Ann Oncol. 2025 Feb 04. pii: S0923-7534(25)00053-5. [Epub ahead of print]
I Garcia-Murillas,
C W Abbott,
R J Cutts,
S M Boyle,
J Pugh,
K C Keough,
B Li,
R M Pyke,
F C P Navarro,
R O Chen,
K Dunne,
C Bunce,
S R D Johnston,
A Ring,
S Russell,
A Evans,
A Skene,
I E Smith,
N C Turner.
BACKGROUND: Circulating tumour DNA (ctDNA) based detection of Molecular Residual Disease (MRD) presents a strategy to identify patients at high risk of relapse. Here we profile early breast cancer patients with an ultrasensitive, whole genome sequencing-based, tumour-informed ctDNA platform.
METHODS: We analysed 617 plasma samples (median 8, range 2-14) from 78 patients (23 TNBC, 35 HER2+, 18 HR+ and 2 unknown). Samples were collected at diagnosis before therapy, cycle 2 of neoadjuvant chemotherapy (NAC), post-surgery after neoadjuvant therapy if administered, every 3 months during the first year, and every 6 months thereafter. Plasma DNA was analysed using the NeXT Personal MRD platform, a tumour-informed whole-genome sequencing approach to produce personalised ctDNA sequencing panels tracking a median of 1,451 variants per patient. MRD detection was correlated with clinical outcomes.
RESULTS: ctDNA was detected at levels ranging from 2.19 parts per million (PPM) to 204,900 PPM (median 405 PPM), with 39% of all ctDNA detections in the ultra-low range <100 PPM. Of patients with samples at diagnosis, 98% (49/50) had ctDNA detected prior to treatment. At a median follow-up of 76 months (range 5-118), detection of ctDNA associated with high risk of future relapse (p<0.0001; log-rank test) and shortened overall survival (p<0.0001) with median lead-time from ctDNA detection to clinical relapse of 15 months (range 0.9-61.5). MRD was identified in 100% (11/11) of patients who relapsed, with a median level of ctDNA at first MRD detection of 13.1 PPM. No ctDNA undetected patients relapsed throughout follow up (64/64). Comparison with exome powered MRD detection assays showed improved sensitivity and lead time.
CONCLUSIONS: A whole genome powered MRD assay detected breast cancer relapse with a long lead-time over clinical relapse, and strongly associated with relapse free survival. Rates of ctDNA detection at diagnosis were higher than those reported with exome-based tumour informed assays.
Keywords: Molecular Residual Disease; Ultrasensitive ctDNA detection; early breast cancer