In neoadjuvant settings, ctDNA monitoring allows for real-time therapy adjustment. Data from the iSpy platform shows 80% of hormone-positive patients clear ctDNA with half the chemotherapy, enabling de-escalation, while the remaining 20% can be identified for escalated treatment.

While not yet validated, ctDNA is being used by clinical experts as a de-escalation tool to provide confidence when stopping long-term maintenance therapies like PARP inhibitors. This novel application focuses on reducing treatment burden rather than solely detecting disease progression.

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.

Upcoming trials like RETAIN and IMVigor011 are using circulating tumor DNA (ctDNA) to guide complex treatment choices in muscle-invasive bladder cancer. This biomarker-driven approach aims to personalize therapy, potentially enabling bladder preservation for some patients and identifying others who need additional adjuvant treatment.

The landmark DYNAMIC-2 study showed that using ctDNA to guide adjuvant therapy decisions in Stage II colon cancer cut chemotherapy use by 50% (from 30% to 15% of patients). This de-escalation was achieved without any negative impact on patient outcomes, validating the approach.

The practice-changing DYNAMIC trial showed that a ctDNA-guided strategy for stage II colorectal cancer reduces adjuvant chemotherapy use by 50%. Despite this significant de-escalation of treatment, patient outcomes and survival rates were identical to the standard-of-care approach.

Despite the success of ctDNA-guided de-escalation in Stage II disease, the DYNAMIC-3 trial in Stage III patients showed that ctDNA-negative patients had worse outcomes with de-escalated therapy. This serves as a critical warning against this de-escalation strategy in higher-risk patients for now.

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.

In neoadjuvant breast cancer treatment, patients with residual cancer post-therapy remain at high risk of recurrence (10-20%) even if their ctDNA tests are negative. This finding suggests that the physical presence of residual disease is a critical factor, and ctDNA status alone cannot justify forgoing additional adjuvant therapy in this cohort.