Genetic and molecular biomarker characterization of KRAS mutant non-small cell lung carcinoma (NSCLC) tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11026-11026
Author(s):  
Li Liu ◽  
Yuan Liu ◽  
Ademi Santiago-Walker ◽  
Hong Shi ◽  
Vivian Zhang ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Direct Sequencing ◽  
Small Cell Lung Carcinoma ◽  
Plasma Samples ◽  
Ion Torrent ◽  
Protein Loss ◽  
Kras Mutations ◽  
Cell Lung Carcinoma ◽  
Mutation Status ◽  
Kras Mutation Status

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.

scholarly journals Ανίχνευση μεταλλάξεων του EGFR και KRAS σε ασθενείς με μη-μικροκυτταρικό καρκίνο του πνεύμονα και διερεύνηση της αξίας τους ως προβλεπτικών παραγόντων ανταπόκρισης στη θεραπεία

2013 ◽  
Author(s):  
Αριστέα Καλυκάκη
Keyword(s):  
Kras Mutation ◽  
Smoking History ◽  
Egfr Mutations ◽  
Front Line ◽  
Kras Mutations ◽  
Primary Tumors ◽  
Mutation Status ◽  
Kras Mutation Status ◽  
Line Chemotherapy ◽  
Exon 19

The purpose of this study was to investigate whether the EGFR and KRASmutation status are predictive factors for Greeks patients with NSCLC. Initially, wecalculated the rate and the pattern of EGFR and KRAS mutations in 639 patients withNSCLC and then we correlated the mutations status with clinicopathologicalcharacteristics, the response to 1st line chemotherapy and patients’ overall survival.We also investigated the association of EGFR mutations with the EGFR geneamplification. Finally, in a group of 25 patients the mutation status of these genes inthe primary tumors and the corresponding metastasis was evaluated.The genetic analysis performed in FFPE tissue samples of primary tumor ormetastasis. DNA was extracted using universal techniques. For mutation analysis exons18, 19, 20 and 21 of the EGFR and exon 2 of KRAS genes were sequentially amplified bypolymerase chain reaction (PCR) and subjected to direct sequencing. Finally, EGFRamplification was determined by quantitative real time PCR.Analysis of EGFR mutations was successful performed in 634 patients andmutations were detected in 100 (15.8%) of them. Activating mutations were detected in 8.4%. The most common mutations were deletions of 4-5 codons in exon 19 (del 19,71.7%, 38/53) and the missense mutation at position 858 (L858R) in exon 21 (22.6%,12/53). Also in 47 (7.4%) patients other mutations were detected in four exons ofEGFR, which have been reported previously or are new. We found that the incidenceof EGFR mutations was statistically significant in women with no smoking history andwith adenocarcinoma histology.The mutation analysis of the KRAS gene was successfully performed on 399patients and mutations detected in 20.8% of them (83/399). Especially, 92.8% of themutations were found at codon 12 and 7.2% at codon 13. KRAS mutations weresignificantly associated with smoking history with higher incidence in smokers thannonsmokers. There was also a significant association between KRAS mutations andadenocarcinoma histology.The predictive value of EGFR and KRAS mutations was examined in a subgroupof patients (n=162) with NSCLC who received chemotherapy as 1st line therapy.Patients with classical EGFR mutations had a higher probability of response (55.6%) to front-line chemotherapy as compared to those with wild type EGFR (21.8%) (p =0.023). Multivariate analysis revealed the 'classical' activating EGFR mutations as anindependent predictive factor for response to 1st line chemotherapy. There was nosignificant correlation between the EGFR or KRAS mutation status and the time totumor progression. The presence of activating EGFR but not of KRAS mutations wasassociated with a significantly higher overall survival compared to patients withoutmutations treated with platinum-based front-line chemotherapy.Epidermal growth factor receptor and KRAS mutation status was differentbetween primary tumors and corresponding metastases in 7 (28%) and 6 (24%) of the25 patients, respectively. This discrepancy was not statistically significant with theMcNemar’s test.EGFR amplification was found in 7.2% (6/83) of primary tumors. Among thepatients with EGFR gene amplification none carried KRAS mutations while 2 had EGFR exon 19 deletion.

Prognostic and predictive effects of KRAS mutation subtype in completely resected non-small cell lung cancer (NSCLC): A LACE-bio study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7007-7007 ◽  
Author(s):  
Frances A. Shepherd ◽  
Abderrahmane Bourredjem ◽  
Elisabeth Brambilla ◽  
Caroline Domerg ◽  
Jean-Yves Douillard ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Cox Model ◽  
Direct Sequencing ◽  
Disease Free Survival ◽  
Kras Mutations ◽  
Specific Amino Acid ◽  
Mutation Status ◽  
Prognostic Effect ◽  
Number Of Patients ◽  
Significant Comparison

7007 Background: We reported previously that KRAS is weakly prognostic and not significantly predictive of benefit from adjuvant chemotherapy (ACT) in NSCLC (Tsao et al. Proc ESMO 2012, Abst 4217). In colorectal cancer (CRC), KRAS mutation predicts resistance to EGFR monoclonal antibodies, but recent reports suggest that this may not be true for all mutation subtypes (De Roock et al. JAMA 2010). Smoking-related KRAS mutations in NSCLC differ from those of CRC. To explore the influence of KRAS mutation subtype, we undertook an analysis of KRAS subtype in LACE-Bio. Methods: KRAS mutation was determined in blinded fashion in 3 laboratories by direct sequencing. Exploratory analyses were performed to identify relationships between mutation status and subtype, overall (OS) and disease-free survival (DFS) using a Cox model stratified by trial and adjusted for covariates. Results: KRAS subtype was available in 1,532 patients (756 observation [OBS], 776 ACT). There were 300 mutations (275 codon 12, 24 codon 13, 1 codon 14). In the OBS arm, there was no difference in prognosis for OS for codon 12 (Hazard Ratio [HR] mutation v wild-type [WT] KRAS 1.04, CI .77-1.4) or codon 13 (HR 1.01, CI 0.47-2.17) mutations. A trend for benefit from ACT was observed in WT (HR ACT v OBS 0.89 CI 0.76-1.04, p=0.15) but not in patients with codon 12 mutations (HR 0.95, CI .67-1.35, p=0.77). In patients with codon 13 mutations, chemotherapy was deleterious (HR 5.78, CI 2.06-16.2, p<0.001), test for equality among 3 HRs p=0.002. Results were similar for DFS. Among codon 12 mutations, there was no prognostic effect based on specific amino acid substitution. Patients with G12A or G12R mutations appeared to derive greater benefit from ACT (HR 0.66 p=0.48) compared to those with G12C or G12V (HR 0.94 p=0.77) or G12D or G12S (HR 1.39 p=0.48) or WT, but the differences were not significant (comparison of 4 HRs p=0.76). Conclusions: In this study, patients with KRAS codon 13 mutations had significantly poorer outcomes with ACT. These results require further confirmation and should be interpreted with caution in view of the small number of patients with codon 13 mutations. Supported by unrestricted grants from Sanofi Aventis and LNCC.

scholarly journals A Nomogram for the Prediction of Kras Mutation in Colorectal Cancer

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 34s-34s
Author(s):  
W. Xiang ◽  
G. Cai
Keyword(s):  
Colorectal Cancer ◽  
Logistic Regression ◽  
Kras Mutation ◽  
Predictive Accuracy ◽  
Multivariate Logistic Regression Model ◽  
Cancer Center ◽  
Multivariate Logistic Regression ◽  
Kras Mutations ◽  
Mutation Status ◽  
Kras Mutation Status

Background: KRAS mutation status is crucial in treatment decisions regarding the use of EGFR tyrosine kinase inhibitors in colorectal cancer (CRC). However, genetic testing is not available for some patients, either because tissue is limited and/or tests are not routinely offered. Aim: We aimed to build a nomogram based on clinical factors for the prediction of KRAS mutations in CRC. Methods: Colorectal cancer patients who had their tumors genotyped for KRAS mutation at Fudan University Shanghai Cancer Center (FUSCC) were retrospectively analyzed. Variables of interest were integrated in a multivariate logistic regression model. Results: A total of 759 hospitalized patients were extracted from FUSCC database. KRAS mutation presented in 40.1% (309/759) cases. Multivariate logistic regression suggested that female (OR 1.47, 95% CI 1.06-2.04), mucinous histology (OR 2.04, 95% CI 1.28-3.25), right-sided tumor (OR 1.65, 95% CI 1.13-2.39) and high levels of preoperative CEA (OR 1.45, 95% CI 1.03-2.03), CA19-9 (OR 3.87, 95% CI 2.70-5.53) and albumin/globular protein (OR 2.02, 95% CI 1.33-3.06) were significantly correlated with KRAS mutation status. A nomogram was established and showed considerable discriminating accuracy (AUC 0.744, 95% CI 0.709-0.779) in this cohort. Patients with the highest score had 88.6% chance to bear a KRAS-mutant tumor. Subgroup analysis based on metastasis status revealed a sound applicability of the established nomogram both in metastatic (AUC 0.723, 95% CI 0.666-0.781) and nonmetastatic (AUC 0.753, 95% CI 0.707-0.798) CRC. Conclusion: Six simple and easy-to-collect characteristics defined a useful nomogram to predict KRAS status both in metastatic and nonmetastatic CRC with great predictive accuracy.

Prognostic and predictive effect of KRAS gene copy number and mutation status in early stage non-small cell lung cancer (NSCLC) patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21080-e21080
Author(s):  
Andrea S. Fung ◽  
Maryam Karimi ◽  
Stefan Michiels ◽  
Lesley Seymour ◽  
Elisabeth Brambilla ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Early Stage ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Kras Mutations ◽  
Mutation Status ◽  
Prognostic Effect ◽  
Early Stage Nsclc ◽  
Kras Mutation Status ◽  
Predictive Effect

e21080 Background: The prognostic and predictive role of KRAS mutations and gene copy number aberrations (CNA) in early stage NSCLC is unclear. In this study, we characterize the prognostic effect of KRAS mutation status and concomitant CN gain in early stage NSCLC, and determine the ability to predict survival benefit from adjuvant chemotherapy. We hypothesize that concomitant KRAS mutations and CN gain will be prognostic of worse survival compared to KRAS mutations alone. Methods: Clinical and genomic data from The LACE (Lung Adjuvant Cisplatin Evaluation)-BIO consortium was utilized. CNA were categorized as Gain or Neutral (Neut)/Loss; mutation status was defined as wild type (WT) or mutant (MUT). WT+Neut/Loss (reference), WT+Gain, MUT+Gain and MUT+Neut/Loss groups were compared in all patients and the adenocarcinoma subgroup. Primary endpoint was lung-cancer-specific survival (LCSS); secondary endpoints were DFS and OS. Survival curves were assessed using Kaplan-Meier and log-rank tests. Concomitant KRAS CNA and mutation status was correlated to endpoints using a Cox proportional hazards model stratified by trial and adjusted for treatment, age, gender, histology, WHO performance status, surgery type, tumor and nodal stage. A treatment-by-variable interaction was added to evaluate predictive effect. Results: 946 (399 adenocarcinoma) patients had complete KRAS mutation, CNA and clinical data: 41 (30) MUT+Gain, 145 (99) MUT+Neut/Loss, 125 (16) WT+Gain, 635 (254) WT+Neut/Loss. There was a negative prognostic effect of KRAS MUT+Neut/Loss for LCSS (HR = 1.32 [1.01-1.71]) on univariable analysis, and to a lesser extent after adjusting for covariates (HR = 1.28 [0.97-1.68]). A similar non-significant trend was observed in KRAS MUT+Gain patients for LCSS (HR = 1.34 [0.83-2.17]), DFS (HR = 1.34 [0.86-2.09]) and OS (HR = 1.59 [0.99-2.54]). There was no significant predictive effect in the overall population; however, a potential predictive effect of KRAS for OS was seen in the adenocarcinoma subgroup (interaction p = 0.046). KRAS MUT+Gain was associated with a beneficial effect of chemotherapy on DFS (HR = 0.33 [0.11-0.99], p = 0.048), with a non-significant trend also seen for LCSS (HR = 0.41 [0.13-1.33]) and OS (HR = 0.40 [0.13-1.26]). Conclusions: A small prognostic effect of KRAS mutation was identified for LCSS. A potential predictive effect of concomitant KRAS mutation status and CNA was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require further validation.

scholarly journals The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4294
Author(s):  
Sissel Gyrid Freim Wahl ◽  
Hong Yan Dai ◽  
Elisabeth Fritzke Emdal ◽  
Thomas Berg ◽  
Tarje Onsøien Halvorsen ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Clinical Characteristics ◽  
Small Cell Lung Carcinoma ◽  
Progression Free Survival ◽  
Small Cell ◽  
Prognostic Impact ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Cell Lung Carcinoma ◽  
Kras Status

Background: due to emerging therapeutics targeting KRAS G12C and previous reports with conflicting results regarding the prognostic impact of KRAS and KRAS G12C in non-small cell lung cancer (NSCLC), we aimed to investigate the frequency of KRAS mutations and their associations with clinical characteristics and outcome. Since mutation subtypes have different preferences for downstream pathways, we also aimed to investigate whether there were differences in outcome according to mutation preference for the Raf, PI3K/Akt, or RalGDS/Ral pathways. Methods: retrospectively, clinicopathological data from 1233 stage I–IV non-squamous NSCLC patients with known KRAS status were reviewed. KRAS’ associations with clinical characteristics were analysed. Progression free survival (PFS) and overall survival (OS) were assessed for the following groups: KRAS wild type (wt) versus mutated, KRAS wt versus KRAS G12C versus KRAS non-G12C, among KRAS mutation subtypes and among mutation subtypes grouped according to preference for downstream pathways. Results: a total of 1117 patients were included; 38% had KRAS mutated tumours, 17% had G12C. Among KRAS mutated, G12C was the most frequent mutation in former/current smokers (45%) and G12D in never smokers (46%). There were no significant differences in survival according to KRAS status, G12C status, among KRAS mutation subtypes or mutation preference for downstream pathways. Conclusion: KRAS status or KRAS mutation subtype did not have any significant influence on PFS or OS.

scholarly journals BIOM-06. CLINICAL AND PROGNOSTIC SIGNIFICANCE OF KRAS MUTATIONS FOR BRAIN METASTASES FROM COLORECTAL ADENOCARCINOMA IN THE UNITED STATES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii2-ii2
Author(s):  
Nayan Lamba ◽  
Timothy Smith ◽  
Bryan Iorgulescu
Keyword(s):  
Kras Mutation ◽  
Colorectal Adenocarcinoma ◽  
Mutation Testing ◽  
Newly Diagnosed ◽  
Kras Mutations ◽  
Mutation Status ◽  
Stage 4 ◽  
Brain Involvement ◽  
Colorectal Adenocarcinomas ◽  
Kras Mutation Status

Abstract BACKGROUND KRAS mutations in colorectal adenocarcinomas have been associated with metastatic involvement of the brain (BM); and predict a lack of benefit to EGFR-targeted antibodies. Herein we leverage national data to evaluate the prevalence and impact of KRAS mutations on colorectal BMs. METHODS Newly-diagnosed patients with stage 4 colorectal adenocarcinoma were identified from the National Cancer Database, comprising &gt;70% of newly-diagnosed cases in the U.S. from 2010–2016. Multivariable logistic regression was used to evaluate predictors of brain involvement, including KRAS mutation status. Overall survival (OS) was estimated with Kaplan-Meier techniques, and compared by logrank test and multivariable Cox regression. RESULTS Of 86,719 patients newly presenting with stage 4 colorectal adenocarcinoma, 1.5% (n=1,318) had BMs. 39.7% of BM cases had KRAS mutation testing, in which 57.9% (n=361) of BM cases were KRAS-mutant, as opposed to only 45.6% (n=13,259) of non-BM cases (p&lt; 0.001). Mutant KRAS persisted as independently associated with BMs (OR 1.37, 95%CI: 1.09–1.72, p=0.006) following adjustment for age at diagnosis, sex, AJCC cT and cN status, and metastatic lung, liver, or bone involvement. Overall, BM patients displayed a median OS of 5.3 months (95%CI: 4.6–6.1): 7.5 months (95%CI: 5.7–10.6) if KRAS-wildtype vs. 12.0 months (95%CI: 10.4–15.4) if KRAS-mutant (p=0.01). The improved OS associated with KRAS-mutant BMs also persisted (HR 0.63, 95%CI: 0.47–0.84, p=0.001) after adjusting for the aforementioned clinical variables, in addition to comorbidity index, chemoradiotherapy, metastasectomy, and treating hospital type. CONCLUSIONS Nationally, testing colorectal BM patients for KRAS mutation status—a predictive biomarker for EGFR-mab therapy—remains underutilized. KRAS-mutant colorectal adenocarcinomas were more likely to have metastatic brain involvement, with KRAS-wildtype BMs demonstrating significantly worse OS than KRAS-mutant BMs. Our data suggest that KRAS mutation testing is underutilized in colorectal BM patients and provides useful prognostic information.

Comparing KRAS mutation testing by pyrosequencing versus allele specific primary extension methods in colorectal cancer specimens.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14522-e14522
Author(s):  
Keeran Ravin Sampat ◽  
Nirali Patel ◽  
Allison Mary Deal ◽  
Karen E Weck ◽  
Bert H. O'Neil
Keyword(s):  
Kras Mutation ◽  
Mutational Analysis ◽  
Clinical Variable ◽  
Metastatic Colon Cancer ◽  
Kras Mutations ◽  
Mutation Status ◽  
Allele Specific ◽  
Kras Codon ◽  
Kras Mutation Status ◽  
Codon 61

e14522 Background: KRAS mutation status is an important clinical variable for targeting treatment in metastatic colon cancer. Many community practices send out mutational analysis to laboratories which utilize allele specific primer extension (ASPE) to identify mutations in only codons 12 or 13 of the KRAS gene. Our institutional molecular pathology laboratory performs pyrosequencing (PS) of KRAS codons 12, 13, and 61 which can potentially identify more KRAS mutations. We undertook this study to determine whether there were analytical differences in the results for specific mutations between these techniques. Methods: We obtained 77 sets of paraffin slides from a local practice from patients with metastatic adenocarcinoma of the colon whose KRAS mutation status had previously been analyzed by ASPE. After macrodissection for tumor enrichment, DNA was extracted from unstained paraffin slides and analyzed for KRAS codon 12, 13, and 61 mutations using the PyroMark KRAS v2.0 test. The results of KRAS testing by PS were then compared to those by ASPE. Exact 95% confidence intervals are reported. Results: None of the patients with KRAS codon 12 or 13 mutations called by ASPE (0/77, 0% [0%-4.7%]) changed to wild-type (WT) upon retesting by PS methodology. However, six patients had a discordant result between their ASPE-based testing and PS-based testing (6/77, 7.8% [2.9%-16.2%]). Two patients had differences in the amino acid (AA) at codon 12 (2/77, 2.6% [0.3%-9.1%]). Three patients were found to have a codon 61 mutation (3/77, 3.9% [0.8%-11.0%]), including two patients who were called KRAS WT by ASPE (2/30, 7% [0.8%-22%]). Finally, one patient with a call of a codon 13 mutation by ASPE changed to WT by PS (1/77, 1.3% [0.0% - 7.0%]). Conclusions: Almost 8% of patients who had KRAS testing by PS had a discrepancy in results compared with commercial ASPE testing alone. Although ASPE appears to be very accurate in detecting KRAS mutations, it missed KRAS codon 61 mutations in about 4% of the samples tested. This may have some clinical impact as we learn more about this subgroup of patients in the future.

Impact of KRAS mutational status on clinical outcomes in patients receiving capecitabine based chemotherapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 436-436
Author(s):  
Nirit Yarom ◽  
Gillian Gresham ◽  
Nana Boame ◽  
Derek J. Jonker
Keyword(s):  
Clinical Outcomes ◽  
Kras Mutation ◽  
Hazard Ratio ◽  
Prognostic Impact ◽  
Kras Gene ◽  
Kras Mutations ◽  
Mutation Status ◽  
Mutational Status ◽  
Kras Mutation Status ◽  
Line Chemotherapy

436 Background: Mutations affecting the KRAS gene are established predictive markers of outcome with anti–epithelial growth factor receptor antibodies in metastatic colorectal cancer (mCRC). The relevance of these markers for chemotherapy has not been established. This analysis was performed to assess the predictive impact of KRAS mutation status in patients receiving chemotherapy. Methods: KRAS mutational status was available for 223 patients treated for mCRC. Predictive analysis of mutational status by type of fluoropyrmidine the 1st-line regimen contained (either capecitabine [C] based chemotherapy or infusional 5Fluorouracil [I-5Fu]) for clinical outcomes: progression-free survival (PFS), time to chemotherapy resistance (TTCR) and overall survival (OS). Results: KRAS mutations were observed in 43.5% of the patients. 165 patients received I-5Fu, 44 patients received C. KRAS mutation status (wild type [WT] v mutated [MT]) had no prognostic impact for OS (hazard ratio [HR], 0.81; CI, 0.69 to 1.1 p=0.17) for PFS (hazard ratio [HR], 0.87; CI, 0.66 to 1.14 p=0.3) and TTCR (hazard ratio [HR], 0.85; CI, 0.65to 1.12 p=0.26). C based 1st-line chemotherapy vs. I- 5FU based was predictive of PFS (hazard ratio [HR], 0.52; CI, 0.37 to 0.74 p=0.0003) and TTCR (hazard ratio [HR], 0.54; CI, 0.38 to 0.75p=0.0005) and not of OS (hazard ratio [HR], 0.74; CI, 0.52 to 1.1 p=0.1). KRAS mutational status had predictive impact in patients receiving C based 1st-line chemotherapy on OS (hazard ratio [HR], 0.47; CI, 0.23 to 0.948 p<0.0001) TTCR (hazard ratio [HR], 0.49; CI, 0.25 to 0.97 p=0.0398) and was not predictive of PFS (hazard ratio [HR], 0.78; CI, 0.4 to 1.53 p=0.47) Conclusions: KRAS gene mutation status was predicitve for OS and for TTCR in patients who received C based 1st-line chemotherapy.

KRAS mutation as a prognostic factor in patients undergoing hepatic resection for metastatic colorectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 444-444
Author(s):  
Justin John Baker ◽  
Rachel Aufforth ◽  
James Todd Auman ◽  
Robert Eil ◽  
Howard L. McLeod ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Resection ◽  
Metastatic Colorectal Cancer ◽  
Kras Mutation ◽  
Tumor Biology ◽  
Disease Free Survival ◽  
Kras Mutations ◽  
Mutation Status ◽  
Cetuximab Therapy ◽  
Kras Mutation Status

444 Background: It is well known that KRAS mutations limit the efficacy of anti-EGFR therapy in patients with metastatic colorectal cancer (mCRC). However the role of KRAS mutations in patients who undergo a curative liver resection for mCRC is less clear. The purpose of our study was to evaluate the relationship between KRAS mutation status and survival in this patient population. Methods: We examined an IRB approved tissue repository and retrospective database of 129 patients from 1998-2010 who underwent curative liver resection for mCRC. Tumors were sequenced for KRAS codons 12, 13, and 61 mutations using pyrosequencing. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression method. Results: The median follow-up for our cohort was 20.4mo (0.4-112). Mean age was 61.4±12.3. Prior to surgical resection 55 (43%) patients received chemotherapy. 35 (27%) tumors were KRAS mutant (mt), 83 (64%) were wild-type (wt), and 11 (9%) were not characterized. Median OS for KRAS wt patients was 40.3mo vs. 27.1mo for KRAS mt patients (p=0.046). Median DFS for KRAS wt was 13.6mo vs. 7.7mo for KRAS mt patients (p=0.037). 8 patients received cetuximab post–operatively. Cetuximab status was unknown in 50 patients. When we excluded those treated with cetuximab, the median OS was 40mo for KRAS wt vs. 25mo for KRAS mt patients (p=0.007). There were no differences in OS or DFS in patients who received cetuximab (p=0.7). In a multivariable model with pre-operative chemotherapy (p=0.2), extent of resection (p=0.053), and cetuximab therapy (p=0.7), the presence of KRAS mutation was independently associated with poor prognosis (HR=2.7 [1.3-5.5]). Conclusions: In patients undergoing curative liver resection for mCRC, KRAS mutation status is independently predictive of a worse outcome regardless of cetuximab therapy. KRAS status may be associated with more aggressive tumor biology. Our data supports the critical need to define KRAS mutation status and to develop therapies against KRAS and its downstream effectors.

Use of RAS pathway activation or KRAS mutation status to predict cetuximab response in CRC patient-derived xenografts.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3544-3544
Author(s):  
Henry Li ◽  
Dawei Chen ◽  
Sheng Guo ◽  
Jie Cai ◽  
Yiyou Chen ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Kras Mutation ◽  
Braf V600e ◽  
Exclusion Criterion ◽  
Study Patient ◽  
Patient Stratification ◽  
Kras Mutations ◽  
Mutation Status ◽  
Ras Pathway ◽  
Kras Mutation Status

3544 Background: Cetuximab was approved for treating EGFR-expressing metastatic colorectal carcinoma (mCRC) without patient stratification. Subsequent retrospective clinical studies resulted in an exclusion criterion for patients with KRAS mutations at codons 12 and 13. However, only a fraction of patients with wtKRAS benefit from the treatment. Recent analyses indicated that patients with KRAS mutation at codon 13 can also benefit. We set out to investigate whether KRAS mutations, or any other factors, are good biomarkers for CRC-cetuximab therapy patient stratification. Methods: We have established patient derived xenografts (PDX) from treatment-naive Asian CRC patients to discover biomarker predictive of cetuximab response. We conducted a clinical trial style study (“patient avatar trial”) of cetuximab using a randomly selected cohort of 26 EGFR+ PDXs. The antitumor activities were analyzed against KRAS mutation status and a published expression-signature. Results: We identified 12/26 (~46%) as cetuximab responders and 14/26 non-responders (defined by 50% tumor growth inhibition threshold). All 14 non-responders are mutated for one or more of KRAS, BRAF (V600E), EGFR, AKT and PIK3CA oncogenes. In contrast, 5/11 responders analyzed are wild-type for all these genes. Importantly, 5/11 responders have activating KRAS mutations at codons 12/13, contradictory to the currently practiced clinical exclusion criteria, but consistent with more recent clinical findings. Most interestingly, the observed cetuximab activity in this cohort of 26 PDXs has a surprisingly strong correlation to a published RAS pathway score. Conclusions: Our results indicated strong predictive power of cetuximab-CRC-PDX trial and RAS signature, and warrant prospective clinical studies for further confirmation.

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