Dataset Information

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

ABSTRACT: PURPOSE:Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing. EXPERIMENTAL DESIGN:We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples. RESULTS:Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% (n = 13/16) in newly diagnosed MBC, 23% (n = 7/30) at postoperative and 19% (n = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months). CONCLUSIONS:Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.

SUBMITTER: Parsons HA

PROVIDER: S-EPMC7654718 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

Parsons Heather A HA Rhoades Justin J Reed Sarah C SC Gydush Gregory G Ram Priyanka P Exman Pedro P Xiong Kan K Lo Christopher C CC Li Tianyu T Fleharty Mark M Kirkner Gregory J GJ Rotem Denisse D Cohen Ofir O Yu Fangyan F Fitarelli-Kiehl Mariana M Leong Ka Wai KW Hughes Melissa E ME Rosenberg Shoshana M SM Collins Laura C LC Miller Kathy D KD Blumenstiel Brendan B Trippa Lorenzo L Cibulskis Carrie C Neuberg Donna S DS DeFelice Matthew M Freeman Samuel S SS Lennon Niall J NJ Wagle Nikhil N Ha Gavin G Stover Daniel G DG Choudhury Atish D AD Getz Gad G Winer Eric P EP Meyerson Matthew M Lin Nancy U NU Krop Ian I Love J Christopher JC Makrigiorgos G Mike GM Partridge Ann H AH Mayer Erica L EL Golub Todd R TR Adalsteinsson Viktor A VA

Clinical cancer research : an official journal of the American Association for Cancer Research 20200313 11

<h4>Purpose</h4>Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.<h4>Experimental design</h4>We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone pros ...[more]

PMID: 32170028

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Project description:Background: Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy. Serum thyroglobulin (Tg) levels are used to monitor PTC treatment response and recurrences however, in about 25% of the cases the sensitivity of this method is compromised due to either the presence of neutralizing anti-Tg antibodies (TgAb) or the absence of Tg in less differentiated tumors. Up to 80% of PTC tumors harbor the c.1799T>A hotspot mutation in the BRAF gene (BRAFV600E). Here, we assessed the potential use of plasma cell-free BRAFV600E mutant tumor DNA (ctDNA) levels in determining the minimal residual tumor status of PTC patients. Methods: Patients were classified as either having persistent disease (PD) or no evidence of disease (NED) based on clinicopathological assessments. Tumor BRAFV600E status was determined by both direct sequencing and digital PCR. Plasma total cell-free BRAFV600 wild type DNA (cfDNA) and ctDNA fractions circulating in the plasma of PTC patients were determined by an emulsion based-digital PCR and total ctDNA was quantified by 3D digital PCR. The total ctDNA levels (copies/ml) were then compared to patients' clinicopathological features. Results: About 74% (28/38) of tumors harbored the BRAFV600E mutation. Percent plasma ctDNA fractions for PD patients with BRAFV600E tumors ranged from 0 to 2.07%, whereas absolute plasma ctDNA copies ranged from 0 to 62 copies. The ctDNA levels accurately detected tumor burden of PTC patients whose tumors harbored BRAFV600E; median plasma ctDNA copy numbers were significantly higher (Wilcoxon test, p = 0.03) in patients with metastasis (MET) (20 copies/ml) compared to patients with non-metastatic (non-MET) tumors (1 copy/ml). The plasma ctDNA levels (copies/ml) accurately determined the disease status of PTC patients with sensitivity of 86% and specificity of 90% as compared to 78% sensitivity and 65% specificity determined by serum Tg levels (ng/ml) with areas under the curves (AUC) of 0.88 and 0.71, respectively. Intriguingly, plasma total cfDNA levels were significantly higher in patients with no evidence of residual disease (NED) compared to persistent disease (PD) patients. Conclusions: Our study supports the clinical applicability of plasma ctDNA as biomarker to determine the residual tumor status and tumor burden of PTC patients.

Dataset Information

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

Publications

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

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