Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer
Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer
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DOI：
10.1200/jco.20.01276
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发表时间：
2020-12-10
影响因子：
45.3
通讯作者：
Carey, Lisa A.
中科院分区：
文献类型：
--
作者：
Fernandez-Martinez, Aranzazu;Krop, Ian E.;Carey, Lisa A.
CALGB 40601评估了新辅助化疗中加入双重与单一人表皮生长因子受体2（HER 2）靶向药物是否会增加病理完全缓解（pCR）。在这里，我们报告无复发生存期（RFS），总生存期（OS），和基因表达的签名，预测pCR和survival.Patients和方法305名未经治疗的第二和第三阶段HER 2阳性乳腺癌的妇女被随机分配到接受每周紫杉醇联合曲妥珠单抗加拉帕替尼（THL），曲妥珠单抗（TH），或拉帕替尼（TL）。主要终点为pCR，次要终点包括RFS、OS和基因表达分析。结果118例患者随机分为THL组，120例TH组，67例TL组。在超过7年的随访中，THL的RFS和OS显著优于TH（RFS风险比，0.32; 95% CI，0.14至0.71; P = 0.005; OS风险比，0.34; 95% CI，0.12至0.94; P = 0.037），TH和TL之间没有差异。在先前描述的688个基因表达特征中，215个与pCR显著相关，45个与RFS显著相关，只有22个与pCR和RFS显著相关（3.2%）。具体而言，8种免疫特征与较高的pCR率和较好的RFS显著相关。残留疾病的患者中，免疫球蛋白G签名是一个独立的，良好的预后因素，而HER 2富集的签名，这是一个较高的pCR率，表现出显着较短的RFS.CONCLUSION在CALGB 40601，双重HER 2靶向导致显着的RFS和OS的好处。整合内在亚型和免疫特征可以预测总体和残留疾病组内的pCR和RFS。这些方法可以为HER 2阳性乳腺癌的合理升级和降级治疗策略提供手段。(C)2020年美国临床肿瘤学会
PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival.PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples.RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS.CONCLUSION In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer. (C) 2020 by American Society of Clinical Oncology