Comprehensive tumor-agnostic evaluation of genomic and epigenomic-based approaches for the identification of circulating tumor DNA in early-stage breast cancer
Year: 2025
Type: article
Study design: Observational Study
Abstract: BACKGROUND: The detection of circulating tumor DNA (ctDNA) after curative-intent therapy, referred to as molecular/minimal residual disease (MRD), is prognostic of disease recurrence in early-stage breast cancer (EBC). Tumor-agnostic approaches that rely on mutation-based assessment in fixed panels of common cancer driver genes have shown limited utility for detecting MRD in EBC. Methylation-based MRD (mMRD) may overcome the limitations of genomic-based MRD (gMRD), though limited clinical validation is available. MATERIALS AND METHODS: To investigate this, we analyzed 290 longitudinally banked plasma samples from 95 participants diagnosed with early-stage estrogen receptor (ER)-positive/human epidermal growth factor receptor 2-negative (ER-positive) and triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy using a high-sensitivity genomic and epigenomic-based, tumor-agnostic ctDNA platform. RESULTS: The baseline (pre-chemotherapy) ctDNA detection (mMRD) rate was 72.5% (66/91) across all participants (ER-positive: 33/48, 69%; TNBC: 33/43, 77%). Baseline ctDNA detection (mMRD) was associated with a higher risk of recurrence [hazard ratio (HR) 9.4, 95% confidence interval (CI) 1.3-70.3, P = 0.03]. Detection of ctDNA (mMRD) in the post-operative and follow-up periods were prognostic of worse event-free survival (EFS) (HR 17.0, 95% CI 6.0-48.0, P < 0.0001) with 62.5% sensitivity and 100% specificity for recurrence (positive predictive value 100%). The median lead time from mMRD detection to clinical recurrence was 152 days (range 15-748 days). gMRD, derived from plasma-only panel-based next-generation sequencing, was evaluated in all matched time points; the prognostic value was limited by clonal hematopoiesis of indeterminate potential, including pathogenic mutations in common cancer driver genes. Despite refinements in gMRD analysis, it remained inferior to mMRD. A combination of mMRD and gMRD did not outperform mMRD alone. CONCLUSION: These results support further development of tumor-agnostic mMRD assays for the detection of ctDNA and assessment of these assays to develop clinical utility in this setting.
Source: ESMO Open
Authors: M.J. Elliott, J. Kim, A. Dou, J. Fuentes Antrás, E. Amir, M.B. Nadler, E. Van de Laar, C. Yu, R. Cheikh, A. Silvestro, L.L. Siu, P.L. Bedard, H.K. Berman, D.W. Cescon
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,910
Funders: Susan G. Komen for the Cure, Conquer Cancer Foundation, Breast Cancer Research Foundation, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Gilead Sciences, American Society of Clinical Oncology, Celgene, Princess Margaret Cancer Foundation, PTC Therapeutics, Seagen, Canadian Cancer Society, University of Toronto, Astellas Pharma, Sociedad Española de Oncología Médica, Servier, Symphogen, Genentech, EMD Serono, Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, National Cancer Institute, Canadian Association of Medical Oncologists
Award: G1894849994
OpenAlex ID: W4411017374