Clinical Implications and Quality Assurance of Molecular Testing for EGFR-Targeting Agents in Colorectal Cancer
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The introduction in clinical practice of anti-epidermal growth factor receptor (EGFR) antibodies has improved the clinical outcome of metastatic colorectal cancer (mCRC) patients. Nevertheless, only 10% of mCRC tumors respond to these treatments, thus rendering the efforts made to maximize their therapeutic index justified. Although several biomarkers have been identified, we do not know yet how to administer these drugs in colorectal cancer patients in a “personalized–targeted manner.” With this review we will try to demonstrate that we need to go beyond the assumption of a binary relationship between one genetic event and response or resistance to anti-EGFR drugs and that several factors can influence the response to these agents. Therefore, the introduction in future approaches of a holistic genomic discovery plan instead of an individual and specific identification of alterations is needed.
KeywordsMetastatic colorectal cancer EGFR dependency Anti-EGFR treatments Cetuximab Panitumumab Anti-EGFR moAbs Personalized cancer medicine Colorectal cancer subgroups Molecular subgroups KRAS BRAF PI3KCA NRAS PTEN Amphiregulin Epiregulin HER2 amplification Gene module Gene expression profile FcγRIIa FcγRIIΙa Let7 Anti-EGFR sensitivity Anti-EGFR resistance KRAS testing
Loredana Vecchione and Zenia Saridaki equally contributed in manuscript writing. Zenia Saridaki is a recipient of a research fellowship from the Hellenic Society of Medical Oncology.
L. Vecchione: none; Z. Saridaki: none; S. Tejpar: honoraria from and educational presentations/speakers’ bureau for Merck Serono.
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- 1.Vecchione L, Jacobs B, Normanno N, et al. EGFR-targeted therapy. Exp. Cell. Res. (2011), doi: 10.1016/j.yexcr.2011.08.021.
- 2.Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525e32.Google Scholar
- 3.Pritchard CC, Grady WM. Colorectal cancer molecular biology moves into clinical practice. Gut 2011;60:116e129.Google Scholar
- 4.Rosen N. Molecular biology of gastrointestinal cancers. In: De Vita VTJ, Hellman S, Rosenberg SA, editors. Cancer—principles and practice of oncology, 5th edn. Lippincott Williams & Wilkins; 1997, p. 971–979.Google Scholar
- 5.Yarden Y: The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001 Sep;37 Suppl 4:S3-8.Google Scholar
- 6.Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37. Review.Google Scholar
- 7.Fedor-Chaiken M, Hein PW, Stewart JC, et al. E-cadherin binding modulates EGF receptor activation. Cell Commun Adhes. 2003;10(2):105-18.Google Scholar
- 8.Morgillo F, Woo JK, Kim ES, et al. Heterodimerization of Insulin-like Growth Factor Receptor/Epidermal Growth Factor Receptor and Induction of Survivin Expression Counteract the Antitumor Action of Erlotinib. Ancer Res 2006;66(20):10100-11).Google Scholar
- 13.Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. JCO April 10, 2005 vol. 23 no. 11 2445-2459.Google Scholar
- 18.Roberts RB, Min L, Washington MK, et al. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis, Proc. Natl. Acad. Sci. U.S.A. 99 (3) (Feb 5 2002) 513 1521–1526 (Epub 2002 Jan 29).Google Scholar
- 19.Hecht J, Mitchell E, Baranda J, et al. Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing low (1–9%) or negative (<1%) levels of epidermal growth factor receptor (EGFR). J. Clin. Oncol. 24 (2006) 157s (abstract).Google Scholar
- 22.Cappuzzo F, Finocchiaro G, Rossi E, et al. EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol. 19 (2008) 717–723.Google Scholar
- 24.Sartore-Bianchi A, Moroni M, Veronese S, et al. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. JCO August 1, 2007 vol. 25 no. 22 3238-3245.Google Scholar
- 30.Lièvre A, Bachet JB, Le Corre D, et al. KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer Cancer Res April 15, 2006 66; 3992.Google Scholar
- 37.Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 360 (2009) 1408–1417. 629.Google Scholar
- 38.Douillard J, Siena S, Cassidy J, et al. Randomized phase 3 study of panitumumab with FOLFOX4 compared to FOLFOX4 alone as 1st-line treatment (tx) for metastatic colorectal cancer (mCRC): the PRIME trial. Eur J Cancer. 7 (2009) S6 (suppl; abstr 10LBA).Google Scholar
- 39.Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27(12):2091–6.PubMedCrossRefGoogle Scholar
- 40.• De Roock W, Claes B, Bernasconiet D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemo-refractory metastatic colorectal cancer: a retrospective Consortium analysis, Lancet Oncol. 2010;11 (8):753–762. By introducing the evaluation of other alterations involved in genes belonging to the EGFR pathway (other than KRAS), the authors improve the selection of patients that will benefit from anti-EGFR moAbs. Google Scholar
- 41.• De Roock W, Jonker DJ, Di Nicolantonio F, et al.: Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab, JAMA. 2010; 304(16):1812–1820. The authors introduce the concept of different mutations in a singular gene occurring in mCRC as responsible for different response to anti-EGFR moAbs. Google Scholar
- 47.Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS Metastatic Colon Cancer JCO December 10, 2009 vol. 27 no. 35 5924-5930.Google Scholar
- 52.Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69:5. 1851-7.Google Scholar
- 54.Loupakis F, Pollina L, Stasi I, et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. JCO June 1, 2009 vol. 27 no. 16 2622-2629.Google Scholar
- 55.Bertotti A, Migliardi G, Galimi F, et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discovery Published OnlineFirst September 2, 2011; doi: 10.1158/2159-8290.CD-11-0109.
- 56.Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3(99):99ra86.Google Scholar
- 57.Personeni N, Fieuws S, Piessevaux H, et al. 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 September 15, 2008 14; 5869.Google Scholar
- 59.http://www.ema.europa.eu/. (2011).
- 60.http://www.fda.gov/. (2011).
- 61.Tabernero J, Cervantes A, Rivera F, et al. Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study. J Clin Oncol. 2010;28:1181–9.Google Scholar
- 62.•• Baker JB, Dutta D, Watson D, et al. Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. BJC 104 (2011) 488–495. The authors show that the evaluation of a gene classifier compared with a single gene study improves the specificity and the positive predictive value of cetuximab benefit. Google Scholar
- 63.•• Rhodes DR, Lockwood Banka W, Chinnaiyan AM. Gene Expression Modules Associated with Cetuximab Response in Metastatic Colorectal Cancer Predict Additional Patient Populations Likely to Respond. AACR Translation of the Cancer Genome, 7-10 FEB 2009, Boston, MA, USA. The authors show that gene modules better predict the response to targeted agents than single gene alterations and that it is even possible to predict gene mutation by gene expression profile.Google Scholar
- 64.•• Tejpar S, Popovici V, Delorenzi M, et al. Mutant KRAS and BRAF gene expression profiles in colorectal cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial, J. Clin. Oncol. 28 (2010) 15s (suppl; abstr 3505). The authors show that a single gene mutation is not homogeneous at its molecular level (eg, at gene expression profile), thus underlying the concept of a single gene mutation occurring in different CRC subgroups and not specific for a singular phenotype.Google Scholar
- 66.Bibeau F, Lopez-Crapez E, Di Fiore F, et al. Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with Cetuximab Plus Irinotecan. JCO March 1, 2009 vol. 27 no. 7 1122-1129.Google Scholar
- 67.Graziano F, Ruzzo A, Loupakis F, et al. Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer. JCO March 20, 2008 vol. 26 no. 9 1427-1434.Google Scholar
- 73.Bellon E, Ligtenberg MJL, Tejpar S, et al. External quality assessment for KRAS testing is needed: Setup of a European Program and Report of the First Joined Regional Quality Assessment Rounds. The Oncologist April 2011 vol. 16 no. 4 467-478.Google Scholar