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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.
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Brugger, Wolfram, Nadja Triller, Maria Blasinska-Morawiec, et al. "Prospective Molecular Marker Analyses of EGFR and KRAS From a Randomized, Placebo-Controlled Study of Erlotinib Maintenance Therapy in Advanced Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 29, no. 31 (2011): 4113–20. http://dx.doi.org/10.1200/jco.2010.31.8162.
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Purpose The phase III, randomized, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study found that erlotinib maintenance therapy extended progression-free survival (PFS) and overall survival in patients with advanced non–small-cell lung cancer (NSCLC) who had nonprogressive disease following first-line platinum-doublet chemotherapy. This study included prospective analysis of the prognostic and predictive value of several biomarkers. Patients and Methods Mandatory diagnostic tumor specimens were collected before initiating first-line chemotherapy and were tested for epidermal growth factor receptor (EGFR) protein expression by using immunohistochemistry (IHC), EGFR gene copy number by using fluorescent in situ hybridization (FISH), and EGFR and KRAS mutations by using DNA sequencing. An EGFR CA simple sequence repeat in intron 1 (CA-SSR1) polymorphism was evaluated in blood. Results All 889 randomly assigned patients provided tumor samples. EGFR IHC, EGFR FISH, KRAS mutation, and EGFR CA-SSR1 repeat length status were not predictive for erlotinib efficacy. A profound predictive effect on PFS of erlotinib relative to placebo was observed in the EGFR mutation–positive subgroup (hazard ratio [HR], 0.10; P < .001). Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup (HR, 0.78; P = .0185). KRAS mutation status was a significant negative prognostic factor for PFS. Conclusion This large prospective biomarker study found that patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy. No other biomarkers were predictive for outcomes with erlotinib, although the study was not powered for clinical outcomes in biomarker subgroups. EGFR IHC–positive KRAS mutations were prognostic for reduced PFS. The study demonstrated the feasibility of prospective tissue collection for biomarker analyses in NSCLC.
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Yokoyama, Masaaki, Hiroaki Ohnishi, Kouki Ohtsuka, et al. "KRAS Mutation as a Potential Prognostic Biomarker of Biliary Tract Cancers." Japanese Clinical Medicine 7 (January 2016): JCM.S40549. http://dx.doi.org/10.4137/jcm.s40549.
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Background The aim of this study was to identify the unique molecular characteristics of biliary tract cancer (BTC) for the development of novel molecular-targeted therapies. Materials and Methods We performed mutational analysis of KRAS, BRAF, PIK3CA, and FBXW7 and immunohistochemical analysis of EGFR and TP53 in 63 Japanese patients with BTC and retrospectively evaluated the association between the molecular characteristics and clinicopathological features of BTC. Results KRAS mutations were identified in 9 (14%) of the 63 BTC patients; no mutations were detected within the analyzed regions of BRAF, PIK3CA, and FBXW7. EGFR overexpression was observed in 5 (8%) of the 63 tumors, while TP53 overexpression was observed in 48% (30/63) of the patients. Overall survival of patients with KRAS mutation was significantly shorter than that of patients with the wild-type KRAS gene ( P = 0.005). By multivariate analysis incorporating molecular and clinicopathological features, KRAS mutations and lymph node metastasis were identified to be independently associated with shorter overall survival ( KRAS, P = 0.004; lymph node metastasis, P = 0.015). Conclusions Our data suggest that KRAS mutation is a poor prognosis predictive biomarker for the survival in BTC patients.
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Papadimitrakopoulou, Vassiliki, Ignacio Ivan Wistuba, J. Jack Lee, et al. "BATTLE-2 program: A biomarker-integrated targeted therapy study in previously treated patients with advanced non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 31, no. 15_suppl (2013): TPS8118. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps8118.
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TPS8118 Background: New strategies incorporating a personalized medicine approach for NSCLC treatment are increasingly explored and were pioneered in the prospective, biomarker-driven clinical program titled Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-1) (Kim et al Cancer Discov 2011;1:44). Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies, with a long-term goal to significantly improve the survival of NCSLC patients (pts) (ClinicalTrials.gov NCT01248247). Methods: This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in refractory NSCLC pts (failed at least 1 prior line of therapy). After a study-entry tumor biopsy, pts are adaptively randomized, based on KRAS status, to 4 trial arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). Baseline tumor testing includes KRAS and EGFR mutations and EML4/ALK translocation, the latter two being exclusion criteria. The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS status while predictive biomarkers are being developed. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers (“signatures”) follows a rigorous, internally and externally reviewed statistical analysis. All Stage 1 and 2 randomization biomarker assays are CLIA-certified. 219 pts have been enrolled and 124 pts randomized. 100 pts are evaluable for the 8-week DCR endpoint. Accrual updates, demographics, and further details will be presented at the meeting. Supported by NCI R01CA155196-01A1. Clinical trial information: NCT01248247.
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Katta, Arvind, Afsaneh Barzi, Brian Thomas Hocum, et al. "Real-world biomarker testing patterns among patients with metastatic colorectal cancer (mCRC) treated with later lines of therapy (LOT) in the United States (US) community oncology setting." Journal of Clinical Oncology 42, no. 3_suppl (2024): 163. http://dx.doi.org/10.1200/jco.2024.42.3_suppl.163.
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163 Background: Testing for BRAF and KRAS/NRAS mutations, HER2 amplifications, and MSI/MMR status is a standard of care for all patients with mCRC. There are limited real-world (RW) data regarding biomarker testing patterns among robust patients who are candidates for multiple LOT. We evaluated biomarker testing patterns among patients treated in community oncology practices who initiated regorafenib (REGO) and/or trifluridine/tipiracil (FTD/TPI), predominantly in 3rd or later lines of therapy. Methods: A retrospective analysis utilizing electronic medical record data from The US Oncology Network examined adult patients with mCRC who initiated REGO and/or FTD/TPI between 09/01/2015 and 11/30/2022 with follow-up until 05/31/2023. The proportion of patients tested for various biomarkers was assessed. Results: A total of 2684 mCRC patients initiated REGO and/or FTD/TPI (including 895 pts receiving both) in any LOT during the study period. The mean age of patients at baseline was 62.9 years, of whom 54.9% were male, 1599 (59.6%) patients were White and 436 (16.2%) were underrepresented minorities (Black or Hispanic/Latino). Patients were most commonly tested for KRAS mutations (75.2%) and least commonly for HER2 amplifications (22.6%). Age, gender, and race/ethnicity characteristics were similar between treatment subgroups, with 29.6% of minority and 23.1% of white patients not undergoing KRAS testing. Types of biomarkers tested and proportion of patients tested are reported in the table below. Conclusions: About one quarter of patients who were sufficiently robust to receive aggressive therapy did not undergo testing for KRAS, the oldest standard of care biomarker in CRC. We observed disparities by race/ethnicity. We also observed a correlation between rates of testing and treatment intensity, with patients who received both REGO and FTD/TPI having a higher rate of testing than those who received only one of the treatments. Understanding the pitfalls in biomarker testing will help pave the way for appropriate and equitable access to cancer care. [Table: see text]
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Lowe, Kimberly, Xin Niu, George Kafatos, and Michael Anthony Kelsh. "Patterns of KRAS, NRAS and BRAF testing among patients with metastatic colorectal cancer in the EU5." Journal of Clinical Oncology 35, no. 4_suppl (2017): 637. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.637.
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637 Background: In mid-2013, the requirement for mCRC patients treated with panitumumab changed from wild-type KRAS to wild-type RAS ( KRAS and NRAS). The objective of this study was to describe patterns of KRAS, NRAS, and BRAF testing among mCRC patients in the EU5 (United Kingdom (U.K.), Germany, France, Italy and Spain). Methods: This descriptive study utilized Oncology Analyzer data (IMS Health Oncology, Fairfield, CT, USA), which provides real-world quarterly cross-sectional, epidemiologic and clinical data for mCRC patients. Trends in biomarker testing during the study period were evaluated by calculating the frequencies and proportions of patients who were /were not tested for combinations of KRAS, NRAS, and BRAF within each of the five countries. KRAS and BRAF data were available in all countries from quarter three (Q3) 2012 to quarter two (Q2) 2015. NRAS was available in all countries from quarter 1 (Q1) 2014 to Q2 2015. Frequencies and proportions were also calculated to summarize patient demographic and clinical characteristics between groups with different testing choices. Results: A total of 32,961 patients with mCRC were included in the analyses. Prior to 2013, the majority of patients in each country were tested for only KRAS. The proportion of patients tested for both KRAS and NRAS increased substantially during the period of data availability for NRAS (Q1 2014 to Q2 2015), including <1% to 19.1% in the U.K., 8.8% to 31.9% in France, 13.1% to 43.2% in Germany, 5.9% to 24.6% in Italy, and 8.7% to 31.4% in Spain. The proportion of patients who were tested for all three biomarkers also increased during the period of data availability for all three biomarkers (Q1 2014 to Q2 2015), including 2.3% to 16.4% in the U.K., 4.8% to 26.6% in France, <1% to 2.4% in Germany, 4.2% to 22.3% in Italy, and 1.5% to 9.3% in Spain. There were few differences in patient demographic or clinical characteristics between those with different testing groups. Conclusions: This analysis provides a description of biomarker testing using read-world data and suggests an overall increase in testing among mCRC patients in the EU5. Although there was a trend towards increased testing, many mCRC patients are still not tested for these important biomarkers.
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Bengala, C., S. Bettelli, A. Fontana, et al. "EGFR gene copy number, KRAS and BRAF status, PTEN and AKT expression analysis in patients with metastatic colon cancer treated with anti-EGFR monoclonal antibodies ± chemotherapy." Journal of Clinical Oncology 27, no. 15_suppl (2009): e15055-e15055. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15055.
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e15055 Background: Cetuximab and panitumumab have proven to be effective in metastatic colon cancer (mCRC). KRAS mutation has been demonstrated to be a biomarker of resistance to both monoclonal antibodies. However the status and expression of other biomarkers of the RAS-RAF-MAPK signalling pathway can have a crucial role in sensitivity to anti-EGFR monoclonal antibodies. Methods: We have retrospectively analyzed tumor tissue biomarkers including EGFR gene copy number (GCN) by FISH, KRAS and BRAF status by PCR-based sequencing, PTEN and AKT expression by IHC in patients with mCRC treated with cetuximab and panitumumab ±chemotherapy. Response to treatment, TTP and OS were evaluated. Results: Sixty-three patients (pts) have been analyzed. Median age was 59 years (34–80); 53 pts had received cetuximab and 10 pts panitunumab. Concomitatnt chemotherapy was FOLFIRI, CPT-11, FOLFOX4 and Xeliri in 35, 13, 6 and 4 pts respectively. Five pts had received monoclonal antibodies only. Twenty- one pts were treated in 1st-2nd line and 42 pts in 3rd-4th line. So far EGFR GCN is available on 55 pts, KRAS and BRAF on 63 pts, PTEN in primary tumor (PT) on 36 pts and in metastatic (MTS) site on 24 pts, AKT on 19 pts. EGFR/nuclei ratio was > 2.9 in 31 % of the pts, KRAS and BRAF were mutated in 36.5 % and 3 % of the pts respectively; PTEN was positive in 42 % and 79 % in PT and MTS respectively. Moreover 21.8 % of the pts had EGFR/nuclei > 2.9 and CEP7 Polisomy > 50 %. Four pts achieved a partial remission (6.3 %). Partial response rate was 17 % vs. 2.6 % in pts with high and low EGFR GCN respectively (p: 0.007) and 13 % vs. 2.5 % in pts with WT and mutated KRAS respectively (p: 0.048). Median TTP was 3 months (0.83–32.9). It was 4.2 vs. 2.3 mos in pts with WT and mutated KRAS respectively (p: 0.001). Median OS was 9.7 mos (2.03–49.0) and no statistically significant differences were observed according to the biomarkers status. However a trend was observed for pts with KRAS WT 10.6 vs. 7.8 mos and for PTEN positive in PT: 9.0 vs. 5.67 mos. Conclusions: Our data confirm the predictive role of EGFR gene copy number and KRAS status on the response and survival. Complete biomarker characterization is ongoing and an analysis for interaction will be performed. No significant financial relationships to disclose.
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Richman, Susan D., Matthew T. Seymour, Philip Chambers, et al. "KRASandBRAFMutations in Advanced Colorectal Cancer Are Associated With Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan: Results From the MRC FOCUS Trial." Journal of Clinical Oncology 27, no. 35 (2009): 5931–37. http://dx.doi.org/10.1200/jco.2009.22.4295.
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PurposeActivating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.Patients and MethodsThe Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.ResultsThree hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).ConclusionKRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.
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Garcia-Carbonero, Nuria, Javier Martinez-Useros, Weiyao Li, et al. "KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study." Cells 9, no. 1 (2020): 219. http://dx.doi.org/10.3390/cells9010219.
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KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086–2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110–2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531–13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.
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Liu, Li, Yuan Liu, Ademi Santiago-Walker, et al. "Genetic and molecular biomarker characterization of KRAS mutant non-small cell lung carcinoma (NSCLC) tumors." Journal of Clinical Oncology 31, no. 15_suppl (2013): 11026. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.11026.
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11026 Background: Preclinical studies demonstrated Brahma related gene 1 (BRG1) mutations or loss of expression, and mutations of LKB1 may be associated with lack of sensitivity for MEK inhibitor trametinib in a subset of KRAS mutant NSCLC lines. This study aimed to evaluate the frequency of KRAS, LKB1 and BRG1 mutations in NSCLC tumors; and determine whether KRAS mutations in corresponding plasma samples could be detected by evaluating circulating cell-free DNA (cfDNA). Methods: Human NSCLC FFPE tumor tissue and matched plasma samples were procured from Indivumed GmbH. KRAS mutation status of 101 NSCLC tumors and matched plasma were determined by direct sequencing of genomic DNA (gDNA) from tissue and/or BEAMing on tissue gDNA or plasma cfDNA. Genetic mutations of LKB1 and BRG1 were determined by direct sequencing. Additional mutations were determined using the Ion Torrent AmpliSeq Cancer Panel. BRG1 protein expression was evaluated by IHC. Results: By direct sequencing and BEAMing we found 27/101 (28.4%) NSCLC tissue and/or plasma samples harbored KRAS mutations: G12V (37.0%), G12C (29.6%), G12D (18.5%), G12S, G13C, G13D and Q61H (3.7% each). The KRAS mutation status concordance (mutant or wild-type) between tumor gDNA and plasma cfDNA was 79-81%. Among the KRAS mutant tumors, LKB1 and BRG1 mutations were detected in 10/26 (38%) and 1/26 (3.8%) tumors respectively by direct sequencing. By IHC, loss of BRG1 expression was detected in 1/21 KRAS mutant tumors. The mutation frequency and variants for KRAS and LKB1 in patient samples were comparable with KRAS mutant NSCLC cell lines and COSMIC database. However the frequency of BRG1 mutation and protein loss were much lower in patient tumors. In a subset of 15 KRAS mutant tumors, Ion Torrent confirmed KRAS and LKB1 mutations and provided additional mutations found in TP53, FGFR2, FGFR3, GNAS, KDR, KIT and MET. Conclusions: This study demonstrates that KRAS mutant NSCLC tissues have high frequency of LKB1 mutations along with other mutations. It also supports the feasibility of detection of KRAS mutations in cfDNA from blood of NSCLC patients using BEAMing technology, providing an alternative to invasive biopsy.
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Sabbagh, Saad, María Herrán, Ali Hijazi, et al. "Biomarker Testing Disparities in Metastatic Colorectal Cancer." JAMA Network Open 7, no. 7 (2024): e2419142. http://dx.doi.org/10.1001/jamanetworkopen.2024.19142.
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ImportanceAmong patients with metastatic colorectal cancer (mCRC), data are limited on disparate biomarker testing and its association with clinical outcomes on a national scale.ObjectiveTo evaluate the socioeconomic and demographic inequities in microsatellite instability (MSI) and KRAS biomarker testing among patients with mCRC and to explore the association of testing with overall survival (OS).Design, Setting, and ParticipantsThis cohort study, conducted between November 2022 and March 2024, included patients who were diagnosed with mCRC between January 1, 2010, and December 31, 2017. The study obtained data from the National Cancer Database, a hospital-based cancer registry in the US. Patients with mCRC and available information on biomarker testing were included. Patients were classified based on whether they completed or did not complete MSI or KRAS tests.ExposureDemographic and socioeconomic factors, such as age, race, ethnicity, educational level in area of residence, median household income, insurance type, area of residence, facility type, and facility location were evaluated.Main Outcomes and MeasuresThe main outcomes were MSI and KRAS testing between the date of diagnosis and the date of first-course therapy. Univariable and multivariable logistic regressions were used to identify the relevant factors in MSI and KRAS testing. The OS outcomes were also evaluated.ResultsAmong the 41 061 patients included (22 362 males [54.5%]; mean [SD] age, 62.3 [10.1] years; 17.3% identified as Black individuals, 78.0% as White individuals, 4.7% as individuals of other race, with 6.5% Hispanic or 93.5% non-Hispanic ethnicity), 28.8% underwent KRAS testing and 43.7% received MSI testing. A significant proportion of patients had Medicare insurance (43.6%), received treatment at a comprehensive community cancer program (40.5%), and lived in an area with lower educational level (51.3%). Factors associated with a lower likelihood of MSI testing included age of 70 to 79 years (relative risk [RR], 0.70; 95% CI, 0.66-0.74; P &amp;lt; .001), treatment at a community cancer program (RR, 0.74; 95% CI, 0.70-0.79; P &amp;lt; .001), rural residency (RR, 0.80; 95% CI, 0.69-0.92; P &amp;lt; .001), lower educational level in area of residence (RR, 0.84; 95% CI, 0.79-0.89; P &amp;lt; .001), and treatment at East South Central facilities (RR, 0.67; 95% CI, 0.61-0.73; P &amp;lt; .001). Similar patterns were observed for KRAS testing. Survival analysis showed modest OS improvement in patients with MSI testing (hazard ratio, 0.93; 95% CI, 0.91-0.96; P &amp;lt; .001). The median (IQR) follow-up time for the survival analysis was 13.96 (3.71-29.34) months.Conclusions and RelevanceThis cohort study of patients with mCRC found that older age, community-setting treatment, lower educational level in area of residence, and treatment at East South Central facilities were associated with a reduced likelihood of MSI and KRAS testing. Highlighting the sociodemographic-based disparities in biomarker testing can inform the development of strategies that promote equity in cancer care and improve outcomes for underserved populations.
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Skoulidis, Ferdinandos, Adrianus De Langen, Luis G. Paz-Ares, et al. "Biomarker subgroup analyses of CodeBreaK 200, a phase 3 trial of sotorasib versus (vs) docetaxel in patients (pts) with pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 41, no. 16_suppl (2023): 9008. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.9008.
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9008 Background: Sotorasib is a first-in-class oral, irreversible KRASG12C inhibitor approved for adults with pretreated KRAS G12C-mutated advanced NSCLC. In CodeBreaK 200, the first KRASG12C inhibitor randomized phase 3 trial, sotorasib demonstrated superior progression-free survival (PFS) and overall response rate (ORR) vs docetaxel and a more favorable safety profile. We report prespecified exploratory biomarker analyses comparing sotorasib vs docetaxel efficacy in molecularly-defined KRAS G12C-mutated advanced NSCLC subsets. Methods: In CodeBreaK 200, 345 pts with KRAS G12C-mutated advanced NSCLC who progressed after platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to oral sotorasib 960 mg daily or IV docetaxel 75 mg/m2 Q3W. Primary endpoint was PFS by blinded independent central review (RECIST 1.1; key secondary endpoint: ORR). In prespecified exploratory analyses, baseline tissue and plasma samples were analyzed for key genomic alterations (eg, STK11, KEAP1, EGFR, MET, TP53), by central targeted next-generation sequencing (Skoulidis N Engl J Med 2021), and PD-L1 protein level by local standard of care testing in biomarker-evaluable cases; biomarker status was correlated with PFS and ORR. Inferred tumor mutation burden by plasma circulating tumor DNA (sum of mutant molecular variant reads) was assessed. Association of baseline genomic alterations with long-term benefit (PFS ≥ 6 m) vs early progression (PFS < 3 m; no complete/partial response) was evaluated. Results: Most prevalent KRAS G12C co-alterations in biomarker-evaluable cases with available tumor and/or plasma samples (n=317) were TP53 (181 [57.1%]), STK11 (119 [37.5%]), and KEAP1 (82 [25.9%]) in CodeBreaK 200, consistent with CodeBreaK 100; 55 (17.4%) pts had STK11 and KEAP1 co-alterations. Sotorasib showed superior clinical benefit vs docetaxel independently of PD-L1 expression and across all prespecified subgroups (eg, STK11, KEAP1, TP53) . No clinical response occurred with either treatment in 26 (8.2%) pts with additional KRAS alterations, including amplifications. High baseline plasma tumor burden was associated with greater odds of early progression vs long-term benefit in both arms (odds ratio, 3.54 [95%CI 1.83-6.85] per tertile increase; p<0.0001). Correlation of KRAS G12C co-alterations with response detected a signal toward shorter median PFS (sotorasib, 2.8 m [95%CI 1.6-3.4]; docetaxel, 7.5 m [95%CI 3.0-NE]) with sotorasib vs docetaxel in pts with KRAS G12C and NOTCH1 co -altered tumors. Conclusions: Sotorasib demonstrated consistent clinical benefit vs docetaxel in all prespecified molecularly-defined subgroups (eg, STK11, KEAP1, TP53) in this exploratory analysis of CodeBreaK 200. No predictive biomarkers were confirmed, but novel hypothesis-generating signals were observed. Clinical trial information: NCT04303780 .
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Kim, E. S., R. S. Herbst, J. J. Lee, et al. "Phase II randomized study of biomarker-directed treatment for non-small cell lung cancer (NSCLC): The BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial program." Journal of Clinical Oncology 27, no. 15_suppl (2009): 8024. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.8024.
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8024 Background: Treatment for patients (pts) with recurrent NSCLC has limited efficacy despite the use of new targeted agents. Identifying biomarkers to predict tumor response will help personalize therapy for individuals. Methods: Eligible pts had prior chemotherapy, ECOG PS 0–2, and when enrolled, required 2 fresh core needle biopsy specimens to test 11 biomarkers related to 4 molecular pathways in NSCLC: EGFR, Kras, and Braf gene mutation (PCR-based sequencing), EGFR and Cyclin D1 copy number analyses (FISH), and 6 proteins via IHC (VEGF/R and RXR receptors/Cyclin D1). Based on eligibility and tumor biomarker analyses, pts were randomized into 1 of 4 treatments: erlotinib (E) 150 mg qd; sorafenib 400 mg bid, vandetanib 300 mg qd; E 150 mg + bexarotene 400 mg/m2 qd. The primary endpoint is 8-week progression-free status. The first 97 pts were equally randomized, with subsequent pts adaptively randomized under a Bayesian framework. Results: Since 11/2006, 227 pts have been enrolled and 171 randomized and treated (median age 62 yrs, 89 males, 137 Caucasians, 11 Asians, 107 former and 38 never smokers). Accrual has proceeded well (average 9 pts per month). 112 of the biopsied lesions were lung, with a pneumothorax rate of 12.1% (15 of 124 pts; grade 1–2 only; lung, mediastinal and pleural sites). 168 pts (74%) have complete biomarker profiles and 7 (3%) have partial. Histology: adenocarcinoma (75%), squamous (11%), large cell (13%). Mutation frequency was 19% EGFR, 15.4% Kras, and 2.9% Braf. 2 tumors contained both EGFR and Kras mutations, and 2 cases had both Kras and Braf mutations. EGFR polysomy by FISH was 36.4%, and gene amplification 21%. Cyclin D1 amplification was 16.3%. Treatment-related adverse events (grade 3 or more) were 6.5%. Conclusions: We have demonstrated that biopsies are safe and feasible for biomarker-directed studies. The study continues enrollment to 200 evaluable pts at which point the results will be unblinded. BATTLE is one of the first studies in advanced lung cancer to prospectively utilize biomarker analysis of fresh biopsies to direct pt treatment, and is a step towards personalizing therapy in NSCLC. Supported by grant DoD W81XWH-6–1-0303. No significant financial relationships to disclose.
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Nono Djotsa, Alice, David Winski, Theresa Hoang-Anh Nguyen, et al. "Real-world rates of FDA-approved targeted therapy and immunotherapy prescriptions for patients with metastatic colorectal cancer in the VA’s National Precision Oncology Program (NPOP)." Journal of Clinical Oncology 41, no. 16_suppl (2023): 3602. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.3602.
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3602 Background: Colorectal cancer is the fourth most common cancer among Veterans and the third leading cause of cancer-related death in the USA. Use of comprehensive genomic profiling (CGP) to guide administration of FDA-approved biomarker directed therapies can improve outcomes among metastatic CRC (mCRC) patients. We sought to compute the rates of actionable biomarkers and prescriptions of associated FDA-approved therapies among Veterans in NPOP. Methods: The NPOP database was queried to identify mCRC patients who had undergone CGP via tissue or liquid biopsy between February 2019 and July 2022 and had one of the following 5 actionable biomarker profiles: NRAS/ KRAS/ BRAF wildtype, BRAF V600E, MSI-H, TMB-H, or NTRK fusion or rearrangement. The VA’s Corporate Data Warehouse (CDW) was queried to extract prescription data for seven FDA-approved biomarker-directed therapies (targeted agents and immune checkpoint inhibitors (ICIs)). Rates of CGP-directed therapy prescriptions were assessed based upon biomarker and patient characteristics (sex, race, ethnicity, and rurality). Results: A total of 908 mCRC patients underwent CGP, with 81.4% bearing colon adenocarcinoma (COAD) and 18.6% rectal adenocarcinoma (READ). Rates of actionable biomarkers associated with FDA-approved therapies were as follows: NRAS/ KRAS/ BRAF wildtype (34.4%), TMB-H (9.6%), BRAF V600E (7.7%), MSI-H (5.6%), TMB-H and MSI-H (5.6%), and NTRK Fusion or rearrangement (0.3%). The combined rates of any actionable variant were 47.4% for COAD and 44.4% for READ patients. Relative to patients without actionable biomarkers, patients with BRAF V600E mutations were more likely to be older and white; patients with NRAS/ KRAS/ BRAF wildtype were more likely to be younger (all p < 0.001). Among the 424 eligible patients, the frequencies of FDA-approved CGP-directed therapy prescriptions were as follows: MSI-H (70.7%), TMB-H (47.4%), NRAS/ KRAS/ BRAF wildtype (38.5%), and BRAF V600E (17.1%). Across all included biomarkers, African Americans (53.4%) were more likely to receive these therapies than whites (36.8%); and patients with prescriptions were more likely to be younger that those without (all p < 0.01). Conclusions: Nearly 30% of patients with MSI-H mCRC did not receive efficacious ICIs, and though disease laterality data was not readily available, a substantial number of eligible patients also did not receive EGFR inhibitors. This underuse of EGFR inhibitors has been reported previously [1].There were racial and age differences in prescription rates. Further studies should evaluate the barriers to prescribing CGP-directed therapies in the care of mCRC patients. Keywords: molecular testing, metastatic colorectal cancer, comprehensive genomic profiling, actionable biomarkers, FDA approved therapies, veterans. [1] Becker et al. 2021 PMID 34250412.
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Weidhaas, Joanne B., Ju-Whei Lee, Robbert Slebos, et al. "Association of the 3'-untranslated region KRAS-variant with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma." Journal of Clinical Oncology 31, no. 15_suppl (2013): 6016. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.6016.
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6016 Background: A germline mutation in let-7 complementary site 6 (LCS6) within the KRAS 3'-untranslated region (rs61764370, the KRAS-variant: TG/GG) is known to associate with poor outcome and drug resistance in various cancers compared to the wild type allele (TT). We examine the prognostic significance of the KRAS-variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods: The KRAS-variant was determined in 116 tumor DNA samples from HNSCC patients enrolled in 3 clinical trials and a tissue collection study using a previously validated PCR-based assay. Results: KRAS-variant status could be determined in 108/116 (93%) samples and an allele frequency of TG/GG was 28.7%. These results were correlated with patient demographics, p16/human papillomavirus (HPV) status and clinical outcome. There was no association between p16/HPV status and the KRAS-variant status (Fisher’s exact test, p=1.0). The KRAS-variant was associated with poor progression-free survival in patients treated with cisplatin+/-cetuximab (log-rank p=0.002) but this association was not observed in docetaxel/bortezomib treated patients (log-rank p=0.89). Conclusions: KRAS-variant is a potentially promising biomarker of poor prognosis and a predictive biomarker of cisplatin resistance in R/M HNSCC. Prospective validation is warranted. Clinical trial information: NCT00003809.
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Jauhri, Mayank, Akanksha Bhatnagar, Satish Gupta, et al. "Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing–based cohort study." Tumor Biology 39, no. 2 (2017): 101042831769226. http://dx.doi.org/10.1177/1010428317692265.
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Colorectal cancer incidences are on a rise in India. In this study, we have analyzed the mutation frequencies of six potential biomarkers, their coexistence, association with clinicopathological characteristics, and tumor location in Indian colorectal cancer patients. Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients. The mutation frequency observed in KRAS, BRAF, PIK3CA, NRAS, TP53, and APC was 35.7%, 7.1%, 16.1%, 6.3%, 39.3%, and 29.5%, respectively. The significant associations of mutations were KRAS with age less than 60 years (p = 0.041), PIK3CA with males (p = 0.032), tumor stage I–II (p = 0.013), lack of metastasis in lymph nodes (p = 0.040), NRAS with rectum (p = 0.002), and APC with T2 stage of tumor growth (p = 0.013). No single patient harbored mutations in these six genes or any five genes simultaneously. Significance was noted in coexistence of KRAS with APC (p = 0.024) and mutual exclusion of KRAS with BRAF (p = 0.029). PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 (p = 0.072). NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations. As per our knowledge, this is the first next-generation sequencing–based biomarker study in Indian colorectal cancer patients. Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease. In addition, infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis.
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Blanc, Simon, Mike Gart, Anupama Vasudevan, Justin Scott, and Fred J. Kudrik. "Comparison of molecular testing rates and biomarker positivity by histology among patients (pts) with stage IV non-small cell lung cancer (NSCLC): A quality initiative by Integra Connect PrecisionQ." JCO Oncology Practice 19, no. 11_suppl (2023): 582. http://dx.doi.org/10.1200/op.2023.19.11_suppl.582.
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582 Background: National Comprehensive Cancer Network guidelines for NSCLC recommend biomarker testing for EGFR, ALK, ROS1, BRAF, NTRK1/2/3, METex14 skipping, KRAS, RET, and ERBB2 (HER2) in advanced or metastatic NSCLC regardless of histology. We sought to understand the testing rates for these markers among pts with a squamous (S) histology compared to pts with a non-squamous (NS) histology, while also assessing positivity rates among pts based on histology by the respective biomarkers for pts with stage IV NSCLC. Methods: We used the Integra Connect PrecisionQ real-world de-identified database of over 2 million cancer pts across 500 sites of care to assess testing rates and biomarker positivity rates based on histology among adult NSCLC patients. We included 3,889 Stage IV NSCLC pts, where we conducted chart reviews, investigating testing rates across each of the biomarkers based on patient histology (group 1). In addition, we evaluated 6,303 stage IV NSCLC pts, regardless of whether we conducted chart reviews, to assess rates of positivity among the respective biomarkers (group 2). Pts included in the analysis were diagnosed on or after 1/1/2019. We assessed rates of biomarker testing in group 1 and biomarker positivity (irrespective of the type of mutation) in group 2 stratified by histology. Descriptive analyses were used and proportions were compared using a two-tailed two-sample z-test. Results: Among the Group 1 stage IV pts in the comparison of tested vs. not-testedbased on histology (N= 3889), the average age was 72.9 (median = 75), 49% were female, 81.6% were NS. We found the testing rates among S pts (N=714) vs. NS (N=3175) as follows: EGFR-S 76% vs. EGFR-NS 92%, ALK-S 77% vs. ALK-NS 92%, BRAF-S 75% vs. BRAF-NS 87%, KRAS-S 71% vs. KRAS-NS 81%, MET-S 72% vs. MET-NS 80%, RET-S 72% vs. RET-NS 79%, ROS1-S 72% vs. ROS1-NS 79%, ERBB2-S 69% vs. ERBB2-NS 76%, and NTRK-S 62% vs. NTRK-NS 68%. All comparisons were statistically significant at P < .01. Among the Group 2 stage IV pts who were tested(N = 6303), the average age was 72.6 (median = 73), 50.8% were female, 86.0% were NS. We found the positivity rates among S pts vs. NS pts as follows: EGFR-S 7.5% (N = 827) vs. EGFR-NS 19.5% (N = 4650), ALK -S 1.3% (N =837) vs. ALK-NS 3.6% (N = 5099), BRAF-S 2.8% (N = 742) vs. BRAF-NS 6.0% (N = 4399), KRAS-S 10.4% (N = 694) vs. KRAS-NS 31.1% (N=3763), MET-S 4.3 (N=645) vs. MET-NS 7.5% (N = 3537), RET-S 0.5% (N = 635) vs. RET-NS 1.4% (N= 3397), ROS1-S 0.6% (N = 629) vs. ROS1-NS 1.4% (N = 3346), ERBB2-S 2.2% (N = 504) vs. ERBB2-NS 3.8% (N = 2510), and NTRK-S 1.0% (N = 486) vs. NTRK-NS 1.5% (N = 2444). Conclusions: Our results indicate a need to increase biomarker testing among pts with S histology to be equivalent to those who were tested with a NS histology, as biomarker positivity rates present in pts with S histology warrant a molecular evaluation regardless of histology.
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Lowe, Kimberly, Xin Niu, and George Kafatos. "Trends in biomarker testing among metastatic colorectal cancer patients: A temporal description of KRAS, NRAS, and BRAF testing in the EU5." Journal of Clinical Oncology 35, no. 15_suppl (2017): e15136-e15136. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15136.
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e15136 Background: The European Medicines Agency (EMA) changed its indication language from wild-type KRAS to wild-type RAS ( KRAS and NRAS) for metastatic colorectal cancer (mCRC) patients treated with panitumumab in July 2013. The objective of this study was to describe patterns of KRAS, NRAS, and BRAF testing among mCRC patients in the EU5 (United Kingdom (U.K.), Germany, France, Italy and Spain) and to evaluate if there were demographic or clinical differences in the patients who were/were not tested. Methods: This descriptive study utilized a serial physician survey from Oncology Analyzer data (IMS Health Oncology, Fairfield, CT, USA), which provides real-world epidemiologic and clinical data. Trends in biomarker testing were evaluated by calculating the proportion of patients who were /were not tested for combinations of KRAS, NRAS, and BRAF within each of the five countries. KRAS and BRAF data were available in all countries from quarter three (Q3) 2012 to quarter two (Q2) 2015. NRAS was available in all countries from quarter 1 (Q1) 2014 to Q2 2015. Frequencies and proportions were also calculated to summarize patient demographic and clinical characteristics between groups with different testing choices. Results: The study included 32,961 mCRC patients. Prior to July 2013, most patients were tested for only KRAS. The proportions of patients tested for both KRAS and NRAS increased substantially during the period of data availability for NRAS, including < 1% to 19.1% in the U.K., 8.8% to 31.9% in France, 13.1% to 43.2% in Germany, 5.9% to 24.6% in Italy, and 8.7% to 31.4% in Spain. The proportions of patients tested for all three biomarkers also increased during the period of data availability for all three biomarkers (Q1 2014 to Q2 2015), including 2.3% to 16.4% in the U.K., 4.8% to 26.6% in France, < 1% to 2.4% in Germany, 4.2% to 22.3% in Italy, and 1.5% to 9.3% in Spain. There were few differences in patient demographic or clinical characteristics between those with different testing choices. Conclusions: This analysis provides a description of the patterns of biomarker testing using read-world data and suggests a consistent increase in testing among mCRC patients in the EU5.
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Mesti, Tanja, Marko Boc, Martina Rebersek, Zvezdana Hlebanja, Neva Volk, and Janja Ocvirk. "KRAS, NRAS and BRAF mutational status and first line treatment patterns in Slovenian population with metastatic colorectal carcinoma: Five year results." Journal of Clinical Oncology 39, no. 15_suppl (2021): e15546-e15546. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15546.
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e15546 Background: A phase IV non-interventional study was performed from 2013 till 2018 including 650 patients with primary aim to assess KRAS, NRAS and BRAF mutational status in Slovenian population with metastatic colorectal carcinoma (mCRC) suitable for first-line treatment. The evaluation of decisions for first-line treatment regarding the biomarkers status and assessing the possible impact of the time period of the biomarker status analysis report on the treatment decision were also incorporated in the analysis. The molecular analyses for KRAS and NRAS gene mutations were performed on exons 2, 3 and 4, and for BRAF gene mutations on exon 15. The first line systemic treatment options for RAS (KRAS/NRAS) wild type (wt) and mutated type (mt) mCRC subjects were as follows: chemotherapy - Fluoropyrimidine based systemic therapy combined with oxaliplatin and/or irinotecan with/without VEGF inhibitor bevacizumab and for RAS wt subjects, with/without EGFR inhibitors, cetuximab or panitumumab. Methods: To indicate the degree of certainty of KRAS, NRAS and BRAF status frequency as being wild type or mutant type 95% confidence interval was calculated. Results: The KRAS/NRAS/BRAF mutation rates were as follows - The distribution of subjects with KRAS mutated and wild-type tumors, was almost equal, 48.8% and 47.9% respectively. Eighty nine percent of the subjects had NRAS wild type tumours and 86.1% had BRAF wild type tumours. The most frequently used treatment regardless the biomarkers status and in accordance with the treatment guidelines was bevacizumab based combination therapy (53.1%). The EGFR inhibitor (cetuximab or panitumumab) based combination therapy was used in one third of mCRC subjects (30.9%), all with mCRC RAS wt. The time period from the initial presentation of the patient until the biomarker status analysis report was two weeks. Conclusions: With this study, we have proven that the distribution of the mutations in exons 2-4 of KRAS and NRAS genes and exon 15 in the BRAF gene in the Slovenian population with metastatic colorectal cancer matches historical data. Based on this, we conclude that the treatment decision in Slovenian population with metastatic colorectal carcinoma should be in the accordance with international treatment guidelines and on evidence based medicine. The molecular analysis performed at the Institute of Oncology Ljubljana was providing necessary biomarkers status report in an acceptable time that didn’t affect the treatment decision or delay the needed cancer treatment.
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Tedeschi, Antonio, Lorenz Herdeis, Valeria Santoro, et al. "Abstract A085: BI KRASmulti, a first-in-class, orally bioavailable and direct inhibitor of diverse oncogenic KRAS variants drives tumor regression in preclinical models and validates wild-type amplified KRAS as a therapeutic target." Molecular Cancer Therapeutics 22, no. 12_Supplement (2023): A085. http://dx.doi.org/10.1158/1535-7163.targ-23-a085.
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Abstract Alterations of KRAS are found in approximately one in seven of all human cancers, making KRAS one of the main oncogenic drivers in cancer. Gain-of-function missense mutations in KRAS are found in ~90% of pancreatic cancer, ~40% of colorectal cancer and ~30% of lung adenocarcinoma. In addition, focal high-level amplification of the KRAS wild-type (wt) allele, an alternative means of activating this oncoprotein, is observed in ~7% of cancers and lacks effective targeted therapies. Thus, there is an urgent need to identify effective therapies to address KRAS-driven tumors. Recently, we have reported the identification of compounds active against a broad range of oncogenic KRAS variants (KRASmulti) that selectively inactivate downstream signaling and tumor growth (Kim et al., Nature 2023). Herein we describe BI 3706674, a novel, potent and orally available small molecule inhibitor of the KRAS oncogene. BI 3706674 binds non-covalently to multiple KRAS mutant alleles, including the KRAS wt allele, in the GDP-bound state and thereby disrupts oncogenic signaling. Using several in vitro assays, we show that BI 3706674 is a) highly selective for KRAS vs HRAS or NRAS; b) blocks the interaction between KRAS mutant/wt and its guanidine exchange factor (GEF) SOS1 and c) shows potent antiproliferative activity in isogeneic cell lines that are dependent on various KRAS mutant alleles. In two large cancer cell line panels, BI 3706674 potently and selectively inhibits proliferation of KRAS mutant cancer cell lines as well as cancer cell lines with an amplification of the KRAS wt allele. Significant pharmacodynamic (PD) biomarker modulation (including inhibition of ERK1/2 phosphorylation and DUSP6 mRNA down-regulation) was observed in cell lines with a KRAS wt relative copy number (CN) &gt; 10, treated with BI 3706674. Amplification of the KRAS wt allele is most frequently observed in gastric (~5%), esophageal (~13%) and gastroesophageal junction cancers (~12%). BI 3706674 was well-tolerated and showed dose-dependent efficacy in cell line-derived and patient-derived xenograft models (CDX and PDX) of human gastric cancer with a KRAS wt CN &gt; 10. A twice daily oral dose of 30 mg/kg was sufficient to induce significant tumor regression. BI 3706674 treatment induced PD biomarker modulation (including inhibition of ERK1/2 phosphorylation, DUSP6 down-regulation, repression of the MAPK Pathway Activity Score (MPAS) signature and Ki67 reduction) in two KRAS wt amplified gastric cancer xenograft models. The depth and duration of PD biomarker responses following treatment correlated well with the doses used in the respective efficacy studies. Finally, these results support the clinical use of biomarkers such as the MPAS signature score and Ki67 to investigate treatment effects elicited by BI 3706674 in tumor biopsies. The KRASmulti inhibitor BI 3706674 is undergoing IND enabling studies and is intended to target tumors driven by KRAS wt amplifications as well as oncogenic KRAS missense mutations. Citation Format: Antonio Tedeschi, Lorenz Herdeis, Valeria Santoro, Fabio Savarese, Birgit Wilding, Matthias Treu, Julian Fuchs, Joachim Bröker, Tobias Wunberg, Michael Gmachl, Rumpel Klaus, Fiorella Schischlik, Jesse Lipp, David H. Peng, Mariah Williams, Charles Deckard, Vandhana Ramamoorthy, Joseph R. Daniele, Jaffer A. Ajani, Funda Meric-Bernstam, Christopher P. Vellano, Joseph R. Marszalek, Timothy P. Heffernan, Darryl McConnell, Mark Pearson, Norbert Kraut, Dorothea Rudolph. BI KRASmulti, a first-in-class, orally bioavailable and direct inhibitor of diverse oncogenic KRAS variants drives tumor regression in preclinical models and validates wild-type amplified KRAS as a therapeutic target [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 A085.
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Drymiotou, Stefania, Efthymia Theodorou, Kathrine Sofia Rallis, Marios Nicolaides, and Michail Sideris. "Molecular Biomarkers in Borderline Ovarian Tumors: Towards Personalized Treatment and Prognostic Assessment." Cancers 17, no. 3 (2025): 545. https://doi.org/10.3390/cancers17030545.
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Borderline Ovarian Tumours (BOTs) are a heterogenous group of ovarian neoplasms which have increased mitotic activity but lack stromal invasion. We performed a narrative review of the literature, aiming to identify prognostic molecular biomarkers that can potentially be used for treatment personalisation. We identified and discussed BRAF/KRAS, Cancer Antigen 125 (Ca 125), Calprotectin, p16ink4a, and Microsatellite instability (MSI) as the most studied biomarkers related to BOTs. Overall, BRAF and KRAS mutations are associated with earlier-stage and favourable prognosis; KRASmt may indicate extraovarian disease in serous BOT (sBOT). Ca125, the only currently clinically used biomarker, can be assessed pre-operatively and has an established role in post-operative surveillance, especially when it is raised pre-operatively or a high potential for malignant transformation is suspected post-operatively. p16ink4a expression trends could also indicate the malignant transformation of the tumour. Calprotectin has an inferior specificity to Ca125 and is not yet established as a biomarker, whilst there is very limited evidence available for MSI. As new evidence is coming along with artificial intelligence platforms, these biomarkers can be integrated and used towards the development of a precision model for treatment stratification and counselling in women diagnosed with BOTs.
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Florea, Ana, Tamer Garawin, Laura Sangaré, Michael Anthony Kelsh, and Kimberly Lowe. "An assessment of KRAS, NRAS, and BRAF testing prior to 1st line of therapy among mCRC patients treated at community cancer centers in the United States." Journal of Clinical Oncology 36, no. 4_suppl (2018): 678. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.678.
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678 Background: We sought to determine the proportion of patients with mCRC in the United States who were tested for KRAS, NRAS, and BRAF mutational status before any 1st line of therapy. Patient demographics that may influence testing, and the turnaround time between key events associated with biomarker testing and utilization of biomarker results were also assessed. Methods: The study utilized the Oncology Services Comprehensive Electronic Records (OSCER) 2.0 dataset, provided by Flatiron Health, which includes mCRC patients from community cancer centers across the United States. Biomarker results are recorded in the Flatiron Electronic Health Record when available. The proportion of patients tested or not tested for KRAS, NRAS, and BRAF mutational status before 1st line of therapy between 2013 and 2017 was calculated, as were the differences in the patient demographics. The median number of days between the date of tissue collection, the date the tissue was received by the laboratory, and the date the oncologist received the test results was calculated. Results: Of the 13,437 patients included in the analysis, the proportion of patients who were tested prior to 1st line of therapy was as follows: KRAS, 30.8%,; NRAS, 9.9%; BRAF, 11.5%. Age, insurance type, race, and presence of liver metastases were all statistically significant factors that influenced testing. Specifically, younger, commercially-insured, Caucasian patients, and those who had liver metastases were more likely to be tested. For KRAS testing, the median time between tissue collection and tissue received by the laboratory was 26 days. Receipt of the results by the oncologist took an additional median number of 27 days. Conclusions: This study found that the testing rate for these key mCRC biomarkers was less than 31% and that the median number of days to assess biomarker results was 26. Further studies conducted in various settings, such as academic cancer clinics, are needed to investigate this low proportion of testing and long time to assess results.
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Wheeler, Josh, Luka Ausec, Miha Štajdohar, Rafael Rosengarten, and Mark Uhlik. "Abstract 3313: GenialisTM Supermodel: A large molecular model enabling monotherapy and combination therapy selection in KRAS-mutated cancers." Cancer Research 85, no. 8_Supplement_1 (2025): 3313. https://doi.org/10.1158/1538-7445.am2025-3313.
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Abstract KRAS mutations drive approximately 25% of human cancers, resulting in 3.9 million new cases annually. Recently approved KRAS inhibition (KRASi) monotherapies demonstrate limited efficacy and durability. Diverse combination therapies are under investigation. This necessitates biomarker strategies for identifying patients most likely to respond to KRASi monotherapy or combination therapy.The Genialis™ Supermodel is a foundation model of cancer biology that can be used to derive novel biomarkers for diagnosis, clinical development, and treatment decision-making in oncology. Trained on nearly 1 million harmonized transcriptomic samples, this large molecular model (LMM) maps individual patient RNA-seq samples into biologically meaningful spaces defined by distinct combinations of biological signatures. Each biological subspace reflects mechanisms relevant to a specific therapeutic class. These mappings enable the selection of core biological features, which are then used in downstream machine-learning models to predict therapeutic response and stratify patients.The Supermodel captures biology linked to responses to KRASi, EGFR inhibitors, ICI (immune checkpoint inhibitors), and standard-of-care chemotherapy, among other therapeutic mechanisms, generating classifiers that predict monotherapy responses in diverse preclinical and clinical cohorts. We further demonstrate that the intersection of these individual classifiers identifies clinical contexts where monotherapy is sufficient and where combination therapies may provide additional benefit. These results refine patient stratification and guide clinical decision-making by aligning treatment selection with the underlying tumor biology and therapeutic context.The Genialis™ Supermodel establishes a novel and robust framework for precision oncology, enhancing patient stratification, optimizing clinical decision-making, and expanding opportunities for effective KRAS-driven cancer treatments. Citation Format: Josh Wheeler, Luka Ausec, Miha Štajdohar, Rafael Rosengarten, Mark Uhlik. GenialisTM Supermodel: A large molecular model enabling monotherapy and combination therapy selection in KRAS-mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3313.
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O’Byrne, Kenneth. "SC27.03 Transforming KRAS into a Clinically Relevant Biomarker." Journal of Thoracic Oncology 12, no. 1 (2017): S139—S140. http://dx.doi.org/10.1016/j.jtho.2016.11.125.
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Tsiouda, Theodora, Kalliopi Domvri, Efimia Boutsikou, et al. "Prognostic Value of KRAS Mutations in Relation to PDL1 Expression and Immunotherapy Treatment in Adenocarcinoma and Squamous Cell Carcinoma Patients: A Greek Cohort Study." Journal of Personalized Medicine 14, no. 5 (2024): 457. http://dx.doi.org/10.3390/jpm14050457.
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Background: Factors that could predict which patients will benefit from Immune Checkpoint Inhibitors (ICIs) are not fully understood. This study aimed to investigate the prognostic value of KRAS biomarker in patients with advanced non-small cell lung cancer (NSCLC) in relation to clinical characteristics, treatment response and PDL1 expression. Patients and methods: The study included 100 patients with NSCLC who received immunotherapy with or without chemotherapy as 1st line treatment. In biopsy samples, the PDL1 biomarker expression rate and somatic mutations of KRAS gene were determined. Results: The mean age of the patients was 67 ± 8 years. Patients were all male and 66% were found with adenocarcinoma whereas 34% with squamous cell carcinoma. The KRAS G12C mutation was found with the highest percentage (73%). In the Kaplan-Meier survival analysis, patients with PDL1 > 49% in combination with a negative KRAS result had a median overall survival of 40 months compared to patients with a positive KRAS result (9 months, p < 0.05). In addition, patients diagnosed with adenocarcinoma, PDL1 < 49% and negative KRAS result had a median overall survival of 39 months compared to patients with a positive result (28 months, p < 0.05). Conclusions: Our study suggests that the presence of KRAS mutations in advanced NSCLC patients has a poor prognostic value, regardless of their PDL1 expression values, after receiving immunotherapy as first-line treatment.
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Hwang, Soon Woo, Young-Seok Cho, Kim Kyeong Ok, Jae Myung Cha, and Young-Eun Joo. "Prognostic value of DNA mismatch repair status and KRAS mutations in Korean colorectal cancer patients." Journal of Clinical Oncology 36, no. 4_suppl (2018): 697. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.697.
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697 Background: The association of DNA mismatch repair (MMR) and KRAS mutation on clinical outcome of patients with colorectal cancer are frequently documented. However, development of more accurate prediction on clinical outcome using combination of both biomarkers remains a worthy area of investigation. The aim of this study was to evaluate the clinical relevance of KRAS mutation and MMR status in Korean patients with colorectal cancer (CRC). Methods: Clinical and pathological information for 1174 patients, who underwent surgery for colorectal cancer in 3 teaching hospitals from 2011 to 2013, were reviewed and recorded. Mutation analysis for exon 2 of KRAS gene was performed by Sanger sequencing. Expression of MMR proteins including MLH1 and MSH2 was evaluated by immunohistochemistry. Results: The overall frequencies of KRAS mutation was 34.9%. Mutations in KRAS codon 12 and codon 13 were detected in 26.7% and 8.2% of patients, respectively. Overall, 90 s (7.7%) tumors that had at least loss of expression for at least one MMR protein were defined as MMR protein deficient (MMR-D), and the remaining tumors were classified as MMR protein intact (MMR-I). According to KRAS mutation and MMR status, CRC was classified to 4 groups: Group 1, KRAS-mutated and MMR-I; Group 2, KRAS-mutated and MMR-D; Group 3, KRAS wild and MMR-I; and Group 4, KRAS wild and MMR-D. We found that patients in Group 4 had the best prognosis, and patients in Group 2 had the worst overall survival. KRAS mutation was independently associated with shorter time to recurrence and poorer overall survival. Conclusions: Combination status of KRAS mutation and MMR provide fundamental genetic signatures affecting tumor behavior, and may be used as a prognostic biomarker for CRC patient. These findings should be validated by further larger prospective study. [Table: see text]
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Dodin, Yasmeen. "Identification of LGR4 as a prognostic biomarker in KRAS-mutant lung adenocarcinoma: Evidence from integrated bioinformatics analysis." Medicine 102, no. 46 (2023): e36084. http://dx.doi.org/10.1097/md.0000000000036084.
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Globally, lung cancer is the leading cause of cancer-related deaths, primarily non-small cell lung cancer. Kirsten Rat Sarcoma Oncogene Homolog (KRAS) mutations are common in non-small cell lung cancer and linked to a poor prognosis. Covalent inhibitors targeting KRAS-G12C mutation have improved treatment for some patients, but most KRAS-mutant lung adenocarcinoma (KRAS-MT LUAD) cases lack targeted therapies. This gap in treatment options underscores a significant challenge in the field. Our study aimed to identify hub/key genes specifically associated with KRAS-MT LUAD. These hub genes hold the potential to serve as therapeutic targets or biomarkers, providing insights into the pathogenesis and prognosis of lung cancer. We performed a comprehensive analysis on KRAS-MT LUAD samples using diverse data sources. This included TCGA project data for RNA-seq, clinical information, and somatic mutations, along with RNA-seq data for adjacent normal tissues. DESeq2 identified differentially expressed genes (DEGs), while weighted gene co-expression network analysis revealed co-expression modules. Overlapping genes between DEGs and co-expression module with the highest significance were analyzed using gene set enrichment analysis and protein-protein interaction network analysis. Hub genes were identified with the Maximal Clique Centrality algorithm in Cytoscape. Prognostic significance was assessed through survival analysis and validated using the GSE72094 dataset from Gene Expression Omnibus (GEO) database. In KRAS-MT LUAD, 3122 DEGs were found (2131 up-regulated, 985 down-regulated). The blue module, among 25 co-expression modules from weighted gene co-expression network analysis, had the strongest correlation. 804 genes overlapped between DEGs and the blue module. Among 20 hub genes in the blue module, leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) overexpression correlated with worse overall survival. The prognostic significance of LGR4 was confirmed using GSE72094, but surprisingly, the direction of the association was opposite to what was expected. LGR4 stands as a promising biomarker in KRAS-MT LUAD prognosis. Contrasting associations in TCGA and GSE72094 datasets reveal the intricate nature of KRAS-MT LUAD. Additional explorations are imperative to grasp the precise involvement of LGR4 in lung adenocarcinoma prognosis, particularly concerning KRAS mutations. These insights could potentially pave the way for targeted therapeutic interventions, addressing the existing unmet demands in this specific subgroup.
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Kohne, Claus-Henning, Ralf Hofheinz, Laurent Mineur, et al. "Amphiregulin (AREG) expression and response to first-line panitumumab (pmab) plus FOLFIRI in metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 33, no. 3_suppl (2015): 731. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.731.
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731 Background: Biomarker analyses have shown that patients (pts) with RAS wild-type (WT) mCRC can achieve overall survival (OS) benefits with first-line pmab plus chemotherapy. Other biomarkers may exist that could optimize pt selection. Epidermal growth factor receptor ligand (eg AREG) levels have been correlated with OS during anti-EGFR therapy. Here we investigate the relationship between AREG expression and treatment outcome in a single-arm first-line mCRC study of pmab + FOLFIRI. Methods: Qualified reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays were used to measure AREG RNA expression in archival formalin-fixed, paraffin embedded tumor samples from mCRC pts in two pmab trials (STEPP and 314). The STEPP analysis was used to establish a cut-off point in AREG expression that identified the best responders. This cut-off was applied prospectively to samples previously analyzed for KRAS in the 314 trial. Using the KRASMT subgroup as a non-responding comparator, Cox proportional hazards (PH) models were used to evaluate AREG expression levels as a continuous covariate. Decision curves were used to estimate the progression-free survival (PFS) hazard ratio (HR) with increasing levels of baseline AREG expression. Results: In the 314 trial 100 pts had evaluable AREG levels. Among 50 KRAS WT pts, high AREG expression was associated with objective response (OR) (Table). The high AREG group had better PFS HRs (KRAS WT/KRAS MT: 0.30 [95% CI, 0.12–0.75]) compared with the low AREG group (PFS HR 0.49 [95% CI 0.21–1.1]). There was a significant biomarker-by-AREG expression interaction in the Cox PH model (p=0.03). Conclusions: Treatment decision curves based on the PH model suggest that most KRAS WT patients express AREG at levels where treatment benefit is predicted. Future analysis of samples from a RASWT population may provide further insights. Clinical trial information: NCT00508404. [Table: see text]
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Jeffers, Michael, Eric Van Cutsem, Alberto F. Sobrero, et al. "Mutational analysis of biomarker samples from the CORRECT study: Correlating mutation status with clinical response to regorafenib." Journal of Clinical Oncology 31, no. 4_suppl (2013): 381. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.381.
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381 Background: In the CORRECT Ph3 trial, regorafenib demonstrated significant improvement in OS and PFS vs. placebo in subjects with metastatic colorectal cancer (mCRC) who had progressed on standard therapies. An exploratory biomarker substudy was conducted on samples collected from subjects enrolled in CORRECT. Methods: DNA was isolated from archival tumor tissue and fresh baseline plasma samples that were available from 239 (31%) and 503 (66%) subjects enrolled in CORRECT, respectively. Mutations in KRAS, PIK3CA and BRAF were evaluated via BEAMing technology. Results: Mutations were readily detected in DNA isolated from both tumor and plasma samples: KRAS: 59/69%; PIK3CA: 12/17% and BRAF: 1.5/3.4%. The frequency of KRAS mutation detected in tumor samples via BEAMing (59%) was identical to the frequency determined from pre-existing “historical” KRAS mutation data that was available from 96% of the subjects enrolled in the study. Concordance among the mutations detected via BEAMing in tumor vs. plasma was 76% (KRAS), 88% (PIK3CA), and 97% (BRAF). A subset of CRC which was found to be KRAS-wildtype in DNA from archival tumor, but KRAS-mutant in DNA from fresh plasma was identified and may represent subjects whose KRAS mutational status had changed during prior therapy. Correlative subgroup analyses demonstrated that regorafenib mediated a trend for clinical benefit vs. placebo in both KRAS wildtype and mutant subgroups identified by plasma BEAMing (OS: KRAS WT, HR: 0.67, 95% CI: 0.41–1.08; KRAS mutant, HR: 0.81, 95% CI: 0.61–1.09; interaction p=0.561). Similar results were noted for PIK3CA WT/mutant subgroups (OS: WT, HR: 0.75, 95% CI: 0.57–0.99; mutant, HR: 0.84, 95% CI: 0.47–1.50; interaction p=0.723). BRAF was not analysed due to the small number of BRAF-mutant samples. Conclusions: The mutational analysis of DNA isolated from fresh plasma is feasible and robust using the BEAMing platform and may better represent the mutational status of the tumor(s) that a mCRC patient harbors at the time of enrollment than does the mutational analysis of archival primary tumor tissue. Regorafenib was associated with clinical benefit (vs. placebo) in all mutational subgroups evaluated. Clinical trial information: NCT01103323.
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Muhammad Akram. "Comprehensive Bioinformatics Analysis Reveals Kirsten Rat Sarcoma Virus Oncogene (KRAS) as the Potential Biomarker of Esophageal Carcinoma." Proceedings of Anticancer Research 8, no. 6 (2024): 209–22. http://dx.doi.org/10.26689/par.v8i6.8144.
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In the current study, the expression of the Kirsten rat sarcoma virus oncogene (KRAS) in esophageal carcinoma (ESCA) was examined for its medical and therapeutic relevance. ESCA has a 20% five-year survival rate, placing it seventh in the world in terms of overall rate of mortality. GEPIA2, UALCAN, OncoDB, cBioPortal, STRING, DAVID, and TIMER2 databases are among the bioinformatics tools used to conduct this investigation. According to the analysis, KRAS was significantly (P < 0.05) elevated in ESCA samples in contrast to normal tissues, demonstrating that it might play an active role in the proliferation of malignancies. Additionally, the study based on several clinicopathological features showed that KRAS were significantly up-regulated. ESCA patients had a worse overall survival rate (OS) as KRAS was significantly overexpressed. Besides this, the study carried out analyses of drug sensitivity, enrichment, and promoter methylation to inquire about their relationships to KRAS expression in ESCA. The KRAS mutation was demonstrated to have a significant impact on the progression of ESCA via the genetic changes that were observed using cBioPortal. In conclusion, the comprehensive analysis of the findings emphasizes the significance of KRAS up-regulation in the development of ESCA and its potential as a potential biomarker.
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Garcia-Foncillas, Jesus. "Determina KRAS: A consolidated project." Journal of Clinical Oncology 30, no. 4_suppl (2012): 428. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.428.
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428 Background: The identification of KRAS mutation status as a predictive biomarker for the activity of anti-EGFR in mCRC patients, was the start of the personalize medicine. ASCO recognized it as a major advance in 2008 and it also gave a clinical opinion so every candidate for anti-EGFR therapy should be tested for KRAS mutations. NCCN guidelines recommends to do it at the first diagnose of metastatic disease. KRAS status testing was no widely available in Spain by 2008. The project Determina KRAS was developed in order to provide access to this test throughout the country to any mCRC patient. Methods: Five well known Spanish centres were trained and provided with equipment so they could analyze KRAS status in a five working day period. First centre was initiated in July 2008, being the last one in October 2008. A validated KRAS mutation kit (DxS Ltd, Manchester, UK) which identifies 7 different somatic mutations located in codons 12 and 13 using allele-specific real-time polymerase chain reaction was used. Results: 15.330 samples from mCRC patients have been analyzed since July 2008. 53,7% samples showed wild type KRAS status. G12D mutation was the most frequent mutation observed in general (35,1% of all mutation). G13D mutation was the most frequent of the codon 13 mutation, with a 20,2% of the global mutations. Conclusions: KRAS status testing allows to patients with mCRC receive a personalized medicine. KRAS status testing is essencial for treatment decision-making in mCRC and access to it must be guaranteed for any patient. The determination of biomarkers to choose the most effective treatment for each patient will be the future of oncology. These futures assessments must be available for all patients through national Networks, as the Determina KRAS project has made with KRAS testing.
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Kim, Eejung, Xinyuan Tong, Ayushi Patel, et al. "Gene expression correlates of adagrasib response in KRASG12C mutated non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 42, no. 16_suppl (2024): 8529. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.8529.
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8529 Background: KRASG12C inhibitors such as adagrasib and sotorasib have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients develop primary or secondary resistance. A biomarker of response to KRASG12C inhibitor is needed for better patient stratification and to understand the resistance mechanism. Methods: We analyzed transcriptional correlates of adagrasib treatment outcome in 68 patients in the KRYSTAL-1 trial, a phase 1/2 clinical trial of adagrasib monotherapy in the second line and beyond treatment for NSCLC. We also treated KRAS-mutated lung cancer mouse models and organoids with a KRAS inhibitor for the long term and characterized the resistant tumors’ transcriptional profile to identify resistance mechanisms. We also performed serial gene expression analysis of KrasG12D mutated lung organoids undergoing squamous transformation to identify transcription factor involved in the resistance process. Results: In patients with lung adenocarcinoma with KRASG12C and STK11/ LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids, treated with KRAS inhibitors adagrasib and MRTX1133, respectively, reveal that tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. We identify TP63 to be a transcription factor whose expression correlated with squamous transformation. The analysis of lineage plasticity program, adagrasib resistant tumors, and p63 regulon revealed KRT6A to be a common biomarker whose expression correlated with overall survival in the KRYSTAL-1 cohort. Conclusions: KRASG12C mutated lung adenocarcinoma patients with a higher expression of squamous cell carcinoma gene expression signature respond poorly to adagrasib treatment. Expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.
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Wang, Yan, Linyan Tian, Chengming Liu, et al. "Abstract 4722: Crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors." Cancer Research 85, no. 8_Supplement_1 (2025): 4722. https://doi.org/10.1158/1538-7445.am2025-4722.
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Abstract Objective: KRAS-G12C inhibitors are promising in targeted therapeutic strategies. However, it remains uncertain to search for biological reminders of clinical outcomes and early resistance. Methods: Systematic review has been performed up to September, 2024 to evaluate treatment efficacy and beneficial patients. We constructed KEAP1 and STK11 knockout mutants with CRISPR/Cas9 technology and PD-L1 overexpression mutants with lentiviral vectors. The sensitivity of cells to different KRAS-G12C inhibitors was assessed using CCK-8 assays. Potential pathways of resistance were identified through comprehensive bioinformatics analyses. Results: 13 clinical trials with 1, 132 enrolled patients indicated remarkable clinical efficacy and benefit the senior and the female. Patients with liver and brain metastases also tends to benefit from KRAS-G12C inhibitors. KEAP1 mutation serves as a critical negative biomarker for early progression and resistance. Validation studies indicated a notable increase in IC50 values for different KRAS-G12C inhibitors after KEAP1 knockout (P &lt; 0.0001). Differentially expressed genes in KEAP1 knockout cells versus contrast groups were conducted with GO, KEGG, and Reactome pathway analyses, suggested evident enrichment in extracellular matrix organization and cell adhesion processes. In addition, STK11 mutations and an increasing PD-L1 expression level reminds of worse prognosis, despite absence of significant difference. Conclusion: This research considered KRAS-G12C inhibitors as optional therapy and selected some subgroups who are more likely gain benefits from targeted therapy. As a key adverse biomarker, KEAP1 mutation tends to affect extracellular matrix organization and cell adhesion and promotes early resistance. Citation Format: Yan Wang, Linyan Tian, Chengming Liu, Sufei Zheng, Huiyang Shi, Fang Wei, Wenxin Jiang, Yucheng Dong, Haiyan Xu, Enzhi Yin, Nan Sun, Jie He. Crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4722.
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Ogata, Misato, Hironaga Satake, Takatsugu Ogata, Yukihiro Imai, Yukimasa Hatachi, and Hisateru Yasui. "No Correlation between KRAS Status and Advanced Pancreatic Adenocarcinoma Survival." Cancer and Clinical Oncology 6, no. 2 (2017): 45. http://dx.doi.org/10.5539/cco.v6n2p45.
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Erlotinib plus gemcitabine is one of the standard chemotherapies for unresectable pancreatic cancer. Pancreatic cancer has the highest frequency of KRAS gene mutations among human cancers, and some studies suggest that KRAS status might be a predictive biomarker for anti-epidermal growth factor receptor treatment. However, the reliability of this biomarker has not been confirmed. Here, we evaluated the impact of KRAS mutations in pancreatic cancer patients treated with first line gemcitabine-based chemotherapy. 23 patients treated with gemcitabine-based chemotherapy whose KRAS status could be examined from primary or metastatic lesions were enrolled. KRAS mutations were analyzed by sequencing codons 12 and 13. We retrospectively evaluated the correlation between KRAS status, and prognosis and treatment efficacy. Patient characteristics were as follows: median age 68 years, male/female=6/17, PS 0/1=9/14, TNM stage III/IV=1/22, and gemcitabine alone/erlotinib plus gemcitabine=13/10. Among the 23 patients, KRAS codon 12 was mutated in 15, one of whom also had mutation on codon 13. Median progression-free survival (PFS) and overall survival (OS) of all patients were 4.3 months (95% confidence interval (CI): 3.1 to 5.4) and 8.1 months (95% CI: 5.9 to 10.0; events in 96%), respectively. KRAS status showed no association with PFS (p=0.310), OS (p=0.934), or the efficacy of treatment with (p=0.833) or without erlotinib (p=0.478). Thus, in this study, there was no correlation between KRAS status and the efficacy of first line chemotherapy with gemcitabine with or without erlotinib. Identification of a rationale for personalized medicine in pancreatic cancer will require further exploratory prospective studies.
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McQuitty, Elizabeth, Wei Zhang, Heather Hendrickson, et al. "Lung Adenocarcinoma Biomarker Incidence in Hispanic Versus Non-Hispanic White Patients." Archives of Pathology & Laboratory Medicine 138, no. 3 (2013): 390–94. http://dx.doi.org/10.5858/arpa.2013-0225-oa.
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Context.—Lung cancer is the leading cause of cancer deaths in the United States and worldwide. Biomarker testing is critical to personalized therapy in lung adenocarcinoma and has been extensively investigated in non-Hispanic whites, Asians, and African Americans. However, little information addresses the underlying genetic changes in lung adenocarcinoma among Hispanic patients in the United States. Objective.—To identify targetable biomarkers other than EGFR and EML4-ALK in Hispanic patients with lung adenocarcinoma. Design.—We tested DNA extracted from 85 lung adenocarcinoma specimens collected from 40 Hispanic and 43 non-Hispanic white patients for previously reported mutations in KRAS, MET, BRAF, mTOR, STAT3, JAK2, PIK3CA, AKT1 through AKT3, and PTEN with a custom Sequenom massARRAY assay (Sequenom, San Diego, California). Results.—Mutations in KRAS were identified in 11 cases (13%; 6 Hispanic [7%], 5 non-Hispanic white [6%]) and had no correlation with sex, age, or smoking history. Mutations in PIK3CA were identified in 2 of the 40 Hispanic patients (5%), including one patient (2.5%) with a concurrent KRAS mutation. The tumors were wild type for all other genes tested. Conclusions.—Targetable biomarkers other than EGFR and EML4-ALK were identified in 7 of the 40 Hispanic patients (18%) and 5 of the 43 non-Hispanic white patients (12%), suggesting a similar mutational frequency. Our highly multiplexed genotyping assay detected actionable mutations in 14% (12 of 83) more patients than would have been identified by EGFR and EML4-ALK testing alone.
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Lazzari, C., A. Verlicchi, C. Codony Servat, et al. "Biomarker driven combinations for synthetic lethal approaches in KRAS mutant (KRASm) lung adenocarcinoma (LAC)." Annals of Oncology 27 (October 2016): vi528. http://dx.doi.org/10.1093/annonc/mdw392.08.
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Polivka, Jiri, Jindra Windrichova, Martin Pesta, et al. "The Level of Preoperative Plasma KRAS Mutations and CEA Predict Survival of Patients Undergoing Surgery for Colorectal Cancer Liver Metastases." Cancers 12, no. 9 (2020): 2434. http://dx.doi.org/10.3390/cancers12092434.
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Colorectal cancer (CRC) belongs to the most common cancers. The liver is a predominant site of CRC dissemination. Novel biomarkers for predicting the survival of CRC patients with liver metastases (CLM) undergoing metastasectomy are needed. We examined KRAS mutated circulating cell-free tumor DNA (ctDNA) in CLM patients as a prognostic biomarker, independently or in combination with carcinoembryonic antigen (CEA). Thereby, a total of 71 CLM were retrospectively analyzed. Seven KRAS G12/G13 mutations was analyzed by a ddPCR™ KRAS G12/G13 Screening Kit on QX200 Droplet Digital PCR System (Bio-Rad Laboratories, Hercules, CA, USA) in liver metastasis tissue and preoperative and postoperative plasma samples. CEA were determined by an ACCESS CEA assay with the UniCel DxI 800 Instrument (Beckman Coulter, Brea, CA, USA). Tissue KRAS positive liver metastases was detected in 33 of 69 patients (47.8%). Preoperative plasma samples were available in 30 patients and 11 (36.7%) were KRAS positive. The agreement between plasma- and tissue-based KRAS mutation status was 75.9% (22 in 29; kappa 0.529). Patients with high compared to low levels of preoperative plasma KRAS fractional abundance (cut-off 3.33%) experienced shorter overall survival (OS 647 vs. 1392 days, p = 0.003). The combination of high preoperative KRAS fractional abundance and high CEA (cut-off 3.33% and 4.9 µg/L, resp.) best predicted shorter OS (HR 13.638, 95%CI 1.567–118.725) in multivariate analysis also (OS HR 44.877, 95%CI 1.59–1266.479; covariates: extend of liver resection, biological treatment). KRAS mutations are detectable and quantifiable in preoperative plasma cell-free DNA, incompletely overlapping with tissue biopsy. KRAS mutated ctDNA is a prognostic factor for CLM patients undergoing liver metastasectomy. The best prognostic value can be reached by a combination of ctDNA and tumor marker CEA.
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Ceddia, Serena, Lorenza Landi, and Federico Cappuzzo. "KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges." International Journal of Molecular Sciences 23, no. 16 (2022): 9391. http://dx.doi.org/10.3390/ijms23169391.
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KRAS is the most frequently mutated oncogene identified in human cancers. Despite the numerous efforts to develop effective specific inhibitors against KRAS, this molecule has remained “undruggable” for decades. The development of direct KRAS inhibitors, such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, was made possible with the discovery of a small pocket in the binding switch II region of KRAS G12C. However, a new challenge is represented by the necessity to overcome resistance mechanisms to KRAS inhibitors. Another area to be explored is the potential role of co-mutations in the selection of the treatment strategy, particularly in the setting of immune checkpoint inhibitors. The aim of this review was to analyze the state-of-the-art of KRAS mutations in non-small-cell lung cancer by describing the biological structure of KRAS and exploring the clinical relevance of KRAS as a prognostic and predictive biomarker. We reviewed the different treatment approaches, focusing on the novel therapeutic strategies for the treatment of KRAS-mutant lung cancers.
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Yang, Kaixin, Chengyun Li, Yang Liu, Xueyan Gu, Longchang Jiang, and Lei Shi. "Prognostic and Immunotherapeutic Roles of KRAS in Pan-Cancer." Cells 11, no. 9 (2022): 1427. http://dx.doi.org/10.3390/cells11091427.
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KRAS is one well-established tumor-driver gene associated with cancer initiation, development, and progression. Nonetheless, comparative studies of the relevance of KRAS across diverse tumors remain sparse. We explored the KRAS expression and prognostic values in diverse cancer types via multiple web-based bioinformatics tools, including cBioPortal, Oncomine, PrognoScan, Kaplan–Meier Plotter, etc. We found that KRAS is highly expressed in various malignancies compared to normal cohorts (BRCA, CHOL, ESCA, HNSC, LIHC, LUAD, LUSC, and STAD) and less expressed in COAD, KIRC, READ, and THCA than in normal samples. We observed the dysregulation of the DNA methylation of KRAS in cancers and discovered that numerous oncogenic and tumor-suppressive transcription factors bind the KRAS promoter region. Pan-cancer analysis also showed that a high level of KRAS is associated with poor outcomes. Additionally, KRAS is remarkably correlated with the level of immune cell infiltration and tumorigenic gene signatures. In conclusion, our findings reveal novel insights into KRAS expression and its biological functions in diverse cancer types, indicating that KRAS could serve as a prognostic biomarker and is associated with immune infiltrates.
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Raza, Syed Hussain, and Akbar Ali. "Clinical and Biological Impact of KRAS Overexpression in Stomach Adenocarcinoma." International Journal of General Practice Nursing 2, no. 3 (2024): 29–41. https://doi.org/10.26689/ijgpn.v2i3.8003.
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This study analyzes Kirsten rat sarcoma viral oncogene (KRAS) expression heterogeneity, and biological and clinical relevance in stomach adenocarcinoma (STAD). The study utilized various tools including UALCAN, GEPIA2, Kaplan-Meier (KM) plotter, cBioPortal, STRING, DAVID, and TIMER 2.0 to conduct this analysis. The results illustrated overexpression of KRAS in STAD and the analysis based on various clinicopathological parameters also verified overexpression of KRAS in STAD. Eventually, this overexpression was linked to poor overall survival (OS) of STAD patients. These results suggested the role of KRAS is involved in the development and progression of STAD. The study also assessed several significant correlations of KRAS expression with promoter methylation tumor purity and immune cell infiltration. Genetic alteration of KRAS revealed to have a strong role in STAD initiation. Gene enrichment analysis highlighted the enrichment of KRAS with various pathways. In conclusion, the findings illustrated the potential of KRAS as a diagnostic, prognostic, and therapeutic biomarker in STAD.
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Chun, Jung Won, Dong-eun Lee, Nayoung Han, et al. "Mutant KRAS and GATA6 Stratify Survival in Patients Treated with Chemotherapy for Pancreatic Adenocarcinoma: A Prospective Cohort Study." Cancers 17, no. 5 (2025): 896. https://doi.org/10.3390/cancers17050896.
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Background: Several pancreatic adenocarcinoma (PA) biomarkers beyond the traditional carbohydrate antigen (CA)19-9 have been identified but are lacking large-scale prospective validation. This prospective cohort study evaluated the prognostic impact of potential PA biomarkers. Methods: We enrolled 238 of 288 patients with histologically proven PA. We assessed candidate biomarkers, including CA19-9, germline BRCA1/2, and ATM mutations, as well as mutant KRAS circulating tumor DNA (ctDNA) in blood samples. Additionally, we evaluated the expression of SLC29A1 (hENT1), DCK, CES2, and GATA6. We examined the association of candidate biomarkers with progression-free survival (PFS) and overall survival (OS). Results: We analyzed biomarker efficacy in 200 (median age 65 years; 55% male) of the enrolled patients who received chemotherapy. A high mutant KRAS ctDNA concentration (hazard ratio [HR]: 1.508 and 95% confidence interval [CI]: 1.052–2.161 for PFS; HR: 1.796 and 95% CI: 1.203–2.681 for OS) and high CA19-9 level (HR: 1.647 and 95% CI: 1.177–2.306 for PFS; HR: 1.803 and 95% CI: 1.248–2.605 for OS) were associated with poor prognosis. High GATA6 RNA expression was linked to longer PFS (HR: 0.336 and 95% CI: 0.195–0.582) and OS (HR: 0.304 and 95% CI: 0.165–0.560). Conclusions: Plasma mutant KRAS ctDNA concentrations and GATA6 expression could serve as significant prognostic biomarkers in patients with PA, potentially guiding therapeutic decisions and prognostication.