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Originally published as JCO Early Release 10.1200/JCO.2008.19.4118 on October 27 2008

Journal of Clinical Oncology, Vol 26, No 33 (November 20), 2008: pp. 5489-5491
© 2008 American Society of Clinical Oncology.
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CORRESPONDENCE

Evidence for Linkage Disequilibrium Between Fc{gamma}RIIIa-V158F and Fc{gamma}RIIa-H131R Polymorphisms in White Patients, and for an Fc{gamma}RIIIa-Restricted Influence on the Response to Therapeutic Antibodies

Julien Lejeune

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6239, Génétique Immunothérapie Chimie et Cancer; Université François-Rabelais de Tours, Tours, France

Gilles Thibault

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6239, Génétique Immunothérapie Chimie et Cancer; Centre Hospitalier Régional Universitaire de Tours, Laboratoire d’Immunologie, Tours; Université d’Auvergne-Clermont 1, Clermont-Ferrand, France

David Ternant

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6239, Génétique Immunothérapie Chimie et Cancer; Université François-Rabelais de Tours, Tours, France

Guillaume Cartron

L’Institut National de la Santé et de la Recherche Médicale U847, Biothérapies des cellules souches normales et cancéreuses and Centre Hospitalier Universitaire Lapeyronie, Service d’Hématologie et Biothérapies, Montpellier, France

Hervé Watier

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6239, Génétique Immunothérapie Chimie et Cancer; Université François-Rabelais de Tours, France; Centre Hospitalier Régional Universitaire de Tours, Laboratoire d’immunologie, Tours, France

Marc Ohresser

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6239, Génétique Immunothérapie Chimie et Cancer; Université François-Rabelais de Tours, Tours, France

To the Editor:

Since our pioneering work demonstrating that a better clinical response to rituximab (anti-CD20, MabThera, Rituxan) was associated with the 158 valine (V) allotype of fragment C receptor [Fc{gamma}R]IIIa, a receptor for the Fc portion of immunoglobulin G (IgG),1 similar results have been obtained in at least four cohorts of patients with non-Hodgkin's lymphoma treated with this antibody.2,3,4,5 However, similar data were not available for antibodies targeting solid tumors. Indeed, the initial study with trastuzumab (anti-ErbB2, Herceptin; Genentech, Inc, South San Francisco, CA) was negative,6 and a study performed on a small cohort of patients treated by cetuximab (anti-ErbB1, Erbitux; ImClone Systems Inc, Branchburg, NJ) led to the opposite conclusion.7 The recent publication by Musolino et al8 in Journal of Clinical Oncology, now convincingly shows that a better response to trastuzumab is associated with the 158 VV genotype. This result is consistent with the corpus of data acquired with rituximab. Similarly, a recent communication at the American Society of Clinical Oncology Annual Meeting concluded that the 158 VV genotype of Fc{gamma}RIIIa is associated with a better response to cetuximab.9 Although the landscape becomes clear for Fc{gamma}RIIIa, this is not the case for Fc{gamma}RIIa, since its histidine (H) 131 arginine (R) polymorphism was found associated with the clinical response in some but not all studies, either independently2,7 or combined with Fc{gamma}RIIIa-V158 phenylalanine (F) polymorphism.8 Clinical results are frequently analyzed on the basis of a presumed random distribution of Fc{gamma}RIIa and Fc{gamma}RIIIa alleles, referring to the article by Lehrnbecher et al,10 which reported "no evidence for nonrandom distribution of combinations of variant genotypes" using a classical {chi}2 test (Table 1).1,2,10,12-14 However, as already discussed,11 linkage disequilibrium (LD) between Fc{gamma}RIIa and Fc{gamma}RIIIa polymorphisms has been demonstrated by a {chi}2 test in a larger group of white patients: 131 RR/158 FF and 131 HH/158 VV frequencies were increased at the expense of 131 RR/158 VV and 131 HH/158 FF genotypes, respectively (Table 1).12 After analysis of available data with two more appropriate and sensitive tests (Linkdis; Department of Entomology, Iowa State Univeristy, Ames, IA13; and Genopop; Laboratoire de Génétique et Environnement, Montpellier, France14), LD was confirmed in the latter group12 and was also demonstrated in the former,10 as well as in a control French white population (Table 1). When applied to clinical studies, this LD was observed in the Cartron et al cohort1 as well as in that from Weng and Levy2 (Table 1). We were unable to perform the same analysis on the cohort of Musolino et al8 because bilocus genotypes were not presented in the article. However, the LD is suggested in their cohort by the 158 VV genotype over-representation in 131 HH individuals (deduced from their Table 3) and probably explains the trend observed for a higher antibody-dependent cell-mediated cytotoxicity in Fc{gamma}RIIa-131 HH individuals (their Fig 3). Finally, we confirm the absence of LD in the Japanese control population,12 whereas only one test revealed LD in the African-American population (Table 1).10


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  		Table 1. Linkage Disequilibrium Between Fc{gamma}RIIa-131 H/R and Fc{gamma}RIIIa-158 V/F Alleles

 
Multivariate analysis such as logistic regression is imposed by the nonrandom distribution of the alleles. Through this approach, Weng and Levy2 have shown independent effects of both Fc{gamma}RIIIa-158 VV and Fc{gamma}RIIa-131 HH genotypes on the clinical response to rituximab,2 whereas we found a VV-restricted effect on this response.1 This difference might be related to a putative different repartition of ethnic origin among the studied populations. In contrast, using a multivariate logistic regression, Musolino et al8 reported that combination of the two favorable Fc{gamma}RIIIa and Fc{gamma}RIIa genotypes (158 VV and/or 131 HH) was the only independent predictive factor for response to trastuzumab. In their opinion, this combined effect could not be ascribed to a LD between Fc{gamma}RIIa and Fc{gamma}RIIIa polymorphisms. Given the highly suspected LD in their white cohort,8 we performed univariate logistic regression15 using Fc{gamma}RIIa (131 HH v R carriers), Fc{gamma}RIIIa (158 VV v F carriers) and the association of both genotypes (131 HH and/or 158 VV v others genotypes) as dependent variables. The Cox-Snell pseudo R2 coefficient which approximates part of data variability explained by the logistic model was calculated for each variable;16 the higher the R2 coefficient, the more the factor included in the model explains the observed variability. Fc{gamma}RIIIa-158 VV genotype was found significantly associated with the response to trastuzumab (odds ratio, 6.9; 95% CI, 1.3 to 35.8; P = .02; R2 = 12%), whereas Fc{gamma}RIIa-131 HH was not (odds ratio, 3.1; 95% CI, 0.7 to 13.5; P = .12; R2 = 4.3%). The association of both genotypes was found significant (odds ratio, 3.9; 95% CI, 1.1 to 13.6; P = .03; R2 = 9.0%), even if R2 for the association of genotypes is weaker than R2 for Fc{gamma}RIIIa alone. A bivariate logistic regression was then performed on these two genetic factors omitting the other covariates (eg, sex, age), which do not influence the response.8 This analysis confirmed the significant influence of the Fc{gamma}RIIIa genotype (P = .02) and indicates that the combined effect of 158 VV and 131 HH reported by Musolino et al8 provides no additional information than, and may be due to, the sole effect of the Fc{gamma}RIIIa genotype. This Fc{gamma}RIIIa-158 VV–restricted effect is concordant with their in vitro results showing that the 158 VV genotype and the combination of 158 VV and/or 131 HH were associated with similar trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (their Fig 3A v 3C) and with the in vivo response to rituximab in white patients.8 This conclusion has important therapeutic implications: for example, it strongly suggests that the use of engineered antibodies with improved binding to Fc{gamma}RIIIa, which is currently evaluated in lymphoproliferative malignancies, may be also applied to solid tumors.17

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Supported by the Institut National du Cancer and Canceropôle Grand Ouest, and the Fondation Langlois. Julien Lejeune is granted by the Région Centre.

NOTES

published online ahead of print at www.jco.org on October 27, 2008

REFERENCES

1. Cartron G, Dacheux L, Salles G, et al: Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor Fc{gamma}RIIIa gene. Blood 99:754-758, 2002[Abstract/Free Full Text]

2. Weng WK, Levy R: Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21:3940-3947, 2003[Abstract/Free Full Text]

3. Ghielmini M, Rufibach K, Salles G, et al: Single agent rituximab in patients with follicular or mantle cell lymphoma: Clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: A study of the Swiss Group for Clinical Cancer Res (SAKK). Ann Oncol 16:1675-1682, 2005[Abstract/Free Full Text]

4. Treon SP, Hansen M, Branagan AR, et al: Polymorphisms in Fc{gamma}RIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenström's macroglobulinemia. J Clin Oncol 23:474-481, 2005[Abstract/Free Full Text]

5. Kim DH, Jung HD, Kim JG, et al: FCGR3A gene polymorphisms may correlate with response to R-CHOP therapy for diffuse large B-cell lymphoma. Blood 108:2720-2725, 2006

6. Foster C, Harris K, Ostland M, et al: FCGR3A V/F polymorphism does not predict response to Herceptin (H) monotherapy. Proc Am Soc Clin Oncol 21:57a, 2002 (abstr 227)

7. Zhang W, Gordon M, Schultheis AM, et al: 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 25:3712-3718, 2007[Abstract/Free Full Text]

8. 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 26:1789-1796, 2008[Abstract/Free Full Text]

9. Bibeau F, Crapez E, Di Fiore F, et al: Association of Fc{gamma}RIIa and Fc{gamma}RIIIa polymorphisms with clinical outcome in metastatic colorectal cancer patients (mCRC) treated with cetuximab and irinotecan. J Clin Oncol 26:579s, 2008 (suppl; abstr 11004)

10. Lehrnbecher T, Foster CB, Zhu S, et al: Variant genotypes of the low-affinity Fc{gamma} receptors in two control populations and a review of low-affinity Fc{gamma} receptor polymorphisms in control and disease populations. Blood 94:4220-4232, 1999[Abstract/Free Full Text]

11. Ternant D, Ohresser M, Thomas C, et al: Dose-response relationship and pharmacogenetics of anti-RhD monoclonal antibodies. Blood 106:1503-1504, 2005[Free Full Text]

12. van der Pol WL, Jansen MD, Sluiter WJ, et al: Evidence for non-random distribution of Fc{gamma} receptor genotype combinations. Immunogenetics 55:240-246, 2003[CrossRef][Medline]

13. Black WC, Krafsur ES: A FORTRAN program for the calculation and analysis of two-locus linkage disequilibrium coefficients. Theor Appl Genet 70:491-496, 1985[CrossRef]

14. Raymond M, Rousset F. Genepop (version 1.2): A population genetics software for exact test and ecumenicism. J Heredity 86:248-249, 1995[Free Full Text]

15. S-Plus 6 User's Guide. Insightful Corporation, Seattle, WA, 2002

16. Long SJ: Regression models for categorical and limited dependent variables. Thousand Oaks, CA, Sage Publications, 1997

17. Sibéril S, Dutertre CA, Fridman WH, et al: Fc{gamma}R: The key to optimize therapeutic antibodies? Crit Rev Oncol Hematol 62:26-33, 2007[CrossRef][Medline]


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  • In Reply
    Antonino Musolino, Nadia Naldi, Beatrice Bortesi, Debora Pezzuolo, Marzia Capelletti, Gabriele Missale, Diletta Laccabue, Alessandro Zerbini, Roberta Camisa, Giancarlo Bisagni, Tauro Maria Neri, and Andrea Ardizzoni
    JCO 2008 26: 5491-5492 [Full Text]

Related Article

  • Two Immunoglobulin G Fragment C Receptor Polymorphisms Independently Predict Response to Rituximab in Patients With Follicular Lymphoma
    Wen-Kai Weng and Ronald Levy
    JCO 2003 21: 3940-3947 [Abstract] [Full Text]



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