epidermal-growth-factor and Rectal-Neoplasms

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are often overexpressed in colorectal cancer and are associated with inferior outcomes. Based on successful randomized phase III trials, anti-EGFR and anti-VEGF therapeutics have entered clinical practice. Cetuximab (Erbitux), an EGFR-specific antibody, is currently approved in the United States in combination with irinotecan (Camptosar) for patients with metastatic colorectal cancer refractory to irinotecan or as a single agent for patients unable to tolerate irinotecan-based therapy. In retrospective analyses, patients with EGFR-expressing rectal cancer undergoing neoadjuvant radiation therapy had a significantly inferior disease-free survival and lower rates of achieving pathologic complete response. Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy seen in preclinical models, there is a strong rationale to combine cetuximab with neoadjuvant radiation therapy and chemotherapy in rectal cancer. Bevacizumab (Avastin), a VEGF-specific antibody, was the first antiangiogenic agent to be approved in the United States for use in combination with standard chemotherapy in the first- and second-line of treatment in metastatic colorectal cancer. VEGF-targeted therapy may lead to indirect killing of cancer cells by damaging tumor blood vessels, and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade can also "normalize" tumor vasculature, thereby leading to greater tumor oxygenation and drug penetration. This review will address completed and ongoing trials that have established and continue to clarify the effects of these agents in rectal cancer.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Camptothecin; Cetuximab; Drug Delivery Systems; Epidermal Growth Factor; Erlotinib Hydrochloride; Gefitinib; Humans; Irinotecan; Neoadjuvant Therapy; Quinazolines; Rectal Neoplasms; Vascular Endothelial Growth Factor A

The key pro-proliferative pathway, based on EGFR-KRAS/BRAF-myc, is seen as the main goal of personalized therapy in rectal cancer. The objective of the study is to assess the EGFR immunoreactivity in rectal cancer and to estimate its relationship with the clinical outcome, especially as a predictor of poor outcomes. Patients: applying exclusion criteria, 102 patients with stage I-IV rectal cancer, who had undergone scheduled surgery during the period 2005-2011, were included in the study. There was a follow-up study with a span of 5 years from the date of the surgery. Immunohistochemistry using EGFR (EGFR Ab10, Clone111.6) was performed to detect an overexpression of the targeted receptor. Digital analysis of positive reactions of membranes was performed utilizing VisiopharmTM. The degree of EGFR intensity (log OR 0.854, OR 2.35, 95% Cl: 1.14-4.85, p = 0.021) is a significant factor in the prognosis of death within 2 years of surgery. The OS curve showed a significant decrease after 40 months from the date of surgery in the cases where EGFR had a high expression. The ROC curve for the cancer stage, according to the UICC classification and EGFR expression, in order to predict a 2-year RFS, reached a high specificity value (ROC = 0.81, p = 0.0408). Immunohistochemical EGFR expression is inexpensive, specific and broadly available.

Topics: Epidermal Growth Factor; ErbB Receptors; Follow-Up Studies; Humans; Prognosis; Rectal Neoplasms

Cetuximab has shown significant clinical activity in metastatic colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response in locally advanced rectal cancer patients in recent phase I/II trials. We evaluated functional germline polymorphisms of genes involved in epidermal growth factor receptor pathway, angiogenesis, antibody-dependent cell-mediated cytotoxicity, DNA repair, and drug metabolism, for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation.. 130 patients (74 men and 56 women) with locally advanced rectal cancer (4 with stage II, 109 with stage III, and 15 with stage IV, 2 unknown) who were enrolled in phase I/II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was done by using PCR-RFLP assays. Fisher's exact test was used to examine associations between polymorphisms and complete pathologic response (pCR) that was determined by a modified Dworak classification system (grade III vs. grade IV: complete response).. Patients with the epidermal growth factor (EGF) 61 G/G genotype had pCR of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) in patients homozygous for the A/A allele (P < 0.001). In addition, this association between EGF 61 G allele and pCR remained significant (P = 0.019) in the 59 patients with wild-type KRAS.. This study suggested EGF A+61G polymorphism to be a predictive marker for pCR, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Combined Modality Therapy; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Mutation; Neoadjuvant Therapy; Polymorphism, Genetic; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Rectal Neoplasms

Besides current clinicopathologic staging system extensively used in clinic, more information of molecular staging is need for more accurate staging of colorectal cancer (CRC). This study was to evaluate the prognostic value of metastasis-related tumor markers in CRC.. The expression of CD44v6, matrix matalloproteinase-2 (MMP-2), cyclooxygenase-2 (COX-2), epidermal growth factor (EGF), epidermal growth factor receptor (EGFR) and vascular epidermal growth factor (VEGF) in a tissue microarray containing 95 specimens of CRC were detected by immunohistochemistry (IHC). The correlations of these tumor markers to the prognosis of CRC patients were analyzed.. In patients with Dukes' A/B disease, the 5-year recurrence rates were significantly higher in CD44v6-, EGF-and EGFR-positive groups than in negative groups (30.9% vs. 8.3%,P=0.045; 38.1% vs. 8.8%, P=0.022; 27.5% vs. 11.8%, P=0.047, respectively). In patients with Dukes' C disease, the 5-year recurrence rates were significantly higher in MMP-2-, COX-2-and VEGF-positive group than in negative groups (73.3% vs. 37.5%, P=0.045; 69.2% vs. 25.0%, P=0.017; 62.5% vs. 25.0%, P=0.03, respectively). In patients with Dukes' A/B disease, there were a significantly higher 5-year recurrence rate and a lower 5-year survival rate in those with more than three positive markers than in those with 1-3 positive markers (P=0.019, P=0.03). However, there was no significant difference in patients with Dukes' C disease in such condition.. Over-expression of CD44v6, EGF and EGFR are related to poor prognosis of Dukes' A/B CRC, while over-expression of MMP-2, COX-2 and VEGF are related to poor prognosis of Dukes' C CRC. For patients with Dukes' A/B CRC, the more positive markers, the higher 5-year recurrence rate and the poorer 5-year survival.

Topics: Adult; Aged; Biomarkers, Tumor; Colonic Neoplasms; Cyclooxygenase 2; Epidermal Growth Factor; ErbB Receptors; Female; Follow-Up Studies; Humans; Hyaluronan Receptors; Male; Matrix Metalloproteinase 2; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Rectal Neoplasms; Survival Rate; Vascular Endothelial Growth Factor A; Young Adult

S100A6 and S100A4, two of S100 protein family, have been suggested to be associated with cancer tumorigenesis and metastasis. The aim of this study was to evaluate the expression levels of S100A6 and S100A4 in matched samples of primary human colorectal adenocarcinomas (T), adjacent normal colorectal mucosa (N) and liver metastases (M). This gave us the advantage of directly comparing levels of S100A6 and S100A4 expression within the same genetic background.. In matched samples of N, T and M from 10 colorectal adenocarcinoma patients, expressions of S100A6 and S100A4 were studied by Western blot and immunohistochemical analyses using specific antibodies against each protein.. The expression levels of S100A6 were significantly higher in T than in N (p < 0.05), while those of S100A4 showed no difference between T and N. There were no significant differences in the expression levels of S100A6 or S100A4 between M and T. Similar results were obtained by immunohistochemical analysis. Moreover, S100A6 was stained more intensely in invading fronts than in central portions of both T and M.. The observed differential expression of S100A6 and S100A4 suggests that S100A6, rather than S100A4, is associated with human colorectal adenocarcinoma tumorigenesis and invasion/metastasis.

Topics: Adenocarcinoma; Aged; Cell Cycle Proteins; Chromosome Mapping; Chromosomes, Human, Pair 1; Colonic Neoplasms; Epidermal Growth Factor; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Rectal Neoplasms; S100 Calcium Binding Protein A6; S100 Calcium-Binding Protein A4; S100 Proteins

The expression of S100A6 (also known as Calcyclin/2A9/ 5B10/PRA) in surgically resected human colorectal adenocarcinomas was examined to investigate whether S100A6 plays a role in the malignancy of human tumor cells. Western blot analysis using the lysates from colorectal adenocarcinomas and adjacent normal mucosa from 10 patients revealed that the average S100A6 level of adenocarcinomas was significantly higher (about 2.4-fold) than that of normal mucosa. Immunohistochemical analysis using formalin-fixed paraffin-embedded surgical specimens and monoclonal anti-S100A6 antibody (mAbA6) demonstrated that 2(5%) of 42 normal mucosa and 6 (46%) of 13 adenoma specimens were mAbA6-positive and showed granular staining localized at the supranuclear regions of epithelial cells, whereas 23 (55%) of 42 adenocarcinomas and 13 (100%) of 13 carcinoma cells that metastasized to the liver were mAbA6-positive and showed diffuse cytoplasmic staining. A significant correlation between S100A6 expression and Dukes' tumor stage or lymphatic permeation but not with other clinicopathological factors was shown. S100A6 was stained more intensely in peripheral portions than in central portions of adenocarcinomas, whereas Ki-67 (a growth marker) was stained equally in these two portions. These results suggest that S100A6 may be involved in the progression and invasive process of human colorectal adenocarcinomas.

Topics: Adenocarcinoma; Adenoma; Blotting, Western; Cell Cycle Proteins; Colonic Neoplasms; Colorectal Neoplasms; Epidermal Growth Factor; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Male; Middle Aged; Neoplasm Staging; Rectal Neoplasms; S100 Calcium Binding Protein A6; S100 Proteins

Membrane extracts of surgically resected colorectal cancer and nearby non-cancerous tissues were prepared and the expression of epidermal growth factor receptor (EGF-R) was examined by 125I-EGF binding assay. Scatchard analysis indicated that a single class of EGF-R was present in the cancer as well as the non-cancerous tissues. EGF-R was found over-expressed in cancer (38.07 +/- 4.75 fmol/mg protein) as compared to that in the non-cancerous tissue (29.31 +/- 1.64 fmol/mg protein) (P < 0.05). However, the difference in binding affinities of EGF-R in the cancer and non-cancerous tissues was not statistically significant. The results suggest an important role of an autocrine/paracrine loop of growth regulation in colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Cell Membrane; Colonic Neoplasms; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Male; Middle Aged; Rectal Neoplasms

A specific two-site ELISA for human epidermal growth factor (hEGF) has been used to measure urinary hEGF/creatinine ratios in 30 normal subjects, 30 hospital in-patients with breast cancer and 30 hospital in-patients with colonic or rectal cancer. There was no significant difference between patients with breast cancer and controls. Although a statistically significant difference between patients with colorectal cancer and controls was observed, the biological significance of this observation is doubtful. No clear effect of the presence of breast or colorectal carcinoma on the urinary excretion of hEGF has been observed.

Topics: Adult; Aged; Breast Neoplasms; Colonic Neoplasms; Creatinine; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Rectal Neoplasms

A monoclonal antibody of IgG2a isotype (425) is described that reacts with the epidermal growth factor receptor on human cells of different tissue origins. Monoclonal antibody 425 mediates tumor cytotoxicity in vitro using mouse and human effector cells and suppresses in vivo tumor cell growth of epidermoid (A 431) and colorectal (SW 948) carcinoma-derived cell lines. The tumoricidal effects in vitro are proportional to the antigen density on target cells. At concentrations higher than 1 nM, monoclonal antibody 425 inhibits growth of epidermal growth factor receptor-bearing A 431 cells, showing an epidermal growth factor-like agonist activity on the growth properties of these cells. A 431 cultures grown in the presence of growth-inhibiting doses of antibody or epidermal growth factor reveal a clear decrease of the relative number of cells in S phase. Additionally, cells treated with the antibody show a decrease of G2-M-phase cells in some, but not all, cultures tested.

Topics: Animals; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Cell Line; Colonic Neoplasms; Dose-Response Relationship, Drug; Epidermal Growth Factor; ErbB Receptors; Flow Cytometry; Humans; Immunoenzyme Techniques; Interphase; Macrophages; Mice; Monocytes; Recombinant Proteins; Rectal Neoplasms

The proliferative response of three human and three 1,2-dimethylhydrazine (DMH)-induced rat colon tumour cell lines to mouse epidermal growth factor (mEGF) and human urogastrone was examined in two in vitro assays (3H-thymidine uptake in liquid microculture and clonogenicity in semi-solid medium). In the 3H-thymidine uptake assay, one of three rat and one of three human colon tumour cell lines, i.e., r237 and LIM1215, were stimulated by mEGF. In the clonogenic assay, mEGF stimulated the one clonogenic rat tumour cell line r113, which did not respond in the 3H-thymidine uptake assay, and the human tumour cell line LIM1215. Urogastrone stimulated LIM1215 in both assay systems. The significance of these in vitro patterns of response to growth stimulatory factors is discussed.

Topics: 1,2-Dimethylhydrazine; Animals; Cell Division; Cell Line; Colonic Neoplasms; Dimethylhydrazines; Epidermal Growth Factor; Humans; Male; Rats; Rats, Inbred Strains; Rectal Neoplasms; Species Specificity; Tumor Stem Cell Assay