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Circulating tumour DNA in metastatic breast cancer to guide clinical trial

Andjelija Zivanovic Bujak, Chen-Fang Weng, Maria João Silva, Miriam Yeung, Louisa Lo, Sarah Ftouni, Cassandra Litchfield, Yi-An Ko, Keilly Kuykhoven, Courtney Van Geelen, Sushma Chandrashekar, Mark A. Dawson, Sherene Loi, Stephen Q. Wong, Sarah-Jane Dawson

Abstract

Background

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.

Introduction

Breast cancer is the most common cancer and the leading cause of cancer-related death in women worldwide [1]. Although targeted therapies for estrogen receptor–positive (ER+) and ERBB2-amplified (human epidermal growth factor receptor 2–positive [HER2+]) breast cancers have become the mainstay of treatment over several decades, a rapidly growing number of novel agents are now emerging whose effectiveness may depend on specific genomic aberrations. Examples include activating mutations in PIK3CA, ERBB2, and AKT1, against which specific inhibitors have been developed and explored in clinical trials, with the first PI3K inhibitor, alpelisib, recently approved in combination with fulvestrant for ER+/HER2-, PIK3CA mutant metastatic breast cancer (mBC) [2–4]. Activating mutations in ESR1 acquired in response to aromatase inhibitor (AI) treatment have also emerged as an important genomic marker in breast cancer, with the ability to predict response to subsequent endocrine treatments [5, 6]. There is also growing development of more potent selective estrogen receptor inhibitors that can potentially overcome endocrine resistance associated with activating ESR1 mutations [7]. Crucial to the success of these novel targeted approaches in breast cancer management is the integration of effective genomic testing programs into routine clinical practice.

Methods

Study design and patient cohort

The Metastatic Breast Circulating Biomarker (MBCB) study was established at the Peter MacCallum Cancer Centre (Melbourne, Australia) in June 2015 to assess the feasibility and utility of applying routine comprehensive ctDNA profiling in mBC patients to guide clinical management. ctDNA results were provided to clinicians in real time, and the impact of these results on influencing clinical decisions was assessed by (1) the proportion of patients found to have actionable mutations using different ctDNA methodologies, (2) the proportion of patients for whom clinical management was changed based on the ctDNA results, and (3) the proportion of patients enrolled into clinical trials as a result of ctDNA testing. The primary objective of the study did not necessitate a prospective statistical analysis plan. Here, we detail our clinical experience over the first 3 years following the establishment of our testing program.

Discussion

In this study, we established a comprehensive ctDNA-based genomic profiling program to guide treatment decisions in mBC. This included the establishment of a workflow for sample collection; the development of rapid, robust, and accurate testing methods; and the delivery of results to clinicians to guide patient management. Identification of actionable alterations was possible in 44% of patients tested, and patient management was affected in 39% of these individuals. Through our program, we also performed serial analysis of plasma for the purposes of disease monitoring or to identify the emergence of actionable mutations. In several cases, de novo actionable mutations were identified at times of relapse on treatment, highlighting the importance of serial ctDNA testing for effective patient management. Finally, in addition to comprehensive molecular profiling, the quantitative information provided from ctDNA analysis also provided important prognostic information. High ctDNA levels, as detected by any methodology, were associated with inferior survival in mBC, and this finding has now been demonstrated consistently across several studies [26, 27].

Acknowledgments

The authors thank Gisela Mir Arnau, Timothy Semple, Sreeja Gadipally, and Timothy Holloway for assistance with LC-WGS; Madawa Jayawardana for assistance with the statistical analysis; and Eric De Vries for assistance with figures. We thank the patients and their families for participation in this study.

Citation: Zivanovic Bujak A, Weng C-F, Silva MJ, Yeung M, Lo L, Ftouni S, et al. (2020) Circulating tumour DNA in metastatic breast cancer to guide clinical trial enrolment and precision oncology: A cohort study. PLoS Med 17(10): e1003363. https://doi.org/10.1371/journal.pmed.1003363

Academic Editor: Charles Swanton, The Francis Crick Institute, UNITED KINGDOM

Received: October 25, 2019; Accepted: August 26, 2020; Published: October 1, 2020

Copyright: © 2020 Zivanovic Bujak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The sequencing data that support the findings of this study have been deposited into the sequence read archive, which is hosted by the National Centre for Biotechnology Information. The BioProject accession number is PRJNA578569. All other data are contained within the manuscript and/or Supporting Information files.

Funding: S-J.D and A.Z.B. received funding for this research. S-J.D received funding through the National Health and Medical Research Council of Australia (grant number APP1085014, https://www.nhmrc.gov.au), the Peter MacCallum Cancer Centre Women’s Cancer Research Program (https://www.petermac.org), Genentech (https://www.gene.com), and the Australian Cancer Research Foundation (https://www.acrf.com.au). S-J.D. was supported by a National Breast Cancer Foundation (https://nbcf.org.au) and Victorian Cancer Agency (http://victoriancanceragency.vic.gov.au) Fellowship and a CSL Centenary Fellowship (https://www.cslfellowships.com.au). A.Z.B. was supported by an Australian Postgraduate Award administered by the University of Melbourne (https://www.unimelb.edu.au) and a PhD Top Up Scholarship administered by Cancer Therapeutics CRC, Melbourne, Australia (https://cancercrc.com). The funders played no role in the study design, data collection and analysis, decision to publish, or the preparation of the manuscript.

Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: M.A.D. has been a member of advisory boards for CTX CRC, Storm Therapeutics, Celgene, Cambridge Epigenetix, and GSK. S. L. receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merk, Roche-Genentech, Puma Biotechnology, Pfizer, and Eli Lilly. She has acted as a consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche-Genentech. She has acted as a consultant (paid to her institution) to Aduro Biotech. S.Q.W. has received travel support from BioRad. S-J. D. has received research funding to her institution from Roche-Genentech and CTX CRC. She has been a member of advisory boards for AstraZeneca.

Abbreviations: AI, aromatase inhibitor; CNA, copy number alteration; CNS, central nervous system; CT, computed tomography; ctDNA, circulating tumour DNA; ddPCR, droplet digital PCR; ER, estrogen receptor; FDA, United States Food and Drug Administration; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; LC-WGS, low-coverage whole-genome sequencing; mBC, metastatic breast cancer; MBCB, Metastatic Breast Circulating Biomarker; NGS, next-generation sequencing; OS, overall survival; PET, positron emission tomography; SISH, silver in situ hybridization; TCGA, The Cancer Genome Atlas; TNBC, triple negative breast cancer; VAF, variant allele fraction; wt, wild type

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