Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer

BMC Cancer

Gérard Milano³  Jean-François Seitz²  L'Houcine Ouafik¹  Stéphane Garcia¹  Jean Gaudart²  Isabelle Nanni¹  Mohamed Gasmi¹  Jean-Louis Formento³  Marie-Christine Etienne-Grimaldi³  Emmanuelle Norguet²  Laetitia Dahan³ 

[1]Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Université de la Méditerranée, Marseille, France

[2]Assistance Publique-Hôpitaux de Marseille, Hôpital Timone, Université de la Méditerranée, Marseille, France

[3]Laboratoire d'oncopharmacologie, Centre Antoine Lacassagne, Nice, France

关键词: polymorphisms;    colorectal cancer;    clinical outcome;    cetuximab;    EGFR inhibitors;   

Others  :  1080639
DOI  :  10.1186/1471-2407-11-496

 received in 2011-06-16, accepted in 2011-11-25,  发布年份 2011

【 摘 要 】

Background

We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (EGFR, EGF, CCND1) or antibody-directed cell cytotoxicity (FCGR2A and FCGR3A) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy.

Methods

Fifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1). The following polymorphisms were analyzed on blood DNA: EGFR (CA repeats in intron 1, -216 G > T, -191C > A, R497K), EGF (A61G), CCND1 (A870G), FCGR2A (R131H), FCGR3A (F158V). Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt vs wt/mut vs mut/mut), with the exception of -191C > A EGFR polymorphism (AA patient merged with CA patients).

Results

Analysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058). CCND1 A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP) was significantly related to EGFR -191C > A polymorphism with a longer TTP in CC patients as compared to others, and to CCND1 A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained CCND1 polymorphism. Overall survival was significantly related to CCND1 polymorphism with a shorter survival in patients bearing the G allele, and to FCGR3A F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). FCGR3A F158V and CCND1 A870G polymorphisms were significant independent predictors of overall survival.

Conclusions

Present original data obtained in wt KRas patients corresponding to the current cetuximab-treated population clearly suggest that CCND1 A870G polymorphism may be used as an additional marker for predicting cetuximab efficacy, TTP and overall survival. In addition, FCGR3A F158V polymorphism was a significant independent predictor of overall survival.

【 授权许可】

   
2011 Dahan et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ: Cancer statistics 2006. CA Cancer J Clin 2006, 56:106-30.
• [2]Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004, 22:1201-8.
• [3]Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004, 351:337-45.
• [4]Tabernero J, Van Cutsem E, Díaz-Rubio E, Cervantes A, Humblet Y, André T, Van Laethem JL, Soulié P, Casado E, Verslype C, Valera JS, Tortora G, Ciardiello F, Kisker O, de Gramont A: Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2007, 25:5225-32.
• [5]Baselga J: The EGFR as a target for anticancer therapy--focus on cetuximab. Eur J Cancer 2001, 37(Suppl 4):S16-22.
• [6]Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008, 359:1757-65.
• [7]Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboüé R, Tuech JJ, Queuniet AM, Paillot B, Sabourin JC, Michot F, Michel P, Frebourg T: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer 2007, 96:1166-9.
• [8]Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 2007, 67:2643-8.
• [9]De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, Biesmans B, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008, 19:508-15.
• [10]Lièvre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouché O, Landi B, Louvet C, André T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008, 26(3):374-9.
• [11]Coate L, Cuffe S, Horgan A, Hung RJ, Christiani D, Liu G: Germline genetic variation, cancer outcome, and pharmacogenetics. J Clin Oncol 2010, 28:4029-37.
• [12]Buerger H, Gebhardt F, Schmidt H, Beckmann A, Hutmacher K, Simon R, Lelle R, Boecker W, Brandt B: Length and loss of heterozygosity of an intron 1 polymorphic sequence of egfr is related to cytogenetic alterations and epithelial growth factor receptor expression. Cancer Res 2000, 60(4):854-7.
• [13]Moriai T, Kobrin MS, Hope C, Speck L, Korc M: A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci USA 1994, 91(21):10217-21.
• [14]Liu W, Innocenti F, Wu MH, Desai AA, Dolan ME, Cook EH Jr, Ratain MJ: A functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter. Cancer Res 2005, 65(1):46-53.
• [15]Shahbazi M, Pravica V, Nasreen N, Fakhoury H, Fryer AA, Strange RC, Hutchinson PE, Osborne JE, Lear JT, Smith AG, Hutchinson IV: Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 2002, 359(9304):397-401.
• [16]Spindler KL, Nielsen JN, Ornskov D, Brandslund I, Jakobsen A: Epidermal growth factor (EGF) A61G polymorphism and EGF gene expression in normal colon tissue from patients with colorectal cancer. Acta Oncol 2007, 46(8):1113-7.
• [17]Le Marchand L, Seifried A, Lum-Jones A, Donlon T, Wilkens LR: Association of the cyclin D1 A870G polymorphism with advanced colorectal cancer. JAMA 2003, 290(21):2843-8.
• [18]Hong Y, Eu KW, Seow-Choen F, Fook-Chong S, Cheah PY: GG genotype of cyclin D1 G870A polymorphism is associated with increased risk and advanced colorectal cancer in patients in Singapore. Eur J Cancer 2005, 41(7):1037-44.
• [19]Weiner GJ: Monoclonal antibody mechanisms of action in cancer. Immunol Res 2007, 39(1-3):271-8. Review
• [20]Kurai J, Chikumi H, Hashimoto K, Yamaguchi K, Yamasaki A, Sako T, Touge H, Makino H, Takata M, Miyata M, Nakamoto M, Burioka N, Shimizu E: Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 2007, 13(5):1552-61.
• [21]van Sorge NM, van der Pol WL, van de Winkel JG: FcgammaR polymorphisms: Implications for function, disease susceptibility and immunotherapy. Tissue Antigens 2003, 61(3):189-202. Review
• [22]Etienne-Grimaldi MC, Pereira S, Magné N, et al.: Analysis of the dinucleotide repeat polymorphism in the epidermal growth factor receptor (EGFR) gene in head and neck cancer patients. Ann Oncol 2005, 16:934-941.
• [23]Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009, 360(14):1408-17.
• [24]Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009, 27(5):663-71. Epub 2008 Dec 29
• [25]Bianchini D, Jayanth A, Chua YJ, Cunningham D: Epidermal growth factor receptor inhibitor-related skin toxicity: mechanisms, treatment, and its potential role as a predictive marker. Clin Colorectal Cancer 2008, 7(1):33-43.
• [26]Amador ML, Oppenheimer D, Perea S, Maitra A, Cusatis G, Iacobuzio-Donahue C, Baker SD, Ashfaq R, Takimoto C, Forastiere A, Hidalgo M: An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res 2004, 64(24):9139-43. Erratum in: Cancer Res. 2007, 67(16):7937
• [27]Graziano F, Ruzzo A, Loupakis F, Canestrari E, Santini D, Catalano V, Bisonni R, Torresi U, Floriani I, Schiavon G, Andreoni F, Maltese P, Rulli E, Humar B, Falcone A, Giustini L, Tonini G, Fontana A, Masi G, Magnani M: Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer. J Clin Oncol 2008, 26(9):1427-34.
• [28]Buerger H, Gebhardt F, Schmidt H, Beckmann A, Hutmacher K, Simon R, Lelle R, Boecker W, Brandt B: Length and loss of heterozygosity of an intron 1 polymorphic sequence of egfr is related to cytogenetic alterations and epithelial growth factor receptor expression. Cancer Res 2000, 60(4):854-7.
• [29]Buerger H, Packeisen J, Boecker A, Tidow N, Kersting C, Bielawski K, Isola J, Yatabe Y, Nakachi K, Boecker W, Brandt B: Allelic length of a CA dinucleotide repeat in the egfr gene correlates with the frequency of amplifications of this sequence--first results of an inter-ethnic breast cancer study. J Pathol 2004, 203(1):545-50.
• [30]Gebhardt F, Zänker KS, Brandt B: Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem 1999, 274(19):13176-80.
• [31]Johnson AC, Ishii S, Jinno Y, Pastan I, Merlino GT: Epidermal growth factor receptor gene promoter. Deletion analysis and identification of nuclear protein binding sites. J Biol Chem 1988, 263(12):5693-9.
• [32]Kageyama R, Merlino GT, Pastan I: Epidermal growth factor (EGF) receptor gene transcription. Requirement for Sp1 and an EGF receptor-specific factor. J Biol Chem 1988, 263(13):6329-36.
• [33]Betticher DC, Thatcher N, Altermatt HJ, Hoban P, Ryder WD, Heighway J: Alternate splicing produces a novel cyclin D1 transcript. Oncogene 1995, 11(5):1005-11.
• [34]Izzo JG, Papadimitrakopoulou VA, Liu DD, den Hollander PL, Babenko IM, Keck J, El-Naggar AK, Shin DM, Lee JJ, Hong WK, Hittelman WN: Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer. J Natl Cancer Inst 2003, 95(3):198-205.
• [35]Matthias C, Branigan K, Jahnke V, Leder K, Haas J, Heighway J, Jones PW, Strange RC, Fryer AA, Hoban PR: Polymorphism within the cyclin D1 gene is associated with prognosis in patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 1998, 4(10):2411-8. Erratum in: Clin Cancer Res 1999, 5(1):222
• [36]Zhang W, Gordon M, Press OA, Rhodes K, Vallböhmer D, Yang DY, Park D, Fazzone W, Schultheis A, Sherrod AE, Iqbal S, Groshen S, Lenz HJ: Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab. Pharmacogenet Genomics 2006, 16(7):475-83.
• [37]Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J, Xie D, Lai J, Stadlen A, Li B, Fox JA, Presta LG: High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem 2001, 276(9):6591-604. Epub 2000 Nov 28
• [38]Wu J, Edberg JC, Redecha PB, Bansal V, Guyre PM, Coleman K, Salmon JE, Kimberly RP: A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 1997, 100(5):1059-70.
• [39]Niwa R, Hatanaka S, Shoji-Hosaka E, Sakurada M, Kobayashi Y, Uehara A, Yokoi H, Nakamura K, Shitara K: Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 Is independent of FcgammaRIIIa functional polymorphism. Clin Cancer Res 2004, 10(18 Pt 1):6248-55.
• [40]van Royen-Kerkhof A, Sanders EA, Wijngaarden S, van Roon JA, Voorhorst-Ogink M, Walraven V, Gerritsen A, van Dijk MA, Kuis W, Rijkers GT, Keler T, Leusen JH, van de Winkel JG: Flow cytometric determination of FcgammaRIIa (CD32) polymorphism. J Immunol Methods 2004, 294(1-2):135-44. Epub 2004 Oct 6
• [41]Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H: Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002, 99(3):754-8.
• [42]Musolino A, Naldi N, Bortesi B, et al.: Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2-neu-positive metastatic breast cancer. J Clin Oncol 2008, 26(11):1789-96.
• [43]Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M, Chang HM, Borucka E, Lurje G, Sherrod AE, Iqbal S, Groshen S, Lenz HJ: FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007, 25(24):3712-8.
• [44]Bibeau F, Lopez-Crapez E, Di Fiore F, Thezenas S, Ychou M, Blanchard F, Lamy A, Penault-Llorca F, Frébourg T, Michel P, Sabourin JC, Boissière-Michot F: Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 2009, 27(7):1122-9. Epub 2009 Jan 21
• [45]Pander J, Gelderblom H, Antonini NF, Tol J, van Krieken JHJM, van der Straaten T, Punt CJA, Guchelaar HJ: Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer. Eur J Cancer 2010, 46:1829-34.