Kim Sung-Bae, Wildiers Hans, Krop Ian E, Smitt Melanie, Yu Ron, Lysbet de Haas Sanne, Gonzalez-Martin Antonio
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
Int J Cancer. 2016 Nov 15;139(10):2336-42. doi: 10.1002/ijc.30276. Epub 2016 Jul 26.
In the phase III TH3RESA study (NCT01419197), 602 patients with HER2-positive advanced breast cancer who received prior taxane therapy and ≥2 HER2-directed regimens, including trastuzumab and lapatinib (advanced setting), were randomized to trastuzumab emtansine (T-DM1) or treatment of physician's choice (TPC). A statistically significant progression-free survival (PFS) benefit favoring T-DM1 was demonstrated. Here, we examine the relationship between HER2-related biomarkers and PFS in an exploratory analysis. Biomarkers assessed included HER2 (n = 505) and HER3 (n = 505) mRNA expression, PIK3CA mutation status (n = 410) and PTEN protein expression (n = 358). For biomarkers with continuous data (HER2, HER3, PTEN), subgroups were defined using median values (>median and ≤median). For all biomarker subgroups, median PFS was longer with T-DM1 vs. TPC. The PFS benefit favoring T-DM1 vs. TPC was numerically greater in the HER2 mRNA >median subgroup (7.2 vs. 3.4 months; unstratified hazard ratio [HR], 0.40; 95% CI, 0.28-0.59; p < 0.0001) vs. ≤median subgroup (5.5 vs. 3.9 months; HR, 0.68; 95% CI, 0.49-0.92; p = 0.0131). The PFS benefit with T-DM1 was similar among HER3, PIK3CA and PTEN subgroups. Consistent with other reports, benefit was seen with T-DM1 regardless of PIK3CA mutation status. In a multivariate analysis including an interaction term (treatment group by log2-transformed HER2 mRNA), patients with higher HER2 mRNA levels benefited more from receiving T-DM1 (HR, 0.84; 95% CI, 0.75-0.94; interaction p value = 0.0027). In summary, T-DM1 prolonged median PFS in all biomarker subgroups analyzed, including activating PIK3CA mutations, with numerically greater benefit in patients with tumors expressing HER2 mRNA >median vs. ≤median.
在III期TH3RESA研究（NCT01419197）中，602例HER2阳性晚期乳腺癌患者接受过紫杉烷类治疗以及≥2种HER2靶向治疗方案（包括曲妥珠单抗和拉帕替尼，晚期治疗阶段），被随机分为接受曲妥珠单抗 emtansine（T-DM1）或医生选择的治疗（TPC）。结果显示T-DM1具有显著的无进展生存期（PFS）获益。在此，我们在一项探索性分析中研究HER2相关生物标志物与PFS之间的关系。评估的生物标志物包括HER2（n = 505）和HER3（n = 505）mRNA表达、PIK3CA突变状态（n = 410）以及PTEN蛋白表达（n = 358）。对于具有连续数据的生物标志物（HER2、HER3、PTEN），亚组通过中位数（>中位数和≤中位数）进行定义。对于所有生物标志物亚组，T-DM1组的中位PFS均长于TPC组。与TPC相比，HER2 mRNA>中位数亚组中T-DM1的PFS获益在数值上更大（7.2个月对3.4个月；非分层风险比[HR]，0.40；95%CI，0.28 - 0.59；p < 0.0001），而≤中位数亚组中为（5.5个月对3.9个月；HR，0.68；95%CI，0.49 - 0.92；p = 0.0131）。T-DM1在HER3、PIK3CA和PTEN亚组中的PFS获益相似。与其他报告一致，无论PIK3CA突变状态如何，T-DM1均显示出获益。在一项包含交互项（治疗组×log2转换后的HER2 mRNA）的多变量分析中，HER2 mRNA水平较高的患者接受T-DM1的获益更大（HR，0.84；95%CI，0.75 - 0.94；交互p值 = 0.0027）。总之，T-DM1延长了所有分析的生物标志物亚组的中位PFS，包括激活的PIK3CA突变，在HER2 mRNA表达>中位数的肿瘤患者中获益在数值上大于≤中位数的患者。
