The Use of Serial Circulating Tumor DNA to Detect Resistance Alterations in Progressive Metastatic Breast Cancer

Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer. This was a retrospective cohort between 2015 and 2019 obtained under an Institutional...

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Bibliographic Details
Published in:Clinical cancer research 2021-03, Vol.27 (5), p.1361-1370
Main Authors: Jacob, Saya, Davis, Andrew A, Gerratana, Lorenzo, Velimirovic, Marko, Shah, Ami N, Wehbe, Firas, Katam, Neelima, Zhang, Qiang, Flaum, Lisa, Siziopikou, Kalliopi P, Platanias, Leonidas C, Gradishar, William J, Behdad, Amir, Bardia, Aditya, Cristofanilli, Massimo
Format: Article
Language:English
Subjects:
Aged
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biomarkers, Tumor - genetics
Breast Neoplasms - blood
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Circulating Tumor DNA - analysis
Circulating Tumor DNA - genetics
Drug Resistance, Neoplasm - genetics
Female
Follow-Up Studies
High-Throughput Nucleotide Sequencing - methods
Humans
Middle Aged
Mutation
Prognosis
Retrospective Studies
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Summary:Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer. This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board-approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression. We identified 44 hormone receptor-positive, 20 HER2 , and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were ( < 0.0075), ( < 0.0126), ( < 0.0126), ( < 0.0455), and ( < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 ( = 0.0026, and < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA ( = 0.0042 and < 0.0001, respectively). Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-20-1566