Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence

作者：Raoul Charles Coombes, Karen Page, Raheleh Salari, Robert Hastings, Anne Armstrong, Samreen Ahmed, Simak Ali, Susan Cleator, Laura Kenny, Justin Stebbing, Mark J. Rutherford, Himanshu Sethi, Anna Boydell, Ryan Swenerton, Daniel Fernández-García, Kelly Gleason, Katie Goddard, David S. Guttery, Zoe J. Assaf, Hsin-Ta Wu, Prashanthi Natarajan, David A. Moore, Lindsay Primrose, Scott Dashner, Antony Tin, Mustafa Balcioglu, Ramya Srinivasan, Svetlana Shchegrova, Alexander Olson, Dina Hafez, Paul R. Billings, Alexey Aleshin, Farah Rehman, Bradley Toghill, Allison Hills, Maggie C. Louie, Cheng-Ho Jimmy Lin, Bernhard Zimmermann, Jacqui Shaw · 发表于：Clinical Cancer Research · 年份：2019 · DOI：10.1158/1078-0432.ccr-18-3663 · 被引用次数：529 · 研究领域：Cancer Genomics and Diagnostics、Cancer Cells and Metastasis、Epigenetics and DNA Methylation

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: = 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.