Home   Chapter Home   Jobs   Conferences   Fellowships   Books



Advertisement

Drugs of interest to pathologists

Drugs related to surgical pathology

Cetuximab


Author: Him G. Kwee, M.D. (see Reviewers/Authors page)
Revised: 31 March 2012, last major update January 2012
Copyright: (c) 2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Cetuximab is a recombinant chimeric (human / mouse) monoclonal IgG1 antibody that can bind the extracellular domain of EGFR, thereby preventing the activation and dimerization of the receptor, resulting in inhibition of signal transduction and cell proliferation (see diagram above)

Trade name
=========================================================================

● Erbitux®

Clinical information
=========================================================================

Approved by US Food and Drug Administration for:
● Locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy or as a single agent for recurrent or metastatic squamous cell carcinoma of the head and neck, in which prior platinum-based therapy has failed (March 1, 2006)
● The first-line treatment of patients with recurrent locoregional squamous cell carcinoma of the head and neck in combination with platinum-based therapy plus 5-fluorouracil and/or metastatic squamous cell carcinoma of the head and neck (November 7, 2011)
● Recurrent or metastatic EGFR expressing colorectal carcinoma in combination with irinotecan for those patients that are refractory to prior irinotecan therapy, or as a single agent for those that cannot tolerate irinotecan therapy (February 12, 2004)
● As a single agent for recurrent or metastatic EGFR expressing colorectal carcinoma after failure of both irinotecan and oxaliplatin-based chemotherapy regimens (October 2, 2007, National Cancer Institutte Cancer Drug Information, November 9, 2011)
● Side effects include hypomagnesemia, hypocalcaemia, hypokalemia, neutropenia, acne-like skin rash, interstitial lung disease, cardiotoxicity and infusion reactions (National Cancer Institutte Cancer Drug Information, November 9, 2011)
● Cost: up to $30,000 for eight weeks of treatment in 2004 (N Engl J Med 2004;351:317), cost on 30 March 2012 at www.drugstore.com was $575 for 100mg/50ml Solution, 50ml Vial

Diagrams
=========================================================================


       
Pathways blocked by cetuximab

● AKT = serine-threonine protein kinase B
● MEK = mitogen- activated protein (MAP) kinase/Erk kinase
● mTOR = mammalian target of rapamaycin
● ERK = extracellular signal-regulated kinase
● |_____ stimulation
● ---------| inhibition

Use for pathologists
=========================================================================

● The American Society of Oncology, the National Cancer Comprehensive Network and the US Food and Drug Administration recommend KRAS mutation testing for patients with colorectal carcinomas if they are considered candidates for anti-EGFR therapy with cetuximab or panitumumab (Vectibix, Adv Anat Pathol 2010;17:23)
● The intended use of the KRAS mutation analysis is for the detection of point mutations (substitutions) in exon 2 (codons 12 and 13) of the KRAS gene (Arch Pathol Lab Med 2012;136:26)

Molecular testing-theory
=========================================================================

● Approximately 40% of colorectal carcinomas have activating KRAS mutations and are associated with a lack of response to anti-EGFR therapy because KRAS is downstream from EGFR in the KRAS-BRAF-MEK-ERK pathway; traditionally, blocking EGFR has little effect because of the downstream activation of KRAS
● The only apparent exception is the KRAS pG13D (codon 13) mutation, which has been associated with longer overall and progression-free survival after treatment with cetuximab (JAMA 2010;304:1812)
● The intended use of the KRAS mutation analysis is to detect point mutations (substitutions) in exon 2 (codons 12 and 13) of the KRAS gene (Arch Pathol Lab Med 2012;136:26)
● At present, only mutation analysis of exon 2 is mandated, although mutations in exons 3 and 4 occur in a small number of colorectal carcinomas, and such mutations also confer resistance to cetuximab (Arch Pathol Lab Med 2011;135:1278)
● Not all patients with wild-type KRAS tumors respond to anti-EGFR therapy; these patients may have a mutation less than the limit of detection of the assay
● In <5% of cases, KRAS analysis show discordant results between the primary tumor and the metastasis (Br J Cancer 2011;104:1020)
● NRAS, BRAF, PI3K (phosphatidylinositol- 3 kinase) activating mutations and loss of PTEN (phosphatase and tensin homolog) may also render anti-EGFR-based therapy ineffective
● Testing for EGFR is not required before treatment with cetuximab for colorectal carcinoma or squamous cell carcinoma of the head and neck

Molecular testing-procedure
=========================================================================

● KRAS mutational analysis is most frequently performed on formalin-fixed, paraffin-embedded tumor specimens
● Five sections (4-7 microns thick) from a block with sufficient tumor cells are cut on uncoated slides
● The tissue size should be at least 0.25 cm2
● A pathologist should provide an estimate, from the slide stained with hematoxylin-eosin, of the percentage of neoplastic cells in the area or areas that will be used for DNA extraction; this estimate is required by the College of American Pathologists (MOL standard 34860)
● That area should exceed the established limit of detection of the assay
● The minimum percentage of neoplastic cells required is dependent on the analytical sensitivity of the testing technology used
● All slides are stored at room temperature and should be sent to the testing laboratory within 5 to 7 days; longer storage may decrease the quality of the isolated DNA (Arch Pathol Lab Med 2012;136:26)

End of Drugs > Drugs related to surgical pathology > Cetuximab


This information is intended for physicians and related personnel, who understand that medical information is often imperfect, and must be interpreted in the context of a patient's clinical data using reasonable medical judgment. This website should not be used as a substitute for the advice of a licensed physician.

All information on this website is protected by copyright of PathologyOutlines.com, Inc. Information from third parties may also be protected by copyright. Please contact us at copyrightPathOut@gmail.com with any questions (click here for other contact information).