Another clue as to why herceptin works in some and not in others...

[Lani]

ABSTRACT: Immunoglobulin G Fragment C Receptor Polymorphisms and Clinical Efficacy of Trastuzumab-Based Therapy in Patients With HER-2/neu-Positive Metastatic Breast Cancer
[Journal of Clinical Oncology]
Purpose: The anti-HER-2/neu monoclonal antibody trastuzumab has been shown to engage both activatory (fragment C receptor [FcγR]IIIa; FcγRIIa) and inhibitory (FcγRIIb) antibody receptors and FcγR polymorphisms have been identified that may affect the antibody-dependent cell-mediated cytotoxicity (ADCC) of natural-killer cells/monocytes. In this study, we tested whether FcγR polymorphisms are associated with clinical outcome of patients with breast cancer who received trastuzumab.
Patients and Methods: Fifty-four consecutive patients with HER-2/neu-amplified breast cancer receiving trastuzumab plus taxane for metastatic disease were evaluated for genotype for the FcγRIIIa-158 valine(V)/phenylalanine(F), FcγRIIa-131 histidine(H)/arginine(R), and FcγRIIb-232 isoleucine(I)/threonine(T) polymorphisms. Trastuzumab-mediated ADCC of patients' peripheral blood mononuclear cells (PBMCs) was measured by chromium-51 release using a HER-2/neu-expressing human breast cancer cell line as a target. Controls comprised thirty-four patients treated with taxane alone.
Results: Our population was in Hardy-Weinberg equilibrium except for the FcγRIIb polymorphism. The FcγRIIIa-158 V/V genotype was significantly correlated with objective response rate (ORR) and progression-free survival (PFS). Also, there was trend significance in ORR and PFS for the FcγRIIa-131 H/H genotype. The combination of the two favorable genotypes (VV and/or H/H) was independently associated with better ORR and PFS compared with the other combinations. The ADCC analysis showed that V/V and/or H/H PBMCs had a significantly higher trastuzumab-mediated cytotoxicity than PBMCs harboring different genotypes.
Conclusion: These data support for the first time the hypothesis that FcγR-mediated ADCC plays an important role in the clinical effect of trastuzumab. Prospective studies are needed to confirm the role of FcγR polymorphisms in predicting clinical outcome of patients with breast cancer treated with trastuzumab-based therapy.
OPEN ACCESS: The "Other" Signaling of Trastuzumab: Antibodies Are Immunocompetent Drugs
[Journal of Clinical Oncology]
The outstanding pace of the clinical success of trastuzumab was always intimately connected to its ability to target and block the erbB2 receptor and to obviate to the malignant consequences of the activation of the intricate network of erbB2-associated intracellular signals. The wealth of data derived from probing the erbB2-associated signals has helped to clarify very relevant features of the mechanisms of sensitivity and resistance to trastuzumab. At the same time, such successful research somewhat obscured the fact that trastuzumab is an immunoglobulin G (IgG) 1 antibody endowed with all of the powerful armamentarium of immunologic effects characteristic of antibodies.
In this issue of the Journal of Clinical Oncology, a report from Musolino et al shows that the likelihood of response to trastuzumab is different in carriers of different variants of the IgG fragment C receptor (FcγR) present on immune effectors, such as neutrophils, macrophages, and natural-killer cells. The FcγR engagement by antibodies linked to cancer cells triggers antibody-dependent cellular cytotoxicity (ADCC) in a critically relevant way in model systems. The study by Musolino et al supports the concept that ADCC is a key mechanism of antitumor activity of trastuzumab in humans and opens scenarios relevant to the current and future use of the monoclonal antibody in the clinic.