血清人表皮生长因子 2 细胞外结构域作为晚期乳腺癌患者拉帕替尼治疗疗效的预测性生物标志物。
Serum Human Epidermal Growth Factor 2 Extracellular Domain as a Predictive Biomarker for Lapatinib Treatment Efficacy in Patients With Advanced Breast Cancer.
机构信息
Chee Khoon Lee, Lucy Davies, Val J. Gebski, Sarah J. Lord, Ian Marschner, and John Simes, University of Sydney; Sarah J. Lord, University of Notre Dame; Ian Marschner, Macquarie University; Paul de Souza, University of Western Sydney, Sydney, New South Wales; Sherene Loi, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Italy; Stephen Johnston, Royal Marsden Hospital, London; David Cameron, University of Edinburgh, Edinburgh, United Kingdom; Charles Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; Michael F. Press, University of Southern California, Los Angeles, CA; and Catherine Ellis, GlaxoSmithKline, Collegeville, PA.
出版信息
J Clin Oncol. 2016 Mar 20;34(9):936-44. doi: 10.1200/JCO.2015.62.4767. Epub 2016 Jan 25.
PURPOSE
We examined the prognostic and predictive value of serum human epidermal growth factor 2 (HER2) extracellular domain (sHER2) in patients with advanced breast cancer treated with lapatinib using data from three randomized trials.
PATIENTS AND METHODS
We analyzed sHER2 and tissue HER2 (tHER2) data from 1,902 patients (84%) who were randomly assigned to receive lapatinib or control in the trials EGF30001, EGF30008, and EGF100151. Cox regression analyses were performed to correlate both biomarkers with progression-free survival (PFS) and overall survival (OS).
RESULTS
Median sHER2 levels were 25.1 and 10.1 ng/mL in tHER2-amplified (tHER-positive) and nonamplified (tHER-negative) populations, respectively (r = 0.42 for sHER2-tHER2 correlation). Lapatinib had significant PFS benefit over control (hazard ratio [HR], 0.855; P = .004), but not OS (HR, 0.941; P = .33). Lapatinib PFS benefit is independently predicted by higher sHER2 values (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.009 v nonlapatinib-containing therapies, 1.044; P(interaction) < .001) and by positive tHER2 (HR [lapatinib v nonlapatinib]: tHER2 positive, 0.638 v tHER2 negative, 0.940; P(interaction) = .001). Within the tHER2-positive subpopulation (n = 515), higher sHER2 values still independently predicted lapatinib PFS benefit (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.017 v nonlapatinib-containing therapies, 1.041; P(interaction) = .008). In control arms (n = 936), higher sHER2 was associated with worse prognosis in multivariable analyses (PFS HR per 10 ng/mL: PFS, 1.024; P < .001; and OS, 1.018; P < .001).
CONCLUSION
Higher sHER2 predicts greater PFS benefit with lapatinib independent of tHER2 status. High sHER2 is also independently prognostic for worse survival in patients who received nonlapatinib-containing therapies. The predictive role of sHER2 for other anti-HER2 agents requires further research.
目的
我们利用三项随机试验的数据，检测了晚期乳腺癌患者接受拉帕替尼治疗时血清人表皮生长因子 2 （HER2）细胞外域（sHER2）的预后和预测价值。
方法
我们分析了试验 EGF30001、EGF30008 和 EGF100151 中 1902 例（84%）随机分配接受拉帕替尼或对照治疗患者的 sHER2 和组织 HER2（tHER2）数据。采用 Cox 回归分析将这两种生物标志物与无进展生存期（PFS）和总生存期（OS）进行相关性分析。
结果
tHER2 扩增（tHER-阳性）和非扩增（tHER-阴性）人群的中位 sHER2 水平分别为 25.1 和 10.1ng/mL（sHER2-tHER2 相关性 r = 0.42）。与对照组相比，拉帕替尼治疗具有显著的 PFS 获益（风险比 [HR]，0.855；P =.004），但 OS 无获益（HR，0.941；P =.33）。sHER2 值越高，预测拉帕替尼 PFS 获益的作用越显著（sHER2 每增加 10ng/mL，接受拉帕替尼治疗的 HR：1.009 比不接受拉帕替尼治疗的 HR：1.044；P（交互作用）<.001），且 tHER2 阳性预测作用更显著（与不接受拉帕替尼治疗相比，接受拉帕替尼治疗的 HR：tHER2 阳性，0.638；tHER2 阴性，0.940；P（交互作用）=.001）。在 tHER2 阳性亚组（n = 515）中，sHER2 值越高，仍然可以独立预测拉帕替尼的 PFS 获益（sHER2 每增加 10ng/mL，接受拉帕替尼治疗的 HR：1.017 比不接受拉帕替尼治疗的 HR：1.041；P（交互作用）=.008）。在对照组（n = 936）中，sHER2 值越高，多变量分析显示预后越差（PFS HR 每增加 10ng/mL：PFS，1.024；P<.001；OS，1.018；P<.001）。
结论
sHER2 水平越高，预测拉帕替尼治疗的 PFS 获益越大，且与 tHER2 状态无关。在接受非拉帕替尼治疗的患者中，sHER2 水平较高也独立预示着生存率更差。sHER2 对其他抗 HER2 药物的预测作用需要进一步研究。
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