Clinical applications of circulating tumor DNA in monitoring breast cancer drug resistance

2020 ◽  
Vol 16 (34) ◽  
pp. 2863-2878
Author(s):  
Yang Liu ◽  
Qian Du ◽  
Dan Sun ◽  
Ruiying Han ◽  
Mengmeng Teng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Clinical Applications ◽  
Current Status ◽  
Cancer Drug ◽  
Genomic Alteration ◽  
Tumor Dna

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. Unfortunately, treatments often fail because of the development of drug resistance, the underlying mechanisms of which remain unclear. Circulating tumor DNA (ctDNA) is free DNA released into the blood by necrosis, apoptosis or direct secretion by tumor cells. In contrast to repeated, highly invasive tumor biopsies, ctDNA reflects all molecular alterations of tumors dynamically and captures both spatial and temporal tumor heterogeneity. Highly sensitive technologies, including personalized digital PCR and deep sequencing, make it possible to monitor response to therapies, predict drug resistance and tailor treatment regimens by identifying the genomic alteration profile of ctDNA, thereby achieving precision medicine. This review focuses on the current status of ctDNA biology, the technologies used to detect ctDNA and the potential clinical applications of identifying drug resistance mechanisms by detecting tumor-specific genomic alterations in breast cancer.

scholarly journals Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer

2020 ◽  
Author(s):  
Ben O’Leary ◽  
Rosalind J Cutts ◽  
Xin Huang ◽  
Sarah Hrebien ◽  
Yuan Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Statistical Tests ◽  
Controlled Trial ◽  
Multivariable Analysis ◽  
Circulating Tumor Dna ◽  
Phase Iii ◽  
Genomic Alteration ◽  
Double Blind ◽  
Early Progression ◽  
Tumor Dna

Abstract Background There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i. Methods PALOMA-3 was a phase III, multicenter, double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor–positive (ER+) breast cancer. Pretreatment plasma samples from 459 patients were analyzed for mutations in 17 genes, copy number in 14 genes, and circulating tumor fraction. Progression-free survival (PFS) was compared in patients with circulating tumor fraction above or below a prespecified cutoff of 10% and with or without a specific genomic alteration. All statistical tests were 2-sided. Results Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.17 to 2.24; P = .004) and placebo plus fulvestrant (HR = 1.77, 95% CI = 1.21 to 2.59; P = .004). In multivariable analysis, high-circulating tumor fraction was associated with worse PFS (HR = 1.20 per 10% increase in tumor fraction, 95% CI = 1.09 to 1.32; P < .001), as was TP53 mutation (HR = 1.84, 95% CI = 1.27 to 2.65; P = .001) and FGFR1 amplification (HR = 2.91, 95% CI = 1.61 to 5.25; P < .001). No interaction with treatment randomization was observed. Conclusions Pretreatment ctDNA identified a group of high-risk patients with poor clinical outcome despite the addition of CDK4/6 inhibition. These patients might benefit from inclusion in future trials of escalating treatment, with therapies that may be active in these genomic contexts.

scholarly journals Concurrent Detection of Circulating Tumor Cells and Circulating Tumor DNA in Triple-negative Breast Cancer

2021 ◽  
Vol 6 (4) ◽  
pp. 373-377
Author(s):  
Henry L Gomez ◽  
Carlos A. Castaneda ◽  
Miluska Castillo ◽  
James Reuben ◽  
Hui Gao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pik3ca Mutation ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Pik3ca Mutations ◽  
Tumor Dna

Objective: Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) provide tumor information in breast cancer. Our objective was to characterize CTCs, and contrasted them with ctDNA PIK3CA mutation in 24 triple-negative breast cancer (TNBC). Methods: CTCs genes were characterized by AdnaTest protocol and ctDNA by digital PCR. Results:  We found CTCs genes in 37.5% and ctDNA PIK3CA mutations in 29.16%. Three cases with CTCs genes had concurrent ctDNA PIK3CA mutations. MUC1 or GA733-2 were found in 4 cases, and 3 of them had concurrent ctDNA PIK3CA. CTCs ALDH1/TWIST1 were found in 2 cases, AKT2 in one and PI3Kα in another, and none had concurrent ctDNA PIK3CA mutations. There was no correlation between CTCs and ctDNA detection. All 3 cases with CTC & cDNA concurrent finding underwent death during follow-up. Conclusion: Infrequent concurrent detection of CTC and ctDNA presence suggests that both represent independent processes in TNBC patients, and could identify worst prognosis cases.

scholarly journals Plasma Circulating Tumor DNA Levels for the Monitoring of Melanoma Patients: Landscape of Available Technologies and Clinical Applications

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Benoit Busser ◽  
Julien Lupo ◽  
Lucie Sancey ◽  
Stéphane Mouret ◽  
Patrice Faure ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Clinical Applications ◽  
Molecular Heterogeneity ◽  
Liquid Biopsies ◽  
Melanoma Patients ◽  
Ctdna Analysis ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna

Melanoma is a cutaneous cancer with an increasing worldwide prevalence and high mortality due to unresectable or metastatic stages. Mutations inBRAF,NRAS, orKITare present in more than 60% of melanoma cases, but a useful blood-based biomarker for the clinical monitoring of melanoma patients is still lacking. Thus, the analysis of circulating tumor cells (CTCs) and/or cell-free circulating tumor DNA (ctDNA) analysis from blood (liquid biopsies) appears to be a promising noninvasive, repeatable, and systemic sampling tool for detecting and monitoring melanoma. Here, we review the molecular biology-based strategies used for ctDNA quantification in melanoma patients, as well as their main clinical applications. Droplet digital PCR (ddPCR) and next generation sequencing (NGS) technologies appear to be two versatile and complementary strategies to study rare variant mutations for the detection and monitoring of melanoma progression. Among the different clinical uses of ctDNA, we highlight the assessment of molecular heterogeneity and the identification of genetic determinants for targeted therapy as well as the analysis of acquired resistance. Importantly, ctDNA quantification might also be a novel biomarker with a prognostic value for melanoma patients.

scholarly journals Reproducibility of Digital PCR Assays for Circulating Tumor DNA Analysis in Advanced Breast Cancer

PLoS ONE ◽  
2016 ◽  
Vol 11 (10) ◽  
pp. e0165023 ◽  
Author(s):  
Sarah Hrebien ◽  
Ben O’Leary ◽  
Matthew Beaney ◽  
Gaia Schiavon ◽  
Charlotte Fribbens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Dna Analysis ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Advanced Breast ◽  
Pcr Assays ◽  
Tumor Dna

scholarly journals Concordance of Genomic Alterations between Circulating Tumor DNA and Matched Tumor Tissue in Chinese Patients with Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Bing Xu ◽  
Guangyu Shan ◽  
Qixi Wu ◽  
Weiwei Li ◽  
Hongjiang Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Circulating Tumor Dna ◽  
Concordance Rate ◽  
Chinese Patients ◽  
Genomic Alteration ◽  
Single Nucleotide Variants ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Wilcoxon Rank Sum Test ◽  
Tumor Dna

Purpose. Circulating tumor DNA (ctDNA) served as a noninvasive method with less side effects using peripheral blood. Given the studies on concordance rate between liquid and solid biopsies in Chinese breast cancer (BC) patients were limited, we sought to examine the concordance rate of different kinds of genomic alterations between paired tissue biopsies and ctDNA samples in Chinese BC cohorts. Materials and Methods. In this study, we analyzed the genomic alteration profiles of 81 solid BC samples and 41 liquid BC samples. The concordance across 136 genes was evaluated. Results. The median mutation counts per sample in 41 ctDNA samples was higher than the median in 81 tissue samples (p=0.0254; Wilcoxon rank sum test). For mutation at the protein-coding level, 39.0% (16/41) samples had at least one concordant mutation in two biopsies. 20.0% tissue-derived mutations could be detected via ctDNA-based sequencing, whereas 11.7% ctDNA-derived mutations could be found in paired tissues. At gene amplification level, the overall concordant rate was 68.3% (28/41). The concordant rate at gene level for each patient ranged from 83.8% (114/136) to 99.3% (135/136). And, the mean level of variant allele frequency (VAF) for concordant mutations in ctDNA was statistically higher than that for the discordant ones (p<0.001; Wilcoxon rank sum test). Across five representative genes, the overall sensitivity and specificity were 49.0% and 85.9%, respectively. Conclusion. Our results indicated that ctDNA could provide complementary information on genetic characterizations in detecting single nucleotide variants (SNVs) and insertions and deletions (InDels).

scholarly journals Association of a novel circulating tumor DNA next-generating sequencing platform with circulating tumor cells (CTCs) and CTC clusters in metastatic breast cancer

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Andrew A. Davis ◽  
Qiang Zhang ◽  
Lorenzo Gerratana ◽  
Ami N. Shah ◽  
Youbin Zhan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Genomic Alteration ◽  
Genomic Alterations ◽  
Disease Heterogeneity ◽  
Tumor Dna

Abstract Purpose Liquid biopsies, including circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), can be used to understand disease prognosis, tumor heterogeneity, and dynamic response to treatment in metastatic breast cancer (MBC). We explored a novel, 180-gene ctDNA panel and the association of this platform with CTCs and CTC clusters. Methods A total of 40 samples from 22 patients with MBC were included in the study. For the primary analysis, all patients had ctDNA sequencing using the PredicinePLUS™ platform. CTCs and CTC clusters were examined using the CellSearch™ System. Clinical and pathological variables were reported using descriptive analyses. Associations between CTC count and specific genomic alterations were tested using the Mann-Whitney U test. Results Of 43 sequenced patients, 40 (93%) had at least one detectable genomic alteration with a median of 6 (range 1–22). Fifty-seven different genes were altered, and the landscape of genomic alterations was representative of MBC, including the commonly encountered alterations TP53, PTEN, PIK3CA, ATM, BRCA1, CCND1, ESR1, and MYC. In patients with predominantly hormone-receptor-positive MBC, the number of CTCs was significantly associated with alterations in ESR1 (P < 0.005), GATA3 (P < 0.05), CDH1 (P < 0.0005), and CCND1 (P < 0.05) (Mann-Whitney U test). Thirty-six percent of patients had CTC clusters, which were associated with alterations in CDH1, CCND1, and BRCA1 (all P < 0.05, Mann-Whitney U test). In an independent validation cohort, CTC enumeration confirmed significant associations with ESR1 and GATA3, while CTC clusters were significantly associated with CDH1. Conclusions We report on a novel ctDNA platform that detected genomic alterations in the vast majority of tested patients, further indicating potential clinical utility for capturing disease heterogeneity and for disease monitoring. Detection of CTCs and CTC clusters was associated with particular genomic profiles.

scholarly journals The Role of Non-Coding RNAs in Breast Cancer Drug Resistance

2021 ◽  
Vol 11 ◽  
Author(s):  
Jin-hai Tian ◽  
Shi-hai Liu ◽  
Chuan-yang Yu ◽  
Li-gang Wu ◽  
Li-bin Wang
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Tumor Development ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Circular Rnas ◽  
Mortality And Morbidity ◽  
Micro Rnas ◽  
Non Coding Rnas

Breast cancer (BC) is one of the commonly occurring malignancies in females worldwide. Despite significant advances in therapeutics, the mortality and morbidity of BC still lead to low survival and poor prognosis due to the drug resistance. There are certain chemotherapeutic, endocrine, and target medicines often used for BC patients, including anthracyclines, taxanes, docetaxel, cisplatin, and fluorouracil. The drug resistance mechanisms of these medicines are complicated and have not been fully elucidated. It was reported that non-coding RNAs (ncRNAs), such as micro RNAs (miRNA), long-chain non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) performed key roles in regulating tumor development and mediating therapy resistance. However, the mechanism of these ncRNAs in BC chemotherapeutic, endocrine, and targeted drug resistance was different. This review aims to reveal the mechanism and potential functions of ncRNAs in BC drug resistance and to highlight the ncRNAs as a novel target for achieving improved treatment outcomes for BC patients.

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