美国《临床肿瘤杂志》2017年7月6日在线先发
http://ascopubs.org/doi/full/10.1200/JCO.2016.71.9815
在HER2阳性早期乳腺癌中的降阶梯策略：“在HER2和HR均阳性的早期乳腺癌中优化风险评价和优化疗效预测并依据标志物进行动态调整的个体化辅助治疗的II期随机化西德研究组临床试验”的终期分析——曲妥珠单抗美坦辛±内分泌治疗对比曲妥珠单抗+内分泌治疗的疗效、安全性和预测性标志物
目的
人表皮生长因子受体2（HER2）阳性/激素受体（HR）阳性乳腺癌是一种独特亚型，与HER2阳性/HR阴性乳腺癌相比，化疗敏感性低，但转归略好。“西德研究组临床试验ADAPT（在早期乳腺癌中优化风险评价和优化疗效预测并依据标志物进行动态调整的个体化辅助治疗试验）”在HER2阳性/HR阳性早期乳腺癌中比较了曲妥珠单抗美坦辛（T-DM1）对比曲妥珠单抗的病理完全缓解率（pCR）。
患者与方法
在这项前瞻性II期新辅助临床试验中，随机将375名HER2阳性、HR阳性的早期乳腺癌患者分组，一组为12周的曲妥珠单抗美坦辛（T-DM1）±内分泌治疗，一组为12周的曲妥珠单抗+内分泌治疗。主要终点为病理完全缓解率（ypT0/is/ypN0），次要终点包括安全性和对病理完全缓解率（pCR）早期反应的预测影响。遵循国家标准进行辅助治疗。
结果
各组间入组时的基线特征基本一致，超过90%的患者按照试验方案完成了治疗。观察到曲妥珠单抗美坦辛（T-DM1）治疗的患者有41.0%获得病理完全缓解，曲妥珠单抗美坦辛（T-DM1）+内分泌治疗的患者有41.5%，曲妥珠单抗+内分泌治疗的患者有15.1%（P<0.001）。早期有治疗响应者（占可评价治疗响应患者的67%）有35.7%获得了病理完全缓解、无响应者有19.8%（比值比，2.2；95%CI，1.24-4.19）。曲妥珠单抗美坦辛（T-DM1）与1、2级毒性发生率明显高相关，特别是血小板减少、恶心和肝酶升高。总的毒性不高，报告了17件治疗相关性严重不良事件（T-DM1组对比曲妥珠单抗+内分泌治疗组分别为5.3%对比3.1%）。
结论
ADAPT HER2阳性/HR阳性试验表明，给予仅2周的曲妥珠单抗美坦辛（T-DM1）（联合或不联合内分泌治疗）新辅助治疗，可获得有临床意义的病理完全缓解，因此，相当数量的患者可免受全身化疗的不利影响。
De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor–Positive Phase II Randomized Trial—Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET
Purpose
Human epidermal growth factor receptor 2 (HER2)–positive/hormone receptor (HR)–positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer.
Patients and Methods
In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards.
Results
Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET (P < .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen therapy-related severe adverse events (T-DM1 arms v trastuzumab plus ET; 5.3% v 3.1%, respectively) were reported.
Conclusion
The ADAPT HER2-positive/HR-positive trial demonstrates that neoadjuvant T-DM1 (with or without ET) given for only 12 weeks results in a clinically meaningful pCR rate. Thus, a substantial number of patients are spared the adverse effects of systemic chemotherapy.
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