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2015年ASCO年会即将揭幕。6月1日上午的乳腺癌口头报告专场上，将公布的一项2期临床研究，评估了12周的新辅助TDM1联合或不联合内分泌治疗对于HER2阳性激素受体阳性的早期乳腺癌的疗效（摘要号506）。医脉通对此进行了报道。

有证据表明，根据激素受体（HR）状态不同，标准新辅助化疗联合靶向治疗在HER2+早期乳腺癌（eBC）的疗效有所不同。ADAPT HER2+/HR+研究旨在确定双靶向治疗的应答者，这一问题也一直没有得到广泛的探讨。

380例患者（pts）接受12周的新辅助治疗。A/B 组：T-DM1(3.6mg/kg q3w）± 内分泌治疗（ET）（绝经前：他莫昔芬；绝经后：芳香化酶抑制剂）；C 组（对照组）：q3w曲妥珠单抗+ ET。手术后，患者每周接受4xEC–12x 紫杉醇（调查人员自由裁量）并完成1年曲妥珠单抗治疗。试验检测A和B 组患者的 pCR（达到yPN0 和 ypT0），检测值与C 组比较。生物标记物在基线和3周后测量。

预先计划中期分析（N=130）的目的是确定一个早应答的生物标记物（如Ki-67的下降），并验证试验的假设。患者中位年龄为49岁；55%为绝经前的患者；40%患者的肿瘤为cT1，51% 为cT2; 68% 为cN0，27%为cN1; 75%为G3。Ki67为中位基线的占30%。三组患者中，95－100%的患者接受了全部4个周期的治疗。12例患者（A组4例; B组6例; C组2例）中发生了15件严重不良事件，大多数是CTC2级（9例）或3级（4例）；所有患者完全恢复，无后遗症。

总pCR 率为30.8%：A、B和C三组分别为40.5%、45.8%和6.7％。A或B与C组之间的差异是具有统计学意义的（p< 0.001），但A、B两组间差异不大。探索性分析表明，对于绝经前患者，在T-DM1中加入内分泌治疗 是有益处的(pCR:单药T-DM1为28.6% vs. T-DM1＋ET为47.6%)，但这对于绝经后患者却不是如此（pCR: 64.3% vs. 50%）。有43.1%的患者3周内活检时不可能实现Ki-67的定量，主要是由于低肿瘤细胞计数（< 500）；其余的肿瘤中，治疗一周期后，有21.6%（16/74）的肿瘤中Ki-67≤10%。这些结果也可能受不同内分泌治疗选择（Tam vs. AI）而影响，仍然需要最终的数据来证实。

中期分析首次证明了，对于HER2+/HR+早期乳腺癌患者，仅12周的T-DM1±ET（没有全身化疗）获得的pCR 率（> 40%）具有临床意义。正在进行的生物标记物分析包括PI3K突变和内在的亚型。在2015年1月，有449例患者完成注册。临床试验信息：NCT01745965

会议专题》》》2015年ASCO年会专题报道

摘要原文（摘要号506）

Background: Evidence suggests differential efficacy of standard neoadjuvant chemo- + targeted therapy in HER2+ early breast cancer (eBC) according to hormone-receptor (HR) status. ADAPT HER2+/HR+ aims to identify responders to dual targeted therapy, which has not been widely explored. 

Methods: 380 patients (pts) receive 12 weeks of neoadjuvant therapy. Arms A/B: T-DM1 (3.6 mg/kg q3w) ± endocrine therapy (ET) (pre-: tamoxifen; postmenopausal: aromatase inhibitor); Arm C (control): q3w trastuzumab + ET. After surgery, pts are to receive 4xEC – 12xpaclitaxel weekly (investigators’ discretion) and complete 1y trastuzumab. Trial tests pCR (yPN0 and ypT0/is) in Arms A and B compared to control (C). Biomarkers are measured at baseline and after 3 weeks. 

Results: Pre-planned interim analysis (n = 130) aimed to identify an early-response biomarker (e.g. Ki-67 drop) and to validate trial assumptions. Median age was 49 years; 55% were pre-menopausal; 40% had cT1 tumors, 51% cT2; 68% had cN0, 27% cN1; 75% had G3. Median baseline Ki67 was 30%. In all arms, 95-100% received all 4 therapy cycles. 15 SAEs occurred in 12 pts (A:4; B:6; C:2), majority are CTC grades 2 (9) or 3 (4); all pts completely recovered without sequelae. Overall pCR rate was 30.8%: A: 40.5%, B: 45.8%, C: 6.7%. The difference between either arm A or B vs. C was significant (p < 0.001), but not A vs. B. Exploratory analysis suggests benefit of adding ET to T-DM1 in pre- (pCR: 28.6% for T-DM1 single agent vs. 47.6% with ET) but not in postmenopausal pts (pCR: 64.3% vs. 50%). Ki-67 quantification in the 3-week biopsy was not possible in 43.1%, mostly due to low tumor cell counts ( < 500); of the remaining tumors, 21.6% (16/74) had Ki-67 ≤ 10% after first cycle. Final data set is required to substantiate these findings which may also be impacted by the different ET options (Tam vs. AI). 

Conclusions: The interim analysis demonstrates for the first time clinically meaningful pCR rates ( > 40%) after only 12 weeks of T-DM1 ± ET without systemic chemotherapy in HER2+/HR+ eBC. Ongoing biomarker analyses include PI3K mutations and intrinsic subtypes. In 1/2015, registration phase was completed at 449 pts. Clinical trial information: NCT01745965