scholarly journals Disease Kinetics Measured By Circulating Tumor DNA Correlates with Treatment Response after Tafasitamab in Combination with R-CHOP with or without Lenalidomide in First Line Treatment of DLBCL

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3498-3498
Author(s):  
Mouhamad Khouja ◽  
Anke Schilhabel ◽  
Michaela Kotrova ◽  
Monika Brüggemann ◽  
Christian Kuffer ◽  
...  
Keyword(s):  
Treatment Response ◽  
Peripheral Blood ◽  
Treatment Cycle ◽  
Metabolic Response ◽  
Response Assessment ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
First Line ◽  
Tumor Dna ◽  
Rapid Treatment

Abstract Background Currently available clinical and biological prognostic factors do not adequately identify first-line DLBCL patients at risk for treatment failure. In DLBCL, circulating tumor DNA (ctDNA) can be utilized as a for molecular disease classification, detect minimal residual disease (MRD) or predict disease progression. We hypothesized that ctDNA detected by the EuroClonality immunoglobulin-based next generation sequencing (IG-NGS) assay correlates with treatment response and outcome. Patients and methods Overall, 451 samples (41 diagnostic fresh frozen paraffin embedded (FFPE) biopsies, 64 peripheral blood mononuclear cells (PBMC) and 346 plasma samples) from patients from a Phase Ib study in de novo DLBCL treated with tafasitamab and R-CHOP or tafasitamab and R-CHOP in combination with Lenalidomide (First-MIND; MOR208C107) were analyzed. DNA from FFPE or diagnostic PBMC was sequenced by using a 2-step PCR approach with the Euroclonality NGS IGH-VJ, IGH-DJ and IGK primer sets (euroclonality.org) (Brüggemann, Leukemia, 2019) with a number of primers adapted for usage in short fragment cfDNA. IG markers were identified at abundance level ≥5% of annotated IG reads and a >1 log higher abundance to the next most frequent clonotype. Disease related clonotypes were traced in plasma during (C2D1 and C4D1 n=34) and at end of treatment (EOT n=32) by a 1-step PCR approach and sequencing of at least 5000 human genome equivalents (hGE) of cell free (cf)DNA. ctDNA levels were determined as the number of specific clonotype molecules per input genome equivalents normalized by a reference standard DNA spiked into each sample as cIT-QC (Knecht, Leukemia, 2019) and reported per plasma volume. Data were analysed by ARResT/Interrogate (Bystry, Bioinformatics, 2017). Patients were reported MRD positive if ≥1 clonal IG rearrangement was detected. Results From 41 patients with available diagnostic FFPE and sufficient DNA quality for marker screening, 34 (89%) had at least 1 detectable clonal marker (IGH-VJ, IGH-DJ or IGK). One clonal IG marker was identified in 20/34 (59%) patients, whereas two or three markers were identified in 9 (27%) and 5 (14%) patients, respectively. Disease specific clonotypes identified in FFPE were recovered in 11/34 PBMC samples (32%) with a median abundance of 0,29% (range 0.006-21.9%) demonstrating a peripheral blood involvement. In 32/33 (97%) pretreatment plasma samples, ctDNA was detected with a median copy number of 172.5/ml plasma. cfDNA and ctDNA levels prior to treatment correlated with IPI and LDH (Fig1). ctDNA dynamics during treatment demonstrated rapid treatment response at C2D1. 23/34 samples were either MRD neg (n=19) or showed a ctDNA reduction ≥ 2 log levels (Fig2). At C4D1 7/34 (20%) samples had low-level detectable MRD and at EOT 29/32 (91%) patients achieved MRD negativity after treatment with tafasitamab and R-CHOP +/- lenalidomide (LOD 2 x 10 -4 for follow-up samples). Early ctDNA dynamics predicted metabolic response when applying a threshold of ctDNA reduction to <1% after the first treatment cycle. 25/28 (89%) patients completing treatment and achieving PET-response could be identified early during treatment by ctDNA assessment. Conclusion Baseline ctDNA levels determined by the EuroClonality IG-NGS assay and absolute cfDNA amounts correlated with pre-treatment risk factors. ctDNA dynamics after the 1 st treatment cycle demonstrated rapid treatment response to tafasitamab + RCHOP +/- lenalidomide and correlated with metabolic response. Assessment of ctDNA dynamics allows early response assessment and might be useful for risk stratification in patients with DLBCL. Figure 1 Figure 1. Disclosures Kuffer: Morphosys AG: Current Employment. Blair: Morphosys AG: Current Employment.

scholarly journals Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yongliang Zhang ◽  
Yu Yao ◽  
Yaping Xu ◽  
Lifeng Li ◽  
Yan Gong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Chinese Patients ◽  
Plasma Samples ◽  
Small Cell Lung ◽  
Pan Cancer ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R2 = 0.87, p < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies.

scholarly journals Circulating tumor DNA as a prognostic marker in high-risk endometrial cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Weiwei Feng ◽  
Nan Jia ◽  
Haining Jiao ◽  
Jun Chen ◽  
Yan Chen ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
High Risk ◽  
Tumor Recurrence ◽  
Disease Free Survival ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
Free Survival ◽  
Tumor Relapse ◽  
Disease Free ◽  
Tumor Dna

Abstract Background Currently, there is no reliable blood-based marker to track tumor recurrence in endometrial cancer (EC) patients. Liquid biopsies, specifically, circulating tumor DNA (ctDNA) analysis emerged as a way to monitor tumor metastasis. The objective of this study was to examine the feasibility of ctDNA in recurrence surveillance and prognostic evaluation of high-risk EC. Methods Tumor tissues from nine high-risk EC patients were collected during primary surgery and tumor DNA was subjected to next generation sequencing to obtain the initial mutation spectrum using a 78 cancer-associated gene panel. Baseline and serial post-operative plasma samples were collected and droplet digital PCR (ddPCR) assays for patient-specific mutations were developed to track the mutations in the ctDNA in serial plasma samples. Log-rank test was used to assess the association between detection of ctDNA before or after surgery and disease-free survival. Results Somatic mutations were identified in all of the cases. The most frequent mutated genes were PTEN, FAT4, ARID1A, TP53, ZFHX3, ATM, and FBXW7. For each patient, personalized ddPCR assays were designed for one-to-three high-frequent mutations. DdPCR analysis and tumor panel sequencing had a high level of agreement in the assessment of the mutant allele fractions in baseline tumor tissue DNA. CtDNA was detected in 67% (6 of 9) of baseline plasma samples, which was not predictive of disease-free survival (DFS). CtDNA was detected in serial post-operative plasma samples (ctDNA tracking) of 44% (4 of 9) of the patients, which predicted tumor relapse. The DFS was a median of 9 months (ctDNA detected) versus median DFS undefined (ctDNA not detected), with a hazard ratio of 17.43 (95% CI, 1.616–188.3). The sensitivity of post-operative ctDNA detection in estimating tumor relapse was 100% and specificity was 83.3%, which was superior to CA125 or HE4. Conclusions Personalized ctDNA detection was effective and stable for high-risk EC. CtDNA tracking in post-operative plasma is valuable for predicting tumor recurrence.

scholarly journals Detection of KRAS Mutations in Circulating Tumor DNA by Digital PCR in Early Stages of Pancreatic Cancer

2016 ◽  
Vol 62 (11) ◽  
pp. 1482-1491 ◽  
Author(s):  
Nora Brychta ◽  
Thomas Krahn ◽  
Oliver von Ahsen
Keyword(s):  
Pancreatic Cancer ◽  
Early Stage ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Surgical Removal ◽  
Plasma Samples ◽  
Kras Mutations ◽  
Detection Rates ◽  
Early Stages ◽  
Tumor Dna

Abstract BACKGROUND Since surgical removal remains the only cure for pancreatic cancer, early detection is of utmost importance. Circulating biomarkers have potential as diagnostic tool for pancreatic cancer, which typically causes clinical symptoms only in advanced stage. Because of their high prevalence in pancreatic cancer, KRAS proto-oncogene, GTPase [KRAS (previous name: Kirsten rat sarcoma viral oncogene homolog)] mutations may be used to identify tumor-derived circulating plasma DNA. Here we tested the diagnostic sensitivity of chip based digital PCR for the detection of KRAS mutations in circulating tumor DNA (ctDNA) in early stage pancreatic cancer. METHODS We analyzed matched plasma (2 mL) and tumor samples from 50 patients with pancreatic cancer. Early stages (I and II) were predominant (41/50) in this cohort. DNA was extracted from tumor and plasma samples and tested for the common codon 12 mutations G12D, G12V, and G12C by chip-based digital PCR. RESULTS We identified KRAS mutations in 72% of the tumors. 44% of the tumors were positive for G12D, 20% for G12V, and 10% for G12C. One tumor was positive for G12D and G12V. Analysis of the mutations in matched plasma samples revealed detection rates of 36% for G12D, 50% for G12V, and 0% for G12C. The detection appeared to be correlated with total number of tumor cells in the primary tumor. No KRAS mutations were detected in 20 samples of healthy control plasma. CONCLUSIONS Our results support further evaluation of tumor specific mutations as early diagnostic biomarkers using plasma samples as liquid biopsy.

Residual of circulating tumor DNA (ctDNA) indicated therapeutic efficacy of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21207-e21207
Author(s):  
Zhehai Wang ◽  
Xiao Han ◽  
Jun Guo ◽  
Ming Jia ◽  
Changbin Zhu ◽  
...  
Keyword(s):  
Disease Progression ◽  
Advanced Nsclc ◽  
Objective Response ◽  
Synergetic Effect ◽  
Circulating Tumor Dna ◽  
First Line ◽  
Long Term Outcome ◽  
Significant Difference ◽  
Previously Treated ◽  
Tumor Dna

e21207 Background: The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting for patients with advanced NSCLC. As previously reported, sintilimab plus docetaxel in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. This exploratory study aims to investigate putative biomarker(s) predicting therapeutic response and long-term outcome for eligible patients. Methods: Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. Thirty-nine eligible patients received comprehensive genomic profiling of circulating tumor DNA (ctDNA) via a 448-gene panel before treatment. ctDNA from twenty-three patients were dynamically assessed after two courses (at 6th week). Eventually, 22 patients were enrolled into analysis, one patient was lost. White blood cells were used to filter germline variants from ctDNA sequencing data. Results: Of 22 patients with paired ctDNA profiling results at 6th week, 11 patients (50%) were defined as ctDNA residual due to presence of ≥2 somatic variants; Another 11 patients (50%) who had ≤1 somatic variant were defined as non-ctDNA residual. Significant difference of best objective response rate (ORR) (63.64% vs 0%, P=0.0039, two-sided Fisher’s Exact Testing for non-ctDNA residual vs ctDNA residual patients) was observed between these two populations. And numerically higher disease control rate (DCR) was seen in non-ctDNA residual patients (100% vs 63.64%, non-ctDNA residual vs ctDNA residual). Further, patients with ctDNA residual after 2 courses of sintilimab plus docetaxel (at 6th week) displayed higher risk of disease progression [Hazard Ratio (95%CI), 9.91(2.09-46.97), P=0.0038] and inferior prognosis (median PFS, ctDNA residual vs non-ctDNA residual, 3.0 months vs NR, P=0.0007). In addition, mutations of EGFR and LRP1B were enriched in ctDNA residual group. Especially, LRP1B gene mutations associated with shorter PFS period, which should be further investigated. Conclusions: Residual of ctDNA at 6th week was able to indicate inferior response to sintilimab plus docetaxel in patients with previously treated advanced NSCLC. Further validation of ctDNA residual as a robust predictive biomarker is warranted. [Table: see text]

scholarly journals Identification of molecular signatures of cystic fibrosis disease status with plasma-based functional genomics

2019 ◽  
Vol 51 (1) ◽  
pp. 27-41 ◽  
Author(s):  
Hara Levy ◽  
Shuang Jia ◽  
Amy Pan ◽  
Xi Zhang ◽  
Mary Kaldunski ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Flow Cytometry ◽  
Functional Genomics ◽  
Treatment Response ◽  
Peripheral Blood ◽  
Disease Status ◽  
Enzyme Linked Immunosorbent Assay ◽  
Molecular Signatures ◽  
Healthy Controls ◽  
Plasma Samples

Although cystic fibrosis (CF) is attributed to dysfunction of a single gene, the relationships between the abnormal gene product and the development of inflammation and progression of lung disease are not fully understood, which limits our ability to predict an individual patient’s clinical course and treatment response. To better understand CF progression, we characterized the molecular signatures of CF disease status with plasma-based functional genomics. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with plasma samples from CF patients ( n = 103) and unrelated, healthy controls ( n = 31). Gene expression levels were measured with an Affymetrix microarray (GeneChip Human Genome U133 Plus 2.0). Peripheral blood samples from a subset of the CF patients ( n = 40) were immunophenotyped by flow cytometry, and the data were compared with historical data for age-matched healthy controls ( n = 351). Plasma samples from another subset of CF patients ( n = 56) and healthy controls ( n = 16) were analyzed by multiplex enzyme-linked immunosorbent assay (ELISA) for numerous cytokines and chemokines. Principal component analysis and hierarchical clustering of induced transcriptional data revealed disease-specific plasma-induced PBMC profiles. Among 1,094 differentially expressed probe sets, 51 genes were associated with pancreatic sufficient status, and 224 genes were associated with infection with Pseudomonas aeruginosa. The flow cytometry and ELISA data confirmed that various immune modulators are relevant contributors to the CF molecular signature. This study provides strong evidence for distinct molecular signatures among CF patients. An understanding of these molecular signatures may lead to unique molecular markers that will enable more personalized prognoses, individualized treatment plans, and rapid monitoring of treatment response.

Circulating tumor DNA as a prognostic factor in peritoneal carcinomatosis after hyperthermic intraperitoneal chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16280-e16280
Author(s):  
Zongyuan Li ◽  
Xiaolin Pu ◽  
Hua Jiang
Keyword(s):  
Peritoneal Carcinomatosis ◽  
Tumor Markers ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Peritoneal Cancer Index ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
Peritoneal Cancer ◽  
Time Points ◽  
Tumor Dna

e16280 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is the main treatment for peritoneal carcinomatosis (PC).However, It is still a major problem to predict the efficacy of HIPEC. Some studies have shown that peritoneal cancer index (PCI) can be used to predict the efficacy of HIPEC, but the invasiveness and inaccuracy are shortcomings. Therefore, we need a minimally invasive and accurate prediction biomarker. Many studies have confirmed that circulating tumor DNA (ctDNA) can accurately predict the efficacy and prognosis of various solid tumors. This study aimed to evaluate the predictive value of ctDNA from ascites and plasma for HIPEC. Methods: Eligible PC patients should be defintive diagnosed by pathology or cytology. Each patient was treated with HIPEC for 4 times, with an interval of 3 days each time. Plasma and ascites samples were collected before HIPEC and after the last HIPEC. All samples were detected by next generation sequencing (NGS). The molecular tumor burden index (mTBI) and main clone variant allele fraction (VAF) changes were used as the prediction indexes of efficacy. In addition, The changes of common tumor markers such as CEA during the same period were used as controls. Results: A total of 19 patients with PC were enrolled from November 2018 to January 2020. Firstly, the mTBI changes of 14 patients whom had plasma samples at two time points (baseline and postHIPEC)were analyzed. Among them, 3 patients had no gene mutation were detected in two time points. There were significant differences in mTBI before and after HIPEC in the remaining 11 patients (Wilcoxon， p = 0.026). the median Ascites progression free survival (PFS) was 3.35 months (95% CI: 2.34 – 5.13 months), and the median overall survival (OS) was 5.93 months (95% CI: 4.93 – 11.17 months). The mTBI decline was significantly positively correlated with ascites PFS (Spearman r = 0.673, p = 0.023) and moderately positively correlated with OS (Spearman r = 0.510, p = 0.109). The highest VAF in plasma samples was defined as the main clone mutation. The main clone VAF decline was moderately positively correlated with ascites PFS (Spearman r = 0.588, p = 0.057) and slightly positively correlated with OS (Spearman r = 0.386, p = 0.241). As the controls, We found that the common tumor markers decline was no correlated with ascites PFS(Spearman r = 0.091, p = 0.790) and OS (Spearman r = 0.287, p = 0.396). We further analyzed the correlation of VAF between ascites and plasma co-mutation genes in 12 patients. The VAF of co-mutated genes in plasma and ascites was positively correlated (Spearman r = 0.794, p = 0.001). Conclusions: Plasma ctDNA can be used as a biomarker for predicting the efficacy of HIPEC for peritoneal carcinomatosis, and its accuracy is significantly higher than comon tumor markers. However, a larger sample size study are needed to validate our results.

A graphene oxide coated gold nanostar based sensing platform for ultrasensitive electrochemical detection of circulating tumor DNA

2020 ◽  
Vol 12 (4) ◽  
pp. 440-447 ◽  
Author(s):  
Mahbubur Rahman ◽  
Daxiang Cui ◽  
Shukui Zhou ◽  
Amin Zhang ◽  
Di Chen
Keyword(s):  
Graphene Oxide ◽  
Gastric Carcinoma ◽  
Electrochemical Reduction ◽  
Electrochemical Detection ◽  
Peripheral Blood ◽  
High Performance ◽  
Circulating Tumor Dna ◽  
Electrochemical Sensing ◽  
Sensing Platform ◽  
Tumor Dna

A high-performance electrochemical sensing platform inspired by a functional ‘green’ electrochemical reduction pathway was developed to identify and detect circulating tumor DNA (ctDNA) of gastric carcinoma in peripheral blood.

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