Co-Expression of HER Family Members in Patients with Dukes’ C and D Colon Cancer and Their Impacts on Patient Prognosis and Survival

Abstract

The human epidermal growth factor receptor (EGFR) is an important therapeutic target in patients with metastatic colorectal cancer and anti-EGFR antibodies cetuximab and panitumumab have been approved for the treatment of such patients. Despite these advances, the duration of response in some patients can be limited. Since, EGFR is capable of forming heterodimers with the other members of the HER (Human epidermal receptor) family, it is important to investigate the co-expression and prognostic significance of all members of the HER family in colorectal cancer patients. The expression of the HER family members were determined in tumour specimens from 86 patients with Dukes’ C and D (metastatic) colon cancer using immunohistochemistry. Sections were scored by the percentage of positive tumour cells and intensity of staining. Their associations with clinicopathological parameters, and overall survival and disease free survival were evaluated using univariate and multivariate analysis. Overall, 43%, 77%, 52% and 92% of the cases were EGFR, HER-2, HER-3 and HER-4 positive respectively. Interestingly, 35%, 24%, 43%, and 18% of the cases had co-expression of EGFR/HER-2, EGFR/HER-3, EGFR/HER-4 and all four members of the HER family respectively. Of these, only the expression of EGFR and co-expression of EGFR/HER-4 were associated with poorer disease-free survival in both univariate and multivariate analysis. Co-expression of all members of the HER family in colon cancer supports the need for further investigations on their predictive value for response to therapy with anti-EGFR mAbs and whether such sub-population of patients may benefit from therapy with the new generation of pan-HER inhibitors.

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

“…Cetuximab is a chimeric human-murine monoclonal IgG1 antibody that binds to the extracellular domain of EGFR and inhibits ligand binding, dimerization and ultimately its activation. Cetuximab has shown efficacy in treating HNSCC, mCRC and NSCLC however, several clinical studies have shown that intrinsic and acquired resistances are common (27)(28)(29)(30)(31)(32). Determining why tumors are initially resistant to cetuximab or develop resistance during the course of therapy represents a major clinical challenge.…”

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

“…EGFR signaling can involve a number of intracellular molecules such as extracellular signal-regulated kinase (ERK), cyclin D1 and β-catenin [51]. The presence of EGFR is detected in a wide range of cancer types (Table 3 [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77]). Normally, the EGFR gene is located on chromosome 7.…”

Photochemical internalization (PCI) of HER2-targeted toxins

“…Head and neck Up to 90% Rarely detectable (Grandis and Tweardy, 1993;Hanken et al, 2014) Non-small cell lung carcinoma 34-62% 16-35% (Hirsch et al, 2003;Hirsch et al, 2002;Brabender et al, 2001) Colorectal 43-80% 6-77% (Spano et al, 2005;Seo et al, 2014;Khelwatty et al, 2014) Breast 6-18% 20-30% (Sorlie et al, 2001;Slamon et al, 1987;Rimawi et al, 2010;van, V et al, 1988;Bhargava et al, 2005;Lazaridis et al, 2014) Ovarian 48-62% 11-40% (Verri et al, 2005;Tuefferd et al, 2007;Nielsen et al, 2004;Lafky et al, 2008) Pancreatic 42-69% 61% (Uegaki et al, 1997;Tobita et al, 2003;Bloomston et al, 2006;Komoto et al, 2009) Glioma 40-50% Rarely detectable (Shinojima et al, 2003;Faulkner et al, 2014;Haynik et al, 2007) Cervical 33-73% 19-42% (Kim et al, 1996;Oka et al, 1994;Tangjitgamol et al, 2005) It was originally thought that EGFR amplification promoted tumor growth exclusively by enhancing signaling through wild-type EGFR. Since then, several EGFR mutations in both the intracellular and extracellular domain have been identified as predictors for response to EGFR-targeted therapies (Sok et al, 2006;Kobayashi et al, 2005).…”