High ctDNA molecule numbers relate with poor outcome in advanced ER+, HER2− postmenopausal breast cancer patients treated with everolimus and exemestane

• Published in: Molecular oncology 2020-03, Vol.14 (3), p.490-503
• Main Authors: Kruger, Dinja T., Jansen, Maurice P.H.M., Konings, Inge R.H.M., Dercksen, Wouter M., Jager, Agnes, Oulad Hadj, Jamal, Sleijfer, Stefan, Martens, John W.M., Boven, Epie
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Analysis; Androstadienes - therapeutic use; Antineoplastic Combined Chemotherapy Protocols; Aromatase; Bar codes; biomarker; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blood & organ donations; Breast cancer; Breast Neoplasms - blood; Breast Neoplasms - drug therapy; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer; Cancer patients; Care and treatment; Circulating Tumor DNA - blood; Circulating Tumor DNA - genetics; ctDNA; Deoxyribonucleic acid; DNA; Epidermal growth factor; ErbB-2 protein; Ethylenediaminetetraacetic acid; everolimus; Everolimus - therapeutic use; Female; Genes; Genetic aspects; High-Throughput Nucleotide Sequencing; Humans; Library collections; Medical prognosis; Metastases; Metastasis; metastatic breast cancer; Middle Aged; Mutation; Mutation hot spots; Mutation, Missense; Neoplasm Metastasis; Patient outcomes; Plasma; Post-menopause; Postmenopausal women; Postmenopause; Progression-Free Survival; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - metabolism; Retrospective Studies; Software; Statistics; Tumors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12617

We determined whether progression‐free survival (PFS) in metastatic breast cancer (MBC) patients receiving everolimus plus exemestane (EVE/EXE) varies depending on circulating tumour DNA (ctDNA) characteristics. Baseline plasma cell‐free DNA (cfDNA) from 164 postmenopausal women with ER‐positive, HER2‐negative MBC refractory to a nonsteroidal aromatase inhibitor and treated with standard EVE/EXE (Everolimus Biomarker Study, Eudract 2013‐004120‐11) was characterised for 10 relevant breast cancer genes by next‐generation sequencing with molecular barcoding. ctDNA molecule numbers, number of mutations and specific variants were related with PFS and overall survival (OS). Missense hotspot mutations in cfDNA were detected in 125 patients. The median of 54 ctDNA molecules per mL plasma distinguished patients with high and low/no ctDNA load. Patients with low/no ctDNA load (N = 102) showed longer median PFS of 5.7 months (P = 0.006) and OS of 124.8 months (P = 0.008) than patients with high ctDNA load (N = 62; 4.4 months and 107.7 months, respectively) in multivariate analyses. Patients with