Prospective testing of circulating tumour DNA in metastatic breast cancer facilitates clinical trial enrollment and precision oncology

Abstract

Background: The increasing availability of targeted agents for treatment of metastatic breast cancer (mBC) necessitates accurate and timely molecular characterisation of disease. As a minimally invasive test, circulating tumour DNA (ctDNA) is well positioned to overcome many of the limitations associated with traditional tumor biopsies. Here, we established a program to assess the feasibility of routine prospective ctDNA testing for the clinical management of mBC patients. Method(s): Detection of somatic mutations from patient plasma was performed using a multiplexed droplet digital PCR (ddPCR) approach to identify hotspot mutations in PIK3CA, ESR1, ERBB2 and AKT1. In parallel, a subset of samples were also analysed via next generation sequencing (targeted amplicon (TA) sequencing and low-coverage whole-genome sequencing). Results were discussed at a multidisciplinary breast cancer meeting prior to therapy selection. Result(s): 234 mBC patients were enrolled on this study, with a median age at diagnosis of 54 years (28-80) and a median of 2 lines of prior therapy. The average turnaround time for ctDNA testing using ddPCR was 9 days (1-49). Using ddPCR, 80/234 (34.2%) patients had >=1 mutation identified, with 52/234 (22.2%) patients having an alteration in PIK3CA, 35/234 (15.0%) in ESR1, 9/234 (3.8%) in AKT1 and 2/234 (0.9%) in ERBB2. TA sequencing performed in the first 159 patients, identified actionable mutations (classified using the OncoKB database) in 63 patients (39.6%) and showed that a mean variant allele fraction of > 5% was significantly associated with inferior overall survival (Hazard ratio: 1.8; 95% Confidence interval: 1.1-3.1; p < 0.02). Of 97/234 patients where an actionable alteration was identified, the result influenced clinical management in 41 (42.3%), including 18 who were enrolled in a clinical trial. In one patient initially diagnosed with ER+/HER2- disease, a HER2 gene amplification was identified through ctDNA analysis leading to the initiation of HER2-targeted treatment and a near complete metabolic response to treatment. Conclusion(s): Prospective ctDNA testing of mBC patients is a practical and feasible approach to guide clinical trial enrolment and patient management. Legal entity responsible for the study: The authors. Funding(s): National Health and Medical Research Council Australia. Disclosure: S.Q. Wong: Travel / Accommodation / Expenses: Bio-Rad Laboratories. S. Dawson: Research grant / Funding (self): Genentech. All other authors have declared no conflicts of interest.Copyright © 2019 European Society for Medical Oncology