Oncology Frontier:The response to BRAF inhibitors of course you said is highly variable and so is there any sort of biomarkers that we can look at to try at see what the outcome would be?

　　《肿瘤瞭望》：对BRAF抑制剂治疗的反应高度不同。有没有什么生物标记物可以预测对治疗的反应？

　　Prof. Flaherty: Since early days in terms of being able to really nail down a predictive way which patients would have various short lived response and long lasting responses but a few key insights have been obtained and really now need to be more firmly validated. One is simply disease burden， in the standard classification of metastatic disease， using the AGCC staging criteria， we subset metastatic patients into so-called M1A， M1B and M1C; M1A patients having cutaneous， sub-cutaneous and distant lymph node metastases， M1B to the lung and M1C more distant visceral sites beyond that or elevations in serum LDH. Regardless of disease site elevations in LDH put a patient in the M1C category. Not surprisingly it’s with increasing end stage that prognosis is more poor， absent treatment but also predictive of outcome in the treatment setting which is to say that the overall response rate， median progression pre-survival and overall survival are best for patients with M1A disease， next best for M1B and then M1C one can still see a response rate that is impressive compared to conventional chemotherapy but the duration of response or disease control is the shortest and overall survival is the shortest in that high disease burden population. That is a relative discerning factor in terms of likelihood of short term versus long term benefit from therapy. If you were just to focus on the subset of patients who develop long term responses lasting a year and a half to two years and even longer and then ask the question “what are the characteristics of those patients?” Those patients are nearly exclusively patients who had low disease burden at base line， typically M1A patients you will not find M1C patients amongst those who have the most durable responses. So many people recognize that the palliative symptom improving effects of BRAF inhibitor therapy are clearly robust in high disease burden patients， M1C patients specifically and that is no doubt true. It is simply the case that those tumors are the least to have very durable responses and it’s the low disease burden asymptomatic patients who are the most likely to have that type of long term outcome. That is a clinical feature if you will and not truly a biomarker.

　　A brief comment on the status of nailing down biomarkers is that we have preliminary evidence that the presence of concurrent genetic alterations beyond BRAF. For example in tumor suppressor genes such as P-10 or CDN2K which encodes B-16 in activating mutations in either of those appear to confer relative resistance in clinical trial populations. The data supports that statement is relative preliminary and needs to corroborate at the scale of hundreds of patients treated and followed in the context of these clinical trials but such analyses are underway. So it may be in fact that we were able to simply take the genetic landscape that has been thoroughly catalogued now in melanoma overlay that on clinical trial populations and discern those tumors that have additional genetic alterations in key pathways as being the markers of relative resistance and the absence of those alterations being the marker or the moniker of patients who are most likely to have durable disease control.