Academic literature on the topic 'KRAS biomarker'
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Journal articles on the topic "KRAS biomarker"
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Wheeler, Josh, Anže Lovše, Klemen Žiberna, et al. "Abstract 6446: ResponderID™ KRAS: Biology-driven machine learning to personalize KRAS inhibitor therapeutics." Cancer Research 84, no. 6_Supplement (2024): 6446. http://dx.doi.org/10.1158/1538-7445.am2024-6446.
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Abstract Breakthroughs in targeted KRAS therapeutics (KRASi) have the potential to transform the treatment landscape for several of the most common cancers including lung, colorectal, and pancreatic. Despite the recent approvals of KRASi and the anticipation of more to come, both the rate of patient response and the durability of these responses remain significant areas requiring improvement. Biomarkers that can predict response to KRASi and guide effective patient selection and drug combination strategies will be key to realizing the full potential of this emerging therapeutic field. While most biomarkers predominantly rely on a single analyte (e.g. KRAS mutation status), Genialis’ biomarkers are constructed using high-dimensional and/or multimodal data that capture the underlying biological complexity unique to each individual patient. Genialis' ResponderID™ is a machine learning-based biomarker discovery framework that models fundamental aspects of cancer biology to predict the clinical benefit based on the patient’s own biology. Here we report progress towards the development of a first-in-class, RNA-based biomarker, ResponderID™ KRAS, capable of stratifying KRAS G12C inhibitor response in lung cancer patients using RNA sequencing data. Trained on thousands of lung cancer samples, our biomarker models therapeutic response by unifying two core KRAS biologic axes, dependency and activation, to identify those patients most likely to respond. The performance characteristics of ResponderID™ KRAS thus far has been evaluated on a real world dataset of lung cancer patients treated with Sotorasib. ResponderID™ KRAS serves as an independent biomarker designed to inform clinical trial design, select for therapeutic efficacy, identify rational combination strategies, and expedite approvals across various therapeutic contexts. Citation Format: Josh Wheeler, Anže Lovše, Klemen Žiberna, Miha Štajdohar, Luka Ausec, Janez Kokošar, Daniel Pointing, Aditya Pai, Rafael Rosengarten, Mark Uhlik. ResponderID™ KRAS: Biology-driven machine learning to personalize KRAS inhibitor therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6446.
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Manolakos, Peter, and Linda D. Ward. "A Critical Review of the Prognostic and Predictive Implications of KRAS and STK11 Mutations and Co-Mutations in Metastatic Non-Small Lung Cancer." Journal of Personalized Medicine 13, no. 6 (2023): 1010. http://dx.doi.org/10.3390/jpm13061010.
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The Kirsten rat sarcoma viral oncogene homolog (KRAS) and serine/threonine kinase 11 (STK11) co-mutations are associated with the diverse phenotypic and heterogeneous oncogenic subtypes in non-small cell lung cancer (NSCLC). Due to extensive mixed evidence, there needs to be a review of the recent KRAS and STK11 mutation literature to better understand the potential clinical applications of these genomic biomarkers in the current treatment landscape. This critical review highlights the clinical studies that have elucidated the potential prognostic and predictive implications of KRAS mutations, STK11 mutations, or KRAS/STK11 co-mutations when treating metastatic NSCLC across various types of treatments (e.g., immune checkpoint inhibitors [ICIs]). Overall, KRAS mutations are associated with poor prognoses and have been determined to be a valid but weak prognostic biomarker among patients diagnosed with NSCLC. KRAS mutations in NSCLC have shown mixed results as a predictive clinical biomarker for immune checkpoint inhibitor treatment. Overall, the studies in this review demonstrate that STK11 mutations are prognostic and show mixed results as predictive biomarkers for ICI therapy. However, KRAS/STK11 co-mutations may predict primary resistance to ICI. Prospective KRAS/STK11-biomarker-driven randomized trials are needed to assess the predictive effect of various treatments on the outcomes for patients with metastatic NSCLC, as the majority of the published KRAS analyses are retrospective and hypothesis-generating in nature.
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Loubière, Sandrine, Alexandre Drezet, Michèle Beau-Faller, et al. "Cost-effectiveness of KRAS, EGFR and ALK testing for decision making in advanced nonsmall cell lung carcinoma: the French IFCT-PREDICT.amm study." European Respiratory Journal 51, no. 3 (2018): 1701467. http://dx.doi.org/10.1183/13993003.01467-2017.
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ALK rearrangement and EGFR/KRAS mutations constitute the primary biomarkers tested to provide targeted or nontargeted therapies in advanced nonsmall cell lung cancer (NSCLC) patients. Our objective was to assess the cost-effectiveness of biomarker testing for NSCLC.Between 2013 and 2014, 843 treatment-naive patients were prospectively recruited at 19 French hospitals into a longitudinal observational cohort study. Two testing strategies were compared, i.e. with “at least one biomarker status known” and “at least KRAS status known”, in addition to “no biomarker testing” as the reference strategy. The Kaplan–Meier approach was employed to assess restricted mean survival time. Direct medical costs incurred by hospitals were estimated with regard to treatment, inpatient care and biomarker testing.Compared with “no biomarker testing”, the “at least one biomarker status known” strategy yielded an incremental cost-effectiveness ratio of EUR13 230 per life-year saved, which decreased to EUR7444 per life-year saved with the “at least KRAS status known” testing strategy. In sensitivity analyses, biomarker testing strategies were less costly and more effective in 41% of iterations.In summary, molecular testing prior to treatment initiation proves to be cost-effective in advanced NSCLC management and may assist decision makers in defining conditions for further implementation of these innovations in general practice.
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Kim, Min Kyeong, Sang Myung Woo, Boram Park, et al. "Prognostic Implications of Multiplex Detection of KRAS Mutations in Cell-Free DNA from Patients with Pancreatic Ductal Adenocarcinoma." Clinical Chemistry 64, no. 4 (2018): 726–34. http://dx.doi.org/10.1373/clinchem.2017.283721.
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Abstract BACKGROUND Cell-free DNA (cfDNA) is known to provide potential biomarkers for predicting clinical outcome, but its value in pancreatic ductal adenocarcinoma (PDAC) has not been fully evaluated. The aim of this study was to evaluate the clinical applicability of quantitative analysis of multiplex KRAS mutations in cell-free DNA from patients with PDAC. METHODS A total of 106 patients with PDAC were enrolled in this prospective study. The concentration and fraction of KRAS mutations were determined through multiplex detection of KRAS mutations in plasma samples by use of a droplet digital PCR kit (Bio-Rad). RESULTS KRAS mutations were detected in 96.1% of tissue samples. Eighty patients (80.5%) harbored KRAS mutations in cfDNA, with a median KRAS mutation concentration of 0.165 copies/μL and a median fractional abundance of 0.415%. Multivariable analyses demonstrated that the KRAS mutation concentration [hazard ratio (HR), 2.08; 95% CI, 1.20–3.63] and KRAS fraction (HR, 1.73; 95% CI, 1.02–2.95) were significant factors for progression-free survival. KRAS mutation concentration (HR, 1.97; 95% CI, 1.05–3.67) also had prognostic implications for overall survival. Subgroup analyses showed that KRAS mutation concentration and fractional abundance significantly affected progression-free survival in resectable PDAC (P = 0.016). Moreover, when combined with the cancer biomarker CA19-9, the KRAS mutation concentration in cfDNA showed additive benefits for the prediction of overall survival. CONCLUSIONS This study demonstrates that multiplex detection of KRAS mutations in plasma cfDNA is clinically relevant, providing a potential candidate biomarker for prognosis of PDAC.
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Papadimitrakopoulou, Vassiliki, J. Jack Lee, Ignacio I. Wistuba, et al. "The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 34, no. 30 (2016): 3638–47. http://dx.doi.org/10.1200/jco.2015.66.0084.
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Purpose By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non–small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers. Patients and Methods Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling–targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. Results Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02). Conclusion Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.
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Piao, Shengyue, Miller Harris, and Kevin McHugh. "Abstract LB156: Early mutation-mediated detection of cancers via biomarker production." Cancer Research 85, no. 8_Supplement_2 (2025): LB156. https://doi.org/10.1158/1538-7445.am2025-lb156.
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Abstract Background: Cancer remains one of the leading causes of mortality worldwide, with early detection pivotal to improving patient outcomes. Current diagnostic methods often lack the sensitivity and specificity to identify cancers at their earliest stages, especially for KRAS-driven cancers such as pancreatic cancer and non-small cell lung cancer (NSCLC). This challenge is further exacerbated for high-risk populations, where invasive biopsies, imaging, or endogenous biomarkers fail to meet clinical needs. There is a critical need for non-invasive, reliable, and continuous cancer detection methods capable of diagnosing tumors at nascent stages. To address this, we developed a mutation-mediated synthetic biomarker-based blood test specifically targeting early-stage cancers with KRAS G12 mutations. This study evaluates its performance in detecting KRAS-driven cancers using synthetic biomarkers and controls. Methods: A CRISPR-based gene editing system was designed to insert synthetic biomarker genes, such as Gaussia luciferase (GLuc), into cancer cells harboring KRAS G12 mutations. Using Gibson assembly, we constructed a donor plasmid carrying the GLuc gene alongside a plasmid encoding Cas9 VQR and sgRNA targeting the KRAS G12V locus. These plasmids were co-transfected into NCI-H727 human lung tumor cells. Single-cell sorting yielded 29 clonal lines with stable GLuc expression. Sequencing confirmed precise knock-in at the KRAS G12V target in 21 lines, with qPCR verifying exclusive insertion. GLuc secretion was measured via luciferase assays, and limits of detection (LOD) were assessed in vitro. To test biomarker detection in vivo, GLuc-expressing tumor cells were inoculated into SCID/NOD mice at varying numbers. Serum GLuc levels were measured using luciferase assays at defined time points. Results: In vitro, the LOD for GLuc-expressing cancer cells was 5,775 cells/mL. In vivo, SCID/NOD mice injected with GLuc-expressing tumor cells showed time-dependent increases in serum luminescence. Two weeks post-inoculation with 106 cells, serum luminescence in the experimental group was 8.24-fold higher than controls (8.24 ± 0.32), with a tumor lesion size of 29.86 ± 7.26 mm3. Conclusion: This mutation-mediated synthetic biomarker platform detected tumor lesions as small as millimeter-scale in vivo with high sensitivity and specificity after a single injection. Its non-invasive, scalable design offers the potential to transform early detection and monitoring of KRAS-driven cancers, addressing critical unmet needs for high-risk populations. Citation Format: Shengyue Piao, Miller Harris, Kevin McHugh. Early mutation-mediated detection of cancers via biomarker production [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB156.
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Yu, Irene S., Francine Aubin, Rachel Goodwin, et al. "Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline." Therapeutic Advances in Medical Oncology 14 (January 2022): 175883592211117. http://dx.doi.org/10.1177/17588359221111705.
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The systemic therapy management of metastatic colorectal cancer (mCRC) has evolved from primarily cytotoxic chemotherapies to now include targeted agents given alone or in combination with chemotherapy, and immune checkpoint inhibitors. A better understanding of the pathogenesis and molecular drivers of colorectal cancer not only aided the development of novel targeted therapies but led to the discovery of tumor mutations which act as predictive biomarkers for therapeutic response. Mutational status of the KRAS gene became the first genomic biomarker to be established as part of standard of care molecular testing, where KRAS mutations within exons 2, 3, and 4 predict a lack of response to anti- epidermal growth factor receptor therapies. Since then, several other biomarkers have become relevant to inform mCRC treatment; however, there are no published Canadian guidelines which reflect the current standards for biomarker testing. This guideline was developed by a pan-Canadian advisory group to provide contemporary, evidence-based recommendations on the minimum acceptable standards for biomarker testing in mCRC, and to describe additional biomarkers for consideration.
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Batra, Ullas, and Shrinidhi Nathany. "Biomarker series: KRAS- A narrative review." Cancer Research, Statistics, and Treatment 4, no. 3 (2021): 516. http://dx.doi.org/10.4103/crst.crst_189_21.
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Karapetis, Christos Stelios, Heshan Liu, Michael Sorich, et al. "Treatment effects (TEs) of EGFR monoclonal antibodies (mAbs) in metastatic colorectal cancer (mCRC) patients (pts) with KRAS, NRAS, and BRAF mutation (MT) status: Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database." Journal of Clinical Oncology 38, no. 15_suppl (2020): 4090. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.4090.
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4090 Background: EGFR mAbs have become incorporated into clinical practice for the management of mCRC over the last decade. KRAS and NRAS mutations are used as predictive biomarkers and BRAF V600E mutations are associated with an adverse prognosis. The observed TE within biomarker subpopulations has varied between studies. Methods: IPD from randomized trials with head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or BSC) in mCRC, across all lines of therapy (first, second and later), were pooled. Biomarker subpopulations are defined in the table. Overall survival (OS) and progression-free survival (PFS) were compared between groups by Cox model, stratified by studies and adjusted by age, gender, and performance status. TEs were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). Within each biomarker subgroup, EGFR mAb efficacy was explored according to multiple exploratory factors, including line of therapy, type of backbone chemo, gender, sidedness and site of metastasis. Interaction tests were performed. P-values < 0.01 were considered statistically significant to account for multiple comparisons. Results: 5729 pts from 8 studies with data available for ≥ 1 biomarker were analysed. PFS benefits (median 9.2 mos in EGFR mAbs, 8.0 mos in no EGFR mAbs) were confirmed in triple-WT pts, but not for OS (refer to table). No OS/PFS benefits were observed for pts with any of the MT tumors. Exploratory analyses showed a potential detrimental TE of EGFR mAbs in KRAS MT mCRC with liver metastasis (OS: HRadj 1.22, p = .003, pinteraction .0056; PFS: HRadj 1.24, p = .0009, pinteraction .0008). These results were confirmed within the subgroup of pts with all 3 biomarkers available. Conclusions: This is the largest IPD analysis to explore the predictive value of RAS/BRAF biomarkers in mCRC. Our findings demonstrate that there is no evidence of efficacy of EGFR mAbs in KRAS, BRAF and/or NRAS MT mCRC. EGFR mAbs might have a detrimental effect in KRAS MT mCRC with liver metastases. [Table: see text]
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Schischlik, Fiorella, Antonio Tedeschi, Dorothea Rudolph, et al. "Abstract A092: Determinants of sensitivity to BI KRASmulti inhibitor using high-throughput in-vitro drug screens." Molecular Cancer Therapeutics 22, no. 12_Supplement (2023): A092. http://dx.doi.org/10.1158/1535-7163.targ-23-a092.
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Abstract BI 3706674 is a novel small molecule inhibitor targeting KRAS in its inactive (GDP-bound) state and is currently undergoing IND enabling studies. Here, we assess the sensitivity of BI 3706674 in a large panel of cancer cell lines with the aim to identify biomarkers predictive of patient response. We employ two complementary, high-throughput cell viability screening setups: the pooled PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) platform (868 cancer cell lines representing 80 tumor types) and a well-based custom screen performed in collaboration with Horizon Discovery (292 cell lines representing 32 tumor types). Based on correlation with publicly available data of over 1464 drug sensitivity profiles, the top 10 correlated drugs (ranked by Pearson correlation) are exclusively MEK inhibitors. This analysis shows that compounds with high similarity in their sensitivity profile to our KRAS inhibitor target proteins in the MAPK pathway. Correlation of drug sensitivity data with CRISPR gene dependency data for KRAS showed that drug selectivity of BI 3706674 is specific for KRAS (Pearson R = -0.49) compared to other members of the RAS family, such as HRAS or NRAS (R=0.03 & R=0.16). BI 3706674 shows sensitivity across a wide range of KRAS alleles (KRAS wild-type (wt) copy number amplification, G12V, G12C, G13D, G12D, G12A, Q61H) with the highest sensitivity for cell lines with KRAS wt amplifications (relative copy number of &gt; 10) followed by cell lines with a KRAS G12V and G12C mutant alleles. Efficacy was observed in 8/9 cell lines with KRAS wt relative copy number of &gt; 10 (sensitivity threshold of 1- AUC = 0.25) in the PRISM screen, emphasizing the utility of KRAS copy number as a predictive biomarker for drug response. Furthermore, KRAS copy number amplifications and KRAS expression are highly correlated features across cell lines (Pearson R = 0.72, P=2.2e-16), indicating that both KRAS copy number amplification and KRAS expression could serve as sensitivity biomarkers for BI 3706674. In this study, we show that BI 3706674 is a potent and selective KRAS inhibitor and that KRAS copy number alterations represent a highly predictive biomarker. Conclusively, high-throughput drug screens are powerful tools to define and further refine biomarkers and study drug mechanism of actions. Citation Format: Fiorella Schischlik, Antonio Tedeschi, Dorothea Rudolph, Daniel Gerlach, Birgit Wilding, Matthias Treu, Julian Fuchs, Lorenz Herdeis, Joachim Broeker, Tobias Wunberg, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Darryl McConnell, Mark Pearson, Norbert Kraut, Christian Haslinger, Jesse Lipp. Determinants of sensitivity to BI KRASmulti inhibitor using high-throughput in-vitro drug screens [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A092.
Dissertations / Theses on the topic "KRAS biomarker"
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Pechanska, Paulina. "A novel approach to develop predictive biomarkers." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://dx.doi.org/10.18452/16967.
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Die Behandlung von Krebserkrankungen wurde in den letzten Jahren von zwei großen Trends beeinflusst. Statt zytotoxischer Therapien, wurden zielgerichtete monoklonale Antikörper entwickelt. Zudem verstärkten sich die Bemühungen in der Entwicklung prädiktiver Biomarker, die die Stratifizierung von Patienten vor der Behandlung ermöglichen. Obwohl hunderte von zielgerichteten Krebsmedikamenten entwickelt wurden, erreichten nur wenige davon eine Zulassung. Grund hierfür ist die noch hohe Ausfallrate bei der „Übersetzung“ von vielversprechenden präklinischen Daten, die mit Krebs-Zelllinien und Xenograft-Modellen von Krebs-Zelllinien erlangt wurden, in positive klinische Phase II- und Phase III-Daten. Das Ziel der Forschung ist es, neue zielgerichtete Therapien und gleichzeitig prädiktive Marker, mit Hilfe von verbesserten präklinischen Tumormodellen zu entwickeln. Ein Panel von 133 Xenograftmodellen aller vier UICC-Stadien wurde etabliert. Zur Überprüfung dieses Modells wurde die Wirksamkeit von Cetuximab, Bevacizumab und Oxaliplatin getestet. Für dieses Experiment benutzten wir 67 Xenograft-Modelle, die aus chemonaiven CRC-Patienten entwickelt wurden. Die Behandlung mit einer Cetuximab-Monotherapie ergab eine objektive Ansprechrate von 27%. Dank dieser hohen Ansprechrate, konnten wir das verfügbare Tumorgewebe zur Vorhersage der Reaktion auf die Anti-EGFR-Antikörper in den Xenograft-Modellen verwenden. Wir untersuchten die Genauigkeit von Mutations-Markern (KRAS, BRAF und PIK3CA) kombiniert mit RNA-Expressionsdaten von Amphiregulin und Epiregulin. Weiterhin wurden neue prädiktive Marker-Kombinationen, basierend auf einer mRNA- und microRNA- Expressionsanalyse, ermittelt. Aufgrund der erfolgreichen Nachbildung der klinischen Situation in unserem Panel von Xenograft-Modellen, zeigt dieser Modellansatz vielversprechendes Potenzial für eine zukünftige Anwendung in der Erprobung neuartiger Krebsmedikamente und der Entwicklung von prädiktiven Biomarkern.<br>Over the last ten years two major trends have influenced drug development. Instead of cytotoxic therapies a variety of targeted monoclonal antibodies have been developed. In parallel, higher attention has been paid to the identification and validation of predictive markers, which allow the stratification of patients prior to the treatment. Hundreds of targeted cancer drugs have been developed, but only a few have been approved. Despite these two trends, there is still a high rate of failure in translating promising preclinical data obtained with cancer cell lines and xenograft models derived from cancer cell lines into positive clinical phase II and phase III data. The goal of the scientific community is to develop novel targeted therapies and predictive biomarkers using better preclinical tumour models. To bridge the gap between preclinical and clinical development a panel of 133 patients-derived CRC xenografts of all four UICC stages was established. An efficacy of cetuximab, bevacizumab and oxaliplatin was tested in the subset of 67 models. In the treatment experiment with cetuximab monotherapy an objective response rate of 27% was obtained. This high response rate allowed the use of the tumour tissues for evaluating molecular markers for predicting response to the anti-EGFR antibody in the xenograft models. The accuracy of three mutation markers including KRAS, BRAF and PIK3CA was investigated in combination with RNA expression levels of two EGFR ligands – amphiregulin and epiregulin. Novel predictive markers panels based on gene expression profiling of mRNA and microRNA were also tested and compared with the established biomarkers. Successful reconstruction of the clinical situation in the panel of xenograft models proves their potential for future use in testing of novel anti-cancer drugs. Moreover, their broad molecular characterization allows the simultaneous development of predictive biomarkers along with the testing of novel cancer drugs.
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Moulière, Florent. "Etude de la structure et de l'origine des ADN circulants : application à la mise au point d'un test de détection des mutations KRAS et BRAF dans le cancer colorectal." Thesis, Montpellier 2, 2012. http://www.theses.fr/2012MON20245/document.
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Les ADN circulants extracellulaires (ADNcf) sont considérés comme des biomarqueurs potentiels non invasifs de la progression tumorale. Ils présentent l'avantage d'être porteurs des altérations génétiques des tumeurs dont ils sont issus. Les connaissances sur les formes, les mécanismes de libération et les actions biologiques des ADNcf sont cependant encore peu caractérisées.Nous avons émis l'hypothèse que se focaliser sur l'étude de la structure et des origines des ADNcf issus des tumeurs permettrait d'ouvrir de nouvelles perspectives d'applications en génomique personnalisée.Nos travaux ont démontré à l'aide d'un animal modèle que les ADNcf issus des tumeurs de cancers colorectaux sont hautement fragmentés à des tailles inférieures à 145 bp. Cette observation a été confirmée sur plasma humain en réalisant par AFM la première image directe d'ADNcf issu de tumeurs. Nous avons déterminé que les proportions d'ADNcf mutés varient fortement dans la circulation sanguine, mais que près d'un tiers des individus présentaient des proportions d'ADNcf mutés supérieures à 25 % de tous les ADNcf retrouvés dans le sang. Ces découvertes nous ont permis de participer au développement d'une méthode d'analyse spécifique des ADNcf du plasma permettant de déterminer par Q-PCR la concentration en ADNcf, sa fragmentation ainsi que la présence des mutations KRAS et BRAF. Cette méthode a été validée cliniquement sur 79 échantillons de patients atteints de cancer colorectal métastatique en la comparant avec une concordance de 96 % à la technique de référence clinique utilisant l'ADN de tissu tumoral. L'utilisation des ADNcf en tant que « biopsie liquide » devrait être un biomarqueur central dans l'approche de génomique personnalisée des années à venir et les résultats de ces travaux de thèse participer au développement de cette nouvelle approche<br>Cell-free circulating DNA (cfDNA) are considered as potentials non invasive biomarkers of tumor progression. They present the advantage to exhibit the genetic alterations from their tumor of origin. Knowledge on the forms, mechanism of release, and biological effect of cfDNA are however still less characterized. We have hypothesized that focalizing on the study of cfDNA structure and origin will open new perspectives of application in personalized genomic. Our works demonstrated, with an animal model, that cfDNA from colorectal cancer tumor are highly fragmented at size lower than 145 bp. This observation was confirmed on human plasma with AFM by realizing the first direct picture of tumor-derived cfDNA. We have determined that cfDNA proportion highly varied in bloodstream, but more than a third of individual exhibit proportions larger than 25 % of blood total cfDNA.These discoveries let us participate to the development of a specific analysis method of plasma cfDNA owing to determinate by Q-PCR the cfDNA concentration, its fragmentation and the presence of KRAS and BRAF mutation. This method has been clinically validated on 79 samples of metastatic colorectal cancer patients by comparing it, with a concordance of 96 %, with the technique of reference using DNA from tumoral tissue.cfDNA could be used as « liquid biospy » and could be a central biomarker in the personalized genomic for the future years, and this thesis work participate to the development of this new approach
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Sefrioui, David. "Aspect pré analytique et intérêt clinique de la détection d'ADN tumoral circulant par PCR digitale en oncologie digestive." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMR075/document.
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L'ADN tumoral circulant (ADNtumc) est apparu depuis plusieurs années comme un biomarqueur prometteur susceptible d'apporter des informations permettant l'optimisation de la prise en charge du patient en oncologie. L'objectif de cette thèse était double et s'articule autour de deux axes : i) évaluer différentes conditions préanalytiques et analytiques (digitale PCR (dPCR) principalement) pour la détection de ce biomarqueur ii) évaluer l'intérêt clinique potentiel de ce biomarqueur en oncologie digestive. La première partie rapporte 3 travaux (3 articles originaux dont une collaboration nationale (équipe parisienne dirigée par J. Tost)). Dans le travail n°1, nous avons montré la faisabilité de détecter l'ADNtumc par dPCR directement à partir du plasma de 43 prélèvements de patients avec cancer colorectal métastatique (CCRm). Il n'y avait pas de différence significative pour le taux de détection des mutations KRAS circulantes entre les groupes avec et sans extraction d'ADN (93 % (40/43) versus 88 °A) (38/43), respectivement). Dans le travail n°2, nous avons mis au point une méthode basée sur l'apport d'héparinase pour la détection d'ADNtumc à partir de 194 prélèvements héparinés de patients suivis en oncologie. Ce traitement des échantillons par l'héparinase permettait l'analyse de l'ADNtumc pour 117/194 (60 %) patients avec inhibition Préalable de la dPCR par l'héparine. Enfin, dans le travail n°3, nous avons comparé plusieurs plate-formes de détection d'ADNtumc et montré que la dPCR affichait des résultats de détection comparables sur le plan qualitatif et quantitatif avec une plateforme ultrasensible d'Enhanced-ice-COLD-PCR (E-ice-COLD-PCR) pour les échantillons avec une fréquence allélique d'ADNtumc >0,4 °A La deuxième partie rapporte 3 travaux (3 articles originaux) sur l'intérêt clinique de la détection d'ADNtumc par dPCR en oncologie digestive. Nous avons ainsi montré que ce biomarqueur conférait un intérêt diagnostique (travail n°4), Pronostique (travail n 4 à 6) et prédictif de la réponse aux traitements (travail n°6) chez les Patients avec adénocarcinome pancréatique (AP) (travail n°4) et CCRm (travail n°5 à 6)<br>For several years, circulating tumor DNA (ctDNA) has emerged as a promising biomarker providing relevant information to optimize patient care in oncology. The aim of this thesis was both: (i) to evaluate different preanalytical and analytical conditions (digital PCR (dPCR) mainly) for the detection of this biomarker; (ii) to evaluate the potential clinical interest of this biomarker in digestive oncology. The first part reports 3 works (3 original articles including a national collaboration (Parisian team led by J. lost)). In work no. 1, we have shown the feasibility of ctDNA detection by dPCR directly from the plasma of 43 samples from patients with metastatic colorectal cancer (mCRC). There was no significant difference in the detection rate of circulating KRAS mutations between groups with and without DNA extraction (93% (40/43) versus 88% (38/43), respectively). In work no. 2, we developed a method based on the heparinase addition for the ctDNA detection from 194 heparinized samples of patients followed in oncology. This treatment of samples by heparinase allowed the ctDNA analysis of 117/194 (60%) patients with prior inhibition of dPCR by heparin. Finally, in work no. 3, we compared several ctDNA detection platforms and snowed that dPCR displayed qualitatively and quantitatively comparable detection results with an ultrasensitive platform of E-ice-COLD-PCR for the samples with ctDNA allelic fraction ?.0 4%. The second part reports 3 works (3 original articles) on the clinical interest of the ctDNA detection by dPCR in digestive oncology. We have thus shown that this biomarker had a diagnostic (work no. 4). prognostic (works no. 4 to 6) and predictive response to treatments (work no. 6) interest in patients with pancreatic adenocarcinoma (work no. 4) and mCRC (works no. 5 to 6)
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Krau, Nora-Christina [Verfasser]. "Minimal invasiver Aortenklappenersatz (TAVI) bei degenerativer, kalzifizierender Aortenklappenstenose – Risikostratifizierung anhand des neuen Biomarkers Growth Differentiation Factor 15 (GDF15) / Nora-Christina Krau." Kiel : Universitätsbibliothek Kiel, 2018. http://d-nb.info/1165051257/34.
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Sree, Kumar Shalini. "Biomarkers of resistance to anti-EGFR in wild type KRAS/BRAF colorectal cancer cell lines." Thesis, 2015. http://hdl.handle.net/2440/104679.
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Colorectal cancer (CRC) is a leading cause of cancer death worldwide and despite significant improvement the median survival remains relatively poor. The use of targeted therapies like cetuximab and panitumumab inhibiting the epidermal growth factor receptor (EGFR) offer promise in improving patient outcomes. However, a high proportion of CRC patients show resistance to anti-EGFR therapy. Biomarkers such as mutant KRAS or BRAF predict resistance to anti-EGFR therapy in only a subset of patients and we hypothesise that other biomarkers for resistance to EGFR targeted therapies exist. The studies presented in this thesis aimed to determine other biomarkers of resistance to anti-EGFR therapy in wild type KRAS and BRAF CRC cell lines. Following RT-Profiler Array analysis, the 3 most significantly upregulated genes amongst the 3 anti-EGFR resistant CRC cell lines (SNU-C1, SW48 and COLO-320DM) were chosen as candidate biomarkers of resistance: HBEGF (heparin-binding epidermal growth factor-like growth factor), EGR1 (early growth response protein 1) and AKT3 (protein kinase B gamma) were validated using qRT-PCR. HBEGF is a member of EGF-like growth factor family is a potent inducer of tumour growth, angiogenesis, and implicated in metastasis. EGR1 is a transcription factor implicated in cell growth, survival, transformation, tumour progression. AKT3 is a serine/threonine kinase and a downstream mediator of PI3K-AKT-mTOR pathway resulting in cell proliferation, cell survival and angiogenesis. HBEGF was knocked down by 79.4% in SNUC1, EGR1 was knocked down by 85.6% in SW48 and AKT3 was knocked down by 95.3% in COLO-320DM, as validated by qRT-PCR and western blot. Following knockdown, these cell lines were treated with anti-EGFR, and SNU-C1 had proliferation rate of 49.1% (83.8% before knockdown), SW48 yielded proliferation rate of 46.9% (70% before knockdown) and COLO-320DM had proliferation rate of 64.1% (68.3% before knockdown). This suggests that the resistant phenotype of these cell lines was reversed. The expression of these markers was also elucidated using immunohistochemistry on mCRC primary tumour tissues from 10 patients that had undergone cetuximab monotherapy. Some 50% of these patients had overexpression of two or more of these markers, and these patients did not respond to cetuximab, suggesting that these overexpressed biomarkers might be involved in circumventing cetuximab to confer resistance. One of the studies presented in this thesis also explored the KRAS G13D phenomenon and the effect of cetuximab and panitumumab on cell lines harbouring different mutational status. Previous clinical studies have demonstrated that a proportion of KRAS G13D harbouring tumour patients respond to the anti-EGFR therapies, and a large proportion of KRAS WT patients do not respond. After treatment with cetuximab or panitumumab, the KRAS G13D mutant cell lines showed intermediate sensitivity to both treatments, between the resistant KRAS G12V mutant cell line and the sensitive WT KRAS cell line. One of the G13D cell lines was significantly more sensitive to panitumumab than to cetuximab. This study demonstrated that specific KRAS mutation determines the responsiveness to anti-EGFR monoclonal antibody treatment, corresponding to previously reported clinical observations. In conclusion, the studies presented in this thesis have demonstrated that components of EGFR signalling cascade have emerged as important biomarkers of resistance for anti-EGFR targeted therapies. Further assessment of the molecular mechanisms that dictate this resistance and identification of other specific biomarkers for these agents will provide valuable information to identify the most effective therapy for primary and mCRC patients.<br>Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Medical Sciences, 2015.
Book chapters on the topic "KRAS biomarker"
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Molinari, Chiara, and Elisa Chiadini. "Mutational Analysis in Urinary Cell-Free DNA: KRAS in Colorectal Cancer." In Urinary Biomarkers. Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1354-2_3.
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Verma, Muskan, Dr Asghar Ali, and Dr Mohan Kamthan. "SIGNIFICANCE OF BIOMARKERS IN INTESTINAL DISORDERS AND CANCERS." In Futuristic Trends in Biotechnology Volume 3 Book 23. Iterative International Publishers, Selfypage Developers Pvt Ltd, 2024. http://dx.doi.org/10.58532/v3bdbt23p1ch4.
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This chapter explores the magnitude of biomarkers in understanding, diagnosing, and treating intestinal cancers and disorders. It mainly focuses on intestine-related cancers like colorectal cancer, small intestine cancer, and intestinal disorders, such as inflammatory bowel disease (IBD). The specific biomarkers related to intestinal cancers (with a particular emphasis on colorectal cancer) and disorders (especially IBD) are discussed. Furthermore, genetic biomarkers like KRAS, BRAF, TP53, and APC mutations are examined, along with epigenetic biomarkers such as DNA methylation and his tone modifications. Additionally, protein biomarkers like CEA, Ki-67, and p53 are highlighted, each offering valuable insights into disease development, prognosis, and treatment response. Future perspectives and challenges surrounding biomarkers in intestinal cancers and disorders are then explored. Precision medicine, liquid biopsies, multi-omics integration, early detection and screening, prognostic and predictive biomarkers, and challenges related to validation, standardization, cost, accessibility, ethical considerations, biomarker combinations, and the heterogeneity of intestinal cancers and disorders are addressed.
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Effendi-YS, Rustam, Amido Rey, and Imelda Rey. "Biomarkers as a Therapeutic Approach in Colorectal Carcinoma." In Advances in Diagnosis and Therapy of Colorectal Carcinoma [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.1004189.
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This review highlights the most promising biomarker tests of tumor tissue from colonoscopy biopsy for more individualized therapeutic approaches to patients with colorectal carcinoma (CRC). Biomarkers are a key tool in early detection, survival, and predicting treatment response and prognostic value. The tests can help doctors to select a specific CRC treatment and targeted therapy. CRC is the third most common cancer diagnosed, and the second leading cause of cancer-related deaths worldwide, despite the progress made in detection and management through surgery, chemotherapy, radiotherapy, and immunotherapy. With a population totaling 273,523,621 people, Indonesia has estimated 396,914 new cases of all cancer and 234,511 cancer-related deaths. Among those cancer cases, estimated 34,189 new CRC cases and 17,786 CRC deaths occurred in 2020. Most of CRC cases were located in the rectum compared to those in the distal colon or proximal colon. CRC is a heterogeneous cancer. Its therapeutic approaches vary, depending on the tumor location (proximal, distal colon, or rectum), clinical signs and symptoms, staging and biomarkers such as KRAS and NRAS, BRAF V600E, MSI high (dMMR), CIN, HER2-amplified, PD-1, CTLA-4, MEK, and NTRK gene fusion-positive. CSCs and other biomarkers are being developed and remain under investigation.
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Rajendiran, Selvam, and Sathanraj Natarajan. "Role of Prognostic Biomarkers and their Importance as a Drug Therapeutic Target in Colorectal Cancer Therapy." In Therapeutic Plants: Recent Advances in the Use of Herbs as Alternative Medications. BENTHAM SCIENCE PUBLISHERS, 2025. https://doi.org/10.2174/9789815322910125010009.
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Cancer, a multifaceted disease, continues to challenge the global healthcare landscape, with colon cancer being a prominent contributor to its burden. Colon cancer, also known as colorectal cancer (CRC), arises from the colon or rectum and ranks among the most prevalent malignancies worldwide. Its emergence can be attributed to a complex interplay of genetic, environmental, and lifestyle factors. Despite advancements in diagnostics and treatment modalities, the incidence of CRC has witnessed a concerning rise in recent years, prompting an urgent need for innovative therapeutic strategies. Surgical resection remains the primary curative option for localized disease, while systemic treatments are employed for advanced stages. Biomarkers, pivotal in elucidating CRC pathogenesis and progression, play a crucial role in guiding therapeutic interventions and prognostication. Molecular biomarkers like microsatellite instability (MSI) and mutations in genes like KRAS, BRAF, and TP53 serve as prognostic indicators and guide treatment selection. Understanding the intricate signaling pathways involved in CRC development has led to the exploration of novel therapeutic targets. Targeting key signaling pathways, such as the Wnt/β-catenin pathway, PI3K/Akt/mTOR pathway, and the MAPK pathway, has shown potential in preclinical studies and clinical trials, offering avenues for innovative treatment modalities. Overall, the evolving landscape of CRC demands a multidisciplinary approach integrating advanced diagnostics, targeted therapies, and personalized medicine. Biomarkers, with their pivotal role in elucidating molecular pathways and guiding treatment decisions, stand as a beacon of hope in the pursuit of more effective and tailored therapeutic interventions for colorectal cancer.
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Słodkowska Janina and García-Rojo Marcial. "Digital Pathology in Personalized Cancer Therapy." In Studies in Health Technology and Informatics. IOS Press, 2012. https://doi.org/10.3233/978-1-61499-086-4-143.
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The development of small molecule inhibitors of the growth factor receptors and discovery of somatic mutations of the thyrosine kinase domain resulted in new paradigms for the cancers therapy. Digital microscopy is an important tool for surgical pathologists. The achievements in the digital pathology field have modified the workflow of pathomorphology labs, enhanced the pathologists' role in the diagnostics and increased their contribution to the personalized targeted medicine. Digital image analysis is now available in a variety of platforms to improve quantification performance of diagnostic pathology. The authors describe the state of digital microscopy as it applies to the field of quantitative immunohistochemistry of biomarkers related to the clinical personalized targeted therapy of breast cancer, non-small lung cancer and colorectal cancer: HER-2, EGFR, KRAS and BRAF genes. The information is derived from the experience of the authors and review of the literature.
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Juliana Nordin, Fariza, Lim Wan Ming, Michelle Yee Mun Teo, and Lionel Lian Aun In. "Aptamer Development for Cancer Diagnostics." In Rapid Antigen Testing [Working Title]. IntechOpen, 2023. http://dx.doi.org/10.5772/intechopen.1001613.
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Early diagnosis improves the prognosis for cancer patients by allowing early intervention to slow or prevent cancer development and lethality. Aptamers are short single-stranded oligonucleotides that have a length of about 25-80 bases. They are produced chemically and extracted using the systematic evolution of ligands by exponential enrichment (SELEX). The use of aptamers as diagnostic tools in cancer is highly recommended due to their ability to recognize various cancer-related molecules and biomarkers with high affinity and specificity. Despite the clear advantages of aptamers, the potential of aptamers in cancer diagnosis is yet to be reached. This chapter will present the best available knowledge on using aptamers as the biorecognition element in the development of cancer biosensor. We will first present the advantages of aptamers in cancer diagnosis as well as various types of SELEX methods with emphasis on clinically relevant samples such as serum, whole cells, and tissue slices. We will also cover the various aptamer detection platforms such as colorimetric, fluorescence and electrochemical platforms. Furthermore, the updates on aptamers specific to KRAS mutation detection in cancer will be reviewed. Finally, the future direction of aptamers in cancer diagnosis will also be discussed.
Conference papers on the topic "KRAS biomarker"
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Drozd, V. S., D. S. Rybalko, A. A. Salimova, D. M. Kolpashchikov, and A. A. Eldeeb. "BINARY ANTISENSE OLIGONUCLEOTIDES ACTIVATE DEGRADATION OF THE TARGETED MRNA IN KRAS-DEPENDENT MANNER IN K562 CELL LINE." In X Международная конференция молодых ученых: биоинформатиков, биотехнологов, биофизиков, вирусологов и молекулярных биологов — 2023. Novosibirsk State University, 2023. http://dx.doi.org/10.25205/978-5-4437-1526-1-318.
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Biomarker-dependent degradation of target gene mRNA in the K562 cell line induced by binary antisense oligonucleotides (BiASO) was demonstrated. When BiASO was integrated into the DNA system, a 12-fold increase in mRNA degradation in the presence of the biomarker was achieved. The new BiASO technology is characterized by simplicity of design and also opens the possibility of directly targeting the most vulnerable housekeeping genes in cancer therapy.
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Weidhaas, Joanne B., and Frank Slack. "Abstract 1856: A KRAS-variant as a putative biomarker of ovarian cancer risk." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1856.
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Rooney, Claire, Sarah Ross, Anna Staniszewska, et al. "Abstract 5095: Development of a pharmacodynamic biomarker assay for AZD4785, an antisense oligonucleotide targeting KRAS." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-5095.
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Van Schaeybroeck, Sandra, Joan Kyula, Dan Longley, and Patrick Johnston. "Abstract B243: Kras mutation status as biomarker for response to TRAIL treatment in colorectal cancer." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-b243.
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Paranjape, Trupti S., Helen Heneghan, Cory Pelletier, et al. "Abstract 3029: A KRAS microRNA binding site polymorphism as a novel biomarker of risk in triple negative breast cancer." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-3029.
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Deng, Zaian, Karen M. Mann, Eugene J. Koay, et al. "Abstract 1833: KRAS-regulated P4HA1 in pancreatic tumor and its hydroxylated peptide as a serum biomarker for early diagnosis." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-1833.
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Wu, Nandie, Ying Huang, Xiangshan Fan, et al. "Abstract 3177: KRAS gene status in gastric signet-ring cell carcinoma patients and act as biomarker of MEK inhibitor." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-3177.
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Wu, Nandie, Ying Huang, Xiangshan Fan, et al. "Abstract 3177: KRAS gene status in gastric signet-ring cell carcinoma patients and act as biomarker of MEK inhibitor." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-3177.
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Sasaki, Yusuke, Yasuhide Yamada, Masahiro Kamita, and Masaya Ono. "Abstract A27: Discovery of predictive biomarker of adjuvant chemotherapy in stage III colorectal cancer related to KRAS/NRAS mutation status using proteomic approach: results from the two randomized phase 3 trials (NSAS-CC/RC)." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1535-7163.targ-15-a27.
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Paweletz, Cloud P., Geoffrey R. Oxnard, Nora Feeney, et al. "Abstract 3157: Serial droplet digital PCR (ddPCR) of plasma cell-free DNA (cfDNA) as pharmacodynamic (PD) biomarker in Phase 1 clinical trials for patients (pts) with KRAS mutant non-small cell lung cancer (NSCLC)." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-3157.
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