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      Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer

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          Abstract

          This validation study assesses the clinical validity of molecular relapse detection with circulating tumor DNA analysis in early-stage breast cancer. What is the clinical validity of molecular relapse detection with circulating tumor DNA analysis in early-stage breast cancer? This independent, prospective, multicenter, validation study of 101 women early-stage breast cancer assessed circulating tumor DNA mutation tracking and found that detection of circulating tumor DNA during follow-up had a median lead time of 10.7 months compared with clinical relapse, anticipating relapse in all major breast cancer subtypes. Brain-only metastasis was detected less frequently by circulating tumor DNA analysis, potentially requiring alternative surveillance. The findings suggest that molecular relapse detection has high levels of clinical validity, and clinical trials of treatment initiated at molecular relapse without waiting for incurable metastatic disease to develop are needed. Current treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse. To assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer. This prospective, multicenter, sample collection, validation study conducted at 5 United Kingdom medical centers from November 24, 2011, to October 18, 2016, assessed patients with early-stage breast cancer irrespective of hormone receptor and ERBB2 (formerly HER2 or HER2/neu) status who were receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. The study recruited 170 women, with mutations identified in 101 patients forming the main cohort. Secondary analyses were conducted on a combined cohort of 144 patients, including 43 patients previously analyzed in a proof of principle study. Primary tumor was sequenced to identify somatic mutations, and personalized tumor-specific digital polymerase chain reaction assays were used to monitor these mutations in serial plasma samples taken every 3 months for the first year of follow-up and subsequently every 6 months. The primary end point was relapse-free survival analyzed with Cox proportional hazards regression models. In the main cohort of 101 female patients (mean [SD] age, 54 [11] years) with a median follow-up of 35.5 months (interquartile range, 27.9-43.0 months), detection of ctDNA during follow-up was associated with relapse (hazard ratio, 25.2; 95% CI, 6.7-95.6; P  < .001). Detection of ctDNA at diagnosis, before any treatment, was also associated with relapse-free survival (hazard ratio, 5.8; 95% CI, 1.2-27.1; P  = .01). In the combined cohort, ctDNA detection had a median lead time of 10.7 months (95% CI, 8.1-19.1 months) compared with clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients (96%). Brain-only metastasis was less commonly detected by ctDNA (1 of 6 patients [17%]), suggesting relapse sites less readily detectable by ctDNA analysis. The findings suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage breast cancer. Prospective studies are needed to assess the potential of molecular relapse detection to guide adjuvant therapy.

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          Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling

          Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profi ling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I–III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the fi rst posttreatment blood sample, indicating reliable identifi cation of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profi les associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest.
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            Assessment of Minimal Residual Disease in Standard-Risk AML

            Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission.
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              False positive plasma genotyping due to clonal hematopoiesis

              Purpose: Plasma cell-free DNA (cfDNA) genotyping is increasingly used in cancer care, but assay accuracy has been debated. Because most cfDNA is derived from peripheral blood cells (PBC), we hypothesized that nonmalignant mutations harbored by hematopoietic cells (clonal hematopoiesis, CH) could be a cause of false-positive plasma genotyping.Experimental Design: We identified patients with advanced non-small cell lung cancer (NSCLC) with KRAS, JAK2, or TP53 mutations identified in cfDNA. With consent, PBC DNA was tested using droplet digital PCR (ddPCR) or next-generation sequencing (NGS) to test for CH-derived mutations.Results: We first studied plasma ddPCR results from 58 patients with EGFR-mutant NSCLC. Two had KRAS G12X detected in cfDNA, and both were present in PBC, including one where the KRAS mutation was detected serially for 20 months. We then studied 143 plasma NGS results from 122 patients with NSCLC and identified 5 JAK2 V617F mutations derived from PBC. In addition, 108 TP53 mutations were detected in cfDNA; for 33 of the TP53 mutations, PBC and tumor NGS were available for comparison, and 5 were present in PBC but absent in tumor, consistent with CH.Conclusions: We find that most JAK2 mutations, some TP53 mutations, and rare KRAS mutations detected in cfDNA are derived from CH not tumor. Clinicians ordering plasma genotyping must be prepared for the possibility that mutations detected in plasma, particularly in genes mutated in CH, may not represent true tumor genotype. Efforts to use plasma genotyping for cancer detection may need paired PBC genotyping so that CH-derived mutations are not misdiagnosed as occult malignancy. Clin Cancer Res; 24(18); 4437-43. ©2018 AACRSee related commentary by Bauml and Levy, p. 4352.
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                Author and article information

                Journal
                JAMA Oncology
                JAMA Oncol
                American Medical Association (AMA)
                2374-2437
                August 01 2019
                Affiliations
                [1 ]Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom
                [2 ]Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom
                [3 ]Ralph Lauren Centre for Breast Cancer Research, London, United Kingdom
                [4 ]Breast Unit, Royal Marsden Hospital, London, United Kingdom
                [5 ]Hinchingbrooke Hospital, Huntingdon, United Kingdom
                [6 ]Poole General Hospital, Dorset, United Kingdom
                [7 ]Royal Bournemouth Hospital, Bournemouth, United Kingdom
                [8 ]Department of Oncology, Royal Cornwall Hospitals National Health Service Trust, Truro, United Kingdom
                Article
                10.1001/jamaoncol.2019.1838
                6681568
                31369045
                0326b450-c9f7-43fe-8980-d454aacb0c81
                © 2019
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