Effects Of Anti-epidermal Growth Factor Receptor Research Articles

Efficacy of Magnesium Supplementation in Cancer Patients Developing Hypomagnesemia Due to Anti-EGFR Antibody: A Systematic Review.

Hypomagnesemia is a common side effect of anti-epidermal growth factor receptor (EGFR) antibodies, which may lead to arrhythmia. However, there are no evidence-based guidelines for magnesium (Mg) supplementation in the management of hypomagnesemia in patients with anti-EGFR antibodies. Therefore, we performed a systematic review to address clinical questions regarding these cancer patients. Three electronic databases were searched for articles published until June 18, 2021. The main outcomes used were "anti-EGFR antibody" and "hypomagnesemia". After screening 78 references in PubMed, Cochrane Library, and ICHUSHI-web databases, three studies were included in the review. One study revealed the effectiveness of Mg supplementation in the management of hypomagnesemia in patients receiving cetuximab. However, no studies have investigated whether correcting hypomagnesemia can lead to the suppression of arrhythmias as a clinical outcome. Weak evidence suggests that Mg supplementation, as a preventive measure when developing hypomagnesemia following the initiation of anti-EGFR antibody therapy, may prevent the worsening of hypomagnesemia, and subsequently prevent associated arrhythmia occurrence.

Altered gene expression due to aberrant DNA methylation correlates with responsiveness to anti-EGFR antibody treatment.

The cetuximab gene expression signature and DNA methylation status of colorectal cancer (CRC) are predictive of the therapeutic effects of anti‐epidermal growth factor receptor (EGFR) antibody therapy. As DNA methylation is a means of regulating gene expression, it may play an important role in the expression of cetuximab signature genes. This study aims to determine the effects of aberrant DNA methylation on the regulation of cetuximab signature gene expression. Comprehensive DNA methylation and gene expression data were retrieved from CRC patients in three tumor tissue (TT) cohorts and three normal colorectal mucosa/tumor tissue paired (NCM‐TT) cohorts. Of the 231 cetuximab signature genes, 57 exhibited an inverse correlation between the methylation of promoter CpG sites and gene expression level in multiple cohorts. About two‐thirds of the promoter CpG sites associated with the 57 genes exhibited this correlation. In all 57 gene promoter regions, the methylation levels in NCMs did not differ according to comparisons based on cetuximab signature or DNA methylation status classification of matched TTs. Thus, the altered expression of 57 genes was caused by aberrant DNA methylation during carcinogenesis. Analysis of the association between cetuximab signature or DNA methylation status and progression‐free survival (PFS) of anti‐EGFR antibody agents in the same cohort showed that DNA methylation status was most associated with PFS. In conclusion, we found that aberrant DNA methylation regulates specific gene expression in cetuximab signature during carcinogenesis, suggesting that it is one of the important determinants of sensitivity to anti‐EGFR antibody agents.

Roles of CD133 in microvesicle formation and oncoprotein trafficking in colon cancer.

Extracellular vesicles contain various cellular components that are involved in tumor growth, metastasis, and immune escape. Extracellular vesicles are classified into 2 groups, namely, exosomes and microvesicles (MV). Although the formation and roles of exosomes have been studied, the exact functions of MVs and mechanisms underlying MV release are not fully understood. We found that epidermal growth factor accelerates the release of MVs from the plasma membrane by inducing NF-κB activation and CD133 expression. The amount and sizes of budding MVs were found to be dependent on the expression level of CD133, which regulates the activities of the small guanosine 5'-triphosphatases RhoA and Rac1. CD133-containing MVs released from KRAS mutant colon cancer cells delivered KRAS mutant to adjacent nontumorigenic cells and activated KRAS downstream signaling. CD133-containing MVs were found to promote the migration and invasion of adjacent cells. CD133-containing MVs induced the development of chemoresistance by abolishing the inhibitory effects of anti-epidermal growth factor receptor (EGFR) drugs on cell proliferation and motility in colon cancer. These results suggest that CD133 acts as a novel modulator in MV release and in oncoprotein trafficking. CD133 can serve as a therapeutic target for treatment of anti-EGFR drug-resistant colon cancer.-Kang, M., Kim, S., Ko, J. Roles of CD133 in microvesicle formation and oncoprotein trafficking in colon cancer.

Immunological Effect of Anti-Epidermal Growth Factor Receptor (EGFR) Antibodies in Squamous Cell Carcinoma of the Head and Neck (HNSCC): the Present and the Future

Targeted therapy with anti Epidermal growth factor receptor (EGFR) monoclonal Antibodies (mAbs) offers the potential to improve outcomes in HNSCC. EGFR is over-expressed in 80 to 90% of HNSCC and leads to tumor cell proliferation and invasion. HNSCC is an immunogenic disease, it has a multiplicity of non-mutually exclusive mechanisms of immune suppression (e.g., reduction CD8+ cell influx and altered function of intra-tumoral CD4+ cells). Monoclonal Abs possess the potential advantage of recruiting immune effector mechanisms, such as complement-dependent cytotoxicity (CDC) and Ab-dependent cellular cytotoxicity (ADCC), as additional mechanisms of tumor cell killing. However immunotherapy with the EGFR-specific mAb Cetuximab is clinically effective in 10-20% of patients. There is a need to further understand the immunological mechanism of the mAbs to optimize the design of a target-based immunotherapy.

Pitfalls of KRAS Testing for Treating Patietns with Metastatic Colorectal Cancer

Background: KRAS testing is a critical initial step of the treatment for metastatic colorectal cancer patients. However, recent clinical trials have raised the issue of whether patient selection as determined by KRAS testing is appropriate. Method: Here, we reviewed guidelines, literatures and clinical trials to elucidate whether detection threshold of KRAS testing is appropriate. Results: It has been recommended that a detection threshold within 1–10% should be considered for RAS testing in Japan, but there is insufficient evidence for widespread adoption in the guideline. In literatures, retrospective studies have shown that high-sensitivity KRAS testing is more effective in the secondor third-line setting but no study has been conducted in the first-line setting. High-sensitivity KRAS testing in recent clinical trials has revealed undetectable mutant clones in tumors before chemotherapy. These clones have been shown to influence the outcome of second-line treatment, but there is no evidence of their influence in the first-line setting. On the other hands, there are accumulating data showing an additional effect of anti-epidermal growth factor receptor (EGFR) antibodies in patients harboring minor KRAS mutations determined by a low detection threshold of 5–10% in the first-line setting. These findings indicate that high-sensitivity KRAS testing have enabled to select super-responders, but may lead to exclusion of patients who could benefit from drug therapy. Conclusion: In order not to deprive patients of the chance to benefit from anti- EGFR antibodies, the optimal cut-off value for KRAS testing should be determined for selection of patients likely to benefit from treatment in the first-line setting.

Anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer: a meta-analysis.

To investigate the correlation between Kirsten rat sarcoma viral oncogene homolog (KRAS) status and the therapeutic effects of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC). Randomized controlled trials (RCTs) were identified and the association between KRAS mutation and clinical outcome in mCRC patients treated with anti-EGFR MoAbs was investigated. Ten RCTs were included in this meta-analysis. Progression-free survival and overall survival were used to assess the strength of the relationship between KRAS mutation and clinical outcome. In first-line treatment, survival benefit was confined to patients with wild-type KRAS. Chemotherapy regimens and angiogenesis inhibitor treatment influenced the results of the analysis. Wild-type KRAS mCRC patients did not seem to benefit from oxaliplatin-based chemotherapy (PFS: HR = 0.88, 95%CI: 0.70-1.10; OS: HR = 0.93, 95%CI: 0.82-1.04). Clinical benefit in mCRC patients was limited to therapeutic regimens which included anti-EGFR MoAbs and fluorouracil-based therapy (PFS: HR = 0.77, 95%CI: 0.69-0.86; OS: HR = 0.85, 95%CI: 0.75-0.95). When anti-EGFR MoAbs were used as second- or further-line treatment, clinical benefit was still confined to patients with wild-type KRAS. KRAS status is a potential predictive marker of clinical benefit due to anti-EGFR MoAb therapy in mCRC patients.

Risk of anti-EGFR monoclonal antibody-related hypomagnesemia: systematic review and pooled analysis of randomized studies

Introduction:The typical class side effect of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (panitumumab and cetuximab) is a cutaneous maculopapular rash, although hypomagnesemia is also described to be a frequent adverse event. The purpose of our meta-analysis is to evaluate the frequency and the relative risk of hypomagnesemia in patients treated with cetuximab or panitumumab in randomized trials.Area covered:Eligible studies included prospective randomized Phase III controlled trials in which cetuximab or panitumumab were compared with standard anti-neoplastic therapy or best supportive care. Summary incidence rates and relative risks with 95% confidence intervals were calculated.Expert opinion:The overall incidence of hypomagnesemia was 17% among the patients who received the treatment, whose risk of developing hypomagnesemia turned out to be significantly increased compared with the patients treated with control medication, with an overall relative risk of 5.83 (p < 0.00001), where 3.87 refers to cetuximab and 12.55 to panitumumab. The addition of anti-EGFR monoclonal antibodies to standard anticancer therapy showed a significantly increased risk of hypomagnesemia compared with controls. The risk seems to be even higher for panitumumab, probably correlated with the increased risk of other adverse events (e.g., diarrhea and dehydration). Hypomagnesemia does not seem to be linked with any serious complications.

The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer

BackgroundThe effect of anti-epidermal growth factor receptor (EGFR) antibodies (mAb) in metastatic colorectal cancer seems limited to KRAS wild-type (wt) tumours, but still a major fraction of KRASwt patients are nonresponders and supplementary selection criteria are needed. We investigated methodological aspects of KRAS testing and the predictive and prognostic value of KRAS status combined with three EGFR-related gene polymorphisms [single-nucleotide polymorphisms (SNPs)] in patients treated with cetuximab and irinotecan. Patients and methodsThe study included 71 patients referred to third-line cetuximab–irinotecan. Blood samples were analysed for SNPs. KRAS analysis was carried out by sequencing analysis and quantitative PCR (DxS kit) in primary tumour and distant metastases. ResultsThere was a clear correlation between KRAS status in primary tumours and metastasis. The DxS kit presented the highest sensitivity. Response was confined to KRASwt patients (40% response rate versus 0%, P < 0.1-3), which translated into a significant difference in PFS. The EGF61A>G polymorphism showed relation to clinical outcome. A combined biomarker analysis showed a 19% progression rate in KRASwt-EGF61 homozygote patients and 60% in the EGF61A/G patients (P = 0.006) and a significant increase in overall survival (17.1 versus 5.9 months, log-rank, P = 0.002). ConclusionThe combined biomarker analysis maybe an attractive approach to selection of patients for third-line treatment including anti-EGFR mAbs.

Effects of anti-epidermal growth factor (EGF) receptor antibodies and an anti-EGF receptor recombinant-ricin A chain immunoconjugate on growth of human cells.

The effects of antiepidermal growth factor (EGF) receptor monoclonal antibodies (MAbs) 528 and 225 and a 528-ricin A conjugate on the growth of normal and malignant human cells were tested in vitro. Malignant human cell lines with EGF receptor numbers ranging from 0 to 4 X 10(5) receptors/cell, human fetal fibroblasts, and normal marrow granulocyte/macrophage progenitors (CFU-gm) showed no effect when grown with 10(-12) M to 10(-7) M MAb 225 or 528. MAbs 225 and 528 and EGF also had no effect on the ability of marrow stromal cells to maintain CFU-gm viability in long-term marrow cultures. Reversible growth inhibition of A431 epidermoid and MDA-468 breast carcinoma cells with 2 and 3 X 10(6) EGF receptors/cell, respectively, was observed with both antibodies and with 10(-8) M EGF. In contrast, an immunoconjugate prepared with MAb 528 and recombinant ricin A chain (528-rRA) showed dose-dependent killing over a concentration range of 10(-12) M to 10(-8) M against cells with greater than or equal to 1.2 X 10(5) EGF receptors/cell [concentration that causes 50% inhibition of growth (IC50) values, approximately 10(-12) M to 10(-10) M]. Human fetal fibroblasts (5.6 X 10(4) EGF receptors/cell), melanoma cells without detectable EGF receptors, and human CFU-gm showed IC50 values of greater than 10(-8) M. Killing of KB epidermoid carcinoma cells and 547 ovarian carcinoma cells with 4 and 1.2 X 10(5) EGF receptors/cell by 10(-10) or 10(-11) M 528-rRA was time dependent, but cytotoxicity to 547 cells was not complete even with 48 hours of immunotoxin treatment. Cytotoxicity of 528-rRA was not enhanced by chloroquine or verapamil. In vitro, anti-EGF receptor MAbs cause reversible antiproliferative effects only against malignant cell lines with amplified EGF receptor expression. In contrast, 528-rRA shows potent, specific toxicity to cells with greater than 50,000 EGF receptors/cell. However, kinetics of cell killing with 528-rRA are protracted, suggesting that prolonged exposure may be required for in vivo antitumor effects.