Bello Danielle M, Dematteo Ronald P, Ariyan Charlotte E
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Ann Surg Oncol. 2014 Jun;21(6):2059-67. doi: 10.1245/s10434-013-3373-z. Epub 2014 Feb 15.
The high response rates to the tyrosine kinase inhibitor imatinib in KIT-mutated gastrointestinal stromal tumors (GIST) has led to a paradigm shift in cancer treatment. In a parallel fashion, the field of melanoma is shifting with the utilization of targeted therapy to treat BRAF-mutated melanoma. We reviewed published literature in PubMed on GIST and melanoma, with a focus on both past and current clinical trials. The data presented centers on imatinib, vemurafenib, and most recently dabrafenib, targeting KIT and BRAF mutations and their outcomes in GIST and melanoma. The BRAF(V600E) melanoma mutation, like the KIT exon 11 mutation in GIST, has the highest response to therapy. High response rates with inhibition of KIT in GIST have not been recapitulated in KIT-mutated melanoma. Median time to resistance to targeted agents occurs in ~7 months with BRAF inhibitors and 2 years for imatinib in GIST. In GIST, the development of secondary mutations leads to resistance; however, there have been no similar gatekeeper mutations found in melanoma. Although surgery remains an important component of the treatment of early GIST and melanoma, surgeons will need to continue to define the thresholds and timing for operation in the setting of metastatic disease with improved targeted therapies. Combination treatment strategies may result in more successful clinical outcomes in the management of melanoma in the future.
酪氨酸激酶抑制剂伊马替尼对KIT突变的胃肠道间质瘤（GIST）具有高反应率，这导致了癌症治疗模式的转变。同样，黑色素瘤领域也在随着靶向治疗用于治疗BRAF突变的黑色素瘤而发生转变。我们检索了PubMed上关于GIST和黑色素瘤的已发表文献，重点关注过去和当前的临床试验。所呈现的数据集中在伊马替尼、维莫非尼以及最近的达拉非尼，它们针对KIT和BRAF突变及其在GIST和黑色素瘤中的疗效。BRAF（V600E）黑色素瘤突变与GIST中的KIT外显子11突变一样，对治疗的反应最高。在KIT突变的黑色素瘤中，尚未重现GIST中抑制KIT时的高反应率。BRAF抑制剂治疗黑色素瘤的中位耐药时间约为7个月，GIST中伊马替尼的中位耐药时间为2年。在GIST中，继发突变的发生导致耐药；然而，在黑色素瘤中尚未发现类似的守门人突变。尽管手术仍然是早期GIST和黑色素瘤治疗的重要组成部分，但随着靶向治疗的改进，外科医生需要继续确定转移性疾病情况下手术的阈值和时机。联合治疗策略可能会在未来黑色素瘤的管理中带来更成功的临床结果。
