# ctDNA-guided adjuvant decisions after residual disease: escalate the positive, spare the negative

Source: https://onco.cc/ideas/idea-tnbc-ctdna-guided-adjuvant-decisions/  
OnCo record `idea-tnbc-ctdna-guided-adjuvant-decisions` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

After pre-surgery chemotherapy leaves tumour behind, a blood test for tumour DNA triples the risk of distant relapse when positive. The one trial that acted on it found the DNA usually appeared too late. A trial that tests at surgery with a tumour-informed assay, escalates positives to an antibody-drug conjugate and observes negatives has not been run.

## Summary

In BRE12-158 ctDNA detected after neoadjuvant chemotherapy carried a distant disease-free survival hazard ratio of 2.99 and an overall survival hazard ratio of 4.16, and two-year distant disease-free survival was 56 versus 81 percent. c-TRAK TN tracked one or two mutations by digital PCR every three months: 27 percent turned positive within a year but 72 percent of those already had metastases and none of five given pembrolizumab cleared. The residual disease trials now running (ASCENT-05, TROPION-Breast03) enrol on residual cancer burden alone and treat everyone; the residual cancer burden pooled analysis shows RCB-I patients have ten-year relapse-free survival of 81 percent and may be over-treated, while RCB-III patients relapse in three quarters of cases and may need more than one agent. Tumour-informed assays and a first sample at surgery are the design changes c-TRAK TN's authors called for.

## Fields

- Kind: Idea
- Last checked: 2026-09-24
- Tags: tnbc-evidence
- Hypothesis: Among patients with residual cancer burden II or III after chemotherapy plus pembrolizumab, a tumour-informed ctDNA test at surgery and at three months identifies a positive group in whom adding a TROP2 antibody-drug conjugate to standard post-neoadjuvant therapy improves three-year distant recurrence-free survival by at least 15 percentage points, and a persistently negative group in whom standard therapy alone yields three-year distant recurrence-free survival above 85 percent.
- Rationale: Residual cancer burden is prognostic but coarse; ctDNA adds a dynamic measure of whether disease persists after surgery, and the antibody-drug conjugates now have first-line activity strong enough to clear micrometastatic disease that pembrolizumab alone did not.
- Proposed test: A two-cohort randomised trial nested in the post-neoadjuvant pathway: ctDNA-positive patients randomised to standard care with or without an antibody-drug conjugate; ctDNA-negative RCB-II patients randomised to standard care or observation; about 800 patients over four years, with ctDNA clearance at six months as an early endpoint.
- Maturity: early-clinical
- Actor: research

## Sources

- Radovich et al.: ctDNA and circulating tumour cells after neoadjuvant chemotherapy, BRE12-158 (JAMA Oncol 2020): https://europepmc.org/article/MED/32644110
- c-TRAK TN (Ann Oncol 2023): https://europepmc.org/article/MED/36423745
- ClinicalTrials.gov NCT05633654: https://clinicaltrials.gov/study/NCT05633654
- ClinicalTrials.gov NCT05629585: https://clinicaltrials.gov/study/NCT05629585

## Connected records

- roadmaps: [ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment](https://onco.cc/roadmaps/ctdna-tests/), [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/)
- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/)
- drugs: [Capecitabine](https://onco.cc/drugs/capecitabine/), [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [Signatera](https://onco.cc/drugs/signatera/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/), [Residual cancer burden (RCB)](https://onco.cc/terms/rcb/)
- trials: [ASCENT-05 / OptimICE-RD (AFT-65, GBG 119, NSABP B-63)](https://onco.cc/trials/ascent-05/), [KEYNOTE-522](https://onco.cc/trials/keynote-522/), [TROPION-Breast03](https://onco.cc/trials/tropion-breast03/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Dormant cells and minimal residual disease](https://onco.cc/bottlenecks/b-dormancy-mrd/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- key papers: [Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy](https://onco.cc/key-papers/paper-create-x-adjuvant-capecitabine-nejm-2017/), [Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial](https://onco.cc/key-papers/paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020/), [Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype](https://onco.cc/key-papers/paper-symmans-rcb-long-term-prognosis-subtype-jco-2017/), [Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients](https://onco.cc/key-papers/paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022/), [Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer](https://onco.cc/key-papers/paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023/)

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