Molecular Disease Rather Than Visible Disease! Where Do ctDNA Tests Stand in Bladder and Colon Cancer?
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Will blood tests now determine adjuvant treatment decisions?
Two major phase 3 trials presented at the 2025 ESMO Congress— IMvigor011 (bladder cancer) and DYNAMIC-III (colon cancer)—showed that, after cancer surgery, measuring circulating tumor DNA (ctDNA) could guide adjuvant treatment decisions and spare many patients unnecessary chemotherapy.
These studies are milestones in bringing into clinical practice the concept of the risk of cancer recurrence being predicted earlier and more sensitively than conventional pathological staging through molecular residual disease (MRD) assessment.
In particular, IMvigor011 showed that adjuvant immunotherapy (atezolizumab) in bladder cancer provided a significant survival benefit only in ctDNA-positive patients, supporting the view that ‘treatment should be given to those with persistent molecular disease, rather than to most patients.’
Meanwhile, DYNAMIC-III showed that reducing chemotherapy in ctDNA-negative colon cancer patients may be possible, but the evidence for this strategy is not yet sufficient to replace standard care.
Figure Explained
Minimal Residual Disease (MRD)refers to microscopic cancer cells remaining after surgical tumor removal. MRD can be detected through circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in the bloodstream.
ctDNA has a very short half-life (minutes). Therefore, ctDNA detected immediately after surgery generally comes not from the primary tumor but from remaining disseminated tumor cells (DTCs) or developing micrometastases instead.
Dormant DTCs may reactivate over time, increase ctDNA release, and acquire metastatic potential, initiating new tumor sites in distant organs such as bone marrow, liver, or lungs.
Why does it matter?
While detecting recurrence through conventional radiological imaging takes months, ctDNA testing can identify microscopic traces of cancer within weeks. This represents a revolutionary approach for both early intervention and prevention of unnecessary toxicity.
The concept of ‘molecular disease’ is now gaining prominence over ‘visible disease,’ and planning treatment through a blood test is becoming very close to reality.
IMvigor011: Personalized Follow-Up with ctDNA in Bladder Cancer
Study aim
After radical cystectomy for muscle-invasive bladder cancer (MIBC), approximately 50% of patients experience recurrence. Conventional methods, however, struggle to predict which patients will relapse.
IMvigor011 investigated whether detecting circulating tumor DNA (ctDNA) in postoperative blood samples could guide adjuvant immunotherapy decisions.
Study design
- A total of 607 patients were enrolled (MIBC, after cystectomy).
- All patients, during 6–24 weeks after surgery, underwent serial ctDNA testing as part of follow-up.
- 250 ctDNA-positive patients were randomized to two arms:
- Atezolizumab (n = 167) – every 4 weeks for 1 year
- Placebo (n = 83)
- 357 ctDNA-negative patients were observed only.
Key findings
- Median time to disease (DFS): In the atezolizumab arm, 9.9 months versus, in the placebo arm, 4.8 months (HR: 0.64; p=0.0047).
- Overall survival (OS): In the atezolizumab arm, 32.8 months, and in the placebo arm, 21.1 months (HR: 0.59; p=0.0131).
- Adverse-event rates: Grade 3–4 toxicity in the atezolizumab arm: 28.5%, versus placebo: 21.7%.
- Fatal adverse-event rate: 1.8% (atezolizumab) vs 0% (placebo).
Clinical significance
These results demonstrated that ctDNA positivity is a strong biomarker predicting response to adjuvant immunotherapy . Atezolizumab provided significant benefit in ctDNA-positive patients, while ctDNA-negative patients achieved excellent survival even without treatment: 95% at 1 year and 88% at 2 years.
Thus, ‘adjuvant treatment for everyone’ began giving way to ‘treatment only for those with molecular disease.’
DROZDOGAN Academy Commentary
IMvigor011 strongly illustrates shifting oncology paradigms. Whether a patient receives adjuvant treatment is no longer determined solely by pathological stage but also by the presence of molecular traces in the blood itself.
This approach demonstrates that cancer biology is much more dynamic than appearances suggest and that disease can be detected ‘before it is seen’ . An era is beginning in which decisions rely not on CT scans but on the disease’s genetic echo instead.
We see this transformation as more than technological progress: it is a turning point in oncology’s philosophy. ‘Our aim is no longer to treat disease, but to recognize it before it starts again.’
DYNAMIC-III: Can ctDNA Help Reduce Chemotherapy in Colon Cancer?
Study aim
Adjuvant chemotherapy after colon cancer surgery is standard for reducing recurrence risk. However, giving every patient the same chemotherapy intensitycauses unnecessary toxicity in some.
DYNAMIC-III evaluated whether, after surgery, ctDNA-negative patients could safely receive shorter, less intensive chemotherapy (de-escalation). The aim was to reduce treatment adverse effects while preserving efficacy in low-risk patients.
Study design
- 702 patients with stage III colon cancer were enrolled.
- Patients were assessed 5–6 weeks after surgery using ctDNA testing.
- ctDNA-negative patients were divided into two arms:
- Standard care: 6 months of chemotherapy determined by the clinical team (mostly oxaliplatin + fluoropyrimidine)
- ctDNA-guided arm: Treatment duration was shortened or drug intensity reduced based on a negative test result
- De-escalation approaches included shortening treatment from 6 to 3 months or using fluoropyrimidine alone.
Key findings
- Oxaliplatin use: In the standard arm, 89% compared with the ctDNA-guided arm, where it fell to 35%of patients.
- Hospitalization rate: In the standard arm, 13.2%, and in the ctDNA-guided arm, 8.5% (p = 0.047).
- Grade ≥3 adverse events: In the standard arm, 10.6%, and in the ctDNA-guided arm, 6.2% (p = 0.037).
- 3-year recurrence-free survival (RFS): With standard care, 88.1%, and in the ctDNA-guided arm, 85.3%.
Consequently, the study did not statistically meet the threshold for being non-inferior (that is, it did not establish ‘no worse’ efficacy).
Subgroup analyses
- Low-risk (T1–3N1) patients: 3-year RFS 93.2% (standard) vs 91.0% (ctDNA-guided) → nearly equivalent.
- High-risk (T4 and/or N2) patients: 3-year RFS 78.6% (standard) vs 72.8% (ctDNA-guided) → the difference became more pronounced.
These findings suggest that reducing chemotherapy in ctDNA-negative, low-risk stage III patients may be a reasonable option, but caution is still required in high-risk cases.
DROZDOGAN Academy Commentary
ctDNA negativityis a strong indicator of low recurrence risk and supports the possibility of reducing chemotherapy intensity in some patients. Current evidence, however, does not allow this strategy to replace standard care for all stage III cases.
We see this study as an important step in clinical oncology toward measuring risk at the molecular level, rather than only through a microscope . Future decision algorithms are expected to combine ctDNA, tumor biology, microsatellite status, and radiological dynamics.
Overall Assessment and Outlook: The Era of Monitoring Cancer Through Blood Tests
What have we learned?
IMvigor011 and DYNAMIC-III together clearly show the beginning of an era of molecular personalization in cancer treatment. ctDNA is beginning to become more than a research tool: it is a clinical guide capable of directing treatment decisions in practice.
In bladder cancer, IMvigor011 demonstrated genuine survival benefit from immunotherapy in ctDNA-positive patients—the first evidence in oncology for selective adjuvant treatment as a concept.
In colon cancer, DYNAMIC-III suggested chemotherapy reduction may be safe in certain ctDNA-negative subgroups, indicating that the ‘same treatment for everyone’ era is nearing its end.
Shared implications
- ctDNA positivityis a strong biomarker for predicting adjuvant treatment response.
- ctDNA-negative patients have a lower recurrence risk in many cancers and may benefit from treatment de-escalation.
- This test shifts treatment decisions away from dependence on radiological imaging toward a blood-based approach.
- However, ctDNA remains a supportive decision-making tool and should be assessed alongside clinical, pathological, and genetic information.
Looking Ahead
Over the next few years, ctDNA tests are expected to enter routine follow-up protocols for cancer patients. The goal is to detect recurrence before imaging and eliminate unnecessary toxicity.
Oncology now focuses not only on ‘where’ a tumor is but on what it is doing at the molecular level . This brings us toward medicine that ‘recognizes disease in advance rather than simply monitoring it.’
In brief, future oncology may one day be shaped by blood tests rather than CT scans —and studies such as IMvigor011 and DYNAMIC-III are opening the door to that future.
📚 Sources
- Powles T, et al. IMvigor011: ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. The New England Journal of Medicine; 2025. Article link
- Tie J, et al. DYNAMIC-III: ctDNA-guided de-escalation in stage III colon cancer. Nature Medicine; 2025. Article link
- IMvigor011 Study Group. ESMO 2025 Annual Meeting — Abstract LBA##. ESMO abstract page
- DYNAMIC-III Investigators. ESMO 2025 Annual Meeting — Abstract LBA##. ESMO abstract page
- Science Media Centre (UK). Expert reaction: ctDNA-guided adjuvant therapy in colon cancer (comment by Marco Gerlinger, MD). 2025. Statement link
- IMvigor010 Exploratory Analysis: ctDNA positivity and adjuvant atezolizumab outcomes in MIBC. Source link
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