Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations.
Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations.
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DOI：
10.1158/1535-7163.mct-13-0319-t
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发表时间：
2013-12
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：
Ganesan P;Janku F;Naing A;Hong DS;Tsimberidou AM;Falchook GS;Wheler JJ;Piha-Paul SA;Fu S;Stepanek VM;Lee JJ;Luthra R;Overman MJ;Kopetz ES;Wolff RA;Kurzrock R
在具有PIK 3CA突变的多种晚期癌症患者中使用PI 3 K/AKT/mTOR通路抑制剂的靶向匹配治疗已显示出前景。分析来自结直肠癌（CRC）患者的肿瘤的PIK 3CA、KRAS和BRAF突变。在可行的情况下，使用靶向PI 3 K/AKT/mTOR途径的药物治疗PIK 3CA突变肿瘤。在分析的194例患者中，31例（16%）有PIK 3CA突变，189例（97%）进行了KRAS突变评估。与野生型（wt）PIK 3CA患者相比，PIK 3CA突变患者同时发生KRAS突变的患病率更高（71%，22/31 vs. 43%，68/158; p=0.006）。在31例PIK 3CA突变患者中，17例（55%）接受了含有PI 3 K/AKT/mTOR通路抑制剂的方案治疗（中位年龄57岁;既往治疗中位次数4次; mTORC 1抑制剂[11]、PI 3 K抑制剂[5]或AKT抑制剂[1]）。无患者（0/17）部分或完全缓解（PR/CR），仅1例患者（6%，95% CI 0.01-0.27）的患者病情稳定（SD）≥6个月，与SD≥6个月/PR/CR率16%无显著差异（11/67; 95% CI 0.09-0.27）（p=0.44）。中位无进展生存期为1.9个月（95% CI 1.5-2.3）。总之，我们的数据提供了初步证据，表明在患有PIK 3CA突变型晚期CRC的重度预治疗患者中，合并PI 3 K/AKT/mTOR抑制剂的方案具有最小的活性。PIK 3CA突变与同时发生的KRAS突变相关，可能导致治疗耐药。
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 (CRC) 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 (wt) 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; median number of prior therapies, 4; mTORC1 inhibitors [11], PI3K inhibitors [5] or an AKT inhibitor [1]). None (0/17) had a partial or complete response (PR/CR) and only 1 (6%, 95% CI 0.01–0.27) had stable disease (SD)≥6 months, which was not significantly different from a SD≥6 month/PR/CR rate of 16% (11/67; 95% CI 0.09–0.27) in CRC patients 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 CRC, protocols incorporating PI3K/AKT/mTOR inhibitors have minimal activity. PIK3CA mutations are associated with simultaneous KRAS mutations, possibly accounting for therapeutic resistance.