Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling.
Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling.
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DOI：
10.1186/1756-0500-6-507
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发表时间：
2013-12-05
影响因子：
1.8
通讯作者：
O'Shaughnessy JA
中科院分区：
文献类型：
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作者：
Holmes FA;Espina V;Liotta LA;Nagarwala YM;Danso M;McIntyre KJ;Osborne CR;Anderson T;Krekow L;Blum JL;Pippen J;Florance A;Mahoney J;O'Shaughnessy JA
确定术前人表皮生长因子受体2（HER 2）靶向治疗前后肿瘤细胞的蛋白质分子特征，这些特征与术前HER 2靶向治疗和化疗的病理完全缓解（pCR）或无缓解（无pCR）相关。这项开放标签、II期研究将HER 2阳性II期或III期浸润性乳腺癌患者随机分配至曲妥珠单抗、拉帕替尼或两者，在化疗前2周和化疗期间使用FEC 75治疗4个疗程;然后紫杉醇80 mg/m2每周一次治疗12个疗程，然后进行手术。在基线时和化疗前抗HER 2治疗2周后收集芯针活检。数据与pCR相关，pCR定义为乳腺和淋巴结中没有浸润性肿瘤。在100例入组患者中，分析人群包括接受手术和接受≥75%化疗的患者（78% [n = 78]）。各组的pCR为：曲妥珠单抗（n = 26），54% [n = 14];拉帕替尼（n = 29），45% [n = 13];曲妥珠单抗+拉帕替尼（n = 23），74% [n = 17]。49例患者（63%）的配对活检标本可用。曲妥珠单抗或拉帕替尼治疗组中pCR患者的肿瘤细胞显示非磷酸化FOXO、磷酸化Stat 5和稀疏信号转导蛋白网络串扰，与无pCR患者相比，代表与PI 3 K和自噬蛋白的不同连接模式。在这项探索性研究中，术前抗HER 2治疗和化疗的pCR与肿瘤细胞中特定基线信号通路蛋白的水平和磷酸化状态相关。这些数据可能提供候选生物标志物，以分层初始治疗和潜在的联合治疗，用于未来的研究。这里介绍的组织保存技术使这一程序广泛可行。ClinicalTrials.gov：NCT00524303
To define protein molecular characteristics of tumor cells prior to, and immediately following, preoperative human epidermal growth factor receptor 2 (HER2)-targeted therapy that correlate with pathologic complete response (pCR) or non response (no pCR) to preoperative HER2-directed therapy and chemotherapy. This open-label, phase II study randomized patients with HER2-positive stage II or III invasive breast cancer to trastuzumab, lapatinib, or both, 2 weeks prior to and during chemotherapy with FEC75 for 4 courses; then paclitaxel 80 mg/m2 weekly for 12 courses, then surgery. Core needle biopsies were collected at baseline and after 2 weeks of anti-HER2 therapy prior to chemotherapy. Data were correlated with pCR, defined as absence of invasive tumor in breast and lymph nodes. Of 100 enrolled patients, the analysis population included those who had surgery and received ≥75% chemotherapy (78% [n = 78]). pCRs by arm are: trastuzumab (n = 26), 54% [n = 14]; lapatinib (n = 29), 45% [n = 13]; trastuzumab plus lapatinib (n = 23), 74% [n = 17]). Paired biopsy specimens were available for 49 patients (63%). Tumor cells of patients with pCR in the trastuzumab or lapatinib treatment arms showed nonphosphorylated FOXO, phosphorylated Stat5, and sparse signal-transduction protein network crosstalk representing different patterns of connections with PI3K and autophagy proteins compared with no pCR. In this exploratory study, pCR with preoperative anti-HER2 therapy and chemotherapy correlated with the levels and phosphorylation status of specific baseline signal pathway proteins in tumor cells. These data may provide candidate biomarkers to stratify initial treatment and potential combination therapies for future study. Tissue preservation technology introduced here makes this procedure widely feasible. ClinicalTrials.gov: NCT00524303