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EGFR immunohistochemistry (IHC) status is not a reliable predictive marker for response to EGFR-targeted therapies. The present study compares the EGFR status at DNA, RNA and protein level. Blood samples, corresponding normal colon and colorectal cancer tissue were collected from 199 colorectal cancer (CRC) patients. EGFR status was evaluated by FI...
Citations
... EGFR is routinely analyzed by FISH. Likewise, HER2 and EGFR copy number is evaluated by EGFR/CEP7 ratio and can be affected by intra-and inter-laboratories variability [124][125][126]. The study of EGFR with other techniques such as MLPA and ddPCR are few and concern gene mutations instead of copy number variations. ...
The cytogenetic and molecular assessment of deletions, amplifications and rearrangements are key aspects in the diagnosis and therapy of cancer. Not only the initial evaluation and classification of the disease, but also the follow-up of the tumor rely on these laboratory approaches. The therapeutic choice can be guided by the results of the laboratory testing. Genetic deletions and/or amplifications directly affect the susceptibility or the resistance to specific therapies. In an era of personalized medicine, the correct and reliable molecular characterization of the disease, also during the therapeutic path, acquires a pivotal role. Molecular assays like multiplex ligation-dependent probe amplification and droplet digital PCR represent exceptional tools for a sensitive and reliable detection of genetic alterations and deserve a role in molecular oncology. In this manuscript we provide a technical comparison of these two approaches with the golden standard represented by fluorescence in situ hybridization. We also describe some relevant targets currently evaluated with these techniques in solid and hematologic tumors.
... X. maculatus is one such species where oncogenicity of a mutant EGFR (i.e., xmrk) is compromised by a regulatory allele R(Diff). EGFR is one of the most prevalent oncogenes exhibiting mutation and/or dysregulation in many varied human cancers (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53). Despite over 40 y of effort in attempting to inhibit EGFR by blocking its kinase activity, and development of four generations of small molecules, or monoclonal antibodies, success in disease control is very limited to three cancer subtypes, that is, nonsmall cell lung cancers with kinase-activating mutations in EGFR (54)(55)(56), ∼10% of metastatic colorectal cancers (57,58), and a subcategory of advanced head and neck cancers (59,60). ...
Significance
The Bateson–Dobzhansky–Muller (BDM) model describes negative epistatic interactions that occur between genes with a different evolutionary history to account for hybrid incompatibility and is a central theory explaining genetic mechanisms underlying speciation. Since the early 1900 s when the BDM model was forwarded examples of BDM incompatibility have been described in only a few nonvertebrate cases. This study reports the only vertebrate system, with clearly defined interacting loci, that supports the BDM model. In addition, this study also poses that tumorigenesis serves as a novel mechanism that accounts for postzygotic isolation.
... Therefore, there has been a growing interest in determining EGFR expression levels as a strong prognostic indicator associated with more aggressive and treatment-resistant tumors [1,3]. Several techniques such as immunohistochemistry (IHC) on tumor tissues [4], western blotting (WB) on cell lysate [5,6], immunoassay on cell lysate or patients' serum [4,7,8] have Page 4 of 36 A c c e p t e d M a n u s c r i p t 4 been adopted to evaluate EGFR expression at the DNA, RNA, and protein levels [7,9]. ...
Abstract
A novel chip format sandwich electrochemical immunoassay was developed for ultrasensitive detection of epidermal growth factor receptor (EGFR) using Fe3O4/N-trimethyl chitosan/gold (Fe3O4/TMC/Au) nanocomposite as a tracing tag to label anti-EGFR VHH antibody (or nanobody) and polythiophene (PT) as immobilization platform. The EGFR is considered as an important biomarker because its overexpression is commonly observed in many aggressive cancer types. The nano-immunoassay (combination of nanocomposite and nanobody) was performed on a commercial screen-printed platinum electrode and provided sensitivity within femtogram/milliliter levels of soluble EGFR in 25 μL samples. Furthermore, the study of long-term stability demonstrated the acceptable efficiency of this nanoimmunosensor for more than eight weeks. Apart from demonstration of using nanobodies for nano-electrochemical based immunoassays, the extremely low and clinically relevant detection limits of EGFR demonstrate the direct applicability of this nanoimmunosensor to fast and sensitive biomarker detection in clinical diagnostics.
... However, EGFR overexpression identified by immunohistochemistry was not associated with EGFR gene amplification by FISH. This apparent disconnect between the immunohistochemical and FISH results is not uncommon and may represent variation in the mechanics of EGFR kinase activity dysregulation [31]. As there was consistent expression of EGFR across all cases, our data would imply that targeted anti-EGFR therapy may be beneficial in the clinical management of basal cell carcinoma. ...
... The main research areas in this setting have focused on the role of (1) EGFR protein expression; (2) EGFR gene copy number; (3) EGFR gene mutations; (4) overexpression of EGFR ligands (such as epiregulin and amphiregulin); and (5) markers of EGFR downstream signaling [13][14][15][16][17] . ...
Colorectal cancer (CRC) is one of the most common human malignant diseases and the second leading cause of cancer-related deaths worldwide. The treatment of advanced CRC has improved significantly in recent years. With the emergence of two targeted antibodies, cetuximab (Erbitux), an anti-epidermal growth factor receptor monoclonal antibody and bevacizumab (Avastin), a vascular endothelial growth factor monoclonal antibody, the treatment of metastatic CRC has entered the era of personalized therapy. Predictive and prognostic biomarkers have, and will continue to, facilitate the selection of suitable patients and the personalization of treatment for metastatic CRC (mCRC). In this review, we will focus primarily on the important progresses made in the personalized treatment of mCRC and discuss the potentially novel predictive and prognostic biomarkers for improved selection of patients for anti-cancer treatment in the future.
... In response to this data, attention was directed toward EGFR variants, and indeed it was shown that many EGFR polymorphisms play a significant role in the development and prognosis of CRC. [21][22][23][24][25] One of these is R521K, or R497K according to an older nomenclature, which is a functional polymorphism in EGFR that arose from a G-to-A transition, resulting in an Arg to Lys substitution. Substituting arginine by lysine in codon 521 on the border between extracellular subdomains III and IV of EGFR causes a reduction in the activity of the receptor. ...
Colorectal cancer contributes heavily to cancer morbidity and mortality worldwide. Numerous therapies are currently in use, including monoclonal antibodies against cellular components involved in tumorigenesis such as epidermal growth factor receptors (EGFRs). Studies showed the polymorphism [R521K] GàA in the EGFR gene to be involved in both colorectal cancer susceptibility and clinical response to therapeutics (e.g., Cetuximab).
We aimed at uncovering allele frequencies of this polymorphism among Syrian colorectal cancer patients and healthy individuals.
Forty-seven patients with colorectal cancer were included in a case-control study along with 48 healthy subjects, all native Syrians. Individuals were genotyped using PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) and results were statistically analyzed to elucidate significant differences between the two groups.
Allele frequencies were 40.4% (G/G), 57.4% (G/A) and 2.1% (A/A) in colorectal cancer patients and 41.6% (G/G), 43.7% (G/A) and 14.5% (A/A) in healthy subjects. The A/A genotype was significantly lower in colorectal cancer patients than in the control group.
Homozygosity for the A allele is linked to reducing the risk of developing colorectal cancer in Syrian patients. The lower prevalence of (A/A) locally may predict sub-optimal rates of clinical response to Cetuximab compared with populations with higher frequencies of the A allele. Larger scale investigations are needed for a stronger conclusion.
... Although EGFR is overexpressed in up to 82% of CRCs (5) and is associated with tumor development and progression, its role is not entirely clear. EGFR amplification is correlated with but does not reliably predict EGFR overexpression (6), and EGFR mutations that occur regularly in other cancer types such as lung cancer are rare in CRC (7,6). ...
... Concerning EGFR quantification some studies suggested that increased EGFR copy number is uncommon in mCRC [27,28] although the frequency of high copy number could increase in chemorefractory patients. High copy number was shown to be linked to response to treatment by anti-EGFR antibodies [14,24]. ...
Background
The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab).Patients and methodsKRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks.ResultsSixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation.Conclusion
Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers.ClinicalTrials.gov IdentifierNCT00655499.
... However, the clinical predictive factors that indicate the response or resistance to anti-EGFR therapy should be identified before beginning such a treatment in patients with CRC to prevent drug-induced toxicity and avoid unnecessary expenses. The main research areas in this setting have been focusing on the role of (i) EGFR protein expression, (ii) EGFR gene copy number, (iii) EGFR gene mutations, (iv) overexpression of EGFR ligands (such as epiregulin and amphiregulin), (v) methylation of the EGFR promoter, and (vi) markers of EGFR downstream signaling [8,9,[23][24][25][26][27][28]. ...
KRAS and BRAF mutations lead to the constitutive activation of EGFR signaling through the oncogenic Ras/Raf/Mek/Erk pathway. Currently, KRAS is the only potential biomarker for predicting the efficacy of anti-EGFR monoclonal antibodies (mAb) in colorectal cancer (CRC). However, a recent report suggested that the use of cetuximab was associated with survival benefit among patients with p.G13D-mutated tumors. Furthermore, although the presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent CRC, it remains unknown whether patients with BRAF-mutated tumors experience a survival benefit from treatment with anti-EGFR mAb. Thus, the prognostic or predictive relevance of the KRAS and BRAF genotype in CRC remains controversial despite several investigations. Routine KRAS/BRAF screening of pathological specimens is required to promote the appropriate clinical use of anti-EGFR mAb and to determine malignant phenotypes in CRC. The significance of KRAS/BRAF mutations as predictive or prognostic biomarkers should be taken into consideration when selecting a KRAS/BRAF screening assay. This article will review the spectrum of KRAS/BRAF genotype and the impact of KRAS/BRAF mutations on the clinicopathological features and prognosis of patients with CRC, particularly when differentiating between the mutations at KRAS codons 12 and 13. Furthermore, the predictive role of KRAS/BRAF mutations in treatments with anti-EGFR mAb will be verified, focusing on KRAS p.G13D and BRAF mutations.
... Studies failed to show the relation between the EGFR expression and the clinical efficiency of the target therapy [33][34][35][36] . Such difference brought to life some explanations regarding this event, including tumor heterogeneity, low sensitivity to the method that detects EGFR and the lack of a standard methodology related to the studies 33,[37][38] . ...
... In this study, the analysis of EGFR expression did not identify a significantly higher number of lymph nodes that were compromised by neoplasm in the patients with EGFR hyperexpression. Likewise, McKay et al. 26 , Scartozzi et al. 33 , Bralet et al. 32 and Spindler et al. 38 demon-strated that EGFR hyperexpression was not significantly related to the presence of lymph node metastases. Doger et al. 37 studied 60 specimens of colorectal carcinoma and did not observe a relation between EGFR hyperexpression and the presence of lymph node, liver and distance metastases. ...
Introduction: The study of tissue immunostaining of the epidermal growth factor receptor (EGFR) may contribute with the understanding of its role in the prognosis of colorectal carcinoma. Objective: To analyze the immunohistochemical expression of EGFR in colorectal carcinoma tissues and transitional tumor-mucosa and mucosa adjacent to neoplasia, and its relation with cancer. Method: The study was conducted with 40 patients with colorectal carcinoma who had surgery with curative intent in order to analyze the immunoexpression of EGFR with anti-EGFR. We used parametric and nonparametric tests. Results: The immunohistochemical expression of EGFR in tumor samples showed a significant difference as to the level of immunostaining in tissue specimens of transitional tumor-mucosa (p=0.01) and the level of immunoreactivity in tissues of the adjacent mucosa (p=0, 04). The immunoexpression of EGFR showed no significant relation with the size of the tumor, angiolymphatic invasion, neural invasion, cellular differentiation, level of carcinoma infiltration in the intestinal wall, lymph node metastases and liver metastases. Conclusions: The EGFR showed a more intense expression in the mucosa of colorectal carcinoma than in the transitional epithelium and adjacent non-neoplastic mucosa. The immunoexpression of EGFR did not correlate with pathological parameters of colorectal carcinoma and liver metastases.
