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.
J Clin Oncol. 2016 Mar 20;34(9):936-44. doi: 10.1200/JCO.2015.62.4767. Epub 2016 Jan 25.
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.
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).
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).
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.
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。
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。
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）。
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。
