Oncology Frontier: How can you determine the impact of novel agents targeting  gene related endocrine resistant breast cancer?

　　《肿瘤瞭望》：针对基因突变导致的内分泌治疗耐药，您如何评价的抗耐药新药物的疗效？

　　Dr. Ellis: In the advanced disease setting there is an obvious answer to that. You just monitor and see if the patient gets better but in the early disease setting that is a very difficult question if you are going to use standard adjuvant approaches so you cannot use standard adjuvant approaches to develop that strategy because to develop genome direct therapies you need to know the genome and then you need to treat that genome with intelligently design trios of drugs. What we would do is we would do that in the neo adjuvant setting looking for complete remission of the disease in the breast and the regional lymph nodes， in other words， pathologically complete response. We know that pathological complete response in triple negative disease for example， is a beautiful surrogate for a systemic cure. If you give the drugs before surgery and the breast is cleared of disease and the nodes are cleared of disease the patients do great but if they are not and there is chemotherapy resistant cells in the breast， then the patient does terribly. In hormone receptor positive disease the path CR (pCR) rate either chemotherapy or anti-hormone approaches is vanishingly rare - typically less than 5% and in ER positive lobular carcinoma probably less than 1% that you get path CR with chemotherapy or hormone therapy. If we can actually combine drugs in a rational way and start seeing complete remissions of the disease in the breast before surgery then we will be bench marking very effectively our ability to cure patients， and may be if we can really learn how to do this， patients will not require 10 years of endocrine therapy which is just holding the disease at bay.  You will actually cure the patients and therefore these acquired resistance mechanisms that occur because you are only partially treating the tumor， will be a thing of the past.

　　Ellis博士：在乳腺癌晚期阶段药物评价较明确，我们只需要对患者进行监测，看患者应用这种新药后是否会有所好转即可。但是在乳腺癌早期阶段时，则难以对新药疗效进行评价。这主要是在早期阶段时我们通常会应用标准辅助治疗方法，而要想应用直接针对基因组的治疗，我们必须要先了解患者的基因组然后才能智能设计针对其基因组的药物。一般情况下我们会在新辅助治疗时应用这类新药，以期促进乳腺及局部淋巴结中的癌症完全缓解或达到病理上的完全缓解。例如，据我们所知，三阴性乳腺癌患者的病理完全缓解是系统治愈的良好替代指标。如果在手术前用药并将患者乳腺及淋巴结中的病灶清除，则患者预后可能会非常好。但是，如果患者乳腺中存在对化疗耐药的癌细胞，则患者的预后将非常差。在ER阳性的乳腺癌患者中，化疗或抗激素治疗的病理完全缓解率非常低，通常不足5%；ER阳性的小叶癌患者化疗或激素治疗后的病理完全缓解率可能还不足1%。实际上，如果能合理地药物联合治疗，在手术前就使乳腺中的病灶达到完全缓解，则能非常有效地治愈患者；如果我们真能做到这一点，则患者不需要为期十年的内分泌治疗。这样就可以治愈患者，不再出现因治疗不彻底而导致内分泌治疗耐药。