背景: 选择性降阶梯治疗特别是豁免化疗在 HER+ 性早期乳腺癌中生存获益数据有限, ADAPT-HR-/HER2 前期研究结果显示,在 HR-/ HER2+早期乳腺癌中新辅助紫杉醇治疗 12 周加双靶 pCR 率可达 90%,单独使用 PT 治疗具有实质性和临床意义的 pCR 率为 34%。此次第一次报告生存数据。 Background: Optimal use of de-escalate
背景: 选择性降阶梯治疗特别是豁免化疗在 HER+ 性早期乳腺癌中生存获益数据有限, ADAPT-HR-/HER2 前期研究结果显示,在 HR-/ HER2+早期乳腺癌中新辅助紫杉醇治疗 12 周加双靶 pCR 率可达 90%,单独使用 PT 治疗具有实质性和临床意义的 pCR 率为 34%。此次第一次报告生存数据。
Background: Optimal use of de-escalated, particularly chemotherapy(CT)-free, neoadjuvant regimens in HER2+ early breast cancer (EBC) is currently unclear as there are limited survival data so far. In ADAPT-HR-/HER2+, we previously showed an excellent pCR rate of 90% after 12-week neoadjuvant paclitaxel (Pac) +pertuzumab (P) +trastuzumab (T) and a substantial and clinically meaningful pCR rate of 34% after P+T alone in HR-/HER2+ EBC. Here, we present first survival data.
方法:前瞻性多中心 WSG-ADAPT-HR-/HER2Ⅱ期试验是 ADAP 伞形研究的一部分。共 134 例cT1-cT4c、cN0-3 HR-/HER2 乳腺癌患者随机分配至 4 个周期 pertuzumab+trastuzumabPT 加减紫衫 d1、8、15q3w 两组。所有肿瘤 HR 阴性(ER 和 PR<1%),HER2 阳性(中心实验室,2+ FISH检测阳性,免疫组化 3+)。主要研究终点为 pCR(ypT0/is/ypN0);此研究旨在比较 P+T+pac 组与单纯 P+T 组的 pCR 及早期治疗应答反应(定义为低细胞数和/或 3 周后 Ki67 下降>30%)。由于在 P+T+pac 臂中观察到 pCR 优越性,试验提前停止。次要终点包括安全性、5-年 DFS、OS和转化研究。应用 Cox 回归分析。采用 BC360 量表评估 PAM50 亚型。
Methods: The prospective multicenter WSG-ADAPT-HR-/HER2+ phase II-trial is part of the ADAPT-umbrella protocol. Patients with cT1-cT4c, cN0-3 HR-/HER2+ EBC (n = 134) were randomized to 4 cycles of P+T +/- pac d1,8,15 q3w. All tumors were HR-negative (ER and PR < 1%) and HER2-positive (central lab, i.e., 2+ FISH positive or 3+ by immunohistochemistry. Primary endpoint was pCR (ypT0/is/ypN0); omission of further CT was allowed in pts with pCR. Trial objective was to compare pCR in P+T+pac arm vs. early responders in P+T arm (defined as low cellularity and/or Ki67 decrease >30% after 3 weeks). The trial was stopped early due to the observed pCR superiority in the P+T+pac arm. Secondary endpoints included safety, 5-y (distant)-DFS, OS and translational research. Cox-regression analysis was applied. PAM50 subtype was assessed using the BC360 panel.
结果:134 例患者随机分 P+T 组(92 例)和 P+T+pac 组(42 例),60%患者 cT2-4, 42%患者淋巴结阳性。中位随访 5 年,研究组之间在 DFS、dDFS 和 OS 方面无显著差异;整个 ITT 人群中仅观察到 13 例 iDFS 事件(7 例 DDF)。12 周治疗后 pCR 组患者及 non-pCR 患者(不考虑 study arm)与 iDFS 改善密切相关(5yDFS 98.5%与 82%,HR=0.14,95%CI0.03-0.64)。在 69 例 pCR患者中,39 例(56.5%)未接受进一步 CT(P+T 组:n=9,29%;P+T+pac 组:n=30,79%),在这些患者中仅观察到 1 例远处复发(1.4%)。在无化疗的的 P+T 组中,HER2 低表达(IHC1/2和 FISH 阳性)和/或 PAM50 基底样亚型患者(n=17,19%)未观察到 pCR。在整体研究人群中,HER2 低表达和/或无早期反应与更差 dDFS(p=0.029)和 iDFS(p=0.068)密切相关。没有观察到新的安全信号。
Results: 134 patients were randomized to P+T (n = 92) or P+T+pac (n = 42). 60% of tumors were cT2-4, 42% clinically node-positive. After a median follow-up of 5 years, no significant differences between study arms were observed regarding DFS, dDFS, and OS; only 13 iDFS events (7 dDFS) were observed in the whole ITT population. pCR (vs. non-pCR) after the 12-week study treatment (irrespective of study arm) was strongly associated with improved iDFS (5y DFS 98.5% vs. 82%, HR = 0.14, 95% CI 0.03-0.64). Of the 69 patients with pCR, 39 (56.5%) received no further CT (P+T arm: n = 9, 29% vs. (P+T+pac arm n = 30, 79%); only 1 distant relapse (1.4%) was observed in these patients. In the CT-free P+T arm, no pCR was observed in patients with low HER2 expression (IHC 1+/2+ and FISH positive) and/or basal-like subtype by PAM50 (n = 17, 19%). In the total study population, low HER2 expression and/or no early response was strongly associated with worse dDFS (p =.029) and iDFS (p =.068). No new safety signals were observed.
结论:在前瞻性多中心研究中,首次显示无论是否行进一步化疗,新辅助降阶梯治疗 CT+P+T都有良好的 PCR 及生存 。无化疗方案的治疗方案可能需要选取(例如 HER2 高表达/非基底样肿瘤)的患者。ADAPT HR-/HER2+研究中,12 周期 P+T+pac 治疗后 pCR 与预后改善密切相关,因此可以作为进一步(降阶梯)治疗的预测性指标。
Conclusions: For the first time, we have shown both excellent pCR and survival in patients treated by de-escalated neoadjuvant CT+P+T irrespective of further CT use in a prospective multicenter study. Investigation of CT-free regimens may need to be focussed on selected patients only (e.g. with high HER2 expression/non-basal-like tumors). In ADAPT HR-/HER2+, early pCR after only 12 weeks of neoadjuvant P+T+pac was strongly associated with improved outcome and may thus serve as a predictive clinical marker for further treatment (de)-escalation.
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