2008 Summer Meeting - Leeds - The Pathological Society of Great ...

S17Pitfalls in Immunohistochemistry of the Epidermal GrowthFactor ReceptorPJ Van Diest* 1 , P Van Der Groep* 1 , E Van Der Wall# 11 University Medical Centre Utrecht, Departments of *Pathology and#Division of Internal Medicine and Dermatology, the NetherlandsThe Epidermal Growth Factor Receptor (EGFR, HER1) is a prognostic factorand therapeutic target in various types of cancers. Besides looking at geneticalterations in EGFR such as amplifications and mutations,immunohistochemistry has been employed to assess overexpression.There are many commercially available antibodies against EGFR raised againstdifferent epitopes in EGFR that provide varying results with regard torobustness and pattern of staining, varying from cytoplasmic to membranestaining, and clinical value. Besides, antibodies have been raised thatspecifically recognize phosphorylated EGFR. All this has caused muchconfusion and may explain the varying results between studies. Thispresentation will give an overview the specifics of these various antibodies,critically reviews the results obtained and will try to come up with someguidelines with regard to their usefulness for clinical practice or researchapplications.S19Oestrogen receptors and targeted therapyV Speirs 11 Leeds Institute of Molecular MedicineTargeted cancer therapy is aimed at targeting critical molecular pathways whichare necessary for cancer cell survival and has received much attention in recentyears. Targeted therapy is much more refined than conventional regimes whichsimply target rapidly dividing cells - unsatisfactory as this can also affect somerapidly dividing normal cells, causing multiple side effects. In recent years,targeted therapies for breast cancer have been developed. These includetrastuzamab (Herceptin), lapatinib (Tykerb) and bevicizumab (Avastin).However, the first true therapeutic target in breast cancer was the oestrogenreceptor (ER) which mediates the action of oestrogens and antioestrogens. ERis expressed by 2/3 of breast tumours, can be measured reproducibly andcorrelates with clinical benefit – all hallmarks of a robust clinical target.Subsequently, two ERs have been described; ER and ER. Oestrogen action ismediated by these receptors and also by non-receptor mechanisms. In thislecture I shall outline the cell and molecular mechanisms surrounding oestrogenaction and discuss how these could provide new opportunities for targetedcancer therapy of hormone-dependent cancers.S18Targeting EGFR in Clinical OncologyF. Eskens 11 Erasmus University Medical Centre RotterdamThe Epidermal Growth Factor Receptor is being expressed on numerous humanepithelial tumours.Constitutive activation of the EGFR, more than just simpleimmunohistochemical expression, is a hallmark of these tumours, and thereforethe EGFR is an important target in anticancer treatment.To inhibit or stop the sequelae of the activated EGFR, two appoaches have beenexplored;Monoclonal antibodies (MoAb) (trastuzumab, cetuximab and panitumumab) aregiven intravenously on an intermittend basis and block the extracellular domainof EGFR. Results of randomised studies have lead to regulatory approval forvarious indications. Clinical activity has been observed as single-agenttreatment and in combination with chemotherapy.Small molecule tyrosine kinase inhibitors (TKI) are give orally usually on acontinuous basis. Here a ‘tsunami’ of compounds has been developed, of whichsome (gefitinib, erlotinib, lapatinib) have gained regulatory approval. Clinicalactivity has been observed as single-agent and in combination withchemotherapy.Whereas the current MoAbs target either HER-1 / EGFR or HER-2,increasingly novel TKIs inhibit both receptors. The underlying mechanism ofcross-talk between HER-1 and -2 is underlying the principal thought that asmall spectrum target inhibition might probably lead to unsatisfactory resultswhen using TKI.Clinical data of the currently registered MoAbs and TKIs will be discussed, andsome of the newer compounds will be mentioned. Epidemiology and potentialtreatment options for toxicities will be discussed.S20The Role of DNA Methylation in Colorectal NeoplasiaAIbrahim 1 , AL Silva 1 , AH Wyllie 1 , MJ Arends 1 ,JD Brenton 21 Department of Pathology, University of Cambridge, 2 Cancer ResearchUK, Cambridge Research Institute.There is abundant evidence that human carcinogenesis (and particularlycolorectal neoplasia) is linked to disruption of normal patterns of DNAmethylation (1,2,3). Using Pyrosequencing and microarray technology (4), weshow that CpG-island hypermethylation of genes is an early cumulative eventduring the multi-step pathogenesis of colorectal cancer. We also confirmfindings that aberrant DNA methylation of CpG islands “CpG IslandMethylator Phenotype” (CIMP) is a critical pathway for inactivation of multiplecancer-related genes by promoter hypermethylation in colorectal cancer (1,2).Our findings also provide a useful platform for the use DNA methylation inearly detection and screening of colorectal cancer.[1] Toyota, M. et al. CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci U S A 96, 8681–8686 (1999).[2] Issa, J.-P. CpG island methylator phenotype in cancer. Nat Rev Cancer 4,988–993 (2004).[3] Kim, Y.-H. et al. CpG island methylation of genes accumulates during theadenoma progression step of the multistep pathogenesis of colorectal cancer.Genes Chromosomes Cancer 45, 781–789 (2006).[4] A. Ibrahim, N. Thorne, K. Baird, N. Barbosa-Morais, S. Tavar`e, V. Collins,A. Wyllie, M. Arends, and J. Brenton. MMASS: an optimized array-basedmethod for assessing CpG island methylation. Nucleic Acids Res, 2006.92 Summer Meeting (194 th ) 1–4 July 2008 Scientific Programme