背景： 選擇性降階梯治療特別是豁免化療在 HER+ 性早期乳腺癌中生存獲益數據有限， ADAPT-HR-/HER2 前期研究結果顯示，在 HR-/ HER2+早期乳腺癌中新輔助紫杉醇治療 12 周加雙靶 pCR 率可達 90%，單獨使用 PT 治療具有實質性和臨床意義的 pCR 率為 34%。此次第一次報告生存數據。

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期試驗是 ADAP 傘形研究的一部分。共 134 例cT1-cT4c、cN0-3 HR-/HER2 乳腺癌患者隨機分配至 4 個周期 pertuzumab+trastuzumabPT 加減紫衫 d1、8、15q3w 兩組。所有腫瘤HR 陰性（ER 和 PR＜1%），HER2 陽性（中心實驗室，2+ FISH檢測陽性，免疫組化 3+）。主要研究終點為 pCR（ypT0/is/ypN0）；此研究旨在比較 P+T+pac 組與單純 P+T 組的 pCR 及早期治療應答反應（定義為低細胞數和/或 3 周後 Ki67 下降＞30%）。由於在 P+T+pac 臂中觀察到 pCR 優越性，試驗提前停止。次要終點包括安全性、5-年 DFS、OS和轉化研究。應用 Cox 回歸分析。采用 BC360 量表評估 PAM50 亞型。

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.

結果：134 例患者隨機分 P+T 組（92 例）和 P+T+pac 組（42 例），60%患者 cT2-4， 42%患者淋巴結陽性。中位隨訪 5 年，研究組之間在 DFS、dDFS 和 OS 方麵無顯著差異；整個 ITT 人群中僅觀察到 13 例 iDFS 事件（7 例 DDF）。12 周治療後 pCR 組患者及 non-pCR 患者（不考慮 study arm）與 iDFS 改善密切相關（5yDFS 98.5%與 82%，HR=0.14，95%CI0.03-0.64）。在 69 例 pCR患者中，39 例（56.5%）未接受進一步 CT（P+T 組：n=9，29%；P+T+pac 組：n=30，79%），在這些患者中僅觀察到 1 例遠處複發（1.4%）。在無化療的的 P+T 組中，HER2 低表達（IHC1/2和 FISH 陽性）和/或 PAM50 基底樣亞型患者（n=17，19%）未觀察到 pCR。在整體研究人群中，HER2 低表達和/或無早期反應與更差 dDFS（p=0.029）和 iDFS（p=0.068）密切相關。沒有觀察到新的安全信號。

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.

結論：在前瞻性多中心研究中，首次顯示無論是否行進一步化療，新輔助降階梯治療 CT+P+T都有良好的 PCR 及生存 。無化療方案的治療方案可能需要選取（例如 HER2 高表達/非基底樣腫瘤）的患者。ADAPT HR-/HER2+研究中，12 周期 P+T+pac 治療後 pCR 與預後改善密切相關，因此可以作為進一步（降階梯）治療的預測性指標。

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.