背景：在HR+/HER2-N0-1早期乳腺癌中，RSTM＞25的绝经后患者和相当大比例的绝经前患者似乎受益于辅助化疗（CT）和内分泌治疗（ET）。然而，这种治疗强度的绝对获益程度似乎取决于临床病理和生物学预后因素。首次报告前瞻性III期WSG-ADAPTHR/HER试验中CT结合了基线RS评分及动态（Ki67反应）生物标志物的结果，以优化管腔型乳腺癌的辅助治疗决策。

Background: In HR+/HER2- N0-1 early BC, postmenopausal patients (pts) with RS™> 25 and a substantial proportion of premenopausal pts seem to benefit from addition of adjuvant chemotherapy (CT) to endocrine therapy (ET). However, the magnitude of absolute benefit from this treatment intensification seems to depend on clinical-pathological and biological prognostic factors. For the first time, we present outcome from the CT part of the prospective phase III WSG-ADAPT HR+/HER- trial combining both static (RS in baseline core biopsy (CB) and dynamic (Ki67 response) biomarkers to optimize adjuvant therapy in luminal EBC.

方法：对临床高危型 HR/HER2-EBC（cT2-4 或临床 N+或 G3 或 Ki67＞15%）的乳腺癌患者，在手术或后续治疗前先给予标准内分泌治疗治疗 3 （+/-1） 周（绝经后 AI；绝经前：TAM）。然后 cN2-3 或 G3/Ki67＞40%的患者直接分配进一步化疗组。RS 评分 0-11 的 pN0-1 患者或 RS 评分 12-25 患者中内分泌反应可（内分泌后肿 中心区 Ki67＜10%）者仅接受单纯内分泌治疗；剩下的高危患者在初始内分泌治疗后随机进入化疗组接受辅助剂量密集化疗（4xPaclitaxela√4xEC q2w vs. 8xNab-Paclitaxel q1wa√4xEC q2w）。主要研究终点是 CT 生存期有效比较；次要终点包括关键预后因素对生存率的影响。Kaplan-Meier 和 Cox 比例风险模型用于估计生存曲线和风险比。在这一分析中，通过 RS/ET 反应确定了无选择偏差的亚组。

Methods: Pts with clinically high-risk HR+/HER2- EBC (cT2-4 OR clinically N+ OR G3 OR Ki67>15%) were initially treated by 3 (+/-1) weeks of standard ET (postmenopausal: mostly AI; premenopausal: TAM) before surgery or sequential CB. Pts with cN2-3 or G3/Ki67>40% were randomized directly to the CT trial. pN0-1 pts with RS0-11 OR RS12-25/ET-response (central Ki67postendocrine<10%) received ET alone; the remaining high-risk cohort was randomized to the CT trial: (neo)adjuvant dose-dense CT (4xPaclitaxelà4xEC q2w vs. 8xNab-Paclitaxel q1wà4xEC q2w) followed by ET. Primary endpoint is efficacy comparison of CT schedules for survival; secondary endpoints reported here involve impacts of key prognostic factors on survival. Kaplan-Meier and Cox proportional hazard models were used to estimate survival curves and hazard ratios. For this analysis, subgroups free of selection bias by RS/ET-response were defined.

结果：筛查 5625 例患者，4621 例（ITT）意向性人群入组。中位随访 4.9 年后，内分泌后较高基线的 Ki-67 水平与较差的 iDFS 相关（均 p＜0.001）。在化疗组（n=2331）中，高 RS 评分、淋巴结状态和肿瘤大小通常与较差的 IDF 相关。然而，iDFS 在 N1 and N0 患者中的差异仅存在年龄＜50 岁患者中。在 LN＞4 阳性的患者中（n=390），低 RS 与 iDFS 改善相关（RS0-11vsRS＞25：plogrank=0.016，5y-iDFS90%vs.64%）。在 RS＞25（n=965）的患者中，内分泌后低 Ki67、N0 状态和 c/pT1 状态与 iDFS 改善相关。尤其是内分泌治疗应答有反应者的 5y-iDFS（84%）高于 ET 无应答者（77%）；plog-rank=0.040）。年龄小于 50 岁的 N0-1 RS 12-25 的患者中， 无内分泌治疗应答反应的患者后续接受化疗的 5 年 iDFS（89%）与有内分泌应答反应仅接受内分泌治疗的 5 年 iDFS（92%）相比无显著性差异（plog-rank=0.249）。

Results: 5625 pts were screened and 4621 (ITT) entered the trial. After 4.9y median follow-up, higher baseline and post-endocrine Ki-67 levels were associated with poorer iDFS (both p < 0.001). In the CT cohort (n = 2331), higher RS, nodal status, and tumor size were generally associated with poorer iDFS. However, iDFS differed between N1 and N0 status only among younger pts (<50 years). In pts with >4 positive LN (n = 390), lower RS was associated with improved iDFS (RS0-11 vs RS > 25: plog-rank= 0.016, 5y-iDFS 90% vs. 64%). In pts with RS > 25 (n = 965), low Ki67postendocrine, N0 status, and c/pT1 status were associated with improved iDFS. In particular, ET-responders had higher 5y-iDFS (84%) than ET-non-responders (77%; plog-rank= 0.040). Younger patients (<50 years old) with N0-1 RS 12-25/ ET-non-responders treated by CT had non-significantly poorer 5-year iDFS (89%) compared to those with ET-response treated by ET only (92%) (plog-rank= 0.249).

结论：大型前瞻性 III 期临床研究 ADAPT 试验的前瞻性高危队列研究结果首次为部分 LN＞4 阳性和低 RS 评分的乳腺癌患者的良好预后提高研究证据。此外，内分泌治疗后较低的 Ki-67 和有限的肿瘤负荷可能是 CT 降阶治疗策略选择的一个有价值指标。

Conclusion: First results from the prospective high risk cohort from a large prospective phase III ADAPT trial provide evidence for good prognosis in some pts with >4 positive LN and e.g. low RS. Moreover combination of lower post-endocrine Ki-67 and limited tumor burden may be a promising criterion for CT de-escalation strategies even in patients with high RS.