Circulating tumour DNA in metastatic breast cancer to guide clinical trial enrolment and precision oncology: A cohort study
Andjelija Zivanovic Bujak aff001; Chen-Fang Weng aff001; Maria João Silva aff001; Miriam Yeung aff001; Louisa Lo aff001; Sarah Ftouni aff001; Cassandra Litchfield aff001; Yi-An Ko aff001; Keilly Kuykhoven aff001; Courtney Van Geelen aff001; Sushma Chandrashekar aff001; Mark A. Dawson aff001; Sherene Loi aff001; Stephen Q. Wong aff001; Sarah-Jane Dawson aff001
Působiště autorů: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia aff001; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia aff002; Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia aff003
Vyšlo v časopise: Circulating tumour DNA in metastatic breast cancer to guide clinical trial enrolment and precision oncology: A cohort study. PLoS Med 17(10): e32767. doi:10.1371/journal.pmed.1003363
Kategorie: Research Article
Metastatic breast cancer (mBC) is a heterogenous disease with increasing availability of targeted therapies as well as emerging genomic markers of therapeutic resistance, necessitating timely and accurate molecular characterization of disease. As a minimally invasive test, analysis of circulating tumour DNA (ctDNA) is well positioned for real-time genomic profiling to guide treatment decisions. Here, we report the results of a prospective testing program established to assess the feasibility of ctDNA analysis to guide clinical management of mBC patients.
Methods and findings
Two hundred thirty-four mBC patients (median age 54 years) were enrolled between June 2015 and October 2018 at the Peter MacCallum Cancer Centre, Melbourne, Australia. Median follow-up was 15 months (range 1–46). All patient samples at the time of enrolment were analysed in real time for the presence of somatic mutations. Longitudinal plasma testing during the course of patient management was also undertaken in a subset of patients (n = 67, 28.6%), according to clinician preference, for repeated molecular profiling or disease monitoring. 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, subsets of samples were also analysed via next-generation sequencing (targeted panel sequencing and low-coverage whole-genome sequencing [LC-WGS]). The sensitivity of ddPCR and targeted panel sequencing to identify actionable mutations was compared. Results were discussed at a multidisciplinary breast cancer meeting prior to treatment decisions. ddPCR and targeted panel sequencing identified at least 1 actionable mutation at baseline in 80/234 (34.2%) and 62/159 (39.0%) of patients tested, respectively. Combined, both methods detected an actionable alteration in 104/234 patients (44.4%) through baseline or serial ctDNA testing. LC-WGS was performed on 27 patients from the cohort, uncovering several recurrently amplified regions including 11q13.3 encompassing CCND1. Increasing ctDNA levels were associated with inferior overall survival, whether assessed by ddPCR, targeted sequencing, or LC-WGS. Overall, the ctDNA results changed clinical management in 40 patients including the direct recruitment of 20 patients to clinical trials. Limitations of the study were that it was conducted at a single site and that 31.3% of participants were lost to follow-up.
In this study, we found prospective ctDNA testing to be a practical and feasible approach that can guide clinical trial enrolment and patient management in mBC.
Biopsy – Breast cancer – Cancer genomics – Cancer treatment – Circulating tumor DNA – Gene sequencing – Metastasis – Mutation detection
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