Abstract
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 < 3 specific mutations (N = 135) had longer median PFS of 5.4 months compared to those with ≥ 3 mutations (3.4 months; P < 0.001). In conclusion, MBC patients with low/no ctDNA load or < 3 hotspot mutations experience longer PFS while treated with EVE/EXE.
Highlights
Everolimus with exemestane (EVE/EXE) has been registered for treatment for patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer (MBC) to prevent cancer cell survival caused by an activated PI3K pathway (Zoncu et al, 2011)
Most patients received prior systemic treatment for their metastatic disease; for 17 patients (10%), EVE/EXE was given as first-line therapy in the metastatic setting
We are the first to report this finding in a cohort of ER+/HER2- MBC patients treated with EVE/EXE
Summary
Everolimus with exemestane (EVE/EXE) has been registered for treatment for patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer (MBC) to prevent cancer cell survival caused by an activated PI3K pathway (Zoncu et al, 2011). Abbreviations AEs, adverse events; cfDNA, cell-free DNA; CI, confidence interval; COSMIC, catalogue of somatic mutations in cancer; CTC-AE, common terminology criteria for adverse events; ctDNA, circulating tumour DNA; DFI, disease-free interval; ECOG, Eastern Cooperative Oncology Group; ER (ESR1), estrogen receptor-a (gene); EVE/EXE, everolimus/exemestane; HBD, healthy blood donor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IARC, International Agency for Research on Cancer; MBC, metastatic breast cancer; METABRIC, Molecular Taxonomy of Breast Cancer International Consortium; MSK, Memorial Sloan Kettering (Cancer Center); NGS, next-generation sequencing; NSAI, nonsteroidal aromatase inhibitor; OS, overall survival; PFS, progression-free survival; TCGA, The Cancer Genome Atlas. Tools are required to select patients who will likely benefit from EVE/EXE or, the reverse, withhold treatment from patients with resistant disease
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