单靶向？双靶向？II/III期HER-2阳性乳腺癌治疗方案的选择

　　Charles Geyer教授指出，在美国，曲妥珠单抗和帕妥珠单抗的双靶向治疗已经成为HER-2阳性早期乳腺癌的标准治疗方式。主要有3个临床试验支持：①CLEOPATRA研究显示双靶向治疗使转移性乳腺癌的OS延长了15个月；②NeoSphere临床实验显示双靶向治疗极大地提高了pCR率；③德国的TRYPHENA试验在标准TCH方案（多西他赛加卡铂序贯曲妥珠单抗）基础上加入帕妥珠单抗，结果显示毒性反应无明显增加，但pCR率明显提高，特别是ER阴性患者pCR率高达80%。因此，帕妥珠单抗在新辅助治疗方面有极大的作用，再结合转移性乳腺癌的临床试验结果，双靶向治疗已经得到大部分美国肿瘤专家的认可。而且FDA已经批准了帕妥珠单抗联合曲妥单抗治疗，尤其是新辅助治疗，这极大地推动了美国抗HER-2治疗实践。

　　HER-2阳性乳腺癌新辅助治疗的适应证

　　在美国，对于肿瘤≥2 cm的HER-2阳性的乳腺癌，无论淋巴结状态如何都推荐先行新辅助治疗。原因有三：一是有明确的信息指出当患者获得了完全病理缓解时，肿瘤完全消失，可明显改善生存；二是希望通过肿瘤降期来减少淋巴结的手术清扫范围，或者能免于放疗；三是新辅助治疗给医生提供了鉴别肿瘤对抗HER-2治疗的反应性的机会，也可以指导局部治疗的强度。Geyer教授表示他们也已经开展有残留病灶的乳腺癌临床试验，期待新药如T-DM1的临床试验结果。

　　获得PCR的HER-2阳性乳腺癌患者术后是否还需继续抗HER -2治疗

　　一部分HER-2阳性的乳腺癌患者经抗HER-2新辅助治疗后达到了pCR，术后是否需要继续抗HER-2还需要确切的临床试验来指导，需要在获得pCR的患者中开展继续抗HER-2治疗1年或终止治疗的随机临床试验。Geyer教授认为如果达到pCR的患者因为并发症或其他原因继续抗HER-2治疗有困难的，可以适当考虑停止抗HER-2治疗。但在没有确切临床试验支持的情况下，若将获得pCR后终止抗HER-2治疗作为常规选择，可能存在隐患，特别是考虑到曲妥珠单抗的获益还可能与免疫应答有关。对于ER和HER-2均为阳性的患者，继续抗HER-2也不能达到pCR，可能会考虑终止。而对于达到pCR的ER阴性患者，如果有可靠的科研结果支持，那将会减轻很多经济负担。

　　HER-2阳性老年患者治疗方案的优化

　　Geyer教授表示，老年患者身体情况不佳的情况下，若在抗HER-2治疗和化疗间进行取舍，应坚持抗HER-2治疗。转移性乳腺癌的临床试验提供了很好的证据，HER-2靶向治疗联合化疗治疗效果明显，但不同化疗方案的选择间无明显差别。同时美国联盟合作组织的临床试验显示，对于HER-2阳性的低复发风险患者，采用曲妥珠单抗联合9周的紫杉醇单药化疗结果良好。这都提示抗HER-2治疗有机会减少化疗强度。因此对于老年患者可以适当考虑单药化疗，如紫杉醇。对于抗HER-2，他表示“我不太倾向于减少曲妥珠单抗，因为它耐受性良好，并且HER-2信号是HER-2阳性乳腺癌的驱动因素。”

访谈原文

　　Oncology Frontier:  Would you choose a single targeted or dual targeted neoadjuvant therapy for stage II/III HER2-positive breast cancer? What kind of specific plans would you choose? Please give your opinion.

　　Professor Geyer: In regards to the therapy of HER2-positive early breast cancer， I personally use a combination of dual HER2-targeted therapy with both trastuzumab and pertuzumab. I think this has become largely the standard of care in the United States. The reasons for that are that metastatic breast cancer in the CLEOPATRA study saw a substantial improvement in overall survival of 15 months; the NeoSphere trial showed significant increase in the PCR rates; and another important study was the German TRYPHENA study， that took the standard TCH regimen， added pertuzumab， and found that the toxicity profile really was not changed， but the pCR rates jumped quite dramatically—the pCR rates in the ER-negative patients， in particular， were around 80 percent. So， that striking degree of activity in those neoadjuvant studies， coupled with the metastatic trials， have led most US breast oncologists， I think， to favor TCHP. The other critical thing was that our FDA actually approved pertuzumab with trastuzumab， specifically in neoadjuvant therapy. So， that really became a powerful unifying force in the move to do HER2-targeting in the US.

　　Oncology Frontier: For operable HER2-positive early breast cancer， would you consider relaxing the indications of neoadjuvant therapy to have neoadjuvant chemotherapy and neoadjuvant anti-HER2 therapy before surgery， in order to improve the rate of pCR and improve the prognosis?

　　Professor Geyer: In the United States， in HER-2 positive breast cancer， there has been a definite shift to employ neoadjuvant therapy for patients with breast tumors that are 2 cm or more， irrespective of the lymph node status.Reasons for that is because there is clearly very powerful information gained when a patient’s tumor disappears completely when they have a pathologic complete response. Additionally， we have started doing clinical trials in patients with residual disease， who we know are at high-risk， looking at newer agents—such as TDM1—in clinical trials. There is also the hope that by down staging the tumor， you might be able to lessen the extent of axillary surgery， perhaps omit radiation therapy. So， we think that the high activity level of HER2-positive breast cancer gives us an opportunity to identify women whose cancers are very responsive， and that might allow us to back down on the intensity of the local regional therapy they have to administer.

　　Oncology Frontier: If a HER2-positive early breast cancer patient achieves pCR after neoadjuvant treatment， could they consider not using anti-HER2 treatment after surgery if also considering economics， their physical condition， and other reasons?

　　Professor Geyer: The question of the need to continue HER2-targeted therapy in a patient who has achieved a pCR is a good one that we just don’t know the answer to. We haven’t actually done the clinical trial that would need to be done to really inform us about that， where patients who have a complete pathologic response would be randomized to either continue the HER2-targeted therapy out for a year， or stop. I think， in individual patients， if you have somebody with comorbidity or there are reasons why continuing trastuzumab is difficult， it’s certainly reasonable to have a low threshold for discontinuing. But to stop doing it routinely without a clinical trial， I think， would be potentially problematic， particularly since we think that the benefits of trastuzumab， in part， may be due to the immune response. The other reality is that in the ER-positive， HER2-postive patients， when you continue it most of those patients don’t pCR， and so you do want to take it out. But in the patients who get a pCR who have an ER-negative disease， I think it’s an important research question， because clearly there is a big economic factor to continuing the therapy for so long.

　　Oncology Frontier: For HER2-positive older patients， is there a need to do anti-HER2 therapy strictly with the full anti-HER2 treatment? For older patients with several complicated diseases， such as heart disease and diabetes， how would you optimize the treatment scheme to reduce side effects fromthe treatment?

　　Professor Greyer: In elderly patients， I think， there is a real opportunity with the HER2-targeted therapies to lessen the intensity of the chemotherapy. There is really good evidence from metastatic disease that HER2-targeted therapies work much better in combination with chemotherapy， but it also appears that the actual choice of chemotherapy probably doesn’t matter a great deal. So， I think， in an elderly patient， there is opportunity to consider using a single chemotherapy agent， such as a paclitaxel. The Alliance Cooperative Group in the US actually did a trial in lower risk， HER2-postive patients， looking at trastuzumab and 9 weekly doses of paclitaxel—and those patients did extremely well. So， I think there is a real justification in the elderly patients for backing off on the chemotherapy. I would be less inclined to back off the trastuzumab， because it’s very well tolerated and that’s the driving factor of that patient’s individual cancer.