ctDNA is emerging as a non-invasive disease-monitoring biomarker alternative to a tissue biopsy. In this study, we characterized ctDNA from patients with ER+, HER2- MBC 1) starting first-line non-steroidal aromatase inhibitors (NSAIs) and 2) refractory to treatment with NSAI.
Patients starting treatment with NSAIs (cohort 1, n = 100) and patients refractory to NSAIs, starting treatment with everolimus/exemestane (cohort 2, n = 164) were included in this analysis. Longitudinal plasma samples and whole genome sequencing (WGS) data from paired metastatic tissues, collected at baseline, were available from 23 patients in cohort 1. Cell-free DNA (cfDNA) (10ng) was characterized by targeted next generation sequencing (NGS) for hotspot mutations in 10 genes. Numbers of specific mutations and mutant molecules/mL and numbers were compared for both cohorts and related to PFS for cohort 1.
Patients in cohort 2 more often had detectable ctDNA (76% vs 53%, p < 0.001) and ≥3 specific mutations (18% vs 3%, p = 0.001) when compared to patients in cohort 1. Mutations in ESR1 (40% vs 9%, p < 0.001) and PIK3CA (46% vs 29%, p = 0.009) were enriched in patients in cohort 2, of whom ESR1 mutations were more often polyclonal (11% vs 1%, p = 0.009). The most frequently identified ESR1 variants were p.E380Q in cohort 1 (n = 4) and p.D538G and p.Y537S in cohort 2 (n = 38, n = 27). Mutations in KRAS and ERBB3 were only detected in cohort 2 (p = 0.331, p = 0.232). The median number of mutant molecules/mL in ctDNA-positive patients did not significantly differ between cohort 1 and cohort 2 for all mutations (48 vs 54, p = 0.87). In cohort 1, mutant molecules/mL and numbers of mutations were not significantly associated with PFS (p = 0.393, p = 0.384). Analysis of 23 patients with longitudinal plasma samples and WGS data from metastatic tissue is ongoing and will be presented at the meeting.
Patients refractory to endocrine therapy develop more heterogeneous disease demonstrated by higher number of mutations detected in ctDNA.
Plasma samples from cohort 2 were prospectively collected in the Everolimus Biomarker (EB) Study (Eudract 2013-004120-11).
Erasmus Medical Center.
Novartis Merck KGaA.
All authors have declared no conflicts of interest.