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中华乳腺病杂志(电子版)

中华乳腺病杂志(电子版) ›› 2014, Vol. 08 ›› Issue (04) : 236 -243. doi: 10.3877/cma. j. issn.1674-0807.2014.04.003

论著

白蛋白紫杉醇用于乳腺癌新辅助化疗的二期临床研究
余峰1, 刘晶晶1, 张晟1, 张霄蓓1, 张瑾1,†()   
  1. 1.300060 天津医科大学肿瘤医院病理科国家肿瘤临床医学研究中心乳腺癌防治教育部重点实验室
  • 收稿日期:2014-03-11 出版日期:2014-08-01
  • 通信作者: 张瑾
  • 基金资助:
    天津市重大科技专项(工程)项目抗癌重大科技专项(12ZCDZSY15400)

A phase II clinical study of albumin-bound paclitaxel used in neoadjuvant therapy in breast cancer women

Feng Yu1, Jinjin Liu1, Sheng Zhang1, Xiaobei Zhang1, Jin Zhang1,†()   

  1. 1.Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
  • Received:2014-03-11 Published:2014-08-01
  • Corresponding author: Jin Zhang
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引用本文：

余峰, 刘晶晶, 张晟, 张霄蓓, 张瑾. 白蛋白紫杉醇用于乳腺癌新辅助化疗的二期临床研究[J]. 中华乳腺病杂志(电子版), 2014, 08(04): 236-243.

Feng Yu, Jinjin Liu, Sheng Zhang, Xiaobei Zhang, Jin Zhang. A phase II clinical study of albumin-bound paclitaxel used in neoadjuvant therapy in breast cancer women[J]. Chinese Journal of Breast Disease(Electronic Edition), 2014, 08(04): 236-243.

目的

比较白蛋白紫杉醇联合表柔比星及环磷酰胺(TEC)方案与含以聚氧乙烯蓖麻油为溶剂紫杉醇注射液的TEC 方案应用于乳腺癌新辅助化疗的有效性及安全性。

方法

研究共纳入120 名乳腺癌患者,随机分为研究组和对照组,分别给予白蛋白紫杉醇260 mg/m2+表柔比星60 mg/m2+环磷酰胺500 mg/m2的TEC 新辅助化疗3 周方案,和紫杉醇注射液175 mg/m2+表柔比星60 mg/m2+环磷酰胺500 mg/m2 的TEC 新辅助化疗3 周方案。 两组患者均行4 个周期的化疗。 观察两组的病理完全缓解率(pCR),临床完全缓解率(cCR),临床部分缓解率(cPR)和临床治疗反应率(cRR),以及用药的安全性和不良反应。 同时进一步比较两组治疗前后磷脂酰肌醇3-激酶(PI3K)、蛋白激酶B(AKT)、哺乳动物雷帕霉素靶蛋白(mTOR),促凋亡基因(BAD)等的表达水平。 以χ2 检验进行组间率的比较及临床病理特征的分析,计量资料比较采用t 检验。

结果

两组患者均获得良好的治疗反应率,研究组cCR 率为46.7%(28/60),对照组为18.3%(11/60),差异具有统计学意义(χ2=10.978, P=0.001);其中研究组16.67%(10/60)的患者达到pCR,较对照组(5.0%,3/60)有所提高(χ2=4.227, P=0.040)。 两组患者均未发生3、4 度不良反应或治疗相关的死亡。 研究组化疗期间主要不良反应为周围感觉神经毒性、中性粒细胞数减少、恶心呕吐;研究组患者化疗期间中性粒细胞减少的发生率为31.7%(19/60),而对照组为51.6%(31/60)(χ2=4.937, P=0.026);研究组感觉神经毒性的发生率为38.3% (23/60),对照组为51.6%(31/60) (χ2=5.910, P=0.015);两组患者左心室射血分数均在正常范围内(＞50%),用药前后均未发生明显改变;研究期间两组均无因药物不良反应所致的停药、用药延迟、药量减少、药物相关高血压及手术延迟。 用药前后研究组PI3K 阳性率降低45.0%,mTOR 阳性率降低43.3%,AKT 阳性率降低41.7%, BAD 的阳性率升高21.6%,差异均具有统计学意义(P 均=0.000)。 与对照组相比,新辅助化疗后研究组的PI3K、AKT、mTOR 的阳性率明显下调(58.3%比28.3%,χ2=10.995, P=0.001;46.7%比16.7%,χ2=13.713, P=0.000,75%比40%,χ2=15.038, P=0.000),差异具有统计学意义。 但是,两组的BAD 蛋白阳性率差异不具有统计学意义(33.3%比48.3%,χ2=2.794, P=0.095)。

结论

含白蛋白紫杉醇的TEC 方案作为乳腺癌新辅助化疗方案较含以聚氧乙烯蓖麻油为溶剂紫杉醇注射液的TEC 方案可获得更好的临床疗效,中性粒细胞减少和感觉神经毒性的发生率较低,并可以显著地降低PI3K、AKT、mTOR 的表达,具有一定的临床应用价值。

关键词: 乳腺肿瘤, 化学疗法、辅助, 白蛋白结合型紫杉醇

Objective

To compare the efficacy and safety of two neoadjuvant therapies: albuminbound paclitaxel combined with epirubicin and cyclophosphamide, and cremophor-formulated paclitaxel combined with epirubicin and cyclophosphamide in breast cancer patients.

Methods

A total of 120 breast cancer patients were enrolled and randomly divided into study group (n=60) and control group (n=60). In study group, albumin-bound paclitaxel 260 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 500 mg/m2 were administrated every 3 weeks for 4 cycles as neoadjuvant therapy; in control group, cremophor-formulated paclitaxel 175 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 500 mg/m2 were administrated every 3 weeks for 4 cycles as neoadjuvant therapy during the same time period. The pathologic complete response(pCR) rate, clinical complete remission (cCR) rate, clinical partial remission(cPR) rate, clinical response rates (cRR), safety and toxicity in the two groups were recorded. The expressions of PI3K, AKT, mTOR and BAD in tumor tissue were examined and compared before and after chemotherapy in two groups. χ2 test was used for rate comparison between groups and clinicopathological analysis. t test was used for measurement data.

Results

The patients in two groups achieved good clinical response: 28 patients (46.7%, 28/60) in study group and 11 (18.3%, 11/60) achieved cCR, the difference was statistically significant (χ2=10.978, P=0.001). The pCR rate was 16.7% (10/60) in study group, higher than 5%(3/60) in control group (χ2=4.227, P=0.040). There were no treatment-related deaths or grade 3 and 4 toxicity in both groups. The most common adverse events in study group were periphery sensory neuropathy, neutropenia, nausea and vomiting.The neutropenia occurred in 31.7% of the patients(19/60) in study group, in 51.6% of the patients(31/60)in control group(χ2=4.937, P=0.026). And sensory neuropathy occurred in 38.3% of the patients (23/60)in study group and in 18.3% of the patients (11/60) in control group during chemotherapy. All patients had normal left ventricular ejection fraction range (＞50%) before and after therapy in both groups. No drug discontinuation, drug delay, drug reduction, drug-related hypertension or postponed operation occurred during the study period. After chemotherapy, in study group, the positive rate of PI3K was decreased by 45.0%,mTOR by 43.3% and AKT by 41.7% and BAD positive rate was increased by 21.6% (all P=0.05).Compared with control group, the positive rates of PI3K,AKT and mTOR in the study group were significantly decreased (58.3% vs 28.3%,χ2=10.995, P=0.001;46.7% vs 16.7%, χ2=13.713, P=0.000, 75% vs 40%, χ2=15.038, P=0.000), but there was no difference in the positive rate of BAD between two groups(33.3% vs 48.3%, χ2 = 2.794, P = 0.095).

Conclusion

Albumin-bound paclitaxel combined with epirubicin and cyclophosphamide as neoadjuvant therapy has the advantages over cremophor-formulated paclitaxel combined with epirubicin and cyclophosphamide in breast cancer patients, including better clinical response, lower incidence of neutropenia and sensory neuropathy and decreased expression of PI3K, AKT and mTOR, which is worthy of clinical application.

Key words: Breast neoplasms, Neoadjuvant therapy, Albumin-bound paclitaxel
表1 患者的临床病理资料
组别 例数 月经状态 组织学类型 ECOG评分 肿瘤分期 ER和/或PR阳性 三阴性乳腺癌
绝经前 绝经后 浸润性导管癌 浸润性小叶癌 其他 PS 0 PS 1 ⅡA ⅡB ⅢA ⅢB ⅢC
研究组 60 41 19 50 2 8 55 5 21 24 7 5 3 39 9
对照组 60 43 17 53 3 4 53 7 23 21 9 4 3 41 8
检验值 0.159 0.370 0.150 0.069
P值 0.690 0.594a 0.543 0.964a 0.699 0.793
图1 两组乳腺癌患者新辅助化疗后临床疗效评价 a:χ2=10.978,P=0.001;b:χ2 =4.227;P=0.040,与对照组比较;cRR:临床反应率;cCR:临床完全缓解;pCR:病理完全缓解
表2 两组患者用药期间的不良反应(例)
组别 例数 中性粒细胞减少 血小板减少 感觉神经毒性 脱发 恶心、呕吐 腹泻 色素沉着
研究组 60 19 1 23 3 4 0 1
对照组 60 31 2 11 5 3 1 2
χ 2值 4.937 5.910
P值 0.026 1.000a 0.015 0.717a 1.000a 1.000a 1.000a
图2 研究组和对照组乳腺癌患者新辅助化疗前各蛋白的阳性率 a:P＞0.05,与对照组比较
图3 研究组乳腺癌患者新辅助化疗前后各蛋白的阳性率 a:P=0.000,与新辅助化疗前比较
图4 研究组和对照组乳腺癌患者新辅助化疗后各蛋白的阳性率 a:χ2=10.995,P=0.001;b:χ2 =13.713,P=0.000;c:χ2 =15.038,P=0.000;d:χ2=2.794,P=0.095
图5 化疗后两组乳腺癌组织中蛋白表达免疫组织化学图(HE ×100) PI3K:磷脂酰肌醇3-激酶;AKT:蛋白激酶B;mTOR:哺乳动物雷帕霉素靶蛋白;BAD:促凋亡基因;a:对照组PI3K 呈阳性表达;b:对照组AKT 呈阳性表达;c:对照组mTOR 呈阳性表达;d:对照组BAD 呈阴性表达;e:研究组PI3K 呈阴性表达;f:研究组AKT 呈阴性表达;g:研究组mTOR 呈阴性表达;h:研究组BAD 呈阳性表达。
表3 研究组和对照组新辅助治疗前各蛋白表达情况
组别 总例数 PI3K阳性 AKT阳性 mTOR阳性 BAD阳性
例数 阳性率(%) 例数 阳性率(%) 例数 阳性率(%) 例数 阳性率(%)
研究组 60 44 73.3 36 60.0 49 81.7 16 26.7
对照组 60 43 71.7 37 61.7 51 85 16 26.7
χ 2值 0.042 0.035 0.240 0.000
P值 0.838 0.852 0.624 1.000
表4 研究组和对照组治疗前后各蛋白表达变化
组别 总例数 PI3K阳性 AKT阳性 mTOR阳性 BAD阳性
例数 阳性率(%) 例数 阳性率(%) 例数 阳性率(%) 例数 阳性率(%)
研究组
新辅助前 60 44 73.3 36 60.0 49 81.7 16 26.7
新辅助后 60 17 28.3 10 16.7 24 40 29 48.3
P值 0.000 0.000 0.000 0.000
对照组
新辅助前 60 43 71.7 37 61.7 51 85.0 16 26.7
新辅助后 60 35 58.3 29 46.7 45 75 20 33.3
P值 0.008 0.008 0.031 0.125
表5 研究组和对照组新辅助治疗后各蛋白表达情况
组别 总例数 PI3K阳性 AKT阳性 mTOR阳性 BAD阳性
例数 阳性率(%) 例数 阳性率(%) 例数 阳性率(%) 例数 阳性率(%)
研究组 60 17 28.3 10 16.7 24 40 29 48.3
对照组 60 35 58.3 29 46.7 45 75 20 33.3
χ 2值 10.995 13.713 15.038 2.794
P值 0.001 0.000 0.000 0.095
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