Kefah Mokbel, Chair of Breast Cancer Surgery at London Breast Institute, shared on LinkedIn:
“ctDNA two years after adjuvant chemotherapy identifies the patients who will relapse – but not yet what to do about it
Friedl et al., JCO (published today): a landmark analysis of 313 stage I–III patients from SUCCESS-A, tested with a tissue-free epigenomic assay (Guardant Reveal) roughly 2 years after adjuvant chemotherapy.
- ctDNA detected in 18/313 (5.8%)
- 17 of 18 positives developed distant recurrence – PPV 94%
- Median lead time: 7.9 months
- DRFI: HR 33.3 (95% CI 4.12–268); OS: HR 27.3 (95% CI 1.15–647)
- Sensitivity 73% (11/15) within a year of recurrence; specificity 99.6%
Why it matters: tumour-informed panels need archival tissue, bespoke design and turnaround. A tissue-free assay removes all three, which is what makes population-level surveillance plausible.
Where I would be cautious:
- The hazard ratios are directionally certain and quantitatively meaningless – 18 events cannot support a CI of 4 to 268.
- The 73% sensitivity applies only to samples drawn within 12 months of recurrence. Across the cohort it is lower. This is a rule-in test; a negative result reassures no one.
- Detection rate reflects the platform as much as the cohort. Reveal is a methylation assay with a fixed genomic footprint; tumour-informed ultra-deep panels report higher MRD positivity and longer lead times. The four missed recurrences are consistent with sub-threshold shedding rather than absent disease.
- SUCCESS-A recruited in the mid-2000s – no pertuzumab, T-DM1, T-DXd, CDK4/6 inhibitors, olaparib or immunotherapy. Neither the positivity rate nor the lead time can be assumed to transfer.
- A single draw at 2 years suits TNBC but is poorly timed for ER-positive disease, which recurs across two decades and sheds less. No subtype breakdown is given.
- Most importantly: prognostic is not actionable. No completed randomised evidence shows that intervening on MRD changes survival. DARE, ZEST and TRAK-ER will answer that. Until then, a positive result buys eight months of knowing.
The biology is convincing. The clinical utility question remains open.”
Title: Clinical Relevance of Post-Treatment Circulating Tumor DNA Detection in Early Breast Cancer Using a Tissue-Free Epigenomic Assay: A 2-Year Landmark Analysis
Authors: Thomas W. P. Friedl, Peter A. Fasching, Andreas D. Hartkopf, Hans Tesch, Ralf Lorenz, Georg Heinrich, Jens-Uwe Blohmer, Tanja Fehm, Volkmar Mueller, Andreas Schneeweiss, Matthias W. Beckmann, Matthias Ruebner, Nadia Harbeck, Klaus Pantel, Derek Dustin, Mingyang Cai, Brigitte Rack, Wolfgang Janni
You can also read: ctDNA During Neoadjuvant Therapy: Toward Real-Time Risk Stratification in Early Breast Cancer
