{"entity":{"id":"idea-tnbc-ctdna-guided-adjuvant-decisions","kind":"idea","name":"ctDNA-guided adjuvant decisions after residual disease: escalate the positive, spare the negative","aka":[],"tldr":"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.","asOf":"2026-09-24","links":[{"label":"Radovich et al.: ctDNA and circulating tumour cells after neoadjuvant chemotherapy, BRE12-158 (JAMA Oncol 2020)","url":"https://europepmc.org/article/MED/32644110"},{"label":"c-TRAK TN (Ann Oncol 2023)","url":"https://europepmc.org/article/MED/36423745"},{"label":"ClinicalTrials.gov NCT05633654","url":"https://clinicaltrials.gov/study/NCT05633654"},{"label":"ClinicalTrials.gov NCT05629585","url":"https://clinicaltrials.gov/study/NCT05629585"}],"tags":["tnbc-evidence"],"related":["ctdna-tests"],"cancers":["tnbc"],"sections":[],"technologies":["liquid-biopsy","mrd-testing","adc"],"targets":[],"drugs":["sacituzumab-govitecan","datopotamab-deruxtecan","capecitabine","pembrolizumab","signatera"],"companies":[],"institutions":[],"pathways":[],"terms":["ctdna","mrd","rcb","neoadjuvant-adjuvant"],"trials":["ascent-05","tropion-breast03","keynote-522"],"people":[],"bottlenecks":["b-dormancy-mrd","b-biomarker-validation","b-trial-design"],"keyPapers":["paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020","paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023","paper-symmans-rcb-long-term-prognosis-subtype-jco-2017","paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022","paper-create-x-adjuvant-capecitabine-nejm-2017"],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"large","horizonYears":6},"route":"/ideas/idea-tnbc-ctdna-guided-adjuvant-decisions/","neighbours":{"roadmap":[{"id":"ctdna-tests","kind":"roadmap","name":"ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment","route":"/roadmaps/ctdna-tests/"},{"id":"tnbc-roadmap","kind":"roadmap","name":"Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem","route":"/roadmaps/tnbc-roadmap/"}],"cancer":[{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/"}],"drug":[{"id":"capecitabine","kind":"drug","name":"Capecitabine","route":"/drugs/capecitabine/"},{"id":"datopotamab-deruxtecan","kind":"drug","name":"Datopotamab deruxtecan","route":"/drugs/datopotamab-deruxtecan/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"sacituzumab-govitecan","kind":"drug","name":"Sacituzumab govitecan","route":"/drugs/sacituzumab-govitecan/"},{"id":"signatera","kind":"drug","name":"Signatera","route":"/drugs/signatera/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"},{"id":"neoadjuvant-adjuvant","kind":"term","name":"Neoadjuvant / adjuvant / perioperative","route":"/terms/neoadjuvant-adjuvant/"},{"id":"rcb","kind":"term","name":"Residual cancer burden (RCB)","route":"/terms/rcb/"}],"trial":[{"id":"ascent-05","kind":"trial","name":"ASCENT-05 / OptimICE-RD (AFT-65, GBG 119, NSABP B-63)","route":"/trials/ascent-05/"},{"id":"keynote-522","kind":"trial","name":"KEYNOTE-522","route":"/trials/keynote-522/"},{"id":"tropion-breast03","kind":"trial","name":"TROPION-Breast03","route":"/trials/tropion-breast03/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-dormancy-mrd","kind":"bottleneck","name":"Dormant cells and minimal residual disease","route":"/bottlenecks/b-dormancy-mrd/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"}],"paper":[{"id":"paper-create-x-adjuvant-capecitabine-nejm-2017","kind":"paper","name":"Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy","route":"/key-papers/paper-create-x-adjuvant-capecitabine-nejm-2017/"},{"id":"paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020","kind":"paper","name":"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","route":"/key-papers/paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020/"},{"id":"paper-symmans-rcb-long-term-prognosis-subtype-jco-2017","kind":"paper","name":"Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype","route":"/key-papers/paper-symmans-rcb-long-term-prognosis-subtype-jco-2017/"},{"id":"paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022","kind":"paper","name":"Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients","route":"/key-papers/paper-yau-rcb-pooled-analysis-5161-lancet-oncol-2022/"},{"id":"paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023","kind":"paper","name":"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","route":"/key-papers/paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023/"}]}}