HER2-positive, and the RAS-mutated "catch-all") to select the optimal initial therapy.

The clinical definition of "high-risk" prostate cancer is evolving due to improved diagnostics. The move from digital rectal exams to more sensitive MRI for T-staging means more patients meet the criteria for being high-risk. This "stage migration" makes it challenging to apply findings from older clinical trials to a contemporary patient population.