Oncology Frontier : Focusing on HER2 could you talk about the future perspectives of treatment for HER2 positive breast cancer?

　　肿瘤瞭望：您能否谈一下HER-2阳性乳腺癌的未来治疗愿景？

　　Dr. Osbourne: I think there has been a lot of work， some originating in my own laboratory first at dual blockade of the HER family of receptors， and it provides an additional advantage. That is there are 4 members of the HER family， all 4 can signal particularly HER1， HER2， and HER3 and trastuzumab only blocks one of those. It also has its ADCC effect as well but we have found that blocking the other receptors too， like HER1 or HER3 with either lapatinib or EGFR inhibitor or pertuzumab to block HER3 or HER2 heterodimers provides additional advantage. That advantage is somewhat lost if you give aggressive chemotherapy like in the ALTTO trial that did not show much of an advantage for the dual blockade but as we back off on chemotherapy， I think that there is a group of patients that will probably only need to be treated with dual blockade of the HER2 family and maybe initially with a little bit of chemotherapy like the Dana Farber study where they gave taxol plus herceptin in low risk patients but I think based on studies that have been done in the neoadjuvant setting where you get pretty high path CR rates， even in the absence of chemotherapy， that tells us that there is a group of patients with large tumors， because these studies were done in tumors averaging 5 and 6 cm in size， that might only need 12 weeks of dual receptor blockade and that is it， without any chemotherapy at all. One of the things we are studying right now is trying to identify which patients need chemotherapy or which patients need other types of therapy because they are resistant to blocking the receptors themselves. The clues we have there are if you have PI3 kinase mutation which activates downstream from the receptors then you may be resistant to those drugs or if you have a low p10 which activates the PI3 kinase pathway， then you may be resistant to those receptor inhibitors and a lot more work has been done in that area to try and figure out again， what the compensatory pathways are.

　　Osbourne博士：目前已经有很多HER-2阳性乳腺癌治疗的相关研究。我自己的实验室首创了“HER家族双受体信号通路阻滞”的方法，这种方法有额外的优势。即HER家族4名成员皆可进行信号转导，特别是HER1，HER2，HER3。曲妥珠单抗能阻断其中之一，其也有抗体依赖细胞介导的细胞毒性作用（ADCC）。但我们已发现，同时用拉帕替尼或EGFR抑制剂阻断HER1或HER-3，或用帕妥珠单抗阻断HER-3、HER-2异二聚体化可产生更多疗效。大量化疗并没有显示出疗效 （如ALTTO试验），却使双受体信号通路阻滞的优势有所丧失。我认为有些患者可只进行两个HER受体信号通路阻滞治疗，顶多在治疗初期少量化疗（如Dana Farber研究中低危患者用紫杉醇和赫赛汀化疗）。不过新辅助治疗的研究显示患者不化疗也能获得很高的pCR率，也就是说，有些肿瘤较大患者（上述研究的患者肿瘤平均5、6厘米）不需化疗，只进行12周双受体阻滞治疗即可。现在我们需要确定哪些患者需要化疗，哪些患者会发生受体阻断治疗耐药而需要其它类型的治疗。我们找到了一个线索，如果存在PI3K突变从HR受体下游激活的信号通路，或存在p10 基因表达量低激活PI3K通路，则可导致受体抑制剂的耐药，我们做了大量相关研究并试图找出那些代偿信号通路。