本期首先为您带来专美国乳腺与肠道外科辅助治疗研究组（NSABP）主席、美国德雷克塞尔大学医学院人类肿瘤学教授、系主任、美国匹兹堡阿勒格尼综合医院人类肿瘤学系主任Norman Wolmark教授的专访，了解NSABP在乳腺癌方面的突出贡献，以及他对未来乳腺癌领域的展望。

　　回顾NSABP半个多世纪的成绩：硕果累累

　　NSABP是全球历史最悠久、最大，可能也是知名度最高的乳腺癌和结直肠癌研究组织。自1958年成立以来，NSABP已走过了半个多世纪。其成员包括200个核心机构和300个卫星中心，遍布美国、加拿大、波多黎各、澳大利亚等国家，超过3000名医生、护士及其他医疗专业人士共同参与NSABP治疗和预防试验的开展。

　　回顾过去的半个多世纪，Wolmark教授表示：在乳腺癌领域“我们一直很幸运，因为我们所致力的临床试验改变了对乳腺癌的生物学认识，还得到了革命性的结果”。这些成绩包括：

　　局部治疗的革命性研究

　　Wolmark教授认为该研究促使了根治性乳房切除术的落幕，它明确表明较小的手术，如乳房肿瘤切除术和放疗与根治性乳房切除术的疗效相当。“这完全改变了外科医生评估乳腺癌生物学行为的方式并且促进了辅助化疗相关临床试验的开展，因为外科医生意识到，在考虑生存时，继续关注手术细节并不能改变结局（就无疾病生存而言）。”这引发了一系列的试验，继而在1975年，首个显示辅助化疗可延长病理确诊的淋巴结阳性女性乳腺癌患者的无病生存期的研究问世。

　　内分泌治疗的第一与革命：证实他莫昔芬疗效；减少不必要的化疗

　　NSABP第一个开展临床试验证实，他莫昔芬在淋巴结阴性、雌激素受体阳性患者中延长无病生存期和总生存期，这项试验是他莫昔芬在美国获得治疗适应证的试验基础。随后的一项研究显示，化疗联合他莫昔芬优于他莫昔芬单独使用，但是只有微小的优势（约5%的差异）。不是所有的患者都能从化疗中获得相同的益处，这促使大家研究不同亚型患者之间的关系。NSABP与Genomic Health合作开发了Oncotype DX检测。这使美国乳腺癌的治疗产生了明显的变化，使得50%的淋巴结阴性、雌激素受体阳性的女性浸润性乳腺癌患者免于化疗。

　　新辅助治疗的第一个吃螃蟹的人

　　NSABP也是第一个开展将术前化疗作为初始干预的组织，挑战了手术的权威地位。随后，当FDA加速批准帕妥珠单抗作为HER-2阳性乳腺癌的辅助治疗时，也意味着FDA同意病理完全缓解可作为药品批准的替代标准。

　　靶向治疗的奠基发现

　　在Wolmark教授看来，NSABP最显著的成就或许要数对HER-2阳性乳腺癌患者使用曲妥珠单抗靶向治疗。2005年，NSABP和北部中心组联合报道，曲妥珠单抗联合化疗用于HER-2阳性乳腺癌有明确、显著的获益。

　　Wolmark教授总结道：“上述以及其他研究使我们对乳腺癌以及其治疗干预的观念发生了天翻地覆的改变。我们很幸运成为这个时代的一部分，而且通过由200个基于大学以及社区的核心机构组成的NSABP开展的前瞻性、随机临床试验。我们也很幸运成为这个过程的一部分。

　　Wolmark教授还介绍，NSABP不仅关注治疗，同时也十分重视乳腺癌的预防。已经开展的2项乳腺癌预防试验一项随机纳入超过13000名女性，另一项随机纳入近2万人，显示他莫昔芬可降低有乳腺癌高危风险的健康女性后续发生乳腺癌的风险。

　　展望未来乳腺癌领域的发展：信心十足

　　对于当下，Wolmark教授认为“现在是一个非常激动人心的时代。”今天，人们已经认识到针对不同的患者应该给予不同的治疗，有个绝佳的例子——雨伞计划，充分反映了这一理念在临床试验上的应用。CDK4/6抑制剂辅助治疗的数据令人兴奋，有望取得实质性成果。虽然这个令人兴奋的数据来自于晚期患者，但Wolmark教授认为它也可转化到辅助治疗领域。另外，NSABP刚刚和SWOG（西南肿瘤学研究组）联合开展了关于免疫检查点抑制剂pembrolizumab用于三阴性乳腺癌患者的临床试验，还参与开展了两个使用PARP抑制剂治疗胚系BRCA阳性乳腺癌以及三阴性乳腺癌的试验。

　　最后，Wolmark教授讲道：“目前的治疗已经不再是‘一刀切’，这个时代已经发生了巨大的变化。我认为我们已经进入了精准医学时代，确定了靶向药物在辅助治疗中的地位，但它们是如何发挥作用的仍需进一步观察。我们将继续推动这一领域的发展，对此我们信心十足且热情高涨”。

 访谈原文

　　Interviewer: Here is Oncology Frontier and today， we have the honor of doing a short interview with Professor Wolmark. Please introduce some outstanding contributions in breast cancer made by NSABP in the past 50 years， and what are the prospects for the future of NSABP?

　　Professor Wolmark: So， that’s a probing question. The NSABP has been in existence for over 50 years，

　　and I think that we’ve been very fortunate in that we have contributed to clinical trials that have changed the biologic perception of breast cancer and have resulted in innovative clinical trials being done. Perhaps our most definitive trial in addressing that question was protocol BO6 which， stimulated the retreat from radical mastectomy and showed definitively that lesser operations—such as lumpectomy and radiotherapy—were the equivalent of doing radical mastectomies. And that completely changed how surgeons viewed the biology of breast cancer and what it led to was the stimulation of clinical trials in adjuvant chemotherapy， because the surgeons realized that attention to operative detail was not going to change outcomes as far as disease-free survival when survival is concerned. That led to a series of protocols that showed for the first time， in 1975， that adjuvant chemotherapy in women with histologically positive nodes prolonged disease-free survival.

　　We were also the first group to do a clinical trial that showed that Tamoxifen in node-negative， ER-positive patients， prolonged disease-freesurvival and subsequently prolonged overall survival—and that was the indication trial for Tamoxifen in the United States. We then showed that adding chemotherapy to Tamoxifen was superior thanTamoxifen alone， but to a small degree (about 5% difference). We knew that all patients did not benefit equally from chemotherapy and that stimulated us to develop a relationship with the Oncotypepeople.We were instrumental in developing the Oncotype DX assay together with Genomic Health. So， that dramatically changed how treatment was delivered in the United States in that it avoided chemotherapy for 50% of women with node-negative， ER-positive invasive breast cancer.

　　We also were the first group to do pre-operative chemotherapy as the primary intervention，challenging the primacy of the operation. Subsequently， the FDA agreed that pathologic complete response could be used as a surrogate for approval and this， in fact， occurred when the FDA provided accelerated approval for pertuzumab in the adjuvant setting for HER2-positive breast cancer.

　　Perhaps our most notable accomplishment was the use of targeted therapy for HER2-positive adjuvant breast cancer with Herceptin. In 2005， we reported， together with the North Central Group， the results of a study that showed an unequivocal and a very substantial benefit for the addition of Herceptin to chemotherapy in the adjuvant setting for HER2-positive breast cancer.

　　So， I think that that spectrum has altered our perception of the disease as well as our therapeutic interventions to a significant degree. I think we are very fortunate to have been part of that era and to have been a part of the process through doing randomized prospective clinical trials with the 200 institutions that comprised the NSABP， the institutions that both were university-based as well as community-based.

　　We’ve also done two prevention trials in breast cancer: P1， which randomized over 13，000 women， and P2， that randomized nearly 20，000， showing that Tamoxifen can reduce the incidents of subsequent breast cancer in high-risk women without breast cancer.

　　So that provides you with a bird’s eye overview of 50 years of what the NSABP has accomplished. Currently， we are， of course， moving away from using therapy for everyone. We’re targeting subsets with umbrella trials， as a case in point. Certainly， the exciting data with CDK4/6 inhibitors in the adjuvant setting， hopefully， will come to fruition. The exciting data from advanced disease， I think， will be translated to the adjuvant setting. The checkpoint inhibitors—we’ve just initiated a trial together with SWOG using pembro7lizumab in patients with triple-negative breast cancer. So this is a very exciting era.

　　We have been part of two clinical trials using PARP inhibitors， both for germline BRCA-positive patients as well as triple-negative patients. So， the era has changed dramatically and， I think， we’re embracing the age of precision medicine and targeted therapy in the adjuvant setting， but it remains to be seen how that is going to play out. We are very hopeful and enthusiastic that we will continue to move the field forward.