Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence

Title: Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence
Authors: Coombes, RC
Page, K
Salari, R
Hastings, RK
Armstrong, A
Ahmed, S
Ali, S
Cleator, S
Kenny, L
Stebbing, J
Rutherford, M
Sethi, H
Boydell, A
Swenerton, R
Fernandez-Garcia, D
Gleason, KLT
Goddard, K
Guttery, DS
Assaf, ZJ
Wu, H-T
Natarajan, P
Moore, DA
Primrose, L
Dashner, S
Tin, AS
Balcioglu, M
Srinivasan, R
Shchegrova, SV
Olson, A
Hafez, D
Billings, P
Aleshin, A
Rehman, F
Toghill, BJ
Hills, A
Louie, MC
Lin, C-HJ
Zimmermann, BG
Shaw, JA
Item Type: Journal Article
Abstract: Purpose: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer. Experimental Design: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X). Results: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5–24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling. Conclusions: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.
Issue Date: 15-Jul-2019
Date of Acceptance: 11-Apr-2019
URI: http://hdl.handle.net/10044/1/84448
DOI: 10.1158/1078-0432.CCR-18-3663
ISSN: 1078-0432
Publisher: American Association for Cancer Research
Start Page: 4255
End Page: 4263
Journal / Book Title: Clinical Cancer Research
Volume: 25
Issue: 14
Copyright Statement: ©2019 American Association for Cancer Research.
Sponsor/Funder: National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: NIHR-RP-011-053
RDB01 79560
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
CLINICAL-PRACTICE GUIDELINES
DROPLET DIGITAL PCR
CELL-FREE DNA
NEOADJUVANT CHEMOTHERAPY
PERIPHERAL-BLOOD
DIAGNOSIS
QUANTIFICATION
MUTATIONS
PLASMA
CEA
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor
Breast Neoplasms
Circulating Tumor DNA
Female
High-Throughput Nucleotide Sequencing
Humans
Middle Aged
Mutation
Neoplasm Metastasis
Neoplasm Recurrence, Local
Precision Medicine
Prognosis
Prospective Studies
Humans
Breast Neoplasms
Neoplasm Metastasis
Neoplasm Recurrence, Local
Prognosis
Prospective Studies
Mutation
Adult
Aged
Aged, 80 and over
Middle Aged
Female
High-Throughput Nucleotide Sequencing
Biomarkers, Tumor
Precision Medicine
Circulating Tumor DNA
Science & Technology
Life Sciences & Biomedicine
Oncology
CLINICAL-PRACTICE GUIDELINES
DROPLET DIGITAL PCR
CELL-FREE DNA
NEOADJUVANT CHEMOTHERAPY
PERIPHERAL-BLOOD
DIAGNOSIS
QUANTIFICATION
MUTATIONS
PLASMA
CEA
1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Open Access location: https://discovery.ucl.ac.uk/id/eprint/10072629/
Online Publication Date: 2019-04-16
Appears in Collections:Department of Surgery and Cancer
Division of Cancer