Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease
Eleonor Olsson, Christof Winter, Anthony George, Yilun Chen, Jillian Howlin, Man-Hung Eric Tang, Malin Dahlgren, Ralph Schulz, Dorthe Grabau, Danielle van Westen, Mårten Fernö, Christian Ingvar, Carsten Rose, Pär-Ola Bendahl, Lisa Rydén, Åke Borg, Sofia K Gruvberger-Saal, Helena Jernström, Lao H Saal, Eleonor Olsson, Christof Winter, Anthony George, Yilun Chen, Jillian Howlin, Man-Hung Eric Tang, Malin Dahlgren, Ralph Schulz, Dorthe Grabau, Danielle van Westen, Mårten Fernö, Christian Ingvar, Carsten Rose, Pär-Ola Bendahl, Lisa Rydén, Åke Borg, Sofia K Gruvberger-Saal, Helena Jernström, Lao H Saal
Abstract
Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0-37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.
Keywords: breast carcinoma; circulating tumor DNA; early detection; liquid biopsy; metastasis.
© 2015 The Authors. Published under the terms of the CC BY 4.0 license.
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References
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