Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2015

Open Access 01-12-2015 | Review

Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer

Authors: Ryan A Hutchinson, Richard A Adams, Darragh G McArt, Manuel Salto-Tellez, Bharat Jasani, Peter W Hamilton

Published in: Journal of Translational Medicine | Issue 1/2015

Login to get access

Abstract

The treatment of cancer is becoming more precise, targeting specific oncogenic drivers with targeted molecular therapies. The epidermal growth factor receptor has been found to be over-expressed in a multitude of solid tumours. Immunohistochemistry is widely used in the fields of diagnostic and personalised medicine to localise and visualise disease specific proteins. To date the clinical utility of epidermal growth factor receptor immunohistochemistry in determining monoclonal antibody efficacy has remained somewhat inconclusive. The lack of an agreed reproducible scoring criteria for epidermal growth factor receptor immunohistochemistry has, in various clinical trials yielded conflicting results as to the use of epidermal growth factor receptor immunohistochemistry assay as a companion diagnostic. This has resulted in this test being removed from the licence for the drug panitumumab and not performed in clinical practice for cetuximab. In this review we explore the reasons behind this with a particular emphasis on colorectal cancer, and to suggest a way of resolving the situation through improving the precision of epidermal growth factor receptor immunohistochemistry with quantitative image analysis of digitised images complemented with companion molecular morphological techniques such as in situ hybridisation and section based gene mutation analysis.
Literature
1.
Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D et al (2012) Unresponsiveness of colon cancer to BRAF[V600E] inhibition through feedback activation of EGFR. Nature 483(7387):100–103PubMed
2.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139PubMed
3.
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566PubMed
4.
Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP et al (2012) EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2(3):227–235PubMedCentralPubMed
5.
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMed
6.
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMed
7.
Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137PubMed
8.
Yarden Y (2001) The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 37(Suppl 4):S3–S8PubMed
9.
Henriksen L, Grandal MV, Knudsen SL, van Deurs B, Grovdal LM (2013) Internalization mechanisms of the epidermal growth factor receptor after activation with different ligands. PLoS One 8(3):e58148PubMedCentralPubMed
10.
McCourt CM, Boyle D, James J, Salto-Tellez M (2013) Immunohistochemistry in the era of personalised medicine. J Clin Pathol 66(1):58–61PubMed
11.
Anagnostou VK, Welsh AW, Giltnane JM, Siddiqui S, Liceaga C, Gustavson M et al (2010) Analytic variability in immunohistochemistry biomarker studies. Cancer Epidemiol Biomarkers Prev 19(4):982–991PubMedCentralPubMed
12.
Rivenbark AG, O’Connor SM, Coleman WB (2013) Molecular and cellular heterogeneity in breast cancer: challenges for personalized medicine. Am J Pathol 183(4):1113–1124PubMed
13.
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339(6127):1546–1558PubMedCentralPubMed
14.
Burrell RA, McGranahan N, Bartek J, Swanton C (2013) The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501(7467):338–345PubMed
15.
Aparicio S, Caldas C (2013) The implications of clonal genome evolution for cancer medicine. N Engl J Med 368(9):842–851PubMed
16.
Almendro V, Marusyk A, Polyak K (2013) Cellular heterogeneity and molecular evolution in cancer. Annu Rev Pathol 24(8):277–302
17.
de Bruin EC, Taylor TB, Swanton C (2013) Intra-tumor heterogeneity: lessons from microbial evolution and clinical implications. Genome Med 5(11):101PubMedCentralPubMed
18.
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892PubMed
19.
Fisher R, Pusztai L, Swanton C (2013) Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer 108(3):479–485PubMedCentralPubMed
20.
Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH et al (2011) Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 377(9783):2103–2114PubMedCentralPubMed
21.
Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ et al (2007) Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer [MRC FOCUS]: a randomised controlled trial. Lancet 370(9582):143–152PubMed
22.
Fitzgibbons PL, Lazar AJ, Spencer S (2014) Introducing new College of American Pathologists reporting templates for cancer biomarkers. Arch Pathol Lab Med 138(2):157–158PubMed
23.
Idikio HA (2009) Immunohistochemistry in diagnostic surgical pathology: contributions of protein life-cycle, use of evidence-based methods and data normalization on interpretation of immunohistochemical stains. Int J Clin Exp Pathol 3(2):169–176PubMedCentralPubMed
24.
Russnes HG, Navin N, Hicks J, Borresen-Dale AL (2011) Insight into the heterogeneity of breast cancer through next-generation sequencing. J Clin Invest 121(10):3810–3818PubMedCentralPubMed
25.
Thomson TA, Hayes MM, Spinelli JJ, Hilland E, Sawrenko C, Phillips D et al (2001) HER-2/neu in breast cancer: interobserver variability and performance of immunohistochemistry with 4 antibodies compared with fluorescent in situ hybridization. Mod Pathol 14(11):1079–1086PubMed
26.
Turashvili G, Leung S, Turbin D, Montgomery K, Gilks B, West R et al (2009) Inter-observer reproducibility of HER2 immunohistochemical assessment and concordance with fluorescent in situ hybridization [FISH]: pathologist assessment compared to quantitative image analysis. BMC Cancer 9:165PubMedCentralPubMed
27.
Gavrielides MA, Gallas BD, Lenz P, Badano A, Hewitt SM (2011) Observer variability in the interpretation of HER2/neu immunohistochemical expression with unaided and computer-aided digital microscopy. Arch Pathol Lab Med 135(2):233–242PubMed
28.
Atkins D, Reiffen KA, Tegtmeier CL, Winther H, Bonato MS, Storkel S (2004) Immunohistochemical detection of EGFR in paraffin-embedded tumor tissues: variation in staining intensity due to choice of fixative and storage time of tissue sections. J Histochem Cytochem 52(7):893–901PubMed
29.
Hewitt SM, Badve SS, True LD (2012) Impact of preanalytic factors on the design and application of integral biomarkers for directing patient therapy. Clin Cancer Res 18(6):1524–1530PubMedCentralPubMed
30.
Neumeister VM, Parisi F, England AM, Siddiqui S, Anagnostou V, Zarrella E et al (2014) A tissue quality index: an intrinsic control for measurement of effects of preanalytical variables on FFPE tissue. Lab Invest 94(4):467–474PubMedCentralPubMed
31.
Press MF, Hung G, Godolphin W, Slamon DJ (1994) Sensitivity of HER-2/neu antibodies in archival tissue samples: potential source of error in immunohistochemical studies of oncogene expression. Cancer Res 54(10):2771–2777PubMed
32.
Tong LC, Nelson N, Tsourigiannis J, Mulligan AM (2011) The effect of prolonged fixation on the immunohistochemical evaluation of estrogen receptor, progesterone receptor, and HER2 expression in invasive breast cancer: a prospective study. Am J Surg Pathol 35(4):545–552PubMed
33.
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25(1):118–145PubMed
34.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013PubMed
35.
Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S (2010) American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract 6(4):195–197PubMedCentralPubMed
36.
Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11(2):155–168PubMed
37.
Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J et al (2011) Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 103(22):1656–1664PubMedCentralPubMed
38.
Won JR, Gao D, Grant D, Cupples J, Rahemtulla A, Wolber R et al (2012) Variable performance of commercial epidermal growth factor receptor antibodies in detection of basal-like breast cancer. Histopathology 61(3):518–519PubMed
39.
Ciardiello F, Tortora G (2003) Epidermal growth factor receptor [EGFR] as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs. Eur J Cancer 39(10):1348–1354PubMed
40.
Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358(11):1160–1174PubMed
41.
Saltz LB, Meropol NJ, Loehrer PJS, Needle MN, Kopit J, Mayer RJ (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22(7):1201–1208PubMed
42.
Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25(13):1658–1664PubMed
43.
Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K et al (2012) EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 13(1):33–42PubMed
44.
You B, Chen EX (2011) Anti-EGFR monoclonal antibodies for treatment of colorectal cancers: development of cetuximab and panitumumab. J Clin Pharmacol
45.
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345PubMed
46.
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634PubMed
47.
Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995PubMed
48.
Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E et al (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26(3):374–379PubMed
49.
Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP et al (2007) Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 96(8):1166–1169PubMedCentralPubMed
50.
Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M et al (2013) Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11):1023–1034PubMed
51.
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M et al (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX4] versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28(31):4697–4705PubMed
52.
Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A et al (2011) Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 22(7):1535–1546PubMed
53.
Stintzing S, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Jager E, Heintges T et al (2012) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306. Ann Oncol 23(7):1693–1699PubMed
54.
Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F et al (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27(5):663–671PubMed
55.
Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357(20):2040–2048PubMed
56.
Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765PubMed
57.
De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G et al (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762PubMed
58.
De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar S (2011) KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 12(6):594–603PubMed
59.
Vale CL, Tierney JF, Fisher D, Adams RA, Kaplan R, Maughan TS et al (2012) Does anti-EGFR therapy improve outcome in advanced colorectal cancer? A systematic review and meta-analysis. Cancer Treat Rev 38(6):618–625PubMed
60.
Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A et al (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23(9):1803–1810PubMed
61.
Wierzbicki R, Jonker DJ, Moore MJ, Berry SR, Loehrer PJ, Youssoufian H et al (2011) A phase II, multicenter study of cetuximab monotherapy in patients with refractory, metastatic colorectal carcinoma with absent epidermal growth factor receptor immunostaining. Invest New Drugs 29(1):167–174PubMed
62.
Cunningham MP, Essapen S, Thomas H, Green M, Lovell DP, Topham C et al (2005) Coexpression, prognostic significance and predictive value of EGFR, EGFRvIII and phosphorylated EGFR in colorectal cancer. Int J Oncol 27(2):317–325PubMed
63.
Allo G, Bandarchi B, Yanagawa N, Wang A, Shih W, Xu J et al (2014) EGFR mutation-specific immunohistochemical antibodies in lung adenocarcinoma. Histopathology 64(6):826–839PubMed
64.
Brabyn CJ, Kleine LP (1995) EGF causes hyperproliferation and apoptosis in T51B cells: involvement of high and low affinity EGFR binding sites. Cell Signal 7(2):139–150PubMed
65.
Braun S, Schlimok G, Heumos I, Schaller G, Riethdorf L, Riethmuller G et al (2001) ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I-III breast cancer patients. Cancer Res 61(5):1890–1895PubMed
66.
Ithimakin S, Day KC, Malik F, Zen Q, Dawsey SJ, Bersano-Begey TF et al (2013) HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res 73(5):1635–1646PubMedCentralPubMed
67.
Hirsch FR, Varella-Garcia M, Bunn PA Jr, Di Maria MV, Veve R, Bremmes RM et al (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21(20):3798–3807PubMed
68.
Hirsch FR, Herbst RS, Olsen C, Chansky K, Crowley J, Kelly K et al (2008) Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 26(20):3351–3357PubMedCentralPubMed
69.
Wulf MA, Bode B, Zimmermann D, Rufibach K, Weder W, Moch H et al (2012) Silver-enhanced in situ hybridization for determination of EGFR copy number alterations in non-small cell lung cancer. Am J Surg Pathol 36(12):1801–1808PubMed
70.
Algars A, Lintunen M, Carpen O, Ristamaki R, Sundstrom J (2011) EGFR gene copy number assessment from areas with highest EGFR expression predicts response to anti-EGFR therapy in colorectal cancer. Br J Cancer 105(2):255–262PubMedCentralPubMed
71.
Werner M, Chott A, Fabiano A, Battifora H (2000) Effect of formalin tissue fixation and processing on immunohistochemistry. Am J Surg Pathol 24(7):1016–1019PubMed
72.
Liotta LA, Espina V, Mehta AI, Calvert V, Rosenblatt K, Geho D et al (2003) Protein microarrays: meeting analytical challenges for clinical applications. Cancer Cell 3(4):317–325PubMed
73.
Sartore-Bianchi A, Fieuws S, Veronese S, Moroni M, Personeni N, Frattini M et al (2012) Standardisation of EGFR FISH in colorectal cancer: results of an international interlaboratory reproducibility ring study. J Clin Pathol 65(3):218–223PubMed
74.
Sartore-Bianchi A, Moroni M, Veronese S, Carnaghi C, Bajetta E, Luppi G et al (2007) Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol 25(22):3238–3245PubMed
75.
Luber B, Deplazes J, Keller G, Walch A, Rauser S, Eichmann M et al (2011) Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie [AIO]. BMC Cancer 11:509PubMedCentralPubMed
76.
Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B et al (2008) Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 14(18):5869–5876PubMed
77.
Mahipal A, Mcdonald MJ, Witkiewicz A, Carr BI (2012) Cell membrane and cytoplasmic epidermal growth factor receptor expression in pancreatic ductal adenocarcinoma. Med Oncol 29(1):134–139PubMed
78.
Pu YS, Huang CY, Kuo YZ, Kang WY, Liu GY, Huang AM et al (2009) Characterization of membranous and cytoplasmic EGFR expression in human normal renal cortex and renal cell carcinoma. J Biomed Sci 16:82PubMedCentralPubMed
79.
Ueda S, Ogata S, Tsuda H, Kawarabayashi N, Kimura M, Sugiura Y et al (2004) The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas 29(1):e1–e8PubMed
80.
Spano JP, Fagard R, Soria JC, Rixe O, Khayat D, Milano G (2005) Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives. Ann Oncol 16(2):189–194PubMed
81.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792PubMed
82.
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M et al (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365(14):1273–1283PubMedCentralPubMed
83.
Mosesson Y, Mills GB, Yarden Y (2008) Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer 8(11):835–850PubMed
84.
Liao HJ, Carpenter G (2009) Cetuximab/C225-induced intracellular trafficking of epidermal growth factor receptor. Cancer Res 69(15):6179–6183PubMedCentralPubMed
85.
Tomas A, Futter CE, Eden ER (2014) EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol 24(1):26–34PubMedCentralPubMed
86.
Piyathilake CJ, Frost AR, Manne U, Weiss H, Bell WC, Heimburger DC et al (2002) Differential expression of growth factors in squamous cell carcinoma and precancerous lesions of the lung. Clin Cancer Res 8(3):734–744PubMed
87.
Einama T, Ueda S, Tsuda H, Ogasawara K, Hatsuse K, Matsubara O et al (2012) Membranous and cytoplasmic expression of epidermal growth factor receptor in metastatic pancreatic ductal adenocarcinoma. Exp Ther Med 3(6):931–936PubMedCentralPubMed
88.
De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13(2):97–110PubMed
89.
Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15(3):178–196PubMedCentralPubMed
90.
Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36(6):320–328PubMedCentralPubMed
91.
Vartanian S, Bentley C, Brauer MJ, Li L, Shirasawa S, Sasazuki T et al (2013) Identification of mutant K-Ras-dependent phenotypes using a panel of isogenic cell lines. J Biol Chem 288(4):2403–2413PubMedCentralPubMed
92.
Parsons BL, Myers MB (2013) Personalized cancer treatment and the myth of KRAS wild-type colon tumors. Discov Med 15(83):259–267PubMed
93.
Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE et al (2014) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer [FIRE-3]: a randomised, open-label, phase 3 trial. Lancet Oncol 15(10):1065–1075PubMed
94.
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319(9):525–532PubMed
95.
Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767PubMed
96.
Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337
97.
Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570PubMed
98.
Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411(6835):375–379PubMed
99.
Emens LA, Silverstein SC, Khleif S, Marincola FM, Galon J (2012) Toward integrative cancer immunotherapy: targeting the tumor microenvironment. J Transl Med 10:70PubMedCentralPubMed
100.
Galon J, Fridman WH, Pages F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 67(5):1883–1886PubMed
101.
Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T et al (2011) Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 29(6):610–618PubMed
102.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964PubMed
103.
Galon J, Pages F, Marincola FM, Thurin M, Trinchieri G, Fox BA et al (2012) The immune score as a new possible approach for the classification of cancer. J Transl Med 10:1PubMedCentralPubMed
104.
Galon J, Pages F, Marincola FM, Angell HK, Thurin M, Lugli A et al (2012) Cancer classification using the Immunoscore: a worldwide task force. J Transl Med 10:205PubMedCentralPubMed
105.
Galon J, Angell HK, Bedognetti D, Marincola FM (2013) The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39(1):11–26PubMed
106.
Angell H, Galon J (2013) From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol 25(2):261–267PubMed
107.
Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C et al (2014) Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol 232(2):199–209PubMedCentralPubMed
108.
Bindea G, Mlecnik B, Angell HK, Galon J (2014) The immune landscape of human tumors: implications for cancer immunotherapy. Oncoimmunology 3(1):e27456PubMedCentralPubMed
109.
Hamilton PW, Bankhead P, Wang Y, Hutchinson R, Kieran D, McArt DG et al (2014) Digital pathology and image analysis in tissue biomarker research. Methods 70(1):59–73PubMed
110.
Van Schaeybroeck S, Allen WL, Turkington RC, Johnston PG (2011) Implementing prognostic and predictive biomarkers in CRC clinical trials. Nat Rev Clin Oncol 8(4):222–232PubMed
111.
Schneider MR, Wolf E (2009) The epidermal growth factor receptor ligands at a glance. J Cell Physiol 218(3):460–466PubMed
112.
Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S et al (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25(22):3230–3237PubMed
113.
Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J et al (2009) Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 27(30):5068–5074PubMed
114.
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487(7408):500–504. doi:10.​1038/​nature11183 (1476-4687 (Electronic); 0028-0836) PubMedCentralPubMed
115.
Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E et al (2012) Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487(7408):505–509. doi:10.​1038/​nature11249 (1476-4687 (Electronic); 0028-0836) PubMedCentralPubMed
116.
Kuramochi H, Nakajima G, Kaneko Y, Nakamura A, Inoue Y, Yamamoto M et al (2012) Amphiregulin and epiregulin mRNA expression in primary colorectal cancer and corresponding liver metastases. BMC Cancer 12:88PubMedCentralPubMed
117.
Sunaga N, Kaira K, Imai H, Shimizu K, Nakano T, Shames DS et al (2013) Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer. Oncogene 32(34):4034–4042PubMedCentralPubMed
118.
Oda K, Matsuoka Y, Funahashi A, Kitano H (2005) A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol 1:2005.0010 (Epub 2005 May 25. (1744-4292 (Electronic); 1744-4292)) PubMedCentralPubMed
119.
Mandell JW (2003) Phosphorylation state-specific antibodies: applications in investigative and diagnostic pathology. Am J Pathol 163(5):1687–1698 (0002-9440 (Print); 0002-9440) PubMedCentralPubMed
120.
121.
122.
Phipps AI, Limburg PJ, Baron JA, Burnett-Hartman AN, Weisenberger DJ, Laird PW et al (2015) Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology 148(1):77–87.e2. doi:10.​1053/​j.​gastro.​2014.​09.​038 (Epub 2014 Sep 30. (1528-0012 (Electronic); 0016-5085)) PubMed
123.
Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S et al (2013) A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 19(5):619–625. doi:10.​1038/​nm.​3175 (Epub 2013 Apr 14. (1546-170X (Electronic); 1078-8956)) PubMedCentralPubMed
124.
125.
126.
Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367(18):1694–1703. doi:10.​1056/​NEJMoa1210093 (Epub 2012 Sep 29. (1533-4406 (Electronic); 0028-4793)) PubMedCentralPubMed
127.
Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M et al (2014) Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371(20):1867–1876. doi:10.​1056/​NEJMoa1408868 (Epub 2014 Sep 29. (1533-4406 (Electronic); 0028-4793)) PubMed
128.
Polley MY, Leung SC, McShane LM, Gao D, Hugh JC, Mastropasqua MG et al (2013) An international Ki67 reproducibility study. J Natl Cancer Inst 105(24):1897–1906PubMedCentralPubMed
129.
Smits AJ, Kummer JA, de Bruin PC, Bol M, van den Tweel JG, Seldenrijk KA et al (2014) The estimation of tumor cell percentage for molecular testing by pathologists is not accurate. Mod Pathol 27(2):168–174PubMed
130.
Viray H, Li K, Long TA, Vasalos P, Bridge JA, Jennings LJ et al (2013) A prospective, multi-institutional diagnostic trial to determine pathologist accuracy in estimation of percentage of malignant cells. Arch Pathol Lab Med 137(11):1545–1549PubMed
131.
Shaw GL, Thomas BC, Dawson SN, Srivastava G, Vowler SL, Gnanapragasam VJ et al (2014) Identification of pathologically insignificant prostate cancer is not accurate in unscreened men. Br J Cancer 110(10):2405–2411PubMedCentralPubMed
132.
Foran DJ, Chen W, Yang L (2011) Automated image interpretation computer-assisted diagnostics. Anal Cell Pathol [Amst] 34(6):279–300
133.
Riley JS, Hutchinson R, McArt DG, Crawford N, Holohan C, Paul I et al (2013) Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer. Cell Death Dis 5(4):e951
134.
Petrovski S, Goldstein DB (2014) Phenomics and the interpretation of personal genomes. Sci Transl Med 6(254):254fs35PubMed
135.
Zemojtel T, Kohler S, Mackenroth L, Jager M, Hecht J, Krawitz P et al (2014) Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome. Sci Transl Med 6(252):252ra123PubMed
136.
Lu JT, Campeau PM, Lee BH (2014) Genotype-phenotype correlation—promiscuity in the era of next-generation sequencing. N Engl J Med 371(7):593–596PubMed
137.
Zbuk KM, Eng C (2007) Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer 7(1):35–45PubMed
138.
Houle D, Govindaraju DR, Omholt S (2010) Phenomics: the next challenge. Nat Rev Genet 11(12):855–866PubMed
139.
Kelloff GJ, Sigman CC (2012) Cancer biomarkers: selecting the right drug for the right patient. Nat Rev Drug Discov 11(3):201–214. doi:10.​1038/​nrd3651 (1474-1784 (Electronic); 1474-1776) PubMed
140.
Kent DM, Rothwell PM, Ioannidis JP, Altman DG, Hayward RA (2010) Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials 11:85PubMedCentralPubMed
141.
Kleppe M, Levine RL (2014) Tumor heterogeneity confounds and illuminates: assessing the implications. Nat Med 20(4):342–344PubMed
142.
Cadioli A, Rossi G, Costantini M, Cavazza A, Migaldi M, Colby TV (2014) Lung cancer histologic and immunohistochemical heterogeneity in the era of molecular therapies: analysis of 172 consecutive surgically resected, entirely sampled pulmonary carcinomas. Am J Surg Pathol 38(4):502–509PubMed
143.
Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH, Gabbert HE (2010) Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res 16(3):790–799PubMed
144.
Xie T, Cho YB, Wang K, Huang D, Hong HK, Choi YL et al (2014) Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing. Genomics 104(4):234–241PubMed
145.
Modjtahedi H, Essapen S (2009) Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs 20(10):851–855PubMed
146.
Modjtahedi H, Khelwatty SA, Kirk RS, Seddon AM, Essapen S, Del Vecchio CA et al (2012) Immunohistochemical discrimination of wild-type EGFR from EGFRvIII in fixed tumour specimens using anti-EGFR mAbs ICR9 and ICR10. Br J Cancer 106(5):883–888PubMedCentralPubMed
147.
Fan QW, Cheng CK, Gustafson WC, Charron E, Zipper P, Wong RA et al (2013) EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell 24(4):438–449PubMed
148.
Bartlett JM, Campbell FM, Ibrahim M, O’Grady A, Kay E, Faulkes C et al (2011) A UK NEQAS ISH multicenter ring study using the Ventana HER2 dual-color ISH assay. Am J Clin Pathol 135(1):157–162PubMed
149.
van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A et al (2002) The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111(2):241–250PubMed
150.
Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL (2012) Feedback upregulation of HER3 [ErbB3] expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci USA 109(8):2718–2723PubMedCentralPubMed
151.
Laurent-Puig P, Manceau G, Zucman-Rossi J, Blons H (2012) Dual blockade of epidermal growth factor receptor-induced pathways: a new avenue to treat metastatic colorectal cancer. J Clin Oncol 30(13):1550–1552PubMed
Metadata
Title
Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer
Authors
Ryan A Hutchinson
Richard A Adams
Darragh G McArt
Manuel Salto-Tellez
Bharat Jasani
Peter W Hamilton
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2015
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-015-0531-z

Other articles of this Issue 1/2015

Journal of Translational Medicine 1/2015 Go to the issue

Research

A novel placental like alkaline phosphate promoter driven transcriptional silencing combined with single chain variable fragment antibody based virosomal delivery for neoplastic cell targeting

Research

Effect of Berberine on promoting the excretion of cholesterol in high-fat diet-induced hyperlipidemic hamsters

Commentary

Evidence-based support for the use of proton pump inhibitors in cancer therapy

Research

Effect of treatment with a JAK2-selective inhibitor, fedratinib, on bone marrow fibrosis in patients with myelofibrosis

Research

Establishment of patient-derived xenograft models and cell lines for malignancies of the upper gastrointestinal tract

Research

Altered microRNAs expression profiling in cumulus cells from patients with polycystic ovary syndrome
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits