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.

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.

scholarly journals Discordance of KRAS Mutational Status between Primary Tumors and Liver Metastases in Colorectal Cancer: Impact on Long-Term Survival Following Radical Resection

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2148
Author(s):  
Francesco Ardito ◽  
Francesco Razionale ◽  
Lisa Salvatore ◽  
Tonia Cenci ◽  
Maria Vellone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Primary Tumor ◽  
Kras Mutation ◽  
Colorectal Tumor ◽  
Term Survival ◽  
Primary Tumors ◽  
Mutation Status ◽  
Primary Colorectal Tumor ◽  
Kras Mutation Status

If KRAS mutation status of primary colorectal tumor is representative of corresponding colorectal liver metastases (CRLM) mutational pattern, is controversial. Several studies have reported different rates of KRAS discordance, ranging from 4 to 32%. Aim of this study is to assess the incidence of discordance and its impact on overall survival (OS) in a homogenous group of patients. KRAS mutation status was evaluated in 107 patients resected for both primary colorectal tumor and corresponding CRLM at the same institution, between 2007 and 2018. Discordance rate was 15.9%. Its incidence varied according to the time interval between the two mutation analyses (p = 0.025; Pearson correlation = 0.2) and it was significantly higher during the first 6 months from the time of primary tumor evaluation. On multivariable analysis, type of discordance (wild-type in primary tumor, mutation in CRLM) was the strongest predictor of poor OS (p < 0.001). At multivariable logistic regression analysis, the number of CRLM >3 was an independent risk factor for the risk of KRAS discordance associated with the worst prognosis (OR = 4.600; p = 0.047). Results of our study suggested that, in the era of precision medicine, possibility of KRAS discordance should be taken into account within multidisciplinary management of patients with metastatic colorectal cancer.

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.

EGFR and KRAS mutation status of lung adenocarcinomas in African Americans

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11065-11065
Author(s):  
M. Reinersman ◽  
G. J. Riely ◽  
A. Nicastri ◽  
G. A. Soff ◽  
A. Getinet ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Tyrosine Kinase ◽  
Mutation Testing ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Mutation Status ◽  
Lung Adenocarcinomas ◽  
Exon 19 ◽  
White Patients

11065 Background: The 2004 discovery of the tyrosine kinase inhibitor-sensitizing mutations in the epidermal growth factor receptor (EGFR) represents a major advance in the study and management of non-small cell lung cancer. Conversely, KRAS mutations in these cancers confer resistance to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. EGFR mutations occur almost exclusively in adenocarcinoma, and are more common in never smokers, women, and people born in East Asian (compared to Whites). No comprehensive studies exist of EGFR and KRAS mutations in lung cancers from African-American patients. Methods: We collected formalin-fixed paraffin-embedded material from 121 resected lung adenocarcinomas from African-American patients for DNA extraction. EGFR exon 19 deletions and exon 21 L858R point mutations were detected by sensitive mutation-specific PCR-based methods. KRAS codon 12 and 13 mutation testing was performed by mass-spectrometry (Sequenom)-based genotyping and direct sequencing. These data were compared to Memorial Sloan-Kettering data for EGFR and KRAS mutations in all resected adenocarcinomas in white patients. Results: EGFR mutations were detected in 23 of 121 cases (19%), while KRAS mutations were found in 21 (17%). Exon 19 deletions accounted for 18 of 23 of the EGFR mutations compared to 5 EGFR L858R mutations. KRAS mutations were primarily the transversion type mutations (17 of 21). When compared to data from Memorial Sloan-Kettering for White patients (81/273, 30%), the 17% rate of KRAS mutations in lung adenocarcinomas from African-Americans was significantly lower (p=0.01). EGFR mutation status was similar between African-Americans and Whites (19% vs 18%, p=0.9) and the proportion of exon 19 deletions and L858R mutations was comparable as well. Conclusions: This is the first large series reporting results of mutation testing in lung adenocarcinoma specimens from African-Americans. African-American patients are less likely than Whites to harbor KRAS mutations in their lung adenocarcinomas. There was no significant difference in the prevalence of EGFR mutations. Since biological characteristics underlie clinical factors, these differences may help explain differences in outcomes comparing African-Americans to other groups. No significant financial relationships to disclose.

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.

Clinical and patho-genomic characteristics of concomitant mutated status of TP53, EGFR, KRAS genes in Chinese patients with resected lung adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21024-e21024
Author(s):  
Qiu Yuan ◽  
Haihong Yang ◽  
Hanzhang Chen ◽  
Qiuhua Deng ◽  
Liping Liu ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Early Stage ◽  
Clinical Stage ◽  
Chinese Patients ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Mutation Status ◽  
Tp53 Mutations ◽  
Mutation Burden ◽  
Ffpe Samples

e21024 Background: Alterations of TP53, EGFR, KRAS genes are of importance in LUAD etiology, vital prognostic markers as well as therapeutic targets as recently reported. In addition, in advanced or metastatic NSCLC, concomitant mutations of TP53 with EGFR or KRAS closely associated with prognosis and TKIs’ efficacy. While, distribution of concomitant mutations of TP53, EGFR and KRAS in early stage or resectable LUAD remained to be elucidated. Methods: 434 patients with defined pathological diagnosis of LUAD were recruited from 1st.Jan.2019-31st.Dec.2019, which made 468 FFPE blocks for the study. Histology and composition were given by authorized by pathologist. Genomic DNA from FFPE samples and peripheral blood was extracted. 636 cancer-related genes were specifically captured and sequenced by MGI-seq 2000. Association of concomitant status with clinical and genomic characteristics was further analyzed. Results: Generally, TP53, EGFR and KRAS mutation rate is 26.7%, 60.9% and 10% respectively. Among these samples, Subtypes of EGFR mutations significantly differed in between tumors rising in left and right lung (P = 0.048). Tumors with KRAS mutations occurred more easily in right lung than those with TP53 or EGFR mutations (P = 0.012, P = 0.043 respectively). In addition, histology subtype and clinical stage were closely associated with TP53, EGFR and KRAS mutation status (P < 0.001). 90 samples (19.2%) carried concomitant TP53 and EGFR mutation, 14 samples (3%) were TP53/KRAS co-mutated. LUAD samples with EGFR amplification had higher rate of concomitant TP53/EGFR mutations (RR:1.1,95%CI: 1.032 to 1.159,P = 0.0009). Moreover, KRAS G13 mutated samples more easily co-mutated with TP53 mutations compared with those with mutations in G12 loci (RR:1.33,95%CI: 1.24 to 1.37,P = 0.024). Further, samples with non-concomitant TP53 mutations had highest level of tumor mutation burden (muts/Mb) (median TMB = 9.74 vs 2.05 for TP53/EGFR/KRAS wild type, P < 0.0001). Samples with concomitant TP53/EGFR mutations and TP53/KRAS mutations displayed higher TMB level than their non-concomitant compartment (P < 0.001 and P = 0.05 respectively). Conclusions: TP53,EGFR and KRAS mutations and their concomitant mutation status displayed diverse correlation with spatial, clinical and genomic characteristics in resectable LUAD patients. This correlation may indicate complex biological heterogeneity of LUAD which may need further exploration.

KRAS gene mutation status and sensitivity to pemetrexed: A retrospective analysis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19154-e19154
Author(s):  
Manali K. Kamdar ◽  
Teresa Parent ◽  
Paul R. Walker
Keyword(s):  
Overall Survival ◽  
Maintenance Therapy ◽  
Lung Adenocarcinoma ◽  
Kras Mutation ◽  
Stage Iv ◽  
Stage Iiib ◽  
Smoking History ◽  
Kras Gene ◽  
Kras Mutations ◽  
Mutation Status

e19154 Background: KRAS is the most frequently mutated oncogene (25%) in lung adenocarcinoma. KRAS mutations are a negative prognostic factor for survival. Recent phase II trial with a MEK inhibitor has shown promising efficacy albeit at the cost of higher adverse events. Preclinical work by Moran et al showed that antifolate therapies like pemetrexed decrease KRAS gene expression in KRAS wild type and KRAS mutant but do not do so in KRAS mutant amplified cells. Targeted therapies for EGFR, ALK and ROS1 have increased the survival for lung adenocarcinoma expressing these actionable targets. No therapies are yet approved for KRAS mutant subsets. Hence therapeutic strategies that target this cohort represent an unmet medical need. Methods: We reviewed data from patients (pts) in our thoracic oncology clinic with stage IIIB and stage IV lung adenocarcinoma with KRAS mutation positive tumours who received pemetrexed either during induction or maintenance therapy. Pt characteristics including age, sex, race, smoking history, KRAS mutation subtype and overall survival were analyzed. Results: Between April 2010 and October 2012 we treated 154 pts with stage IIIB and stage IV lung adenocarcinoma. Of these 154 pts we found 34 patients with KRAS mutation positive tumours. 10 pts out of 34 pts with KRAS mutation positive tumours received pemetrexed during induction or maintenance therapy and were analyzed further. Median age 63. 60% females. 90% Caucasians. 90% were smokers. KRAS 12C mutation was found in 2 pts, KRAS 12V in 4, KRAS 12A in 3 and KRAS 13A in 1 pt. 4(40%) patients died. Median overall survival (OS) in the KRAS 12C, 12V, 12A and 13A was 14, 9.5, 10 and 12 months respectively. Conclusions: The median OS in published series is 15.4, 14, 8 and 7 months in the KRAS 12C, 12V, 12A and 13A cohorts respectively (Rosell et al). Our analysis found that pts with KRAS 12C, 12A and 13A mutation had a survival advantage with pemetrexed therapy as compared to pts with KRAS 12V mutation. Thus this retrospective study supports the concept that KRAS mutation status affects sensitivity to antifolate therapy (pemetrexed).

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.

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.

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