Surveillance of Disease Progression in Metastatic Breast Cancer by Molecular Counting of Circulating Tumor DNA Using Plasma-SeqSensei Breast Cancer in Vitro Diagnostics Assay

• Published in: The Journal of molecular diagnostics : JMD Vol. 27; no. 1; pp. 25 - 35
• Main Authors: Martens, Geert A., Demol, Jan, Dedeurwaerdere, Franceska, De Smet, Kristof, Wesolowski, Janusz, De Smet, Dieter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2025
• Subjects: Adult; Aged; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Breast Neoplasms - blood; Breast Neoplasms - diagnosis; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Circulating Tumor DNA - blood; Circulating Tumor DNA - genetics; Class I Phosphatidylinositol 3-Kinases - genetics; Disease Progression; Female; Humans; Middle Aged; Mutation; Neoplasm Metastasis
• ISSN: 1525-1578; 1943-7811; 1943-7811
• DOI: 10.1016/j.jmoldx.2024.08.011

Circulating tumor DNA (ctDNA) quantification surpasses cancer antigen 15 to 3 for metastatic breast cancer surveillance. Clinical translation, however, is limited because of uncertainties about the optimal method and clinically valid ctDNA decision thresholds. Plasma-SeqSensei Breast Cancer IVD kit (PSS) is a novel assay for ctDNA molecular counting, detecting ≥0.06% variant allele fractions in AKT1, ERBB2, ESR1, KRAS, PIK3CA, and TP53. PSS was validated against droplet digital PCR (ddPCR) in 201 samples from 16 subjects with PIK3CA/TP53-mutated cancers, longitudinally sampled for a median of 93 (range, 18 to 113) weeks, three to five weekly. PSS and ddPCR ctDNA levels correlate significantly (Spearman ρ, 0.923; 95% CI, 0.898–0.941) across 0% to 43% variant allele frequency (VAF) range. PSS predicts 12-week progression with high clinical accuracy (area under the curve, 0.848; 95% CI, 0.790–0.894). PSS validates a previously developed ddPCR classifier: <10 copies/mL (0.25% VAF); excludes >100 copies/mL (2.5% VAF); and confirms progression, with negative predictive value (95% CI) of 83% (76%–88%) and positive predictive value (95% CI) of 91% (81%–96%) (weighted κ, 0.856; 95% CI, 0.797–0.915). PSS thus confirms robust clinical thresholds (10 to 100 copies/mL, 0.25% to 2.5% VAF) for metastatic breast cancer surveillance, using absolute molecular counting.