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Molecular biomarker profile of EGFR copy number, KRAS and BRAF mutations in colorectal carcinoma  [cached]
Rong Rong,Jamie Tull,Shengle Zhang
Journal of Solid Tumors , 2012, DOI: 10.5430/jst.v2n4p27
Abstract: Anti-EGFR therapy is approved by US Food and Drug Administration (FDA) as mono-therapy or as part of combination chemotherapy for metastatic colorectal carcinoma. Monoclonal anti-EGFR antibodies cetuximab and panitumumab have shown benefits for those patients with wild-type KRAS gene. Patients with KRAS mutation in codon 12 or 13 are unresponsive to targeted anti-EGFR therapy. Mutations of BRAF, the main downstream target gene of KRAS, also negatively impact the patients’ response to the therapy. On the contrary, EGFR gene amplification in colon cancer predicts a better response to anti-EGFR therapy. The correlation of EGFR amplification with KRAS and BRAF mutation status is not only of academic interests but also of clinical importance. Previous studies have shown that EGFR mutation is mutually exclusive with KRAS and BRAF mutations in lung cancer. However, there is limited data on colorectal cancer so far. In this study, 28 colorectal cancer samples are tested for KRAS and BRAF mutations by PCR and for EGFR gene copy number by fluorescence in situ hybridization (FISH). EGFR high-copies, KRAS mutation and BRAF mutation are found in 15 (54%), 13 (46%) and 3 (11%) samples, respectively. A mutually-exclusive pattern is seen between KRAS mutations (13 positive samples) and BRAF mutations (3 positive samples). However, high EGFR high copy number is not "mutually-exclusive" with KRAS or BRAF mutations. Six samples with KRAS mutations and 2 with BRAF mutation show "co-existing" high EGFR copy number. These account for 29% of total cases tested. Five cases are triple negative for EGFR, KRAS and BRAF alterations. The results from our study indicate that high EGFR copy number with concurrent KRAS or BRAF mutations is quite common in colon cancer and the therapeutic response with anti-EGFR agents in this patient population requires further investigation.
Heterogeneous EGFR Gene Copy Number Increase Is Common in Colorectal Cancer and Defines Response to Anti-EGFR Therapy  [PDF]
Annika ?lgars, Tuulia Avoranta, Pia ?sterlund, Minnamaija Lintunen, Jari Sundstr?m, Terhi Jokilehto, Ari Ristim?ki, Raija Ristam?ki, Olli Carpén
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099590
Abstract: Anti-EGFR therapy is commonly used to treat colorectal cancer (CRC), although only a subset of patients benefit from the treatment. While KRAS mutation predicts non-responsiveness, positive predictive markers are not in clinical practice. We previously showed that immunohistochemistry (IHC)-guided EGFR gene copy number (GCN) analysis may identify CRC patients benefiting from anti-EGFR treatment. Here we tested the predictive value of such analysis in chemorefractory metastatic CRC, elucidated EGFR GCN heterogeneity within the tumors, and evaluated the association between EGFR GCN, KRAS status, and anti-EGFR antibody response in CRC cell lines. The chemorefractory patient cohort consisted of 54 KRAS wild-type (WT) metastatic CRC patients. EGFR GCN status was analyzed by silver in situ hybridization using a cut-off value of 4.0 EGFR gene copies/cell. KRAS-WT and KRAS mutant CRC cell lines with different EGFR GCN were used in in vitro studies. The chemorefractory CRC tumors with EGFR GCN increase (≥4.0) responded better to anti-EGFR therapy than EGFR GCN (<4.0) tumors (clinical benefit, P = 0.0004; PFS, HR = 0.23, 95% CI 0.12–0.46). EGFR GCN counted using EGFR IHC guidance was significantly higher than the value from randomly selected areas verifying intratumoral EGFR GCN heterogeneity. In CRC cell lines, EGFR GCN correlated with EGFR expression. Best anti-EGFR response was seen with KRAS-WT, EGFR GCN = 4 cells and poorest response with KRAS-WT, EGFR GCN = 2 cells. Anti-EGFR response was associated with AKT and ERK1/2 phosphorylation, which was effectively inhibited only in cells with KRAS-WT and increased EGFR GCN. In conclusion, IHC-guided EGFR GCN is a promising predictor of anti-EGFR treatment efficacy in chemorefractory CRC.
EGFR gene copy number as a predictive biomarker for the treatment of metastatic colorectal cancer with anti-EGFR monoclonal antibodies: a meta-analysis  [cached]
Yang Zu-Yao,Shen Wei-Xi,Hu Xue-Feng,Zheng Da-Yong
Journal of Hematology & Oncology , 2012, DOI: 10.1186/1756-8722-5-52
Abstract: Background Epidermal growth factor receptor gene copy number (EGFR GCN) has been heavily investigated as a potential predictive biomarker for the treatment of metastatic colorectal cancer (mCRC) with anti-EGFR monoclonal antibodies (MAbs). The objective of this study was to systematically review current evidences on this issue. Methods PubMed, EMBASE, The Cochrane Library, Chinese Biomedical Literature Database, Wanfang Data, and the conference abstracts of American Society of Clinical Oncology and European Society of Medical Oncology were comprehensively searched. Studies that reported the objective response rate (ORR), progression-free survival, and/or overall survival of mCRC patients treated with anti-EGFR MAbs, stratified by EGFR GCN status, were included. The effect measures for binary outcome (response) and time-to-event outcomes (progression-free survival and overall survival) were risk difference and hazard ratio, respectively. Statistical heterogeneity among the studies was assessed by the Cochran’s Q-test and the I2 statistic. If appropriate, a quantitative synthesis of data from different studies would be conducted with a random-effects model. Results Nineteen eligible studies were identified. The criteria for increased EGFR GCN (GCN+) were highly inconsistent across different studies. The prevalence of GCN + ranged from 6.9% to 88.9%, and the difference in ORR between patients with GCN + and those with non-increased EGFR GCN (GCN-) varied from 28% to 84%. Because of the significant heterogeneity, no quantitative synthesis of data was performed. There was a general trend towards higher ORR in patients with GCN+. The difference in ORRs between patients with GCN + and those with GCN- was even greater in KRAS wild-type patients, while in KRAS mutated patients the difference often did not exist. Almost all patients with EGFR amplification responded to the treatment. However, the prevalence of EGFR amplification was generally low. Incomplete data on progression-free survival and overall survival seemingly supported the findings on ORR. Conclusions Although increased EGFR GCN is generally associated with a better outcome of anti-EGFR MAbs treatment, especially among patients with wild-type KRAS, the clinical utility of this biomarker for selecting recipients of anti-EGFR MAbs would be severely limited by the heterogeneous scoring system and the poor reproducibility of EGFR GCN enumeration due to technical reasons.
Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients
Leonie J.M. Mekenkamp, Jolien Tol, Jeroen R. Dijkstra, Inge de Krijger, Elisa Vink-Borger, Steven Teerenstra, Eveline Kamping, Eugene Verwiel, Miriam Koopman, Gerrit A. Meijer, Han J.M. van Krieken, Roland Kuiper, Cornelis J.A. Punt, Iris D. Nagtegaal, Shannon van Vliet
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-292
Abstract: Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n?=?17) or poor (n?=?17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR.Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model.Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.
Comparison of EGFR and KRAS Status between Primary Non-small Cell Lung Cancer and Corresponding Metastases: A Systematic Review and meta-analysis  [PDF]
Chengbo HAN,Huawei ZOU,Jietao MA,Yang ZHOU
Chinese Journal of Lung Cancer , 2010,
Abstract: Background and objective Epidermal growth factor receptor (EGFR) and KRAS status were particularly critical for the choice of first-line targeted therapy of non-small cell lung cancer (NSCLC), while the primary tumor and metastases might be different in the EGFR and KRAS gene status. The aim of this pooled analysis is to compare EGFR and KRAS status in matching primary NSCLC and metastases and further to guide clinical practice. Methods Systematic computerized searches of the Pubmed and Medline databases (up to May 10, 2010) meeting specified search criteria were performed, followed by a further screening according to inclusive and exclusive criteria. Results Fourteen articles were selected into the final meta-analysis with paired primary and metastatic cases of 598. Expression level of EGFR protein and mutation frequency of KRAS gene in primary tumors were higher than that in metastases, relative risk (RR)=1.13 (95%CI: 0.98-1.31, P=0.09) and RR=1.39 (95%CI: 0.95-2.03, P=0.09), respectively. EGFR gene copy number in metastases was higher than that in primary tumor, RR=0.74 (95%CI: 0.53-1.02, P=0.06). There was no statistically significant difference of EGFR mutation frequency in primary tumors and metastases (P=0.31). The discordant rate in primary and metastases was 17.09% for EGFR mutation, 27.07% for EGFR amplification, 27.84% for EGFR protein expression and 25.91% for KRAS mutation. Conclusion The systematic analysis showed that the EGFR mutation status in primary lung cancer and corresponding metastases was more stable than KRAS gene. KRAS mutation in primary lung cancerous foci seems to better reflect systemically cancerous genetic characteristics of KRAS gene. Determination of KRAS gene status based merely on metastatic foci might lead to more resistant selections of EGFR tyrosine kinase inhibitor (TKI) therapy. Combined detection of EGFR and KRAS mutation from primary NSCLC foci might serve as a better predictive biomarker for anti-EGFR targeted therapy.
Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to EGFR and KRAS Mutation Status  [PDF]
Maria Planck, Karolina Edlund, Johan Botling, Patrick Micke, Sofi Isaksson, Johan Staaf
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078614
Abstract: Introduction In lung adenocarcinoma, the mutational spectrum is dominated by EGFR and KRAS mutations. Improved knowledge about genomic and transcriptional alterations in and between mutation-defined subgroups may identify genes involved in disease development or progression. Methods Genomic profiles from 457 adenocarcinomas, including 113 EGFR-mutated, 134 KRAS-mutated and 210 EGFR and KRAS-wild type tumors (EGFRwt/KRASwt), and gene expression profiles from 914 adenocarcinomas, including 309 EGFR-mutated, 192 KRAS-mutated, and 413 EGFRwt/KRASwt tumors, were assembled from different repositories. Genomic and transcriptional differences between the three mutational groups were analyzed by both supervised and unsupervised methods. Results EGFR-mutated adenocarcinomas displayed a larger number of copy number alterations and recurrent amplifications, a higher fraction of total loss-of-heterozygosity, higher genomic complexity, and a more distinct expression pattern than EGFR-wild type adenocarcinomas. Several of these differences were also consistent when the three mutational groups were stratified by stage, gender and smoking status. Specific copy number alterations were associated with mutation status, predominantly including regions of gain with the highest frequency in EGFR-mutated tumors. Differential regions included both large and small regions of gain on 1p, 5q34-q35.3, 7p, 7q11.21, 12p12.1, 16p, and 21q, and losses on 6q16.3-q21, 8p, and 9p, with 20-40% frequency differences between the mutational groups. Supervised gene expression analyses identified 96 consistently differentially expressed genes between the mutational groups, and together with unsupervised analyses these analyses highlighted the difficulty in broadly resolving the three mutational groups into distinct transcriptional entities. Conclusions We provide a comprehensive overview of the genomic and transcriptional landscape in lung adenocarcinoma stratified by EGFR and KRAS mutations. Our analyses suggest that the overall genomic and transcriptional landscape of lung adenocarcinoma is affected, but only to a minor extent, by EGFR and KRAS mutation status.
EGFR Gene Copy Number as a Prognostic Marker in Colorectal Cancer Patients Treated with Cetuximab or Panitumumab: A Systematic Review and Meta Analysis  [PDF]
Zheng Jiang, Chunxiang Li, Fuyuan Li, Xishan Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056205
Abstract: Background The epidermal growth factor receptor (EGFR) gene copy number (GCN) has been previously demonstrated to correlate with the clinical outcome of colorectal cancer (CRC) treated with anti-EGFR monoclonal antibodies (mAbs), although it remains controversial. We conducted a systematic review and meta-analysis to assess EGFR GCN as a potential biomarker of survival for patients with advanced CRC receiving treatment with anti-EGFR mAbs. Methods We systematically identified articles investigating EGFR GCN by fluorescent or chromogenic in situ hybridization or other detection techniques in patients with metastatic CRC treated with panitumumab or cetuximab, (last search: 10 August 2012). Eligible studies had to report on overall survival (OS), progression-free survival (PFS) or time-toprogression (TTP), stratified by EGFR GCN. Summary hazard ratios (HRs) were calculated using random-effects models. Results Among 13 identified studies, 10 (776 patients, 302 with increased GCN), 8 (893 patients, 282 with increased GCN) and 3 (149 patients, 66 with increased GCN) were eligible for the OS, PFS and TTP meta-analyses, respectively. Increased EGFR GCN was associated with increased OS (HR = 0.62; 95% CI 0.50–0.77; P<0.001), PFS (HR = 0.65; 95% CI 0.47–0.89; P = 0.008) but not TTP (HR = 0.71; 95% CI 0.44–1.14; P = 0.157). It was also shown that EGFR GCN is independent of other factors such as KRAS status. Among those populations received second-line or higher treatment, increased EGFR GCN was strongly associated with improved survival (for OS, HR = 0.60; 95% CI 0.47–0.75; P<0.001; for PFS, HR = 0.59; 95% CI 0.47–0.75; P<0.001), whereas it did not influence survival in patients that received first-line therapy. Conclusion Among the anti-EGFR-treated patients, increased EGFR GCN appears to be associated with improved survival outcomes. The effect on survival appears to be related to patients receiving the line of treatment.
EGFR and KRAS Gene Mutations in 754 Patients with Resectable Stage I-IIIa Non-small Cell Lung Cancer and Its Clinical Significance  [PDF]
Jing ZHAO, Jie GAO, Liping GUO, Xiaoxu HU, Qi LIU, Jinyin ZHAO, Licheng LIU, Jun JIANG, Mengzhao WANG, Zhiyong LIANG, Yan XU, Minjiang CHEN, Li ZHANG, Longyun LI, Wei ZHONG
- , 2017, DOI: : 10.3779/j.issn.1009-3419.2017.09.05
Abstract: Background and objective Epidermal growth factor receptor (EGFR) and KRAS gene are important driver genes of non-small cell lung cancer (NSCLC). The studies are mainly focused on detection of EGFR gene for advanced NSCLC, and the mutation feature of EGFR and KRAS gene in early NSCLC tissue is unknown. This study aims to investigate the mutations of EGFR and KRAS gene in NSCLC, and the relationship between the genotype and clinicopathologic features. Methods The hotspot mutations in EGFR and KRAS gene in 754 tissue samples of stage I-IIIa NSCLC from Department of Pathology, Peking Union Medical College Hospital were detected by modified amplification refractory mutation system (ARMS) real-time PCR kit, and analyzed their correlation with clinical variables. Results The hotspot mutation rates in EGFR and KRAS were 34.5% and 13.1% respectively, and there were EGFR-KRAS double mutations in 3 samples. The mutation rate of EGFR was higher in females than that in males (39.5% vs 29.4%, P=0.076), significantly increased in adenocarcinomas (38.7%) compared to that in the other forms of NSCLC (P<0.01), but still lower than that reported in some Asian studies of advanced adenocarcinoma (-50%). Meanwhile, the mutation rate of KRAS was remarkably higher in males than that in females (16.6% vs 9%, P=0.048), increased in adenocarcinomas compared to that in the other forms of NSCLC, but the difference was not significant (P=0.268). Samples harbored EGFR mutation were younger than those harbored KRAS mutation (P=0.031,5), and had significant difference in gender between the two groups (P<0.01). Conclusion The mutation rate of EGFR in stag I-IIIa NSCLC patients was lower than that in advanced NSCLC patients. And the percentage of the NSCLC patients with EGFR-KRAS double mutations is 0.9%.
PIK3CA Mutations Frequently Coexist with EGFR/KRAS Mutations in Non-Small Cell Lung Cancer and Suggest Poor Prognosis in EGFR/KRAS Wildtype Subgroup  [PDF]
Lei Wang, Haichuan Hu, Yunjian Pan, Rui Wang, Yuan Li, Lei Shen, Yongfu Yu, Hang Li, Deng Cai, Yihua Sun, Haiquan Chen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088291
Abstract: Purpose PIK3CA gene encoding a catalytic subunit of the phosphatidylinositol-3-kinase (PI3K) is mutated and/or amplified in various neoplasia, including lung cancer. Here we investigated PIK3CA gene alterations, the expression of core components of PI3K pathway, and evaluated their clinical importance in non-small cell lung cancer (NSCLC). Materials and methods Oncogenic mutations/rearrangements in PIK3CA, EGFR, KRAS, HER2, BRAF, AKT1 and ALK genes were detected in tumors from 1117 patients with NSCLC. PIK3CA gene copy number was examined by fluorescent in situ hybridization and the expression of PI3K p110 subunit alpha (PI3K p110α), p-Akt, mTOR, PTEN was determined by immunohistochemistry in PIK3CA mutant cases and 108 patients without PIK3CA mutation. Results PIK3CA mutation was found in 3.9% of squamous cell carcinoma and 2.7% of adenocarcinoma. Among 34 PIK3CA mutant cases, 17 tumors harbored concurrent EGFR mutations and 4 had KRAS mutations. PIK3CA mutation was significantly associated with high expression of PI3K p110α (p<0.0001), p-Akt (p = 0.024) and mTOR (p = 0.001), but not correlated with PIK3CA amplification (p = 0.463). Patients with single PIK3CA mutation had shorter overall survival than those with PIK3CA-EGFR/KRAS co-mutation or wildtype PIK3CA (p = 0.004). A significantly worse survival was also found in patients with PIK3CA mutations than those without PIK3CA mutations in the EGFR/KRAS wildtype subgroup (p = 0.043) Conclusions PIK3CA mutations frequently coexist with EGFR/KRAS mutations. The poor prognosis of patients with single PIK3CA mutation in NSCLC and the prognostic value of PIK3CA mutation in EGFR/KRAS wildtype subgroup suggest the distinct mutation status of PIK3CA gene should be determined for individual therapeutic strategies in NSCLC.
Molecular Markers for the Prediction of Anti-EGFR Monoclonal Antibody Treatment Efficacy in Metastatic Colorectal Cancer  [PDF]
Cheng-Bo Han, Jie-Tao Ma, Fan Li, Hua-Wei Zou
Journal of Cancer Therapy (JCT) , 2011, DOI: 10.4236/jct.2011.25090
Abstract: The implementation of individualized targeted therapy for metastatic colorectal cancer (mCRC), in addition to standard chemotherapeutic regimens, currently is a topic under debate. Approximately 35% - 45% of mCRC patients exhibit mutated KRAS, which is considered to be an independent predictor of poor response to treatment with epidermal growth factor receptor (EGFR) monoclonal antibody. However, only about 50% of patients with wild-type KRAS respond to anti-EGFR therapy. Two major EGFR-dependent signaling pathways, RAS-RAF-MAPK and PI3K-PTEN-AKT, may be involved in the poor response to anti-EGFR. Increased EGFR gene copy number as detected by fluorescence in situ hybridization, but not increased EGFR protein expression, correlates with efficacy of anti-EGFR treatment. The identification of mutations in BRAF and PIK3CA (exon 20) and deletions in PTEN also may help clinicians screen for anti-EGFR resistance in mCRC patients with wild-type KRAS. To guide health professionals through the realm of individualized targeted therapies for mCRC, we review recent progress on identifying negative predictors and prognostic markers of anti-EGFR treatment efficacy.
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