scholarly journals RAS/BRAF Circulating Tumor DNA Mutations as a Predictor of Response to First-Line Chemotherapy in Metastatic Colorectal Cancer Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Jiannan Yao ◽  
Wanchun Zang ◽  
Yang Ge ◽  
Nathaniel Weygant ◽  
Pan Yu ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Tumor Tissue ◽  
Mutation Detection ◽  
Circulating Tumor Dna ◽  
Clinicopathologic Features ◽  
First Line ◽  
Mutation Status ◽  
Free Survival ◽  
Tumor Dna ◽  
Line Chemotherapy

Background. Since circulating tumor DNA (ctDNA) offers clear advantages as a minimally invasive method for tumor monitoring compared with tumor tissue, we aimed to evaluate genotyping ctDNA using a next-generation sequencing- (NGS-) based panel to identify the prognostic value of mutation status in metastatic colorectal cancer (mCRC) patients with primary tumor resected and with subsequent lines of treatment in this study. Methods. 76 mCRC patients treated in Beijing Chao-Yang Hospital from 2011 to 2017 were enrolled. Genotyping of RAS/BRAF in tumor tissue and ctDNA was determined by ARMS PCR and with a 40-gene panel using NGS, respectively. Patient clinicopathologic features and RAS/BRAF gene mutation status were evaluated by survival analysis for disease-free survival (DFS) and progression-free survival (PFS). Results. Among 76 patients, KRAS distributions were not significantly correlated with any clinicopathologic features. The concordance between tumor tissue and ctDNA KRAS mutation was 81.25%. Mutations of RAS/BRAF had no significant impact on DFS after surgery (hazard ratio (HR), 1.205; 95% CI, 0.618 to 2.349; P=0.5837) but prognosticated poorer PFS in subsequent first-line therapy (HR, 3.351; 95% CI, 1.172 to 9.576; P=0.024). Conclusion. ctDNA was comparable with tumor tissue for mutation detection. RAS/BRAF mutations detected in ctDNA predict a worse PFS in mCRC patients with first-line chemotherapy. Our results provide support for the prognostic value of RAS/BRAF ctDNA mutation detection in mCRC patients.

scholarly journals Comparative Analysis of Two Methods for the Detection of EGFR Mutations in Plasma Circulating Tumor DNA from Lung Adenocarcinoma Patients

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 803 ◽  
Author(s):  
Ming-Szu Hung ◽  
Jr-Hau Lung ◽  
Yu-Ching Lin ◽  
Yu-Hung Fang ◽  
Shu-Yi Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Egfr Mutation ◽  
Circulating Tumor Dna ◽  
Egfr Mutations ◽  
Cancer Tissue ◽  
Lung Cancer Tissue ◽  
First Line ◽  
Mutation Status ◽  
Egfr Tki ◽  
Tumor Dna

Mutations in the epidermal growth factor receptor (EGFR) are associated with various solid tumors. This study aimed to compare two methods for the detection of EGFR mutations in circulating tumor DNA (ctDNA) from lung adenocarcinoma (LUAD) patients and to evaluate the clinical significance of EGFR mutations in ctDNA. In this prospective cohort study, the EGFR mutation status of 77 patients with stage IIIB or IV LUAD was first determined using lung cancer tissue. The amplification refractory mutation system (ARMS) and single allele base extension reaction combined with mass spectroscopy (SABER/MassARRAY) methods were also used to detect EGFR mutations in plasma ctDNA from these patients and then compared using the EGFR mutation status in lung cancer tissue as a standard. Furthermore, the relationship between the presence of EGFR mutations in ctDNA after receiving first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and survival was evaluated. The overall sensitivity and specificity for the detection of EGFR mutations in plasma ctDNA by ARMS and SABER/MassARRAY were 49.1% vs. 56% and 90% vs. 95%, respectively. The agreement level between these methods was very high, with a kappa-value of 0.88 (95% CI 0.77–0.99). Moreover, 43 of the patients who carried EGFR mutations also received first-line EGFR-TKI therapy. Notably, patients with EGFR mutations in plasma ctDNA had significantly shorter progression-free survival (9.0 months, 95% CI 7.0–11.8, vs. 15.0 months, 95% CI 11.7–28.2; p = 0.02) and overall survival (30.6 months, 95% CI 12.4–37.2, vs. 55.6 months, 95% CI 25.8–61.8; p = 0.03) compared to those without detectable EGFR mutations. The detection of EGFR mutations in plasma ctDNA is a promising, minimally invasive, and reliable alternative to tumor biopsy, and the presence of EGFR mutations in plasma ctDNA after first-line EGFR-TKI therapy is associated with poor prognosis.

Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20032-e20032
Author(s):  
Qin Feng
Keyword(s):  
Tumor Tissue ◽  
Egfr Mutation ◽  
Circulating Tumor Dna ◽  
Egfr Mutations ◽  
Amplification Refractory Mutation System ◽  
Circulating Dna ◽  
Mutation Status ◽  
Nsclc Patients ◽  
Tumor Dna ◽  
Egfr Tkis

e20032 Background: Tumor tissue is currently used for EGFR testing non-small cell lung cancer (NSCLC) patients, but the detection of circulating tumor DNA (ctDNA) is being actively investigated as a new method for the detection and longitudinal monitoring of actionable mutations in plasma samples. Around 30% patients with EGFR mutation presented inconsistent status of EGFR mutation between in tissues and plasma. We compared EGFR mutation detection in circulating tumor DNA from blood to that in matched tissue. Methods: EGFR mutation status were assessed by the Human EGFR Gene Mutations Detection Kit (Beijing ACCB Biotech Ltd.) both in tissue and plasma. Retrospective analysis to evaluate the concordance of tissue and plasma EGFR determination for assessing eligibility for EGFR-TKIs therapy in NSCLC patients. 10 mL tubes of blood were collected from patients who never had been treated by EGFR TKI, and plasma circulating tumor DNA were extracted from plasma by Biomark Circulating DNA Kit. Qubit2.0 Fluorometer was used to make plasma circulating DNA tumor quantitation. The concentration of final DNA sample is ≦2ng/μl. Results: A total of 224 NSCLC patients were detected by Amplification Refractory Mutation System (ARMS), with 92 tissue positive and 49 blood positive. Results showed 53.3% sensitivity in overall samples, but 81.4% sensitivity in ⅢB~Ⅲ patients. The specificity is 100%. Conclusions: The high sensitivity and specificity between tissue and plasma EGFR determination supports the blood-based EGFR mutation testing to determinate the eligibility of NSCLC patients for EGFR-TKIs treatment, especialy in ⅢB~Ⅲ NSCLC patients. Blood, in particular plasma, is a good screening substitute when tumor tissue is absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment in patients with NSCLC. EGFR mutation positivity in blood could be used to recommend EGFR TKIs treatment, but the blood negativity should be confirmed with other sample, biopsy tissue, pleural effusion, etc..

Trial in progress: A phase II study of second-line FOLFIRI plus panitumumab after first-line FOLFOX plus panitumumab for RAS wild-type colorectal cancer with evaluation of circulating tumor DNA.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS886-TPS886
Author(s):  
Hiromichi Maeda ◽  
Naoki Nagata ◽  
Takeshi Nagasaka ◽  
Koji Oba ◽  
Hideyuki Mishima ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Mutation Status ◽  
Line Therapy ◽  
Tumor Dna

TPS886 Background: The mechanisms underlying the acquired resistance of metastatic colorectal cancer (mCRC) against panitumumab treatment is not fully understood. The efficacy and safety of FOLFIRI with panitumumab as the second-line chemotherapy after failure of FOLFOX with panitumumab treatment has yet to be determined. To address these two points, a multicenter single-arm Phase II clinical trial is being conducted with evaluation of circulating tumor DNA (ctDNA). Methods: The major inclusion criterion is that the patient has refractory measurable tumor that has progressed after the first-line therapy with FOLFOX plus panitumumab. After registration, treatment with the FOLFIRI and panitumumab will be continued in 2-week cycles until disease progression, unacceptable toxicity and/or patients’ refusal. The primary endpoint for this study is six-month progression-free survival (PFS) rate, a simple surrogate endpoint of PFS. According to a clinical trial revealing the median PFS of 4.6 months for FOLFIRI alone and 6.4 months for panitumumab plus FOLFIRI treatment in RAS wild-type patients (Peeters et al. Clin Cancer Res. 2015; 21: 5469-79), we assume the threshold and expected 6-month PFS rate as 35% and 50%, respectively. Under the settings of one-sided alpha = 0.10 and power = 80%, the required sample size is 53 patients. The target number of cases in this study is 55 patients, considering a dropout rate of 5%. The secondary endpoint includes the tumor-related gene mutation status assessed by liquid biopsy. Primary tumor and/or metastatic site tissue samples will be collected by formalin-fixed paraffin-embedded specimens at the time of registration. Blood samples will be collected at 3 time-points: (1) before second-line treatment, (2) at 6 ± 2 weeks after initiation of the treatment protocol, and (3) after confirmation of acquired resistance to this second-line therapy. The multiple evaluation of ctDNA will provide the meaningful information concerning relationship between the tumor resistance against treatment and alterations in gene mutation status. Clinical trial information: UMIN000026817.

Genetic mutation analysis of plasma circulating tumor DNA by ultra-deep sequencing in breast benign lesions and cancers.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14572-e14572
Author(s):  
Qian Wu ◽  
Wenjing Jian ◽  
Xumei Yao ◽  
Xintong Xie ◽  
Hanjie Fang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Cancer Patients ◽  
Tumor Tissue ◽  
Mutation Detection ◽  
Circulating Tumor Dna ◽  
Breast Diseases ◽  
Breast Lesions ◽  
Breast Cancer Patients ◽  
Tumor Dna

e14572 Background: Mammography screening for breast cancer results in large number of impalpable lesions without clear determination of the malignancy. Analysis of breast cancer related gene mutations in blood circulating tumor DNA (ctDNA) may provide clarification. This analysis aims to provide insights into the feasibility of the approach. Methods: The clinical trial was conducted at top tier teaching hospitals in China to recruit patients with breast diseases for surgery. Eligible patients were consented and the breast lesions were pathologically diagnosed. Peripheral blood was collected prior to surgical resection. For breast cancer patients, samples of resected tissue were also collected. The samples were analyzed using our proprietary NGS technique called systematic error correction sequencing (Sec-Seq) (detailed in Abstract ##e23057, ASCO 2018). Results: In total, 69 patients with breast lesions (57 malignant and 12 benign) were included in this analysis. Tumor gDNA and plasma ctDNA were analyzed by deep NGS sequencing using a panel of 62 breast cancer-associated genes. The average sequencing depth is 35000. After deduplication, the average number of unique reads is 1500. Detection limit for mutant allele frequency was set at 0.2% for ctDNA and 1% for tumor tissue. For ctDNA mutation detection, 2 out of 12 patients with benign diseases were found with mutations while 10 out of 55 breast cancer patients had no mutations, resulting in an overall sensitivity of 82% and specificity of 83%. By cancer stage, the two Stage 0 (carcinoma in situ) patients had no mutation, and the range of mutations detected is between 53% to 75% from Stage I to III. The tumor tissue samples have higher rate of mutations (only 2 cancer patients, 1 Stage 0 and 1 Stage 2, had no mutations). 15% patients have at least one common mutation detected in both the tumor tissue and ctDNA, and 27% patients have mutations in the same genes in the two matching samples. The concordance increases as the clinical stage advances. The most commonly mutated genes are previously reported breast cancer drivers of PIK3CA (79% of tumor and 18% of ctDNA samples), TP53 (56% and 39%), and BRCA1 (6% and 15%). Conclusions: In this hypothesis generating analysis, we showed the feasibility of plasma ctDNA sequencing for gene mutation detection in early stage breast cancer and differentiation from the benign breast diseases. Although with limited number of samples, the data encourage further improvement of the gene panel and the validation of ctDNA assay as a non-invasive approach to the cancer screening. Clinical trial information: ChiCTR1800017345.

Analysis of circulating tumor DNA to monitor metastatic breast cancer patients treated with first-line chemotherapy (CAMELLIA study).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14568-e14568
Author(s):  
Zongbi Yi ◽  
Fei Ma ◽  
Guohua Rong ◽  
Jin Li ◽  
Lianpeng Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Therapeutic Response ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Breast Cancer Patients ◽  
First Line ◽  
Tumor Dna ◽  
Line Chemotherapy

e14568 Background: Our precious study indicated that the dynamic changes in circulating tumor DNA (ctDNA) could reflect changes in tumor burden. We conduct this study to validate the role of ctDNA as a therapeutic response biomarker in a larger cohort prospective phase III randomized multicenter study. Methods: In this study, we collected 292 serial ctDNA samples from 125 metastatic breast cancer patients treated with first line chemotherapy. Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA. Results: 81.4% patients had detectable ctDNA at baseline. An undetectable ctDNA at baseline was associated with a lower disease volume (p < 0.05). The commonly mutated genes were PIK3CA (35.0%), TP53 (34.2%), MLL3 (9.4%) and ESR1 (9.4%). Kaplan–Meier analysis showed that TP53 gene mutations and remaining C2 (detected at base line and remaining at the second cycle of chemotherapy) were significantly associated with poor PFS. Longitudinal monitoring of 27 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (P < 0.05). The evaluations based on mTBI values were consistent with those based on CT scans in 87.5% of cases at the endpoint of clinical observation. Conclusions: ctDNA could be used to predict treatment outcomes and the mTBI is a potential method to assess therapeutic response in metastatic breast cancer. Clinical trial information: NCT01917279.

Dynamic assessment of circulating tumor DNA in prediction of response to nab-paclitaxel-based first-line chemotherapy in metastatic pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15769-e15769
Author(s):  
Yan Shi ◽  
Shasha Guan ◽  
Quanli Han ◽  
Jie Li ◽  
Yao Lv ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
No Reduction ◽  
Dynamic Assessment ◽  
Mutant Gene ◽  
Circulating Tumor Dna ◽  
First Line ◽  
Driver Genes ◽  
Response To Chemotherapy ◽  
Tumor Dna ◽  
Line Chemotherapy

e15769 Background: Emerging evidence showed circulating tumor DNA (ctDNA) may be used as biomarker for monitoring tumor response to chemotherapy in pancreatic cancer. This pilot study was to evaluate the clinical application of dynamic assessment ctDNA in MPC. Methods: From December 2016 to June 2018 in our center, 29 MPC patients treated with nab-paclitaxel based first-line chemotherapy (NS or N plus Gemcitabine, NG) had at least 2 ctDNA tests were included for analysis. Plasma samples were prospectively collected at baseline and periodical follow-ups until progression, death, or withdrawal of consent. Next-generation sequencing for a panel of 425 genes covering a wide range of cancer-related loci was performed to profile ctDNA. Progression of ctDNA was defined as increased mutation allelic frequency (MAF) of common mutant gene from baseline or nadir, or the presence of new gene alternations. The clinical relevance of the common alteration, and its dynamic changes in ctDNA were analyzed, and compared to conventional imaging response and survival. Results: In our patient cohort, the best overall response of partial response (PR) was 48.3% (14/29). By February 2019, 18 patients passed away with median follow-up of 9.7 months. At baseline, 22 patients (75.9%, N = 29) had at least one common driver gene alterations ( KRAS, TP53, CDKN2A, SMAD4) detected in ctDNA. Mutant KRAS and TP53 were identified in 72.4% and 62.1% patients with a median MAF of 5.8% and 4.7%, respectively. Of 14 patients achieved PR on image, MAF of the mutant driver genes found declined significantly or mutant gene disappeared. At the time of clinical progressive disease (PD), 24 patients had evaluable image and ctDNA results whereas both demonstrated PD in 23 (95.8%), including 9 found earlier progression of ctDNA with median time of 1.93 months compared to image findings. Among 22 patients with any of the above 4 mutant driver genes in ctDNA at baseline, 13 patients demonstrated significant reduction of MAF (reduction to < 1% or undetectable) within 6 weeks, who had a longer progression free survival (PFS, reduction 6.6m vs no reduction 3.4m, P = 0.001) and overall survival (OS, reduction 12.6m vs no reduction 5.4m, P = 0.001), compared to those who had an increased or stable MAF. Conclusions: Our initial findings demonstrated the changes in MAF of 4 common driver genes in ctDNA was well correlated with treatment response to chemotherapy, PFS and OS in MPC. Peripheral ctDNA was a potential reliable alternative biomarker for efficacy and progression prediction in MPC.

scholarly journals Extracellular Vesicle-Derived DNA vs. CfDNA as a Biomarker for the Detection of Colon Cancer

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1171
Author(s):  
Kavita Thakur ◽  
Manu Smriti Singh ◽  
Sara Feldstein-Davydova ◽  
Victoria Hannes ◽  
Dov Hershkovitz ◽  
...  
Keyword(s):  
Colon Carcinoma ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Mutation Detection ◽  
Extracellular Vesicle ◽  
Circulating Tumor Dna ◽  
P Value ◽  
Liquid Biopsies ◽  
Targeted Ngs ◽  
Tumor Dna

Liquid biopsy has emerged as a promising non-invasive way to diagnose tumor and monitor its progression. Different types of liquid biopsies have different advantages and limitations. In the present research, we compared the use of two types of liquid biopsy, extracellular vesicle-derived DNA (EV-DNA) and cell-free DNA (cfDNA) for identifying tumor mutations in patients with colon carcinoma. Method: DNA was extracted from the tumor tissue of 33 patients diagnosed with colon carcinoma. Targeted NGS panel, based on the hotspots panel, was used to identify tumor mutations. Pre-surgery serum and plasma were taken from the patients in which mutation was found in the tumor tissue. Extracellular vesicles were isolated from the serum followed by the extraction of EV-DNA. CfDNA was extracted from the plasma. The mutations found in the tumor were used to detect the circulating tumor DNA using ultra-deep sequencing. We compared the sensitivity of mutation detection and allele frequency obtained in EV-DNA and cfDNA. Results: The sensitivity of mutation detection in EV-DNA and cfDNA was 61.90% and 66.67%, respectively. We obtained almost identical sensitivity of mutation detection in EV-DNA and cfDNA in each of the four stages of colon carcinoma. The total DNA concentration and number mutant copies were higher in cfDNA vs. EV-DNA (p value = 0.002 and 0.003, respectively). Conclusion: Both cfDNA and EV-DNA can serve as tumor biomarkers. The use of EV-DNA did not lead to improved sensitivity or better detection of tumor DNA in the circulation.

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