Qiao Longwei, Liang Yuting, Mira Ranim R, Lu Yaojuan, Gu Junxia, Zheng Qiping
Department of Hematology and Hematological Laboratory Science, School of Medical Science and Laboratory Medicine, Jiangsu University Zhenjiang 212013, China.
Department of Anatomy and Cell Biology, Rush University Medical Center Chicago, IL 60612, USA.
Int J Clin Exp Med. 2014 Oct 15;7(10):3333-43. eCollection 2014.
The mammalian target of rapamycin (mTOR) inhibitor, in combination with other chemotherapeutic drugs, has been used for treatment of breast cancer that develops resistance to endocrine therapy. However, the efficacy and safety need further evaluation. Here, we report a meta-analysis of randomized controlled trials (RCT) in breast cancer patients undergoing chemotherapy using steroid (exemestane) or nonsteroid (letrozole) aromatase inhibitors with or without mTOR inhibitors (everolimus). The overall response rate (ORR), progression-free survival (PFS), clinical benefi;t rate with 95% confidence interval (CI), and the major toxicities/adverse effects were analyzed. Data were extracted from twelve studies that meet the selection criteria. Among these, six studies that enrolled 3693 women received treatment of everolimus plus exemestane, or placebo with exemestane. The results showed that everolimus plus exemestane significantly increased the ORR relative risk (relative risk = 9.18, 95% CI = 5.21-16.15), PFS hazard ratio (hazard ratio = 0.44, 95% CI = 0.41-0.48), and clinical benefi;t rate (relative risk = 1.92, 95% CI 1.69-2.17) compared to placebo control, while the risks of stomatitis, rash, hyperglycemia, diarrhea, fatigue, anorexia and pneumonitis also increased. Three studies that enrolled 715 women who received everolimus as neoadjuvant therapy were analyzed. Compared to chemotherapy with placebo, chemotherapy plus everolimus did not increase the ORR relative risk (relative risk = 0.90, 95% CI = 0.77-1.05). Meanwhile, two other studies that enrolled 2104 women examined the efficacy of temsirolimus (or placebo control) plus letrozole. The results indicated that emsirolimus plus letrozole did not increase the ORR relative risk and clinical benefi;t rate (p > 0.05). Together, these data suggest that the combined mTOR inhibitor (everolimus) plus endocrine therapy (exemestane) is superior to endocrine therapy alone. As a neoadjuvant, everolimus did not increase the ORR, while temsirolimus plus letrozole treatment has limited effect on the ORR and the CBR of breast cancer patients.
雷帕霉素哺乳动物靶点（mTOR）抑制剂与其他化疗药物联合使用，已用于治疗对内分泌治疗产生耐药性的乳腺癌。然而，其疗效和安全性仍需进一步评估。在此，我们报告一项对乳腺癌患者进行的随机对照试验（RCT）的荟萃分析，这些患者接受使用甾体类（依西美坦）或非甾体类（来曲唑）芳香化酶抑制剂加或不加mTOR抑制剂（依维莫司）的化疗。分析了总缓解率（ORR）、无进展生存期（PFS）、95%置信区间（CI）的临床获益率以及主要毒性/不良反应。数据从符合入选标准的12项研究中提取。其中，6项纳入3693名女性的研究接受了依维莫司加依西美坦或依西美坦加安慰剂的治疗。结果显示，与安慰剂对照相比，依维莫司加依西美坦显著提高了ORR相对风险（相对风险=9.18，95%CI=5.21 - 16.15）、PFS风险比（风险比=0.44，95%CI=0.41 - 0.48）以及临床获益率（相对风险=1.92，95%CI 1.69 - 2.17），同时口腔炎、皮疹、高血糖、腹泻、疲劳、厌食和肺炎的风险也增加。对3项纳入715名接受依维莫司作为新辅助治疗女性的研究进行了分析。与安慰剂化疗相比，化疗加依维莫司并未提高ORR相对风险（相对风险=0.90，95%CI=0.77 - 1.05）。同时，另外2项纳入2104名女性的研究考察了替西罗莫司（或安慰剂对照）加来曲唑的疗效。结果表明，替西罗莫司加来曲唑并未提高ORR相对风险和临床获益率（p>0.05）。总体而言，这些数据表明联合使用mTOR抑制剂（依维莫司）加内分泌治疗（依西美坦）优于单纯内分泌治疗。作为新辅助治疗，依维莫司并未提高ORR，而替西罗莫司加来曲唑治疗对乳腺癌患者的ORR和CBR影响有限。
