PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors.
PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors.
复制标题
用PI3K/AKT/MTOR轴抑制剂治疗的晚期癌症患者的PIK3CA突变。
DOI：
10.1158/1535-7163.mct-10-0994
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发表时间：
2011-03
影响因子：
5.7
通讯作者：
Kurzrock R
中科院分区：
文献类型：
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作者：
Janku F;Tsimberidou AM;Garrido-Laguna I;Wang X;Luthra R;Hong DS;Naing A;Falchook GS;Moroney JW;Piha-Paul SA;Wheler JJ;Moulder SL;Fu S;Kurzrock R
临床前数据表明，PIK 3CA突变可预测对PI 3 K/AKT/mTOR抑制剂的反应。伴随的KRAS或BRAF突变可能介导耐药。因此，使用外显子9和20的基于PCR的DNA测序分析了2008年10月开始的I期靶向治疗项目中患者的肿瘤中的PIK 3CA突变。具有不同肿瘤类型和PIK 3CA突变的连续性患者尽可能使用靶向PI 3 K/AKT/mTOR通路的药物进行治疗。总体而言，217名患者中有25名（11.5%）检测到PIK 3CA突变（第9号外显子，n=11;第20号外显子，n=14）。在>10例受试者的肿瘤类型中，PIK 3CA突变在子宫内膜癌（3/14，21%）、卵巢癌（5/30，17%）、结直肠癌（9/54，17%）、乳腺癌（2/14，14%）、宫颈癌（2/15，13%）和头颈部鳞状细胞癌（1/11，9%）中最常见。25例PIK 3CA突变患者中有17例（68%）接受了包括PI 3 K/AKT/mTOR通路抑制剂的方案治疗，6例（35%）获得部分缓解。相比之下，在241例无PIK 3CA突变记录的患者中，仅15例（6%）在相同方案治疗后出现缓解（p=0.001）。17例PIK 3CA突变患者中有6例（35%）同时发生KRAS或BRAF突变（结直肠，n=4;卵巢，n=2）。携带PIK 3CA和KRAS突变的结直肠癌患者对治疗无应答，而携带PIK 3CA和KRAS或BRAF突变的卵巢癌患者对治疗有应答。总之，在11.5%的各种实体瘤患者中检测到PIK 3CA突变。接受PI 3 K/AKT/mTOR通路抑制剂治疗的PIK 3CA突变患者的缓解率显著高于未记录突变的患者。
Preclinical data suggest that PIK3CA mutations predict response to PI3K/AKT/mTOR inhibitors. Concomitant KRAS or BRAF mutations may mediate resistance. Therefore tumors from patients referred to the Phase I Program for targeted therapy starting in October 2008 were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exons 9 and 20. Consecutive patients with diverse tumor types and PIK3CA mutations were treated whenever possible with agents targeting the PI3K/AKT/mTOR pathway. Overall, PIK3CA mutations were detected in 25 of 217 patients (11.5%) (exon 9, n=11; exon 20, n=14). In tumor types with >10 patients tested, PIK3CA mutations were most frequent in endometrial (3/14, 21%), ovarian (5/30, 17%), colorectal (9/54, 17%), breast (2/14, 14%), cervical (2/15, 13%), and squamous cell cancer of head and neck (1/11, 9%). Seventeen of the 25 patients (68%) with PIK3CA mutations were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor, and 6 (35%) achieved a partial response. In contrast, only 15 of 241 patients (6%) without documented PIK3CA mutations treated on the same protocols responded (p=0.001). Six of the 17 (35%) patients with PIK3CA mutations had simultaneous KRAS or BRAF mutations (colorectal, n=4; ovarian, n=2). Colorectal cancer patients with PIK3CA and KRAS mutations did not respond to therapy, while both ovarian cancer patients with PIK3CA and KRAS or BRAF mutations did. In conclusion, PIK3CA mutations were detected in 11.5% of patients with diverse solid tumors. The response rate was significantly higher for patients with PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors than for those without documented mutations.