scholarly journals Utility of Circulating Tumor DNA in Different Clinical Scenarios of Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3797
Author(s):  
Alexandra Mesquita ◽  
José Luís Costa ◽  
Fernando Schmitt
Keyword(s):  
Breast Cancer ◽  
Tumor Heterogeneity ◽  
Locally Advanced ◽  
Circulating Tumor Dna ◽  
Genetic Alterations ◽  
Biological Behavior ◽  
Early Stage Disease ◽  
Clinical Scenarios ◽  
Metastatic Setting ◽  
Tumor Dna

Breast cancer is a complex disease whose molecular mechanisms are not completely understood. Developing target therapies is a promising approach. Therefore, understanding the biological behavior of the tumor is a challenge. Tissue biopsy in the metastatic setting remains the standard method for diagnosis. Nevertheless, it has been associated with some disadvantages: It is an invasive procedure, it may not represent tumor heterogeneity, and it does not allow for treatment efficacy to be assessed or early recurrences to be detected. Analysis of circulating tumor DNA (ctDNA) may help to overcome this as it is a non-invasive method of monitoring the disease. In early-stage disease, it can detect early recurrences and monitor tumors’ genomic profiles, identifying the emergence of new genetic alterations which can be related to tumor-acquired resistance. In the metastatic setting, the analysis of ctDNA may also allow for the anticipation of clinical and radiological progression of the disease, selection of targeted therapies, and for a photogram of tumor heterogeneity to be provided. It may also detect disease progression earlier in locally advanced tumors submitted to neoadjuvant treatment, and identify minimal residual disease. ctDNA analysis may guide clinical decision-making in different scenarios, in a precision medicine era, once it acts as a repository of genetic tumor material, allowing for a comprehensive mutation profiling analysis. In this review, we focused on recent advances towards the implementation of ctDNA in a clinical routine for breast cancer.

Serial circulating tumor DNA analysis indicating the efficacy and prognosis of neoadjuvant chemotherapy for locally advanced breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12089-e12089
Author(s):  
Yidong Zhou ◽  
Yaping Xu ◽  
Yuhua Gong ◽  
Jiaolin Zhou ◽  
Yaping Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Circulating Tumor Dna ◽  
Her2 Overexpression ◽  
Genomic Profiling ◽  
Blood Samples ◽  
Tumor Dna ◽  
Erbb2 Amplification

e12089 Background: The efficacy evaluation of neoadjuvant chemotherapy (NCT) for locally advanced breast cancer (LABC) is still a questionable issue. The clinical imaging is always discrepant from pathological assessment postoperatively, and conventional tumor markers, such as CEA and CA15-3, did not show significantly correlation with the response to NCT in breast cancer patients. Analysis of circulating tumor DNA (ctDNA) from blood may provide a promising alternative. Methods: Collectively, 63 tissue and 204 blood samples from 32 patients with LABC were collected. There were four sampling nodes for blood collection: at baseline, during chemotherapy, after chemotherapy and after operation. Hybrid capture-based genomic profiling with a 1021-gene panel was carried out for both tissue and blood samples. Results: Totally, 151 somatic mutations were detected in tissue samples from 32 patients. TP53 (n = 14, 43.75%) and PIK3CA (n = 13, 40.63%) were the most recurrent mutant genes. Among 11 patients with HER2 overexpression, 10 (90.91%) carried ERBB2 amplification. All of 21 patients with normal HER2 present diploid ERBB2. The overall concordance between HER2 overexpression and ERBB2 amplification was 96.88%. At least one tissue mutation could be detected in blood collected at baseline for 21 patients, during chemotherapy for three patients, after chemotherapy for nine patients, and after operation for four patients. There was no tissue mutation in blood collected during and after chemotherapy for four patients reached pathologic complete response (pCR). The median of pathological tumor decrease in situ was 54.63% (17.07% to 98.04%) for patients with tissue mutations in blood collected either during or after chemotherapy, and 86.53% (7.69% to 98.04%) for patients without tissue mutation in both blood samples. Furthermore, the median number of pathologically involved lymph nodes was 3.5 (0 to 16) and 1 (0 to 9) for two patients cohort, respectively. All of four patients with tissue mutations in postoperative blood experienced distant metastasis during follow-up, while only 7.14% (2/28) of those without tissue mutation relapsed. The median DFS was 9.8 and 22.7 months, respectively (HR 26.14, 95% CI 1.161 to 588.5, p < 0.0001). Conclusions: Sequential genomic profiling of blood ctDNA can be used to evaluate the therapeutic efficacy of NCT, as well as the postoperative survival. This study highlights the feasibility of integrating ctDNA profiling into the clinical management for LABC undergoing NCT. Clinical trial information: NCT02797652.

Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12502-e12502
Author(s):  
Wang Xiao Jia ◽  
Zhan-Hong Chen ◽  
Tian Sun ◽  
Zi Yan Yang ◽  
Yabing Zheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Liquid Biopsy ◽  
Somatic Mutations ◽  
Target Therapy ◽  
Chemotherapy Resistance ◽  
Circulating Tumor Dna ◽  
Genetic Alterations ◽  
Longitudinal Analyses ◽  
Trastuzumab Resistance ◽  
Tumor Dna

e12502 Background: Circulating tumor DNA (ctDNA) from liquid biopsy provides a valuable assessment of invasive breast cancer (BC). We evaluated the utility of ctDNA to reflect the efficacy of HER2-targeted trastuzumab in treating HER2+ BC patients, as well as chemotherapy in treating HER2- BC patients, to monitor trastuzumab and chemotherapy resistance mechanisms. Methods: Targeted next-generation sequencing (NGS) of 416 cancer-relevant genes was performed in 41 plasma biopsy samples from 19 HER2+ and 12 HER2- BC patients in a retrospective study. We compared ctDNA somatic mutations and germline mutations for analyzing acquired and innate resistance, respectively. Results: ERBB2 somatic copy number of HER2+ BC patients who developed progressed diseases to HER2-target therapy was significantly higher than those benefited from HER2-target therapy. HER2+ BC patients who developed acquired resistance to trastuzumab showed frequent genomic alterations on ERBB2, TP53, EGFR, NF1 and SETD2 genes. Specifically, in longitudinal analyses, somatic mutations found in the original breast tumor can be detected in the liver metastasis and plasma ctDNA with increased allele frequencies. Newly emerged deleterious mutations occurred when the patient was benefiting from trastuzumab, predicting the poor prognosis. From these newly emerged somatic mutations, EBBB2L869R was further investigated in vitro and contributed to trastuzumab resistance. In the HER2- BC patients with chemotherapy resistance, frequently genetic alterations on TP53, PIK3CA and DNA damage repair genes were observed in ctDNA mutation profiling. Conclusions: liquid biopsy ctDNA, particularly longitudinal analyses, provides insights into targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2- BC patients, respectively.

Assessing tumor heterogeneity using circulating tumor DNA to predict and monitor therapeutic response in metastatic breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11543-11543
Author(s):  
Fei Ma ◽  
Yanfang Guan ◽  
Zongbi Yi ◽  
Lianpeng Chang ◽  
Xuefeng Xia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Heterogeneity ◽  
Therapeutic Response ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Response To Treatment ◽  
Clonal Population ◽  
Tumor Dna

11543 Background: Within metastatic breast cancer (mBC), tumor heterogeneity limited efficacy and duration of response to treatment. In this study, circulating tumor DNA (ctDNA) was used to evaluate tumor heterogeneity as a prognostic factor and monitor therapeutic response in patients with mBC. Methods: We collected plasma samples from 37 HER2-positive mBC patients treated with pyrotinib. Target-capture deep sequencing was performed to detect somatic mutations in plasma ctDNA. Clonal population structures were identified based on variations from ctDNA using Bayesian cluster with PyClone. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population. Results: Mutations in TP53 and genes of PI3K/Akt/mTOR pathway were associated with drug resistance for pyrotinib. The result showed that patients with resistant mutations occurring as a truncal event, who receiving monotherapy of pyrotinib, presented worse therapeutic effect (HR, 4.52; P = 0.03). The median PFS of patients with versus without resistant mutations in trunk clonal population was 7.8 weeks (95% CI 7.4 to 26.8 weeks) versus 31.6 weeks (95% CI 15.7 to 60 weeks), respectively. Patients with high heterogeneity (clonal population ≥3) had a significantly worse PFS (HR, 2.79; 95% CI 1.23 to 6.34; P = 0.014). The median PFS among patients with high versus low heterogeneity was 30.0 weeks (95% CI 13.9 to 53.5 weeks) versus 60.0 weeks (95% CI 31.4 to 84 weeks), respectively. Longitudinal monitoring of 21 patients during treatment showed positive correlation between mTBI in ctDNA and tumor size evaluated by CT imaging (P < 0.0001). Monitoring the mTBI in serial ctDNA increased sensitivity for prediction of progressive disease in 6 of 21 patients, with a mean time of 12.7 weeks earlier than using CT scan. ROC curve analysis showed an area under the curve value was 0.97 (p < 0.0001). Conclusions: Assessing tumor heterogeneity in ctDNA provides genetic predictors of treatment outcome. Molecular tumor burden in ctDNA is a potential indicator of therapeutic response. These observations might be supplements for the current therapeutic response evaluation.

scholarly journals Liquid Biopsies: Genotyping Circulating Tumor DNA

2014 ◽  
Vol 32 (6) ◽  
pp. 579-586 ◽  
Author(s):  
Luis A. Diaz ◽  
Alberto Bardelli
Keyword(s):  
Tumor Heterogeneity ◽  
Dna Analysis ◽  
Tumor Tissue ◽  
Tumor Staging ◽  
Circulating Tumor Dna ◽  
Genetic Alterations ◽  
Routine Practice ◽  
Liquid Biopsies ◽  
Tumor Dna ◽  
Single Snapshot

Genotyping tumor tissue in search of somatic genetic alterations for actionable information has become routine practice in clinical oncology. Although these sequence alterations are highly informative, sampling tumor tissue has significant inherent limitations; tumor tissue is a single snapshot in time, is subject to selection bias resulting from tumor heterogeneity, and can be difficult to obtain. Cell-free fragments of DNA are shed into the bloodstream by cells undergoing apoptosis or necrosis, and the load of circulating cell-free DNA (cfDNA) correlates with tumor staging and prognosis. Moreover, recent advances in the sensitivity and accuracy of DNA analysis have allowed for genotyping of cfDNA for somatic genomic alterations found in tumors. The ability to detect and quantify tumor mutations has proven effective in tracking tumor dynamics in real time as well as serving as a liquid biopsy that can be used for a variety of clinical and investigational applications not previously possible.

scholarly journals Genomic Profiling of Premenopausal HR+ and HER2– Metastatic Breast Cancer by Circulating Tumor DNA and Association of Genetic Alterations With Therapeutic Response to Endocrine Therapy and Ribociclib

2021 ◽  
pp. 1408-1420
Author(s):  
Aditya Bardia ◽  
Fei Su ◽  
Nadia Solovieff ◽  
Seock-Ah Im ◽  
Joohyuk Sohn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Genetic Alterations ◽  
Wild Type ◽  
Hormone Receptor Positive ◽  
Epidermal Growth ◽  
Premenopausal Patients ◽  
Tumor Dna

PURPOSE This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor–positive and human epidermal growth factor receptor 2–negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial. METHODS Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib. RESULTS Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status. CONCLUSION In this study—to our knowledge, the first large study of premenopausal patients with hormone receptor–positive and human epidermal growth factor receptor 2–negative advanced breast cancer—multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.

scholarly journals Circulating Tumor DNA and Biomarker Analyses From the LOTUS Randomized Trial of First-Line Ipatasertib and Paclitaxel for Metastatic Triple-Negative Breast Cancer

2020 ◽  
pp. 1012-1024
Author(s):  
Matthew J. Wongchenko ◽  
Sung-Bae Kim ◽  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Doron Lipson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Objective Response ◽  
Circulating Tumor Dna ◽  
Genetic Alterations ◽  
Longitudinal Analyses ◽  
Akt Inhibitor ◽  
First Line ◽  
Tumor Dna

PURPOSE Combining the oral AKT inhibitor ipatasertib with paclitaxel as first-line therapy for metastatic triple-negative breast cancer significantly improved progression-free survival (PFS) in the placebo-controlled, randomized, phase II LOTUS trial, with a more pronounced effect in patients with PIK3CA/AKT1/PTEN-altered tumors. We report findings from the extensive translational research program. PATIENTS AND METHODS Pretreatment plasma and tumor samples were evaluated for genetic alterations using FoundationACT and FoundationOne (Foundation Medicine, Cambridge, MA) hybrid capture next-generation sequencing assays, respectively. Prevalences of the most common mutations and PIK3CA/AKT1 mutation status were determined using both assays, and concordance was assessed. In longitudinal analyses, circulating tumor DNA (ctDNA) mutations were quantified in baseline and on-treatment (cycle 3, day 1 [C3D1]) samples. The relationship between outcomes and ctDNA fraction (CTF; highest variant allele frequency) and CTF ratio (C3D1 CTF to baseline CTF) was explored. RESULTS Among 89 patients evaluable for ctDNA sequencing, 81 patients (91%) had 149 detectable mutations. There was high agreement between plasma- and tissue-based sequencing for known or likely short variant mutations but not amplifications. There was 100% concordance between ctDNA and tissue sequencing in patients with activating PIK3CA or AKT1 mutations. High baseline CTF was associated with shorter PFS in both treatment arms. Longitudinal analyses showed more favorable outcomes with lower absolute CTF at C3D1 and, to a lesser extent, greater CTF decreases. CONCLUSION These results suggest that plasma ctDNA sequencing may allow reliable and convenient assessment of prognosis and identification of genetic markers associated with increased benefit from ipatasertib. On-treatment CTF showed a meaningful association with objective response and PFS.

Analysis of circulating tumor DNA identifies homologous recombination repair molecular features of Chinese breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13006-e13006
Author(s):  
Mingwei Li ◽  
Tongtong Yang ◽  
Huina Wang ◽  
Feng Lou ◽  
Shanbo Cao
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Circulating Tumor Dna ◽  
Genetic Alterations ◽  
Genetic Alteration ◽  
Chinese Patients ◽  
Homologous Recombination Repair ◽  
Molecular Features ◽  
Recombination Repair ◽  
Tumor Dna

e13006 Background: Breast cancer (BC) is the most common cancer in women world-wide. Assessments of genomic variants in circulating tumor DNA (ctDNA) have generated great enthusiasm for their potential application as clinically actionable biomarkers in the management of BC. Alterations in homologous recombination repair (HRR), are a determinant of sensitivity to platinum chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPi) in BC. However, as far as we known, most of HRR genes, except BRCA1/2, have not yet been fully understood to date. In this study, we aimed to elucidate the comprehensive HRR genetic alteration profile of breast tumors among Chinese patients by ctDNA analysis. Methods: Plasma ctDNA from 259 patients with BC were deeply sequenced via next-generation sequencing (NGS) techniques using AcornMed Biotechnology for 808 genes panel. Molecular profiles were reviewed to identify somatic and germline pathogenic mutations in the 14 HRR genes ( ATM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, CDK12, and BARD1) . Results: At our institution, 259 patients underwent NGS analysis of BC specimens. The median age was 46 (range from 31 to 79). Based on the analysis of the genetic alteration profile from our cohort, at least one of the HRR genes was observed from 29.34% of the tumor samples, with BRCA1 (8.11%), BRCA2 (5.79%), RAD51C (5.02%), CDK12 (4.63%), CHEK2 (1.93%), ATM (1.16%), and BARD1 (1.16%) as the most commonly altered genes. As compared with MSKCC dataset (Table), genetic alterations detected from our cohort affected genes involved in HRR (29.34% vs. 14.03%, P＜0.0001) pathways, with statistically different genetic alteration rates. Moreover, BRCA1/2, RAD51C, CDK12 and CHEK2 mutations exhibited higher mutation rates, whereas ATM, BRIP1 and PALB2 mutations presented a lower mutation rate in Chinese patients with breast cancer (P＜0.05). Conclusions: CtDNA can characterize the mutational feature of HRR in BC. our study contributes to the understanding of the HRR pathways and specific genetic alterations harbored by Chinese patients with BC that could potentially be developed as markers of treatment response to targeted therapeutics. Ref: Razavi P, Chang MT, Xu GT, et al. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell. 2018 Sep 10;34(3):427-438.e6. doi: 10.1016/j.ccell.2018.08.008.[Table: see text]

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