Oncology Frontier: Promising pre-clinical evidence shows that the combination and inhibitor of ligan independent ER， fulvestrant， with PI3K inhibitor may be useful for the endocrine resistant ER positive breast cancer. Could you please comment on this regimen and the perspective of its future use?

　　《肿瘤瞭望》：一些临床前期证据显示配体依赖性ER抑制剂氟维司群与PI3K抑制剂可能对内分泌治疗耐药的ER阳性乳腺癌有效。您能否评论一下这种方案及其未来应用前景？

　　Dr. Ellis: Obviously now we are talking about 2 of these 6 nodes， we are talking about estrogen receptor targeting and we are talking about PI3 kinase pathway targeting. Now with respect to the estrogen receptor targeting， we do have to think a bit about that， particularly in the advanced disease， because the estrogen receptor can become mutated and due to phosphorylation events and other poorly understood deregulation of estrogen receptors， it can start signaling in a hormone independent way which is why estrogen receptor degrading agents that bind to the receptor and shuttle it to the proteosome for degradation are very appealing because that would actually get rid of mutant receptors and certainly the high doses of fulvestrant as well as perhaps a newer oral estrogen receptor downgraders are good thoughts there. The combination with PI3 kinase inhibition makes total logical sense. On Friday we will be describing some of our findings in Phase I and II of the combination of a PI3 kinase pathway inhibitor called Buparlisib orBKM120 with fulvestrant. I think that data does support the hypothesis that that will be an active combination. As well of course， we know that targeting mTOR， which is downstream PI3 kinase with an endocrine agent also appears to be an active strategy for metastatic breast cancer. We know we are not curing any body with these regiments. When curing people， you will have to target more of those six nodes to really achieve full therapeutic effect like complete remission， which is obviously something we have never seen with metastatic hormone receptor positive disease.

　　Ellis博士：很显然现在我们谈论的就是6个节点中的其中两个，它们分别以ER及PI3K信号通路为靶标。就以ER为靶标的治疗而言，我们在选用时（尤其是在乳腺癌晚期阶段选用时）需要仔细思考，因为ER可以发生突变，且受磷酸化及其他知之甚少的ER下调的影响，其会以激素依赖性的方式启动信号通路。正是因为如此，应用雌激素受体降解剂与受体结合，将其转化蛋白酶体后实现降解，这样做可摆脱突变受体。应用高剂量氟维司群或新型的雌激素受体降解剂是非常不错的做法。氟维司群与PI3 K抑制剂联用很有道理。周五的时候我们将介绍“PI3 K抑制剂Buparlisib或 BKM120与氟维司群的联用的I 、 II期试验结果”。我认为研究数据支持“二者联合用药有效”的假设。当然，我们知道以PI3 K的下游物质mTOR以靶标的内分泌药物也有望成为转移性乳腺癌的积极治疗策略。我们知道以上方案尚无法治愈乳腺癌患者。我们以更多节点（在6个节点中选择）为靶标，以达到完全缓解的治疗效果。显然，目前对ER阳性的转移性乳腺癌而言我们还尚未做到这一点。