Precision oncology focuses on matching targeted therapies to genetic alterations in a patient’s tumor, usually in a metastatic setting. When responses to such treatments are seen, the long-term benefit remains uncommon. However, a minority of patients are “exceptional responders,” and although no standardized definition of this phenomenon has been established, sustained remissions or lack of progression spanning years to decades has generally characterized this cohort. Presentations vary widely, including stable disease for protracted periods and a few exceptional responders who demonstrate no evidence of metastatic disease even after cessation of antineoplastic therapies. Whether these patients are cured or harbor minimal residual disease (MRD) that may ultimately relapse is unknown.
The use of plasma tumor cell-free DNA (cfDNA) as “liquid biopsies” has been championed for identifying mutations amenable to targeted therapies and for the assessment of MRD.1–4 With the advent of droplet digital PCR (ddPCR) and ultra-deep next-generation sequencing (NGS), clinicians are able to track tumor burden, evaluate response to therapies, and detect MRD using cancer DNA alterations present in cfDNA as a biomarker. Indeed, many studies have supported the feasibility of cfDNA for serial monitoring.5 For example, we and others have demonstrated that ddPCR can detect MRD using cfDNA in patients with early-stage breast cancer after curative-intent therapies.1,3 In addition, we are testing the clinical utility of cfDNA in patients with early-stage, HER2-positive and triple-negative breast cancer in a large-scale, multi-institutional prospective study (ClinicalTrials.gov identifier: NCT02743910).
In this study, we assessed cfDNA from a patient with estrogen receptor (ER)/progesterone receptor (PR)–negative, HER2-positive metastatic breast cancer who received trastuzumab and nab-paclitaxel in 2008 and experienced a complete remission (CR). Remarkably, she continues to have no evidence of disease several years beyond the cessation of any cancer-directed therapies. NGS of her primary tumor tissue showed several mutations, including a PIK3CA mutation, which was used to assess MRD via cfDNA. We also tested several other tissues to rule out germline variants and clonal hematopoiesis (CH). These findings suggest that long-term blood-based monitoring of cfDNA may distinguish patients with MRD from those without molecular evidence of disease, which could potentially help clinicians evaluate the risk versus benefit of ongoing maintenance therapy for patients with metastatic disease who experience extreme responses to treatment.
We thank and acknowledge the support of the Nashville Wine Auction, the Parker Foundation, and Susan G. Komen.
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