Oncology Frontier: What’s the future for neoadjuvant therapy for HER2-positive early-stage breast cancer?

　　《肿瘤瞭望》：您如何看待新辅助治疗在HER-2阳性早期乳腺癌中的未来？

　　Dr Rugo: The guidelines that were recently released have already changed. If there is an improvement in pathologic complete response (no invasive tumor in the breast and lymph node) then that treatment may be better in terms of disease-free survival. This has been very controversial because of the recent data from the ALTTO trial and also the lack of benefit in the NeoALTTO trial in terms of disease-free survival. What we found was that the addition of pertuzumab to standard chemotherapy plus trastuzumab improves the pathologic complete response rate. Unlike the addition of lapatinib， it is extremely well tolerated with only modest toxicity which usually can be managed easily. This lead to the accelerated approval of pertuzumab as neo-adjuvant therapy in combination with chemotherapy and we employ that on a regular basis. The NCCN guidelines also suggested that just because a woman wasn’t offered neo-adjuvant therapy， they shouldn’t then not be allowed to receive pertuzumab. So they have included the choice of pertuzumab as an adjuvant treatment but it is not yet approved in that indication. So there has been a big change in our guidelines for neo-adjuvant therapy based on neo-adjuvant studies showing improved pathologic complete response. The fact that ALTTO didn’t translate into improved outcomes with the addition of lapatinib is an interesting question and I think there are a few important points to keep in mind. The population enrolled in ALTTO was a much lower risk population than in NeoALTTO. Lapatinib is not well-tolerated so compliance could be an issue. Also in NeoALTTO， half of the chemotherapy was given after surgery; patients received only the taxane with trastuzumab and lapatinib and then received their anthracycline post-operatively. The same is true for pertuzumab from the NeoSphere trial， but the difference with pertuzumab is we have a trial in the first-line metastatic setting showing improved overall survival which we don’t have for lapatinib. I think there is a good chance that pertuzumab will show an improvement in disease-free survival in the adjuvant setting despite these issues. It is currently a new standard for neo-adjuvant therapy for HER2-positive breast cancer.

　　Rugo教授：最近发布的指南已经有所改变。如果能获得病理完全缓解（乳腺及淋巴结没有肿瘤侵袭），则此治疗方案对于无病生存可能更佳。但基于近期ALTTO试验的研究数据以及NeoALTTO试验中无病生存获益的依据缺乏，这方面目前仍有很大争议。

　　目前发现，在标准化疗方案联合曲妥珠单抗的基础上加用帕妥珠单抗可提高病理完全缓解率。与拉帕替尼不同的是，帕妥珠单抗具有相当好的耐受性且毒性较轻，通常容易控制。这促使（美国FDA）加速批准帕妥珠单抗作为新辅助治疗中化疗的联合用药，并作为常规基础治疗方案。

　　NCCN指南也指出，若不建议患者接受新辅助治疗，则也不允许使用帕妥珠单抗治疗。可见他们已经将帕妥珠单抗作为辅助治疗的一个选择，但尚未批准其应用。因此，基于新辅助治疗研究显示出病理完全缓解率的提高，对于新辅助治疗指南中已经有了重大改变。

　　事实上，ALTTO试验中加用拉帕替尼并未转化为预后改善，这是一个有趣的问题，对此我有几点想法：①ALTTO试验中入组的受试者与NeoALTTO试验相比，风险更低；②拉帕替尼的耐受性并不令人满意，因此依从性也成为了问题；③在NeoALTTO试验中，半数的化疗是在手术后进行的；患者只接受紫杉醇联合曲妥珠单抗及拉帕替尼，在术后进行蒽环类药物化疗。在NeoSphere试验中，帕妥珠单抗的应用也是如此，但与拉帕替尼不同，帕妥珠单抗一线治疗转移癌能延长总生存期。尽管有这些问题，但我想这是一个好的契机，帕妥珠单抗在辅助治疗中能够改善无病生存率。目前对HER-2阳性乳腺癌新辅助治疗来说，这是一个新的标准方案。