PURPOSE The primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2+) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses. EXPERIMENTAL DESIGN pCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes. RESULTS The numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34-66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24-54]) or neratinib (33% [95%CI 20-50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR-) tumors had a higher pCR rate than HR+ tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR. CONCLUSIONS Combining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR- patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2+ patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting. TRIALS REGISTRATION ClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.

中文翻译：

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NSABP FB-7：在HER2 +乳腺癌中，紫杉醇+曲妥珠单抗和/或neratinib联合化疗和术后曲妥珠单抗的II期随机新辅助试验。

目的NSABP FB-7的主要目的是确定在接受新辅助曲妥珠单抗或那拉替尼或其组合和每周紫杉醇联合标准阿霉素加环磷酰胺治疗的局部晚期HER2阳性（HER2 +）乳腺癌患者中的病理完全缓解（pCR）率。次要目标包括生物标志物分析。实验设计测试了pCR与IgG受体IIIa-158V / F（FCGR3A）的Fc片段的治疗，基因表达和单核苷酸多态性（SNP）的关联。还比较了治疗前的活检和残留肿瘤，以鉴定分子变化。结果：曲妥珠单抗联合那拉替尼组（50％[95％CI 34-66％]）的pCR数值高于曲妥珠单抗（38％[95％CI 24-54]）或那拉替尼（总体队列中有33％[95％CI 20-50]），但无统计学意义。在所有三个治疗组中，激素受体阴性（HR-）肿瘤的pCR率均高于HR +肿瘤，在组合组中pCR率最高。腹泻是最常见的不良事件，几乎发生在所有接受了那拉替尼治疗的患者中。31％的患者报告有3级腹泻。没有4年级的事件。我们的8基因签名先前在佐剂环境中的两项不同临床试验中证实了曲妥珠单抗的益处，并且与NSABP FB-7所有方面的pCR相关。具体来说，预计未获得曲妥珠单抗获益的患者的pCR率显着低于预计获得最大益处的患者（P = 0.03）。FCGR基因分型显示，对于FCGR3A-158V / F的Fc低结合苯丙氨酸（F）等位基因纯合的患者，实现pCR的可能性较小。结论将曲妥珠单抗加纳那替尼与紫杉醇联合使用可增加总体队列和HR患者的绝对pCR率。经过验证可预测曲妥珠单抗在辅助治疗中获益的8基因签名在新辅助治疗中与pCR相关，但在更大的新辅助临床试验中仍有待作为预测标志物进行验证。HR状态和FCGR3A-158V / F基因型，还需要进一步研究，以鉴定可能从曲妥珠单抗以外的其他抗HER2治疗中受益的HER2 +患者。所有这些标记都需要在新辅助治疗中进一步验证。试验注册ClinicalTrials.gov，NCT01008150。追溯注册于2010年10月5日。