Topic:
 
Issue Section:
 Biomarkers, translational research and precision medicine
Background: 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.
Methods: 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.
Results: 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.
Conclusions: Patients refractory to endocrine therapy develop more heterogeneous disease demonstrated by higher number of mutations detected in ctDNA.
Legal entity responsible for the study: Erasmus Medical Center.
Funding: Novartis Merck KGaA.
Disclosure: All authors have declared no conflicts of interest.
© European Society for Medical Oncology 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)