German Breast Group, Neu-Isenburg, Germany; Universität Frankfurt, Frauenklinik, Frankfurt, Germany.
Universität Heidelberg, Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany.
Lancet Oncol. 2014 Jun;15(7):747-56. doi: 10.1016/S1470-2045(14)70160-3. Epub 2014 Apr 30.
Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer.
Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880.
296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5.
The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer.
GlaxoSmithKline, Roche, and Teva.
临床前数据表明，三阴性乳腺癌对链间交联剂敏感，并且对于曲妥珠单抗联合紫杉烷和铂盐治疗 HER2 阳性乳腺癌，可能存在协同作用。因此，我们旨在评估卡铂联合新辅助治疗三阴性和 HER2 阳性乳腺癌的疗效。
招募了先前未经治疗、无转移、ⅡB-ⅢB 期的三阴性乳腺癌和 HER2 阳性乳腺癌患者。患者接受 18 周的紫杉醇（80mg/m²，每周一次）和非聚乙二醇化脂质体多柔比星（20mg/m²，每周一次）治疗。三阴性乳腺癌患者同时接受贝伐珠单抗（15mg/kg，每 3 周静脉注射一次）治疗。HER2 阳性疾病患者同时接受曲妥珠单抗（初始剂量 8mg/kg，随后剂量为 6mg/kg，每 3 周静脉注射一次）和拉帕替尼（750mg/d）治疗。根据生物学亚型和 Ki-67 水平，患者以 1:1 的比例进行随机分组，采用动态分配和最小化分层，同时接受卡铂（AUC 1.5[前 329 例患者为 2.0]，每周一次）或不接受卡铂治疗。主要终点为达到病理完全缓解（定义为 ypT0ypN0）的患者比例，对所有开始治疗的患者进行分析；主要终点的 p 值<0.2 被认为有统计学意义。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01426880。
296 例患者随机分配接受卡铂治疗，299 例患者接受无额外卡铂治疗，分别有 295 例和 293 例患者开始治疗。在最终分析中，卡铂组 129 例（43.7%，95%CI 38.1-49.4）患者达到病理完全缓解，而无卡铂组 108 例（36.9%，31.3-42.4）患者达到病理完全缓解（比值比 1.33，95%CI 0.96-1.85；p=0.107）。在三阴性乳腺癌患者中，卡铂组 158 例患者中有 84 例（53.2%，54.4-60.9）达到病理完全缓解，而无卡铂组 157 例患者中有 58 例（36.9%，29.4-44.5）达到病理完全缓解（p=0.005）。在 HER2 阳性肿瘤患者中，卡铂组 137 例患者中有 45 例（32.8%，25.0-40.7）达到病理完全缓解，而无卡铂组 136 例患者中有 50 例（36.8%，28.7-44.9）达到病理完全缓解（p=0.581；检验交互作用 p=0.015）。卡铂组比无卡铂组更常见的血液学和非血液学毒性反应包括 3 级或 4 级中性粒细胞减少症（192[65%]例 vs 79[27%]例）、3 级或 4 级贫血症（45[15%]例 vs 1[<1%]例）、3 级或 4 级血小板减少症（42[14%]例 vs 1[<1%]例）和 3 级或 4 级腹泻症（51[17%]例 vs 32[11%]例）；卡铂更常导致剂量中断（卡铂组 141 例[48%]，无卡铂组 114 例[39%]；p=0.031）。当卡铂剂量从 AUC 2.0 减少到 1.5 时，卡铂组的 3 级或 4 级血液学事件的频率从 82%（n=135）下降到 70%（n=92），3 级或 4 级非血液学事件的频率从 78%（n=128）下降到 59%（n=77）。
紫杉烷、蒽环类药物和靶向治疗联合新辅助卡铂治疗显著增加了达到病理完全缓解的患者比例。这种方案似乎增加了三阴性乳腺癌患者的反应，但对 HER2 阳性乳腺癌患者没有作用。
葛兰素史克、罗氏和梯瓦制药。
