Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients.
Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients.
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DOI：
10.1158/1078-0432.ccr-11-2294
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发表时间：
2012-06-15
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影响因子：
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通讯作者：
Timmerman JM
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作者：
Hurvitz SA;Betting DJ;Stern HM;Quinaux E;Stinson J;Seshagiri S;Zhao Y;Buyse M;Mackey J;Driga A;Damaraju S;Sliwkowski MX;Robert NJ;Valero V;Crown J;Falkson C;Brufsky A;Pienkowski T;Eiermann W;Martin M;Bee V;Marathe O;Slamon DJ;Timmerman JM
曲妥珠单抗产生临床获益的机制仍不完全清楚。通过与白细胞上的Fcγ受体（FcγR）相互作用的抗体依赖性细胞毒性可能有助于其抗肿瘤作用。FCGR 3A和FCGR 2A基因中的单核苷酸多态性（SNP）分别导致位置158和131处的氨基酸取代，并影响抗体与FcγR的结合，使得158 V/V和131 H/H以最高亲和力结合。本研究旨在确定高亲和力SNP是否与HER 2阳性非转移性乳腺癌患者的无病生存期（DFS）相关。基因组DNA是从1,286名参与曲妥珠单抗辅助化疗试验的患者中分离出来的。使用桑格测序和Sequenom质谱进行基因分型。1，189例患者样本成功进行了FCGR 3A基因分型，1，218例成功进行了FCGR 2A基因分型。与BCIRG 006研究的总体结果相比，在该分析中基因分型的患者亚组中，与对照组相比，曲妥珠单抗组观察到DFS改善不太稳健（HR=0.842，P=0.1925）。根据预后特征分层时，有利于曲妥珠单抗的HR与总体研究一致（HR=0.74，P=0.036）。在曲妥珠单抗治疗患者中，DFS与FCGR 3A/2A基因型之间无相关性（158 V/V vs V/F vs F/F，P=0.98; 131 H/H vs H/R vs R/R，P=0.76; 158 V/V和/或131 H/H vs其他，P=0.67）。该分析评价了FCGR 3A/2A基因型与曲妥珠单抗在HER 2阳性乳腺癌中的疗效之间的相关性，但未证明FCGR 3A-V/F和FCGR 2A-H/R SNP与曲妥珠单抗治疗患者的DFS之间存在相关性。
The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its anti-tumor effects. Single nucleotide polymorphisms (SNPs) in FCGR3A and FCGR2A genes lead to amino acid substitutions at positions 158 and 131 respectively and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity. This study aimed to determine whether high affinity SNPs are associated with disease free survival (DFS) among patients with HER2-positive non-metastatic breast cancer. Genomic DNA was isolated from 1,286 patients enrolled in a trial of adjuvant trastuzumab-based chemotherapy. Genotyping was performed using Sanger sequencing and Sequenom mass spectrometry. 1,189 patient samples were successfully genotyped for FCGR3A and 1,218 for FCGR2A. Compared to the overall results of the BCIRG006 study, in the subset of patients genotyped in this analysis, a less robust improvement in DFS was observed for the trastuzumab arms compared to control arm (HR=0.842, P=0.1925). When stratified for prognostic features, the HR in favor of trastuzumab was consistent with that of the overall study (HR=0.74, P=0.036). No correlation between DFS and FCGR3A/2A genotypes was seen for trastuzumab-treated patients (158V/V vs V/F vs F/F, P=0.98; 131H/H vs H/R vs R/R, P=0.76; 158V/V and/or 131H/H vs others, P=0.67). This analysis evaluating the association between FCGR3A/2A genotypes and trastuzumab efficacy in HER2-positive breast cancer did not demonstrate a correlation between FCGR3A-V/F and FCGR2A-H/R SNPs and DFS in patients treated with trastuzumab.