scholarly journals Methylome Variation Predicts Exemestane Resistance in Advanced ER+ Breast Cancer

2020 ◽  
Vol 19 ◽  
pp. 153303381989633
Author(s):  
Xiao-ran Liu ◽  
Ru-yan Zhang ◽  
Hao Gong ◽  
Hope S. Rugo ◽  
Ling-bo Chen ◽  
...  
Keyword(s):  
Hormone Therapy ◽  
Therapy Resistance ◽  
Circulating Tumor Dna ◽  
Chromosome 3 ◽  
Chromosome 6 ◽  
Breast Cancers ◽  
Differentially Methylated Regions ◽  
Tumor Dna ◽  
Methylation Ratio

Background: More than 30% of estrogen receptor-positive breast cancers are resistant to primary hormone therapy, and about 40% that initially respond to hormone therapy eventually acquire resistance. Although the mechanisms of hormone therapy resistance remain unclear, aberrant DNA methylation has been implicated in oncogenesis and drug resistance. Purpose: We investigated the relationship between methylome variations in circulating tumor DNA and exemestane resistance, to track hormone therapy efficacy. Methods: We prospectively recruited 16 patients who were receiving first-line therapy in our center. All patients received exemestane-based hormone therapy after enrollment. We collected blood samples at baseline, first follow-up (after 2 therapeutic cycles) and at detection of disease progression. Disease that progressed within 6 months under exemestane treatment was considered exemestane resistance but was considered relatively exemestane-sensitive otherwise. We obtained circulating tumor DNA-derived methylomes using the whole-genome bisulfide sequencing method. Methylation calling was done by BISMARK software; differentially methylated regions for exemestane resistance were calculated afterward. Results: Median follow-up for the 16 patients was 19.0 months. We found 7 exemestane resistance-related differentially methylated regions, located in different chromosomes, with both significantly different methylation density and methylation ratio. Baseline methylation density and methylation ratio of chromosome 6 [32400000-32599999] were both high in exemestane resistance. High baseline methylation ratios of chromosome 3 [67800000-67999999] ( P = .013), chromosome 3 [140200000-140399999] ( P = .037), and chromosome 12 [101200000-101399999] ( P = .026) could also predict exemestane resistance. During exemestane treatment, synchronized changes in methylation density and methylation ratio in chromosome 6 [32400000-32599999] could accurately stratify patients in terms of progression-free survival ( P = .000033). Cutoff values of methylation density and methylation ratio for chromosome 6 [149600000-149799999] were 0.066 and 0.076, respectively. Conclusion: Methylation change in chromosome 6 [149600000-149799999] is an ideal predictor of exemestane resistance with great clinical potential.

scholarly journals Circulating Tumor DNA Profiling From Breast Cancer Screening Through to Metastatic Disease

2021 ◽  
pp. 1768-1776
Author(s):  
Karen Page ◽  
Luke J. Martinson ◽  
Daniel Fernandez-Garcia ◽  
Allison Hills ◽  
Kelly L. T. Gleason ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Breast Screening ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Healthy Controls ◽  
Breast Cancers ◽  
Poor Overall Survival ◽  
Tumor Dna

PURPOSE We investigated the utility of the Oncomine Breast cfDNA Assay for detecting circulating tumor DNA (ctDNA) in women from a breast screening population, including healthy women with no abnormality detected by mammogram, and women on follow-up through to advanced breast cancer. MATERIALS AND METHODS Blood samples were taken from 373 women (127 healthy controls recruited through breast screening, 28 ductal carcinoma in situ, 60 primary breast cancers, 47 primary breast cancer on follow-up, and 111 metastatic breast cancers [MBC]) to recover plasma and germline DNA for analysis with the Oncomine Breast cfDNA Assay on the Ion S5 platform. RESULTS One hundred sixteen of 373 plasma samples had one or more somatic variants detected across eight of the 10 genes and were called ctDNA-positive; MBC had the highest proportion of ctDNA-positive samples (61; 55%) and healthy controls the lowest (20; 15.7%). ESR1, TP53, and PIK3CA mutations account for 93% of all variants detected and predict poor overall survival in MBC (hazard ratio = 3.461; 95% CI, 1.866 to 6.42; P = .001). Patients with MBC had higher plasma cell-free DNA levels, higher variant allele frequencies, and more polyclonal variants, notably in ESR1 than in all other groups. Only 15 individuals had evidence of potential clonal hematopoiesis of indeterminate potential mutations. CONCLUSION We were able detect ctDNA across the breast cancer spectrum, notably in MBC where variants in ESR1, TP53, and PIK3CA predicted poor overall survival. The assay could be used to monitor emergence of resistance mutations such as in ESR1 that herald resistance to aromatase inhibitors to tailor adjuvant therapies. However, we suggest caution is needed when interpreting results from a single plasma sample as variants were also detected in a small proportion of HCs.

scholarly journals Circulating tumor DNA is detectable in canine histiocytic sarcoma, oral malignant melanoma, and multicentric lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anaïs Prouteau ◽  
Jérôme Alexandre Denis ◽  
Pauline De Fornel ◽  
Edouard Cadieu ◽  
Thomas Derrien ◽  
...  
Keyword(s):  
Residual Disease ◽  
Specific Antigen ◽  
Point Mutations ◽  
Antigen Receptor ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Histiocytic Sarcoma ◽  
Oncology Research ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) has become an attractive biomarker in human oncology, and its use may be informative in canine cancer. Thus, we used droplet digital PCR or PCR for antigen receptor rearrangement, to explore tumor-specific point mutations, copy number alterations, and chromosomal rearrangements in the plasma of cancer-affected dogs. We detected ctDNA in 21/23 (91.3%) of histiocytic sarcoma (HS), 2/8 (25%) of oral melanoma, and 12/13 (92.3%) of lymphoma cases. The utility of ctDNA in diagnosing HS was explored in 133 dogs, including 49 with HS, and the screening of recurrent PTPN11 mutations in plasma had a specificity of 98.8% and a sensitivity between 42.8 and 77% according to the clinical presentation of HS. Sensitivity was greater in visceral forms and especially related to pulmonary location. Follow-up of four dogs by targeting lymphoma-specific antigen receptor rearrangement in plasma showed that minimal residual disease detection was concordant with clinical evaluation and treatment response. Thus, our study shows that ctDNA is detectable in the plasma of cancer-affected dogs and is a promising biomarker for diagnosis and clinical follow-up. ctDNA detection appears to be useful in comparative oncology research due to growing interest in the study of natural canine tumors and exploration of new therapies.

scholarly journals The mutational landscape of spinal chordomas and their sensitive detection using circulating tumor DNA

2020 ◽  
Author(s):  
Austin K Mattox ◽  
Beibei Yang ◽  
Christopher Douville ◽  
Sheng-fu Lo ◽  
Daniel Sciubba ◽  
...  
Keyword(s):  
Clinical Status ◽  
Spinal Column ◽  
Disease Recurrence ◽  
The United States ◽  
Circulating Tumor Dna ◽  
Blood Draw ◽  
Primary Tumors ◽  
Whole Exome ◽  
Tumor Dna

Abstract Background Chordomas are the most common primary spinal column malignancy in the United States. The aim of this study was to determine whether chordomas may be detected by evaluating mutations in circulating tumor DNA (ctDNA). Methods 32 patients with a biopsy-confirmed diagnosis of chordoma had blood drawn pre-operatively and/or at follow up appointments. Mutations in the primary tumor were identified by whole exome sequencing and liquid biopsy by ddPCR and/or RACE-Seq was used to detect one or more of these mutations in plasma ctDNA at concurrent or later time points. Results 87.1% of patients were ctDNA positive at the time of initial blood draw (p < 0.001). Follow up blood draws in twenty of the patients suggest that ctDNA levels may reflect the clinical status of the disease. Patients with positive ctDNA levels were more likely to have greater mutant allele frequencies in their primary tumors (p = 0.004) and undergo radiotherapy (p = 0.02), and the presence of ctDNA may correlate with response to systemic chemotherapy and/or disease recurrence. Conclusions Detection of ctDNA mutations may allow for the detection and monitoring of disease progression for chordomas.

scholarly journals Plasma circulating tumor DNA in pancreatic adenocarcinoma for screening, diagnosis, prognosis, treatment and follow-up: A systematic review

2020 ◽  
Vol 87 ◽  
pp. 102028 ◽  
Author(s):  
Raëf Abdallah ◽  
Valérie Taly ◽  
Shulin Zhao ◽  
Daniel Pietrasz ◽  
Jean-Baptiste Bachet ◽  
...  
Keyword(s):  
Systematic Review ◽  
Pancreatic Adenocarcinoma ◽  
Circulating Tumor Dna ◽  
Tumor Dna

Clinical implications of monitoring circulating tumor DNA in early- and late-stage non-small cell lung cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20607-e20607
Author(s):  
Muyun Peng ◽  
Lihan Chin ◽  
Qi Huang ◽  
Wei Yin ◽  
Sichuang Tan ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Somatic Mutations ◽  
Residual Disease ◽  
Lung Squamous Cell Carcinoma ◽  
Circulating Tumor Dna ◽  
Small Cell Lung ◽  
Tumor Dna

e20607 Background: Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the most common types of NSCLC are squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The development of noninvasive methods to monitor circulating tumor DNA (ctDNA) continues to be a major challenge in NSCLC. Methods: We investigated if detection of ctDNA after resection of NSCLC identifies the patients with risk of relapse, and furthermore, informs about response to management.In this cohort study, high-throughput 168 target-gene capture technology and high-sensitivity circulating single molecule amplification and re-sequencing technology (cSMART) were used to detect the somatic mutations in tissues and plasma of patients with NSCLC, respectively. Moreover, ctDNA somatic mutations were used to monitor changes in minimal residual disease during a follow-up period. Results: A total of 169 patients with lung squamous cell carcinoma and adenocarcinoma were included. Detectable levels of ctDNA were present in 60.7% of patients with stage I and 68.8% of patients with late-stage. In patients not treated with adjuvant chemotherapy, ctDNA was detected preoperatively in 46 of 81 (56.8%) patients, 14 (30.4%) of whom had recurred at follow-up of 44 months; recurrence occurred in only 2 (5.7 %) of 35 patients with negative ctDNA. Serial ctDNA status changed from positive to negative during the initial phase of post operation in four patients. Then, ctDNA became positive again after 2 weeks to 3 months, all the four patients with relapse during the follow-up of 44 months. Conclusions: Detection of ctDNA supplies evidence of residual disease and identifies patients at risk of relapse. These observations have implications for the intervention of lung squamous cell carcinoma and adenocarcinoma patients.

scholarly journals ctDNAtools: An R package to work with sequencing data of circulating tumor DNA

2020 ◽  
Author(s):  
Amjad Alkodsi ◽  
Leo Meriranta ◽  
Annika Pasanen ◽  
Sirpa Leppä
Keyword(s):  
Residual Disease ◽  
Fragment Size ◽  
R Package ◽  
Monte Carlo Sampling ◽  
Circulating Tumor Dna ◽  
Cancer Diagnostics ◽  
Sequencing Data ◽  
Liquid Biopsies ◽  
Tumor Dna

AbstractSummarySequencing of cell-free DNA (cfDNA) including circulating tumor DNA (ctDNA) in minimally-invasive liquid biopsies is rapidly maturing towards clinical utility for cancer diagnostics. However, the publicly available bioinformatics tools for the specialized analysis of ctDNA sequencing data are still scarce. Here, we present the ctDNAtools R package, which provides functionalities for testing minimal residual disease (MRD) and analyzing cfDNA fragmentation. MRD detection in ctDNAtools utilizes a Monte Carlo sampling approach to test ctDNA positivity through tracking a set of pre-detected reporter mutations in follow-up samples. Additionally, ctDNAtools includes various functionalities to study cfDNA fragment size histograms, profiles and fragment ends patterns.AvailabilityThe ctDNAtools package is freely available under MIT license at https://github.com/alkodsi/ctDNAtools.

Abstract OT1-2-04: TP53 mutants in circulating tumor DNA and follow-up of BRCA1 mutation carriers: The CirCA01 study

2015 ◽  
Author(s):  
Francois-Clement Bidard ◽  
Dominique Stoppa-Lyonnet ◽  
Catherine Nogues ◽  
Olivier Caron ◽  
Suzette Delaloge ◽  
...  
Keyword(s):  
Brca1 Mutation ◽  
Circulating Tumor Dna ◽  
Mutation Carriers ◽  
Tumor Dna
Sign in / Sign up

Export Citation Format

Share Document