Corresponding Author: Filip Janku, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, FC8.2018, Box 0455, Houston, Texas 77030.
Mol Cancer Ther. 2013 Dec;12(12):2857-63. doi: 10.1158/1535-7163.MCT-13-0319-T. Epub 2013 Oct 3.
Target-matched treatment with PI3K/AKT/mTOR pathway inhibitors in patients with diverse advanced cancers with PIK3CA mutations have shown promise. Tumors from patients with colorectal cancer were analyzed for PIK3CA, KRAS, and BRAF mutations. PIK3CA-mutated tumors were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Of 194 patients analyzed, 31 (16%) had PIK3CA mutations and 189 (97%) were assessed for KRAS mutations. Patients with PIK3CA mutations had a higher prevalence of simultaneous KRAS mutations than patients with wild-type PIK3CA (71%, 22/31 vs. 43%, 68/158; P = 0.006). Of 31 patients with PIK3CA mutations, 17 (55%) were treated with protocols containing PI3K/AKT/mTOR pathway inhibitors [median age, 57 years; median number of prior therapies, 4; mTORC1 inhibitors (11), phosphoinositide 3-kinase (PI3K) inhibitors (5), or an AKT inhibitor (1)]. None (0/17) had a partial or complete response (PR/CR) and only 1 [6%, 95% confidence interval (CI), 0.01-0.27] had stable disease 6 months or more, which was not significantly different from a stable disease ≥6 month/PR/CR rate of 16% (11/67; 95% CI, 0.09-0.27) in patients with colorectal cancer without PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors (P = 0.44). Median progression-free survival was 1.9 months (95% CI, 1.5-2.3). In conclusion, our data provide preliminary evidence that in heavily pretreated patients with PIK3CA-mutant advanced colorectal cancer, protocols incorporating PI3K/AKT/mTOR inhibitors have minimal activity. PIK3CA mutations are associated with simultaneous KRAS mutations, possibly accounting for therapeutic resistance.
针对具有 PIK3CA 突变的多种晚期癌症患者，采用靶向 PI3K/AKT/mTOR 通路抑制剂的治疗方法显示出一定的疗效。对来自结直肠癌患者的肿瘤进行了 PIK3CA、KRAS 和 BRAF 突变分析。只要可行，就对 PIK3CA 突变的肿瘤进行针对 PI3K/AKT/mTOR 通路的药物治疗。在分析的 194 名患者中，31 名（16%）存在 PIK3CA 突变，189 名（97%）评估了 KRAS 突变。PI3KCA 突变患者同时存在 KRAS 突变的比例高于 PIK3CA 野生型患者（71%，22/31 比 43%，68/158；P=0.006）。在 31 名 PIK3CA 突变患者中，17 名（55%）接受了包含 PI3K/AKT/mTOR 通路抑制剂的方案治疗[中位年龄 57 岁；中位既往治疗数 4；mTORC1 抑制剂（11）、磷酸肌醇 3-激酶（PI3K）抑制剂（5）或 AKT 抑制剂（1）]。没有患者（0/17）有部分或完全缓解（PR/CR），只有 1 名（6%，95%置信区间[CI]，0.01-0.27）有稳定的疾病 6 个月或更长时间，这与未发生 PIK3CA 突变且接受 PI3K/AKT/mTOR 通路抑制剂治疗的结直肠癌患者的稳定疾病≥6 个月/PR/CR 率（16%，11/67；95%CI，0.09-0.27）没有显著差异（P=0.44）。中位无进展生存期为 1.9 个月（95%CI，1.5-2.3）。综上所述，我们的数据初步表明，在经过大量预处理的存在 PIK3CA 突变的晚期结直肠癌患者中，包含 PI3K/AKT/mTOR 抑制剂的方案几乎没有活性。PI3KCA 突变与同时存在的 KRAS 突变相关，可能导致治疗抵抗。
