FCGR2A and FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin +/- cetuximab

Janne B Kjersem, Eva Skovlund, Tone Ikdahl, Tormod Guren, Christian Kersten, Astrid M Dalsgaard, Mette K Yilmaz, Tone Fokstuen, Kjell M Tveit, Elin H Kure, Janne B Kjersem, Eva Skovlund, Tone Ikdahl, Tormod Guren, Christian Kersten, Astrid M Dalsgaard, Mette K Yilmaz, Tone Fokstuen, Kjell M Tveit, Elin H Kure

Abstract

Background: Polymorphisms of genes encoding the Fcy receptors (Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies. Most studies have been limited by small samples sizes and have reported inconsistent associations between the FCGR2A and the FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab. We investigated the association of these polymorphisms and clinical outcome in a large cohort of mCRC patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin (Nordic FLOX) +/- cetuximab in the NORDIC-VII study (NCT00145314).

Methods: 504 and 497 mCRC patients were evaluable for the FCGR2A and FCGR3A genotyping, respectively. Genotyping was performed on TaqMan ABI HT 7900 (Applied Biosystems, Foster City, CA, USA) with pre-designed SNP genotyping assays for FCGR2A (rs1801274) and FCGR3A (rs396991).

Results: The response rate for patients with the FCGR2A R/R genotype was significantly increased when cetuximab was added to Nordic FLOX (31% versus 53%, interaction P = 0.03), but was not significantly different compared to the response rate of patients with the FCGR2A H/H or H/R genotypes given the same treatment. A larger increase in response rate with the addition of cetuximab to Nordic FLOX in patients with KRAS mutated tumors and the FCGR2A R/R genotype was observed (19% versus 50%, interaction P = 0.04). None of the FCGR3A polymorphisms were associated with altered response when cetuximab was added to Nordic FLOX (interaction P = 0.63). Neither of the FCGR polymorphisms showed any significant associations with progression-free survival or overall survival.

Conclusion: Patients with KRAS mutated tumors and the FCGR2A R/R polymorphism responded poorly when treated with chemotherapy only, and experienced the most benefit of the addition of cetuximab in terms of response rate.

Figures

Figure 1
Figure 1
FCGR2A response rates in the whole study population. The FCGR2A R/R genotype was associated with increased response rate when cetuximab was added to Nordic FLOX (31% in arm A vs 53% in arms B + C, interaction P = 0.03).
Figure 2
Figure 2
FCGR2A response rates in patients with KRAS wild-type tumors. There was no significant difference in response rates when cetuximab was added to Nordic FLOX in the different FCGR2A subgroups (interaction P = 0.27).
Figure 3
Figure 3
FCGR2A response rates in patients with KRAS mutated tumors. The FCGR2A R/R genotype was associated with increased response rate when cetuximab was added to Nordic FLOX (19% in arm A vs 50% in arms B + C, interaction P = 0.04).

References

    1. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B. Colorectal cancer. Lancet. 2010;375:1030–1047. doi: 10.1016/S0140-6736(10)60353-4.
    1. Tol J, Punt CJ. Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review. Clin Ther. 2010;32:437–453. doi: 10.1016/j.clinthera.2010.03.012.
    1. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–1765. doi: 10.1056/NEJMoa0804385.
    1. Lievre A, Bachet JB, Boige V, Cayre A, Le CD, Buc E. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374–379. doi: 10.1200/JCO.2007.12.5906.
    1. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30:1755–1762. doi: 10.1200/JCO.2011.38.0915.
    1. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH. 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. 2011;377:2103–2114. doi: 10.1016/S0140-6736(11)60613-2.
    1. Primrose JN, Falk S, Finch-Jones M, Valle JW, Sherlock D, Hornbuckle J. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: the new EPOC study. ASCO Meeting Abstracts. 2013;31:3504.
    1. Kurai J, Chikumi H, Hashimoto K, Yamaguchi K, Yamasaki A, Sako T. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res. 2007;13:1552–1561. doi: 10.1158/1078-0432.CCR-06-1726.
    1. Desjarlais JR, Lazar GA, Zhukovsky EA, Chu SY. Optimizing engagement of the immune system by anti-tumor antibodies: an engineer’s perspective. Drug Discov Today. 2007;12:898–910. doi: 10.1016/j.drudis.2007.08.009.
    1. van Sorge NM, van der Pol WL, van de Winkel JG. FcgammaR polymorphisms: Implications for function, disease susceptibility and immunotherapy. Tissue Antigens. 2003;61:189–202. doi: 10.1034/j.1399-0039.2003.00037.x.
    1. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940–3947. doi: 10.1200/JCO.2003.05.013.
    1. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002;99:754–758. doi: 10.1182/blood.V99.3.754.
    1. Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G. 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;26:1789–1796. doi: 10.1200/JCO.2007.14.8957.
    1. Tamura K, Shimizu C, Hojo T, Kashi-Tanaka S, Kinoshita T, Yonemori K. FcgammaR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. Ann Oncol. 2011;22:1302–1307. doi: 10.1093/annonc/mdq585.
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. doi: 10.1093/jnci/92.3.205.
    1. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes RF, Barugel MF. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–1034. doi: 10.1056/NEJMoa1305275.
    1. Seymour MT, Brown SR, Middleton G, Maughan TF, Richman S, Gwyther S, Lowe C. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013;14:749–759. doi: 10.1016/S1470-2045(13)70163-3.
    1. De RW, Claes B, Bernasconi D, De SJ, Biesmans B, Fountzilas G. 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. 2010;11:753–762. doi: 10.1016/S1470-2045(10)70130-3.
    1. Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505–514.
    1. Paez D, Pare L, Espinosa I, Salazar J, Del RE, Barnadas A. Immunoglobulin G fragment C receptor polymorphisms and KRAS mutations: are they useful biomarkers of clinical outcome in advanced colorectal cancer treated with anti-EGFR-based therapy? Cancer Sci. 2010;101:2048–2053. doi: 10.1111/j.1349-7006.2010.01621.x.
    1. Zhang W, Yang D, Harbison C, Khambata-Ford S, Malone DP, Ning Y. FCGR2A H131R and FCGR3A V158F polymorphism status in mCRC patients treated with single-agent cetuximab (IMCL 0144 and CA225045) or with second-line irinotecan plus cetuximab (EPIC): a pooled statistical analysis. ASCO Meeting Abstracts. 2011;29:e14025.
    1. Negri FV, Musolino A, Naldi N, Bortesi B, Missale G, Laccabue D. Role of immunoglobulin G fragment C receptor polymorphism-mediated antibody-dependant cellular cytotoxicity in colorectal cancer treated with cetuximab therapy. Pharmacogenomics J. 2013;14:14–19.
    1. Bibeau F, Lopez-Crapez E, Di FF, Thezenas S, Ychou M, Blanchard 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;27:1122–1129. doi: 10.1200/JCO.2008.18.0463.
    1. Rodriguez J, Zarate R, Bandres E, Boni V, Hernandez A, Sola JJ. Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer. Eur J Cancer. 2012;48:1774–1780. doi: 10.1016/j.ejca.2012.01.007.
    1. Etienne-Grimaldi MC, Bennouna J, Formento JL, Douillard JY, Francoual M, Hennebelle I. Multifactorial pharmacogenetic analysis in colorectal cancer patients receiving 5-fluorouracil-based therapy together with cetuximab-irinotecan. Br J Clin Pharmacol. 2012;73:776–785. doi: 10.1111/j.1365-2125.2011.04141.x.
    1. Calemma R, Ottaiano A, Trotta AM, Nasti G, Romano C, Napolitano M. Fc gamma receptor IIIa polymorphisms in advanced colorectal cancer patients correlated with response to anti-EGFR antibodies and clinical outcome. J Transl Med. 2012;10:232. doi: 10.1186/1479-5876-10-232.
    1. Zhang W, Azuma M, Lurje G, Gordon MA, Yang D, Pohl A. Molecular predictors of combination targeted therapies (cetuximab, bevacizumab) in irinotecan-refractory colorectal cancer (BOND-2 study) Anticancer Res. 2010;30:4209–4217.
    1. Dahan L, Norguet E, Etienne-Grimaldi MC, Formento JL, Gasmi M, Nanni I. Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer. BMC Cancer. 2011;11:496. doi: 10.1186/1471-2407-11-496.
    1. Pander J, Gelderblom H, Antonini NF, Tol J, van Krieken JH, van der ST. Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer. Eur J Cancer. 2010;46:1829–1834. doi: 10.1016/j.ejca.2010.03.017.
    1. Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M. 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;25:3712–3718. doi: 10.1200/JCO.2006.08.8021.
    1. Lurje G, Nagashima F, Zhang W, Yang D, Chang HM, Gordon MA. Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab. Clin Cancer Res. 2008;14:7884–7895. doi: 10.1158/1078-0432.CCR-07-5165.
    1. Graziano F, Ruzzo A, Loupakis F, Canestrari E, Santini D, Catalano V. Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer. J Clin Oncol. 2008;26:1427–1434. doi: 10.1200/JCO.2007.12.4602.
    1. Park SJ, Hong YS, Lee JL, Ryu MH, Chang HM, Kim KP. Genetic polymorphisms of FcgammaRIIa and FcgammaRIIIa are not predictive of clinical outcomes after cetuximab plus irinotecan chemotherapy in patients with metastatic colorectal cancer. Oncology. 2012;82:83–89. doi: 10.1159/000335959.
    1. Geva R, Jensen BV, Fountzilas G, Yoshino T, Paez D, Montagut C. An international consortium study in chemorefractory metastatic colorectal cancer (mCRC) patients (pts) to assess the impact of FCGR polymorphisms on cetuximab efficacy. ASCO Meeting Abstracts. 2011;29:3528.
    1. Correale P, Marra M, Remondo C, Migali C, Misso G, Arcuri FP. Cytotoxic drugs up-regulate epidermal growth factor receptor (EGFR) expression in colon cancer cells and enhance their susceptibility to EGFR-targeted antibody-dependent cell-mediated-cytotoxicity (ADCC) Eur J Cancer. 2010;46:1703–1711. doi: 10.1016/j.ejca.2010.03.005.
    1. Schlaeth M, Berger S, Derer S, Klausz K, Lohse S, Dechant M. Fc-engineered EGF-R antibodies mediate improved antibody-dependent cellular cytotoxicity (ADCC) against KRAS-mutated tumor cells. Cancer Sci. 2010;101:1080–1088. doi: 10.1111/j.1349-7006.2010.01505.x.
    1. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6:443–446. doi: 10.1038/74704.
    1. Kono K, Takahashi A, Ichihara F, Sugai H, Fujii H, Matsumoto Y. Impaired antibody-dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer. Cancer Res. 2002;62:5813–5817.
    1. de Souza AP, Bonorino C. Tumor immunosuppressive environment: effects on tumor-specific and nontumor antigen immune responses. Expert Rev Anticancer Ther. 2009;9:1317–1332. doi: 10.1586/era.09.88.

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