Originally published as JCO Early Release 10.1200/JCO.2008.19.4696 on October 27 2008

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In Reply

Antonino Musolino, Nadia Naldi

Medical Oncology Unit, University Hospital of Parma, Parma, Italy

Beatrice Bortesi

Medical Oncology Unit and Medical Genetics Unit, University Hospital of Parma, Parma, Italy

Debora Pezzuolo

Medical Oncology Unit, University Hospital of Parma, Parma, Italy

Marzia Capelletti

Medical Oncology Unit and Medical Genetics Unit, University Hospital of Parma, Parma, Italy

Gabriele Missale, Diletta Laccabue, Alessandro Zerbini

Laboratory of Viral Immunopathology, Department of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy

Roberta Camisa

Medical Oncology Unit, University Hospital of Parma, Parma, Italy

Giancarlo Bisagni

Department of Oncology, S. Maria Nuova Hospital, Reggio Emilia, Italy

Tauro Maria Neri

Medical Genetics Unit, University Hospital of Parma, Parma, Italy

Andrea Ardizzoni

Medical Oncology Unit, University Hospital of Parma, Parma, Italy

First, we would like to thank Lejeune et al for their interest in our work, provision of additional data, and very compelling comments. Lejeune et al draw attention to an important topic in antibody-dependent cell-mediated cytotoxicity of therapeutic immunoglobulin G1 (IgG1) monoclonal antibodies (mAbs), such as trastuzumab,^1,2 rituximab,^3,4 and cetuximab:^5,6 the role of fragment C receptor [FcR]IIa. They provide evidence for linkage disequilibrium between FcRIIIa and FcRIIa polymorphisms, and for an FcRIIIa-restricted influence on the response to therapeutic antibodies.

The human (h) FcRIIa receptor binds to IgG in the form of immune complexes, with a specificity for hIgG1 and hIgG3. Binding to hIgG2 and murine (m) IgG1 depends on the high-responder/ low-responder polymorphism of FcRIIa.⁷ The high-responder allotype which is determined by an arginine (R) at position 131 interacts better with mIgG1, while the low-responder allotype expresses for histidine (H) at residue 131 and has the capacity to bind better to hIgG2. Greater binding affinity of FcRIIa 131 H/H for hIgG2 is expected to trigger stronger inflammatory responses predisposing patients to certain bacterial infections and disease like Guillan-Barre syndrome.^7,8 In contrast to hIgG2,^9,10 a different affinity of the two FcRIIa allelic forms for hIgG1 has not yet been clearly demonstrated. Some findings are, however, consistent with this hypothesis. Cell transfectants expressing the FcRIIa-131 R/R genotype were capable of binding to hIgG1 complexes to a lesser extent than transfectants expressing the FcRIIa-131 H/H variant.⁹ A higher gene frequency for the FcRIIa-131 H allele was reported in patients with heparin-induced thrombocytopenia, and homozygous 131 H/H platelets exhibited the greatest reactivity to sera containing heparin-induced thrombocytopenia antibodies of the IgG1 subclass.¹¹ Consistently with data reported in other hIgG1 mAbs,^4-6 we observed that the FcRIIIa-158 V/V genotype, alone and in combination with the FcRIIa H/H genotype, was significantly associated with better response rate and progression-free survival to trastuzumab compared with other FcR genotypes.² In multivariate analysis, the combination of FcRIIIa 158 V/V and/or FcRIIa 131 H/H was found to be the only independent predictive factor for clinical outcome to trastuzumab therapy.

While previous reports showed a random distribution of combinations of variant genotypes of FcRIIa and FcRIIIa in the normal population,^10,12 linkage disequilibrium between FcRIIa and FcRIIIa polymorphisms was demonstrated 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.¹³ The two-locus genotype frequencies of FcRIIa and FcRIIIa observed in our study are very similar to those reported by Cartron et al³ in a white population of follicular lymphoma patients treated with rituximab. We report a ² value of the FcR genotype distributions of 5.563 (P = .234; Table 1). However, due to the small sample size in the contingency table, the approximation to the ² distribution breaks down. It is therefore presumable that the two more appropriate and sensitive tests suggested by Lejeune et al^14,15 are able to show a nonrandom distribution between FcRIIIa and FcRIIa polymorphisms even in our study population.

View this table: [in this window] [in a new window]   Table 1. Linkage Disequilibrium Analysis Between FcRIIa-131 H/R and FcRIIIa-158 V/F Alleles

In conclusion, the biologic explanation for the association observed between FcRIIa polymorphism and hIgG1 mAbs activity remains to be elucidated. According to Lejeune et al data, the possibility that FcRIIIa or other unidentified polymorphic genes are linked to the FcRIIa-131 H/R locus, and are responsible for the association with clinical outcome to therapeutic mAbs, is a reasonable observation that deserves further study and attention.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

NOTES

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

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