scholarly journals Early identification of treatment benefit by methylated circulating tumor DNA in metastatic colorectal cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592091847
Author(s):  
Caroline B. Thomsen ◽  
Torben F. Hansen ◽  
Rikke F. Andersen ◽  
Jan Lindebjerg ◽  
Lars H. Jensen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Early Identification ◽  
Randomized Clinical Trials ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
First Line ◽  
Treatment Benefit ◽  
Potential Marker ◽  
Tumor Dna

Background: The early identification of treatment effect is wanted in several settings, including the management of metastatic colorectal cancer (mCRC). A potential universal marker is circulating tumor DNA (ctDNA). Our prospective study explored the association between progression-free survival (PFS) and overall survival (OS), and early change of ctDNA after one cycle of chemotherapy in patients with mCRC. Methods: The study included mCRC patients receiving standard first line combination chemotherapy with 5-Fluorouracil (FU), oxaliplatin, and bevacizumab. Hypermethylated neuropeptide Y (NPY) ctDNA (meth-ctDNA) served as a marker analyzed by droplet digital polymerase chain reaction (PCR). The meth-ctDNA level was analyzed in plasma before treatment start and again before cycle two. The patients were divided into two groups according to the dynamics of meth-ctDNA. Low ctDNA (LctDNA) included patients with zero or values of meth-ctDNA decreasing to a level including zero in the 95% confidence interval. High ctDNA (HctDNA) included all other patients (stable, increasing, or slightly decreasing values). The two groups were compared as to PFS and OS. Results: The study included 123 patients. The PFS in the two groups differed significantly with a median of 9.2 and 6.7 months in LctDNA and HctDNA, respectively ( p = 0.0005). This translated into a 12-month difference in OS with a median of 25.4 and 13.5 months, respectively ( p = 0.0001). Conclusions: Early therapeutic reconsideration is of utmost importance. A low level of meth-ctDNA after one cycle of chemotherapy in the first line setting is a potential marker for excellent clinical outcomes. The clinical utility should be confirmed in randomized clinical trials.

scholarly journals Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR

2021 ◽  
Author(s):  
Yoojoo Lim ◽  
Sheehyun Kim ◽  
Jun-Kyu Kang ◽  
Hwang-Phill Kim ◽  
Hoon Jang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
First Line ◽  
Size Change ◽  
First Response ◽  
Potential Association ◽  
Ctdna Analysis ◽  
Colorectal Cancer Patients ◽  
Tumor Dna

Abstract Circulating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation (p = 0.020) and progressive disease (PD) (p = 0.042). Patients whose average VAF decreased below cutoff (< 1%) at the first evaluation showed significantly better PFS (p < 0.001), and the average VAF change further discriminated the PFS in the patients in partial response (p = 0.018). At the time of PD, 54 new mutations including KRAS and MAP2K1 emerged in ctDNA. ctDNA sequencing can provide mutation profile that could better reflect tumor mutation status and predict treatment outcome.

scholarly journals Serial Circulating Tumor DNA Mutational Status in Patients with KRAS-Mutant Metastatic Colorectal Cancer from the Phase 3 AIO KRK0207 Trial

2020 ◽  
Vol 66 (12) ◽  
pp. 1510-1520
Author(s):  
Smiths S Lueong ◽  
Andreas Herbst ◽  
Sven-Thorsten Liffers ◽  
Nicola Bielefeld ◽  
Peter A Horn ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Treatment Initiation ◽  
Multivariable Analysis ◽  
Circulating Tumor Dna ◽  
Post Treatment ◽  
First Line ◽  
Phase 3 ◽  
Tumor Dna

Abstract Background We assessed the usefulness of circulating tumor DNA (ctDNA) pre- or post-treatment initiation for outcome prediction and treatment monitoring in metastatic colorectal cancer (mCRC). Methods Droplet digital PCR was used to measure absolute mutant V-Ki-ras2 Kirsten rat sarcoma viral oncogene ((mut)KRAS) ctDNA concentrations in 214 healthy controls (plasma and sera) and in 151 tissue-based mutKRAS positive patients with mCRC from the prospective multicenter phase 3 trial AIO KRK0207. Serial mutKRAS ctDNA was analyzed prior to and 2–3 weeks after first-line chemotherapy initiation with fluoropyrimidine, oxaliplatin, and bevacizumab in patients with mCRC and correlated with clinical parameters. Results mut KRAS ctDNA was detected in 74.8% (113/151) of patients at baseline and in 59.6% (90/151) at follow-up. mutKRAS ctDNA at baseline and follow-up was associated with poor overall survival (OS) (hazard ratio [HR] =1.88, 95% confidence interval [CI] 1.20–2.95; HR = 2.15, 95% CI 1.47–3.15) and progression-free survival (PFS) (HR = 2.53, 95% CI 1.44–4.46; HR = 1.90, 95% CI 1.23–2.95), respectively. mutKRAS ctDNA clearance at follow-up conferred better disease control (P = 0.0075), better OS (log-rank P = 0.0018), and PFS (log-rank P = 0.0018). Measurable positive mutKRAS ctDNA at follow-up was the strongest and most significant independent prognostic factor on OS in multivariable analysis (HR = 2.31, 95% CI 1.40–3.25). Conclusions Serial analysis of circulating mutKRAS concentrations in mCRC has prognostic value. Post treatment mutKRAS concentrations 2 weeks after treatment initiation were associated with therapeutic response in multivariable analysis and may be an early response predictor in patients receiving first-line combination chemotherapy. Clinicaltrialsgov Identifier NCT00973609.

Effect of subsequent chemotherapy on overall survival in first-line chemotherapy with targeted agents for patients with metastatic colorectal cancer: Systematic review and meta-analysis of randomized control trials.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 782-782
Author(s):  
Daisuke Sakai ◽  
Toshihiro Kudo ◽  
Aya Kato ◽  
Toshinori Sueda ◽  
Hidekazu Takahashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Randomized Clinical Trials ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Phase Iii ◽  
First Line ◽  
Line Chemotherapy

782 Background: One of recent standard first line chemotherapies for metastatic colorectal cancer is doublet of cytotoxic agents, fluorouracil and oxaliplatin or irinotecan, in combination with target agent, bevacizumab, or anti-EGFR antibody as cetuximab or panitumumab for KRAS or RAS wild type (WT). In this decade, nevertheless progression free survival (PFS) of clinical trials was little improved, overall survival (OS) had been increased. Methods: We analyzed data from 14 recently published phase III randomized clinical trials in mCRC to correlate the percentage of patients receiving subsequent chemotherapy with the reported OS. Results: Median PFS and OS were 10.3 and 25.0 months, respectively. In all comer trials, median OS is significantly correlated with the percentage of patients who received subsequent chemotherapy after first line chemotherapy of their disease [regression coefficient (R2) = 0.85 p = 0.0018]. In trials with KRAS WT, a correlation between OS and the rate of subsequent therapy was modest [r2 = 0.605, p = 0.0637]. Median PFS and RR were not correlated with median OS. Conclusions: Our results support the strategy of making salvage chemotherapy available to all patients with advanced CRC to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, PFS might no longer be regarded as the appropriate surrogate end point of OS by which to assess the efficacy of a palliative first-line treatment in CRC.

Serial monitoring of circulating tumor DNA in patients with metastatic colorectal cancer to predict the therapeutic response.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 713-713
Author(s):  
Jianfeng Zhou ◽  
Ning Jia ◽  
Zhao Sun ◽  
Xin Gao ◽  
Yuejuan Cheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progressive Disease ◽  
Therapeutic Response ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Carbohydrate Antigen ◽  
First Line Therapy ◽  
Candidate Mutation ◽  
Tumor Dna

713 Background: Early biomarkers of therapeutic responses could help optimize the treatment of metastatic colorectal cancer (mCRC). This prospective study was designed to explore the serial changes in plasma-circulating tumor DNA (ctDNA) as an early marker of therapeutic response to systemic treatment in mCRC. Methods: Twenty-six mCRC patients receiving standard first-line therapy once every two weeks were enrolled. Plasma ctDNA, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were assessed serially before each of the first four cycles. Somatic mutations in plasma ctDNA were detected via next-generation sequencing using a panel of 50 cancer-related genes, and the mutation of maximal frequency in pretreatment ctDNA was selected as the candidate mutation for analysis. Radiologic responses were assessed after the fourth cycle. Results: Mutations in pretreatment ctDNA could be detected in 25 (96.2%) of the 26 initially enrolled patients. Among the 20 patients monitored serially, changes in ctDNA could differentiate patients with progressive disease two cycles (approximately four weeks) earlier than the changes in CEA and CA19-9 levels could, and changes in ctDNA levels as early as prior to cycle 2 predicted the radiologic responses after cycle 4. A log2 value of fold-change in ctDNA after cycle 1 (log2 (C1/C0)) > 0.044 predicted progressive disease, with a sensitivity and specificity of 100.0% (95%CI: 47.8-100.0%) and 86.7% (95%CI: 59.5-98.3%), respectively, and an accuracy of 90.0% (95%CI: 68.3-98.8%). Patients with log2 (C1/C0) > 0.044 showed worse progression-free survival than did those with log2 (C1/C0) ≤0.044 (median 2.0 versus 17.0 months; P = 0.092). Conclusions: Early changes in ctDNA that are detected via targeted sequencing could predict later radiologic responses in mCRC.

scholarly journals Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoojoo Lim ◽  
Sheehyun Kim ◽  
Jun-Kyu Kang ◽  
Hwang-Phill Kim ◽  
Hoon Jang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
First Line ◽  
Size Change ◽  
First Response ◽  
Potential Association ◽  
Ctdna Analysis ◽  
Colorectal Cancer Patients ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation (p = 0.020) and progressive disease (PD) (p = 0.042). Patients whose average VAF decreased below cutoff (< 1%) at the first evaluation showed significantly better PFS (p < 0.001), and the average VAF change further discriminated the PFS in the patients in partial response (p = 0.018). At the time of PD, 54 new mutations including KRAS and MAP2K1 emerged in ctDNA. ctDNA sequencing can provide mutation profile that could better reflect tumor mutation status and predict treatment outcome.

scholarly journals Monitoring the effect of first-line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3593-3593
Author(s):  
Caroline Brenner Thomsen ◽  
Torben Hansen ◽  
Rikke Fredslund Andersen ◽  
Jan Lindebjerg ◽  
Lars Henrik Jensen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Lead Time ◽  
Progressive Disease ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
First Line ◽  
Fractional Abundance ◽  
Risk Of Progression ◽  
Tumor Dna

3593 Background: Personalized medicine calls for an early indicator of treatment failure. Circulating tumor DNA (ctDNA) is a promising marker in this setting and our prospective study explored the association between disease control and change of ctDNA during first line chemotherapy in patients with RAS/RAF mutated metastatic colorectal cancer (mCRC). Methods: The present study included 138 mCRC patients receiving standard first line combination chemotherapy. In patients with a RAS/RAF mutated tumor the same mutation was quantified in the plasma using droplet digital PCR (ddPCR). The fractional abundance of ctDNA (ctDNA level) was assessed in plasma before treatment start and at every treatment cycle until radiologically defined progressive disease (PD). Results: RAS/RAF mutations were detected in the plasma from 77 patients (94% of patients with a tumor mutation). Twenty patients progressed on treatment and 57 stopped treatment without progression. The presence of a RAS/RAF mutation in plasma correlated to overall survival (OS) with a median of 24.2 months for patients with a wild-type tumor compared to 12.7 months for patients with a mution in plasma. A substantial increase in ctDNA level was highly associated with progression on treatment (risk ratio = 4.58, 95%CI = 1.99-10.51, p < 0.0001). Furthermore, with a stable ctDNA level the chance of non-progression was 88.2% (range 76.1-95.6%). The first substantial increase in ctDNA level occurred at a median of 51 days (range 14-133 days) before radiologically confirmed PD. Conclusions: The results indicate that ctDNA level may be predictive of treatment effect in patients with mCRC. An increase was observed to correlate with high risk of progression with a relevant lead time, whereas an unchanging ctDNA level related to stable disease.

scholarly journals Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406)

2020 ◽  
pp. JCO.20.01994
Author(s):  
Scott Kopetz ◽  
Katherine A. Guthrie ◽  
Van K. Morris ◽  
Heinz-Josef Lenz ◽  
Anthony M. Magliocco ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Molecular Subtype ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Treatment Benefit ◽  
Rna Profiling ◽  
Low Incidence ◽  
Consensus Molecular Subtype

PURPOSE BRAF V600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of BRAF V600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. METHODS One hundred six patients with BRAF V600E-mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily). RESULTS Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, P = .001). The response rate was 17% versus 4% ( P = .05), with a disease control rate of 65% versus 21% ( P < .001). A decline in circulating tumor DNA BRAF V600E variant allele frequency was seen in 87% versus 0% of patients ( P < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype. CONCLUSION Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAF V600E-mutated CRC.

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