HER2靶向治疗的引入和成功是乳腺癌治疗的转折点。曲妥珠单抗仅靶向HER2，但是帕妥珠单抗可阻断HER2和HER3。一项有4805名HER2阳性乳腺癌妇女参加的III期临床试验表明，在手术后标准治疗使用曲妥珠单抗（赫赛汀）的同时加用第二种HER2靶向药物pertuzumab（Perjeta）可增加患者获益。在3年的早期随访中，仅接受曲妥珠单抗的妇女中93.2％没有发生浸润性乳腺癌，而接受帕妥珠单抗和曲妥珠单抗的患者为94.1％，差异为1％。虽然接受标准曲妥珠单抗治疗的患者的预后已经很好，但在该研究中，接受帕妥珠单抗和曲妥珠单抗的患者比只接受曲妥珠单抗的患者发生浸润性乳腺癌的机会低19％。但鉴于添加帕妥珠单抗的绝对好处不是十分明显，因此应该考虑将其主要用于具有淋巴结阳性和激素受体阴性乳腺癌风险最高的女性。
这项研究中部分女性通过两种HER2靶向治疗而不是一种，获益更多，说明这是一个很有前途的疗法。但很明显，这种方法可能不利于复发风险较低的妇女。
—— 《壹篇》按
《新英格兰医学杂志》2017年6月5日在线先发
http://www.nejm.org/doi/full/10.1056/NEJMoa1703643
帕妥珠单抗联合曲妥珠单抗辅助治疗早期HER2阳性乳腺癌
背景
在晚期转移性乳腺癌患者中，当帕妥珠单抗加入曲妥珠单抗+化疗治疗HER2阳性乳腺癌时，帕妥珠单抗可提高术前病理完全缓解率、增加总生存率。在此试验中，我们研究了将帕妥珠单抗加入曲妥珠单抗+化疗时，帕妥珠单抗能否改善早期HER2阳性乳腺癌患者的预后。
方法
我们随机将淋巴结阳性或高风险淋巴结阴性、HER2阳性、可手术的乳腺癌患者分组，一组接受帕妥珠单抗或安慰剂＋标准辅助化疗＋1年曲妥珠单抗治疗，另一组接受安慰剂＋标准辅助化疗＋1年曲妥珠单抗治疗。我们假定的帕妥珠单抗组无浸润性肿瘤3年生存率为91.8%、安慰剂组89.2%。
结果
在这项试验的患者中，随机分组到接受帕妥珠单抗（2400例）或安慰剂（2405例）的患者中，63%的患者为淋巴结阳性乳腺癌、36%的患者为激素受体阴性乳腺癌。帕妥珠单抗组有171名患者（7.1%）出现肿瘤复发，安慰剂组有210名（8.7%）复发（风险比，0.81；95%置信区间[CI],0.66～1.00；P=0.045）。帕妥珠单抗组无浸润性肿瘤3年生存率的估测值为94.1%、安慰剂组93.2%。在淋巴结阳性乳腺癌患者队列中，帕妥珠单抗组无浸润性肿瘤3年生存率为92.0%，而安慰剂组为90.2%（浸润性肿瘤复发事件的风险比，0.77；95%CI，0.62～0.96；P=0.02）。在淋巴结阴性乳腺癌患者队列中，帕妥珠单抗组无浸润性肿瘤3年生存率为97.5%，安慰剂组为98.4%（浸润性肿瘤复发事件的风险比，1.13；95%CI，0.68～1.86；P=0.64）。≥3级腹泻几乎都是在化疗期间出现的，帕妥珠单抗组比安慰剂组更常见（9.8%对比3.7%）。
结论
在HER2阳性、可手术的乳腺癌患者中，当帕妥珠单抗加入曲妥珠单抗+化疗时，帕妥珠单抗显著提高了无浸润性肿瘤生存率。帕妥珠单抗比安慰剂，腹泻更常见。（由罗氏/基因泰克公司资助。APHINITY试验在ClinicalTrials.gov网站注册号，NCT01358877）
《壹篇》孟祥志
Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer
Gunter von Minckwitz, M.D., Marion Procter, Ph.D., Evandro de Azambuja, M.D., Dimitrios Zardavas, M.D., Mark Benyunes, M.D., Giuseppe Viale, M.D., Thomas Suter, M.D., Amal Arahmani, Ph.D., Nathalie Rouchet, M.Sc., Emma Clark, M.Sc., Adam Knott, Ph.D., Istvan Lang, M.D., Christelle Levy, M.D., Denise A. Yardley, M.D., Jose Bines, M.D., Richard D. Gelber, Ph.D., Martine Piccart, M.D., and Jose Baselga, M.D., for the APHINITY Steering Committee and Investigators*
June 5, 2017DOI: 10.1056/NEJMoa1703643
Background
Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer.
Methods
We randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease–free survival rate of 91.8% with pertuzumab and 89.2% with placebo.
Results
In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor–negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease–free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease–free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease–free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).
Conclusions
Pertuzumab significantly improved the rates of invasive-disease–free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann–La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877.)
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