Abstract
Mutation tracking in ctDNA predicts metastatic relapse and defines somatic mutations in MRD.
Major finding: Mutation tracking in ctDNA predicts metastatic relapse and defines somatic mutations in MRD.
Clinical relevance: Serial analysis of plasma ctDNA noninvasively detects MRD in patients with early breast cancer.
Impact: ctDNA analysis may reveal potentially targetable mutations present in micrometastases.
The efficacy of systemic therapy and surgery in patients with early-stage breast cancer is often limited by the presence of micrometastatic disease at diagnosis and the persistence of minimal residual disease (MRD) after treatment. Analysis of plasma circulating tumor DNA (ctDNA) has been investigated as a means to noninvasively detect somatic alterations in patients with advanced cancer. To evaluate the utility of ctDNA analysis in monitoring for MRD, Garcia-Murillas, Schiavon, and colleagues developed personalized digital PCR assays to track tumor-specific mutations in a prospective cohort of 55 patients with early breast cancer who were treated with neoadjuvant chemotherapy and surgery. This approach sensitively detected somatic mutations present in baseline primary tumors and facilitated the detection of mutant ctDNA in single or serial postsurgical samples in a process termed “mutation tracking.” Detection of ctDNA in postsurgical, but not baseline, samples identified the presence of MRD, which was not detectable by conventional imaging in some patients, months prior to clinical relapse, and accurately predicted early metastatic relapse. Furthermore, the genetic profile of MRD could be defined by targeted capture massively parallel sequencing of plasma ctDNA taken prior to clinical relapse. In the majority of patients, the repertoire of somatic mutations in ctDNA arising from MRD exhibited marked divergence from the genetic profile of the primary tumor and more closely resembled the mutations present in biopsies of the corresponding metastatic relapse, suggestive of clonal evolution in response to treatment. Of note, ctDNA sequencing revealed potentially targetable mutations that were absent from the primary tumor and loss of driver mutations in metastatic disease. These findings indicate that noninvasive mutation tracking in ctDNA may identify patients at high risk of relapse and suggest that ctDNA sequencing may allow for improved treatment of patients with micrometastatic disease.
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