早期/局部/可手术乳腺癌治疗方案
权威癌症研究机构美国国家癌症研究所 (NCI)对早期/局部/可手术乳腺癌治疗方案:术前全身治疗(HER2/neu阳性乳腺癌(曲妥珠单抗))。
术前全身治疗(HER2/neu阳性乳腺癌(曲妥珠单抗))治疗早期/局部/可手术乳腺癌医学证据
a.Ⅲ期新辅助赫赛汀 (NOAH) 研究将 HER2 阳性局部晚期或炎性乳腺癌患者随机分配接受术前化疗,伴或不伴 1 年曲妥珠单抗治疗。[1][证据级别:1iiA ]
1.研究结果证实,在术前化疗中加入曲妥珠单抗不仅改善了临床反应(87% 对 74%)和病理反应(乳房和腋窝,38% 对 19%),而且还改善了主要结果 EFS。 1][证据级别:1iiA ]
2.中位随访 5.4 年后,在化疗中加用曲妥珠单抗的 EFS 获益分别为 58%(95% CI,48%–66%)和 43%(95% CI,34%–52%)在化疗组。两个随机 HER2 阳性治疗组之间 EFS 的未调整 HR 为 0.64(95% CI,0.44-0.93;双边对数秩P = .016)。在接受曲妥珠单抗治疗的患者中,EFS 与 pCR 密切相关。[2]
3.两名同时接受多柔比星和曲妥珠单抗治疗两个周期的患者出现症状性心力衰竭。对 LVEF 进行密切的心脏监测以及阿霉素的总剂量不超过 180 mg/m 2是导致 LVEF 下降次数相对较少且仅发生两次心脏事件的原因。[1][证据级别:1iiD ]
b.由于担心曲妥珠单抗和蒽环类药物的共同给药,一项 III 期试验 ( Z1041 [NCT00513292])[4]将可手术的 HER2 阳性乳腺癌患者随机分配接受曲妥珠单抗治疗,与术前化疗方案的蒽环类药物成分 (FEC) 连续或同时接受。 [3][证据级别:1iiDiv ]
1.pCR 是主要结果。两组之间的乳房 pCR 率没有显着差异(56.5% 连续,54.2% 并发;差异为 2.3%,95% CI,-9.3-13.9)。
2.术前化疗期间 LVEF 无症状下降在每组患者中的比例相似。
3.DFS和OS是次要结果。中位随访 5.1 年后,DFS(HR,1.02;95% CI,0.56-1.83,P = .96)或 OS(HR,1.17;95% CI,0.48-2.88;P = .73) 在顺序臂和并行臂之间。 [5]
4.结论是,基于这些发现,曲妥珠单抗与蒽环类药物的同时给药是不合理的。
曲妥珠单抗的皮下制剂也已获批准。
SafeHer ( NCT01566721 )[6]试验评估了自我给药与临床医生给药的 SQ 曲妥珠单抗在 I 期至 III 期 HER2 阳性乳腺癌中的安全性和耐受性。[7] 化疗同时或依次给药。
III 期(HannaH [NCT00950300][8]试验也表明,术前 SQ 曲妥珠单抗的药代动力学和疗效不劣于 IV 制剂。这项国际开放标签试验 (n = 596) 随机分配患有可手术、局部晚期或炎症性 HER2 阳性乳腺癌的女性接受术前化疗(基于蒽环类/紫杉烷),使用 SQ 给药或 IV 给药曲妥珠单抗术前每 3 周一次。患者接受了辅助曲妥珠单抗以完成 1 年的治疗。[9][证据级别:1iiD] 两组的 pCR 率相差 4.7%(95% CI,4.0%–13.4%);IV 给药组为 40.7%,而 SQ 给药组为 45.4%,证明 SQ 制剂的非劣效性。EFS 和 OS 是次要终点。两组的 6 年 EFS 为 65%(HR,0.98;95% CI,0.74-1.29)。两组的 6 年 OS 率为 84%(HR,0.94;95% CI,0.61-1.45)。 [10]
还研究了更新的 HER2 靶向疗法(拉帕替尼、帕妥珠单抗)。似乎 HER2 受体的双重靶向导致 pCR 率增加;然而,迄今为止,这种方法并没有显示出生存优势。 [11,12]
参考资料:
[1]Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375 (9712): 377-84, 2010.
[2]Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 15 (6): 640-7, 2014.
[3]Buzdar AU, Suman VJ, Meric-Bernstam F, et al.: Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol 14 (13): 1317-25, 2013.
[4]Combination Chemotherapy and Paclitaxel Plus Trastuzumab in Treating Women With Palpable Breast Cancer That Can Be Removed by Surgery[NCT00513292].
[5]Buzdar AU, Suman VJ, Meric-Bernstam F, et al.: Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial. JAMA Oncol 5 (1): 45-50, 2019.
[6]A Safety and Tolerability Study of Assisted and Self-Administered Subcutaneous (SC) Herceptin (Trastuzumab) as Adjuvant Therapy in Early Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer (SafeHER)[NCT01566721].
[7]Gligorov J, Ataseven B, Verrill M, et al.: Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study's primary analysis of 2573 patients. Eur J Cancer 82: 237-246, 2017.
[8]A Study to Compare Subcutaneous (SC) Versus Intravenous (IV) Administration of Herceptin (Trastuzumab) in Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Early Breast Cancer[NCT00950300].
[9]Ismael G, Hegg R, Muehlbauer S, et al.: Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13 (9): 869-78, 2012.
[10]Jackisch C, Stroyakovskiy D, Pivot X, et al.: Subcutaneous vs Intravenous Trastuzumab for Patients With ERBB2-Positive Early Breast Cancer: Final Analysis of the HannaH Phase 3 Randomized Clinical Trial. JAMA Oncol 5 (5): e190339, 2019.
[11]Gianni L, Pienkowski T, Im YH, et al.: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13 (1): 25-32, 2012.
[12]Baselga J, Bradbury I, Eidtmann H, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379 (9816): 633-40, 2012.