Fc g R2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer

Background: Antibody-dependent-mediated cytotoxicity (ADCC) is one of the modes of action for trastuzumab. Recent data have suggested that fragment C c receptor (Fc c R) polymorphisms have an effect on ADCC. This prospective phase II trial aimed to evaluate whether these polymorphisms are associated with clinical efﬁcacies in patients who received trastuzumab. Patients and methods: Patients in a neoadjuvant (N) setting received Adriamycin and cyclophosphamide followed by weekly paclitaxel/trastuzumab. Patients in a metastatic (M) setting received single trastuzumab until progression. In total, 384 distinct single nucleotide polymorphisms of different Fc c R, HER2, and fucosyltransferase loci were assessed. Results: Fifteen operable and 35 metastatic HER2-positive breast cancer patients were enrolled in each of the N and M settings, respectively. The Fc c R2A-131 H/H genotype was signiﬁcantly correlated with the pathologically documented response (pathological response) ( P = 0.015) and the objective response ( P = 0.043). The Fc c R3A-158 V/V genotype was not correlated with the pathological response, but exhibited a tendency to be correlated with the objective response. Patients with the Fc c R2A-131 H/H genotype had signiﬁcantly longer progression-free survival in the M setting ( P = 0.034). Conclusion: The Fc c R2A-131 H/H polymorphism predicted the pathological response to trastuzumab-based neoadjuvant chemotherapy in early-stage breast cancer, and the objective response to trastuzumab in metastatic breast cancer. range, PaO 2 ‡ 60 mmHg, baseline left ventricular ejection fraction > 50%). The main exclusion criteria were active concomitant malignancy, congestiveheartfailure,uncontrolledanginapectoris,arrhythmia, symptomatic infectious disease, severe bleeding, pulmonary ﬁbrosis, obstructive boweldiseaseorsevere diarrhea,symptomatic peripheralor cardiac effusion, and symptomatic brain metastasis. This study was conducted according to a protocol approved by the institutional review board/ independent ethics committee, and informed consent was obtained from all patients for the use of blood samples and the analysis of clinical information. patients were according to the selected Fc c R polymorphisms using a two-tailed Fisher’s exact test [23], chi-square test [23], linear correlation test [24], and analysis of variance (ANOVA) test [24]. Linkage disequilibrium was determined using a Fisher’s exact test, chi-square test, and linear correlation test. The PFS was calculated as the length of time between the ﬁrst day of trastuzumab treatment and the ﬁrst observation of disease progression or death from any cause. If a patient had not progressed or died, the PFS was censored at the time of the last follow-up examination. The association of each polymorphism with PFS was analyzed using Kaplan–Meier curves [25] and the log-rank test [26]. All tests of statistical signiﬁcance were two-tailed. The analyses were carried out using the SAS statistical package, version 9.0 (SAS Institute Inc., Cary, NC).