The Era of ctDNA and Treatment Based on Molecular Response Has Begun in Cancer
Reading tools
In this article
ctDNA and TOMR Studies
The "Treat On Molecular Response" Paradigm in Genitourinary, Gastrointestinal, and Breast Cancers
A Paradigm Shift: From "Treat All" to "Treat on Molecular Response"
In oncology, adjuvant (preventive) treatments are traditionally given to broad patient groups based on tumor stage and pathological features to reduce recurrence risk. However, this approach can expose patients who have been cured to unnecessary toxicity ("overtreatment") or result in inadequate treatment of high-risk patients ("undertreatment").
As of 2025, tumor-specific ctDNA (circulating tumor DNA) assays (e.g., Signatera) have become the most powerful biomarker for personalizing treatment by detecting microscopic residual disease (MRD). This monograph reviews the technical details, patient selection criteria, and statistical results (HRs, p values) of landmark studies such as IMvigor011, CheckMate 274, CIRCULATE, and DARE.
Genitourinary (GU) Cancers
CheckMate 274: Adjuvant Nivolumab (5-Year Data) PROGNOSTIC
Study Design
Phase 3, randomized, double-blind, multicenter.
Population (N=709)
High-risk muscle-invasive urothelial carcinoma (MIBC). After radical resection (ypT2-pT4a/ypN+ or pT3-pT4a/pN+ without neoadjuvant therapy).
Arms
Arm A: Nivolumab 240 mg IV q2w (1 year)
Arm B: Placebo
Arm B: Placebo
5-Year Efficacy Results:
- ITT (All Patients): Median DFS 21.9 months (Nivo) vs 11.0 months (Placebo).
- ITT Overall Survival (OS): Median 75.0 months (Nivo) vs 50.1 months (Placebo).
- PD-L1 ≥ 1%: Median DFS 55.5 months (Nivo) vs 8.4 months (Placebo).
ctDNA Analysis (Post Hoc, N=133):
ctDNA was detected at baseline in 40.6% of patients (54/133). In ctDNA-positive patients, nivolumab treatment:
• Doubled median DFS.
• Increased median OS from 19.3 months to 36.2 months .
ctDNA was detected at baseline in 40.6% of patients (54/133). In ctDNA-positive patients, nivolumab treatment:
• Doubled median DFS.
• Increased median OS from 19.3 months to 36.2 months .
IMvigor011: Evidence for the TOMR Paradigm DECISION-GUIDING
Published in NEJM and at ESMO 2025, this study aimed to spare negative patients toxicity by treating only those who developed molecular relapse (ctDNA+).
Study Schema 1. Screening: Patients with (y)pT2-T4aN0M0 or N+ disease after radical cystectomy. No radiographic disease.
2. Monitoring: Serial Signatera ctDNA testing every 6 weeks for 12 months.
3. Intervention: Only patients who became ctDNA-positive were randomized (2:1).
4. Arms: Atezolizumab (1680 mg q4w) vs. placebo.
2. Monitoring: Serial Signatera ctDNA testing every 6 weeks for 12 months.
3. Intervention: Only patients who became ctDNA-positive were randomized (2:1).
4. Arms: Atezolizumab (1680 mg q4w) vs. placebo.
ctDNA-Positive Group (Treated):
• DFS: HR 0.64 (p=0.005). Median DFS 9.9 months (Atezo) vs 4.8 months (placebo).
• OS: HR 0.59 (p=0.01). Median OS 32.8 months (Atezo) vs 21.1 months (placebo).
• The risks of recurrence and death were significantly reduced.
• DFS: HR 0.64 (p=0.005). Median DFS 9.9 months (Atezo) vs 4.8 months (placebo).
• OS: HR 0.59 (p=0.01). Median OS 32.8 months (Atezo) vs 21.1 months (placebo).
• The risks of recurrence and death were significantly reduced.
ctDNA-Negative Group (Monitoring Only):
• Despite receiving no adjuvant treatment:
• Year 1 DFS: 95.4%
• Year 2 DFS: 88.4%
• This group was spared unnecessary immunotherapy and side effects.
• Despite receiving no adjuvant treatment:
• Year 1 DFS: 95.4%
• Year 2 DFS: 88.4%
• This group was spared unnecessary immunotherapy and side effects.
MODERN (A032103) ONGOING
Aim
Treatment escalation and de-escalation.
Cohort A (ctDNA+): Nivolumab vs. nivolumab + relatlimab (LAG-3 inhibitor).
Cohort B (ctDNA-): Monitoring (de-escalation). Nivo is started if ctDNA becomes positive.
Cohort B (ctDNA-): Monitoring (de-escalation). Nivo is started if ctDNA becomes positive.
ARCHER (NRG-GU015) ONGOING
Aim
Optimization of radiotherapy in bladder-preserving treatment.
Arms: Hypofractionated RT vs. SBRT (ultrahypofractionated).
Role of ctDNA: Monitored as a prognostic biomarker from the start of chemotherapy.
Role of ctDNA: Monitored as a prognostic biomarker from the start of chemotherapy.
Gastrointestinal (GI) Cancers
CALGB/SWOG 80702 (JAMA Oncol 2025) POST-HOC
ctDNA analysis of the trial investigating the addition of celecoxib (a COX-2 inhibitor) to standard adjuvant treatment (FOLFOX) in stage III colon cancer.
Population
Stage III colon cancer (N=2526). FOLFOX duration (3 vs 6 months) and celecoxib (3 years vs placebo).
Key Findings:
In the original trial, celecoxib did not benefit the overall population. However, analysis with ctDNA (Signatera) showed:
1. Prognostic Value: In ctDNA(+) patients, DFS HR 6.12, OS HR 5.86 (Poor prognosis).
2. Predictive Value (Celecoxib Benefit):
• ctDNA-Positive Group: Adding celecoxib provided DFS (HR 0.61, p=0.011) and OS (HR 0.62, p=0.034) benefits.
• ctDNA-Negative Group: Celecoxib provided no benefit.
Interpretation: Inflammation (the COX-2 pathway) appeared to be a driver only in the high-risk/residual-disease group.
In the original trial, celecoxib did not benefit the overall population. However, analysis with ctDNA (Signatera) showed:
1. Prognostic Value: In ctDNA(+) patients, DFS HR 6.12, OS HR 5.86 (Poor prognosis).
2. Predictive Value (Celecoxib Benefit):
• ctDNA-Positive Group: Adding celecoxib provided DFS (HR 0.61, p=0.011) and OS (HR 0.62, p=0.034) benefits.
• ctDNA-Negative Group: Celecoxib provided no benefit.
Interpretation: Inflammation (the COX-2 pathway) appeared to be a driver only in the high-risk/residual-disease group.
The CIRCULATE Platform (Colorectal Cancer) GLOBAL
The largest international consortium basing adjuvant chemotherapy decisions entirely on ctDNA results in stage II and III colon cancer.
North America (NRG-GI008) ctDNA-Negative (Cohort A):
• Monitoring (No Chemotherapy) vs. Standard Chemotherapy (De-escalation)
ctDNA-Positive (Cohort B):
• Standard FOLFOX vs. mFOLFIRINOX (Escalation/Intensification)
• Monitoring (No Chemotherapy) vs. Standard Chemotherapy (De-escalation)
ctDNA-Positive (Cohort B):
• Standard FOLFOX vs. mFOLFIRINOX (Escalation/Intensification)
Japan (VEGA & ALTAIR) VEGA (ctDNA-Negative):
• Noninferiority trial of postoperative monitoring without chemotherapy.
ALTAIR (ctDNA-Positive):
• Superiority of TAS-102 (trifluridine/tipiracil) over placebo (Result: Positive).
• Noninferiority trial of postoperative monitoring without chemotherapy.
ALTAIR (ctDNA-Positive):
• Superiority of TAS-102 (trifluridine/tipiracil) over placebo (Result: Positive).
TRINITY: Targeted Adjuvant Treatment in Gastric Cancer INTERVENTIONAL
Patient Group
Resected HER2-positive gastric or gastroesophageal junction (GEJ) cancer.
Criterion
ctDNA positivity (MRD+) in plasma collected at postoperative weeks 2-6.
Intervention
Experimental Arm: T-DXd (Trastuzumab Deruxtecan) 6.4 mg/kg + fluoropyrimidine (6 cycles).
Control Arm: Standard FLOT regimen (4 cycles).
Control Arm: Standard FLOT regimen (4 cycles).
Primary Endpoint: ctDNA clearance rate at year 1.
Breast Cancer
LEADER: Adjuvant Intervention With Ribociclib PHASE 2
Design
Early-stage HR+/HER2- breast cancer. Standard postoperative endocrine therapy (ET) vs. ET + ribociclib (CDK4/6 inhibitor).
ctDNA Findings:
• Among patients who developed recurrence, 100% became ctDNA-positive before recurrence.
• Lead Time (Early Warning): ctDNA was detected a median of 7.5 months before radiological recurrence. This interval offers a critical window for early intervention.
• Among patients who developed recurrence, 100% became ctDNA-positive before recurrence.
• Lead Time (Early Warning): ctDNA was detected a median of 7.5 months before radiological recurrence. This interval offers a critical window for early intervention.
DARE: Treating Molecular Relapse With Palbociclib ASCO 2025
Design
HR+/HER2- patients who became ctDNA-positive during monitoring (without radiological metastases).
Randomization
Arm A (Treatment): Palbociclib + fulvestrant (2 years).
Arm B (Control): Continue current endocrine therapy.
Arm B (Control): Continue current endocrine therapy.
Interim Analysis Results:
• ctDNA Clearance: The treatment arm (Arm A) achieved a clearance rate 2 times higher than the control arm.
• Recurrence: Clinical recurrence was <1% in patients whose ctDNA became negative and remained negative.
• ctDNA Clearance: The treatment arm (Arm A) achieved a clearance rate 2 times higher than the control arm.
• Recurrence: Clinical recurrence was <1% in patients whose ctDNA became negative and remained negative.
PALLAS (Prognostic)
ctDNA analysis of the adjuvant palbociclib study.
MRD-Positive: The recurrence risk in patients who remained ctDNA(+) at the end of treatment was >20 times (HR >20) higher than in negative patients.
MRD-Negative: 5-year distant disease-free survival (DRFI) 95%.
Other TOMR Studies
- ZEST (Niraparib): Planned for TNBC and BRCAm patients but terminated early. Because recurrence in TNBC was very rapid, the interval between ctDNA detection and clinical recurrence was insufficient for intervention.
- SIGNAL-ER 101: Starting CDK4/6 under ctDNA surveillance in intermediate-risk HR+ patients.
- TREAT ctDNA: Use of an oral SERD (elacestrant) in endocrine-resistant (ctDNA+) patients.
Data Source: Natera Signatera Clinical Updates (December 23, 2025) and Related Study Publications • Review: Drozdogan Academy
Was this article helpful?
Your feedback helps us improve our content.
Reader comments
Share your comment
Your name and comment are published only after administrator approval. Your email address is never shown to visitors.
Be the first to comment.