Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib
Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib
复制标题
DOI：
10.1200/jco.2015.62.1268
复制
发表时间：
2016-02-20
影响因子：
45.3
通讯作者：
Hudis, Clifford A.
中科院分区：
文献类型：
--
作者：
Carey, Lisa A.;Berry, Donald A.;Hudis, Clifford A.
目的：双人表皮生长因子受体2 （HER2）靶向治疗可提高转移性疾病患者新辅助治疗的病理完全缓解率（pCRs），提高无进展生存期。CALGB 40601考虑肿瘤和微环境分子特征，研究了曲妥珠单抗和拉帕替尼加入紫杉醇的双重HER2阻断的影响。II至III期her2阳性乳腺癌患者接受肿瘤活检，然后在手术前16周随机分配紫杉醇加曲妥珠单抗（TH）或加用拉帕替尼（THL）。紫杉醇加拉帕替尼（TL）的一个研究组提前结束。主要终点为乳腺pCR；相关终点集中于基于基因表达的检测所鉴定的分子特征。结果305例随机分组患者（THL， n - 118例；TH， n - 120例；TL， n - 67例）中，THL组pCR率为56% (95% CI, 47% ~ 65%)， TH组pCR率为46% (95% CI, 37% ~ 55%) (P = 0.13)，激素受体阳性亚群双治疗无效果，激素受体阴性亚群双治疗pCR率显著增加（P = 0.01）。通过mRNA测序（mRNAseq）进行基因表达分析，发现肿瘤具有分子异质性。不同内在亚型的pCR率差异显著（HER2富集，70%;luminal A, 34%; luminal B, 36%; P < 0.001）。在多变量分析治疗组中，内在亚型、HER2扩增子基因表达、p53突变特征和免疫细胞特征与pCR独立相关。治疗后残留病变主要为腔内A（69%）。结论双HER2靶向治疗的pcr效果不显著高于单HER2靶向治疗。组织分析表明，在肿瘤基因组学和肿瘤微环境方面，肿瘤间存在高度异质性，这显著影响了pCR率。在解释和设计her2阳性疾病的试验时应考虑这些因素。(C) 2015年由美国临床肿瘤学会出版
PurposeDual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features.Patients and MethodsPatients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression-based assays.ResultsAmong 305 randomly assigned patients (THL, n - 118; TH, n - 120; TL, n - 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in pCR with dual therapy in those with hormone receptor-negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P < .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%).ConclusionpCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease. (C) 2015 by American Society of Clinical Oncology