PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials.
PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials.
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DOI：
10.1158/0008-5472.can-12-1726
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发表时间：
2013-01-01
期刊：
影响因子：
11.2
通讯作者：
Kurzrock R
中科院分区：
文献类型：
--
作者：
Janku F;Wheler JJ;Naing A;Falchook GS;Hong DS;Stepanek VM;Fu S;Piha-Paul SA;Lee JJ;Luthra R;Tsimberidou AM;Kurzrock R
PIK3CA突变可能预测晚期癌症患者对PI3K/AKT/mTOR抑制剂的反应，但突变亚型的相关性尚未研究。向临床靶向治疗中心提交的各种癌症患者进行了PIK3CA和KRAS突变分析，如果可能的话。对于PIK3CA突变的患者，只要有可能，就使用靶向PI3K/AKT/mTOR通路的药物进行治疗。总体而言，1012名患者中有105名（10%）携带PIK3CA突变。105名pik3ca突变患者中的66名（中位数为3次既往治疗）（包括同时发生KRAS突变的55名pik3ca突变患者中的16名个体）接受了包括PI3K/AKT/mTOR途径抑制剂的方案治疗；17%（11/66）达到部分缓解（PR）。PIK3CA H1047R突变患者与其他PIK3CA突变患者或采用相同方案治疗的野生型PIK3CA患者相比，PR率更高（分别为6/ 16,38% vs. 5/ 50,10% vs. 23/ 174,13%，均p≤0.02）。在密码子12或13中同时存在PIK3CA和KRAS突变的16例患者中，没有一例达到PR（0/ 16,0%）。联合治疗比单药治疗的患者PR率更高（11/ 38,29%比0/ 28,0%;p=0.002）。多因素分析显示，H1047R是预测反应的唯一独立因素（优势比（OR） 6.6, 95% CI 1.02 ~ 43.0, p = 0.047）。我们的数据表明，PIK3CA突变H1047R与其他畸变之间的相互作用以及对PI3K/AKT/mTOR轴抑制剂的反应值得进一步探索。
PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Overall, 105 (10%) of 1,012 patients tested harbored PIK3CA mutations. Sixty-six (median 3 prior therapies) of the 105 PIK3CA-mutant patients (including 16 individuals (of 55 PIK3CA-mutant patients tested) with simultaneous KRAS mutations) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor; 17% (11/66) achieved a partial response (PR). Patients with a PIK3CA H1047R mutation compared to patients with other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50, 10% vs. 23/174, 13%, respectively; all p ≤ 0.02). None of the 16 patients with co-existing PIK3CA and KRAS mutations in codon 12 or 13 attained a PR (0/16, 0%). Patients treated with combination therapy vs. single-agent therapies had a higher PR rate (11/38, 29% vs. 0/28, 0%; p=0.002). Multivariate analysis showed that H1047R was the only independent factor predicting response (odds ratio (OR) 6.6, 95% CI 1.02–43.0, p = 0.047). Our data suggest that interaction between PIK3CA mutation H1047R vs. other aberrations and response to PI3K/AKT/mTOR axis inhibitors warrants further exploration.