BACKGROUND The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. METHODS The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed. RESULTS Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. CONCLUSIONS MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. TRIAL REGISTRATION ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011.

中文翻译：

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AKT抑制剂MK-2206在患有PIK3CA或AKT突变和/或PTEN缺失/ PTEN突变的晚期乳腺癌患者中进行的II期临床试验。

背景技术PI3K / AKT途径是通过乳腺癌中的PIK3CA或AKT1突变和PTEN缺失激活的。我们对具有PIK3CA / AKT1突变和/或PTEN缺失/突变的晚期乳腺癌患者进行了别构AKT抑制剂MK-2206的II期试验。方法的主要终点是客观反应率（ORR）。次要终点是6个月无进展生存期（6 m PFS），预测和药效指标，安全性和耐受性。患者接受了治疗前和治疗中的活检，以及外周血单核细胞（PBMC）和富血小板血浆（PRP）的收集。进行了下一代测序，免疫组织化学和反相蛋白阵列（RPPA）。结果27例患者接受了MK-2206。18名患者被纳入PIK3CA / AKT1突变组（队列A）：13名具有PIK3CA突变，4名具有AKT1突变，1名具有PIK3CA突变以及PTEN丢失。ORR和6 m PFS均为5.6％（1/18），其中一名HR +乳腺癌和PIK3CA E542K突变患者出现部分反应（治疗36周）。9名患者入选PTEN缺失/突变组（组B）。在三阴性乳腺癌和PTEN缺失的患者中观察到ORR为0％，6 m PFS为11％（1/9）。由于徒劳无功，这项研究被提前终止。最常见的不良事件是疲劳（48％）和皮疹（44％）。在治疗前的活检中，PIK3CA和AKT1突变状态与档案组织测试一致。然而，基于档案测试的两名PTEN丢失患者在治疗前的活检中具有PTEN表达。MK-2206治疗与PBMC和PRP中pAKT S473和pAKT T308的显着下降以及PI3K激活评分相关，但与肿瘤活检无关。通过IHC，pAKT S473或Ki-67的中位数没有显着降低，但是在两个应答者中均观察到了下降。结论在因PIK3CA / AKT1或PTEN突变或PTEN缺失而选择的晚期乳腺癌患者中，MK-2206单一疗法的临床活性有限。这可能部分是由于在经过严格激活的，具有通路激活的患者中，在可耐受剂量下靶标抑制作用不足，以及肿瘤异质性和标记物（例如PTEN）的进化给患者选择带来了挑战。试验注册ClinicalTrials.gov，NCT01277757。2011年1月13日注册。