PI3K/AKT/mTOR Inhibitors in Patients With Breast and Gynecologic Malignancies Harboring PIK3CA Mutations
PI3K/AKT/mTOR Inhibitors in Patients With Breast and Gynecologic Malignancies Harboring PIK3CA Mutations
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DOI：
10.1200/jco.2011.36.1196
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发表时间：
2012-03-10
影响因子：
45.3
通讯作者：
Kurzrock, Razelle
中科院分区：
文献类型：
--
作者：
Janku, Filip;Wheler, Jennifer J.;Kurzrock, Razelle
目的PIK3CA基因突变可预测对磷脂酰肌醇3-激酶(PI3K)/AKT/雷帕霉素(MTOR)抑制剂靶标的反应。患者和方法分析了来自临床靶向治疗中心(第一阶段计划)的乳腺癌、子宫颈癌、子宫内膜癌和卵巢癌患者的PIK3CA、KRAS、NRAS和BRAF突变。结果在分析的140例患者中，25例(18%)存在PIK3CA突变，包括14例宫颈鳞状细胞癌中的5例、29例子宫内膜中的7例、29例乳腺癌中的6例和60例卵巢癌中的7例。在25例PIK3CA突变患者中，23例(之前两种治疗的中位数)接受了包括PI3K/AKT/mTOR途径抑制剂的治疗。23例患者中2例(9%)病情稳定超过6个月，7例(30%)部分缓解。相比之下，在接受相同方案治疗的70名疾病类型相同但携带野生型PIK3CA的患者中，只有7人(10%)有反应(P=0.04)。7例(30%)PIK3CA突变患者同时存在MAPK通路(KRAS、NRAS、BRAF)突变(卵巢癌5例，子宫内膜癌2例)，其中2例卵巢癌患者PIK3CA突变有效。有PIK3CA突变的患者接受PI3K/AKT/mTOR抑制剂治疗的有效率高于无突变的患者。部分同时存在PIK3CA和MAPK突变的卵巢癌患者对PI3K/AKT/mTOR抑制剂有反应，这表明当MAPK途径同时激活时，并不是所有患者都表现出耐药性。J Clin Oncol30：777-782。(C)2012年美国临床肿瘤学会
PurposeMutations of the PIK3CA gene may predict response to phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors. Concomitant mutations in the mitogen-activated protein kinase (MAPK) pathway may mediate resistance.Patients and MethodsTumors from patients with breast, cervical, endometrial, and ovarian cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway.ResultsOf 140 patients analyzed, 25 (18%) had PIK3CA mutations, including five of 14 patients with squamous cell cervical, seven of 29 patients with endometrial, six of 29 patients with breast, and seven of 60 patients with ovarian cancers. Of the 25 patients with PIK3CA mutations, 23 (median of two prior therapies) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Two (9%) of 23 patients had stable disease for more than 6 months, and seven patients (30%) had a partial response. In comparison, only seven (10%) of 70 patients with the same disease types but with wild-type PIK3CA treated on the same protocols responded (P = .04). Seven patients (30%) with PIK3CA mutations had coexisting MAPK pathway (KRAS, NRAS, BRAF) mutations (ovarian cancer, n = 5; endometrial cancer, n = 2), and two of these patients (ovarian cancer) achieved a response.ConclusionPIK3CA mutations were detected in 18% of tested patients. Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors demonstrated a higher response rate than patients without mutations. A subset of patients with ovarian cancer with simultaneous PIK3CA and MAPK mutations responded to PI3K/AKT/mTOR inhibitors, suggesting that not all patients demonstrate resistance when the MAPK pathway is concomitantly activated. J Clin Oncol 30:777-782. (C) 2012 by American Society of Clinical Oncology