KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with early-phase trials with targeted pathway inhibitors.
KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with early-phase trials with targeted pathway inhibitors.
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DOI：
10.1371/journal.pone.0038033
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kurzrock R
中科院分区：
文献类型：
--
作者：
Garrido-Laguna I;Hong DS;Janku F;Nguyen LM;Falchook GS;Fu S;Wheler JJ;Luthra R;Naing A;Wang X;Kurzrock R
评估转移性结直肠癌（mCRC）患者的临床病理和分子特征及其在早期试验中使用途径靶向药物的结果。我们分析了来自MD安德森癌症中心一期临床试验单元的238例mCRC患者的特征。采用基于pcr的DNA测序方法检测KRAS、PIK3CA和BRAF状态。51%的患者携带KRAS突变；15%的人有PIK3CA突变。在临床特征的多变量回归模型中，KRAS突变与肺和骨转移发生率增加以及肾上腺转移发生率降低相关；PIK3CA突变与黏液性肿瘤无显著相关性（p = 0.05）。在单变量分析中，KRAS和PIK3CA突变密切相关。晚期杜克分期（p<0.0001）和KRAS突变（p = 0.01）是生存不良的唯一显著独立预测因子（Cox比例风险模型）。PIK3CA突变的患者在接受抗egfr治疗时，有缩短无进展生存期的趋势（p = 0.07）。78名接受PI3K/Akt/mTOR轴抑制剂治疗的可评估患者中有18名（23%）达到了病情稳定[SD]≥6个月或完全缓解/部分缓解（CR/PR），其中只有1名患者属于PIK3CA突变亚组（N = 15），可能是因为这15名患者中有10名（67%）共存KRAS突变。10例患者采用丝裂原活化蛋白激酶（MAPK）通路靶向药物治疗，均未见SD≥6个月/CR/PR。KRAS和PIK3CA突变在结直肠癌患者中经常共存，并与临床特征和预后相关。克服耐药性可能需要同时针对这两种途径。
To evaluate clinicopathologic and molecular features of patients with metastatic colorectal cancer (mCRC) and their outcomes in early-phase trials using pathway-targeting agents. We analyzed characteristics of 238 patients with mCRC referred to the phase 1 trials unit at MD Anderson Cancer Center. KRAS, PIK3CA and BRAF status were tested using PCR-based DNA sequencing. Fifty-one percent of patients harbored KRAS mutations; 15% had PIK3CA mutations. In the multivariate regression model for clinical characteristics KRAS mutations were associated with an increased incidence of lung and bone metastases and decreased incidence of adrenal metastases; PIK3CA mutations were marginally correlated with mucinous tumors (p = 0.05). In the univariate analysis, KRAS and PIK3CA mutations were strongly associated. Advanced Duke's stage (p<0.0001) and KRAS mutations (p = 0.01) were the only significant independent predictors of poor survival (Cox proportional hazards model). Patients with PIK3CA mutations had a trend toward shorter progression-free survival when treated with anti-EGFR therapies (p = 0.07). Eighteen of 78 assessable patients (23%) treated with PI3K/Akt/mTOR axis inhibitors achieved stable disease [SD] ≥6 months or complete response/partial response (CR/PR), only one of whom were in the subgroup (N = 15) with PIK3CA mutations, perhaps because 10 of these 15 patients (67%) had coexisting KRAS mutations. No SD ≥6 months/CR/PR was observed in the 10 patients treated with mitogen-activating protein kinase (MAPK) pathway targeting drugs. KRAS and PIK3CA mutations frequently coexist in patients with colorectal cancer, and are associated with clinical characteristics and outcome. Overcoming resistance may require targeting both pathways.
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影响因子：
11.5
作者：
Tie, Jeanne;Lipton, Lara;Sieber, Oliver M.
通讯作者：
Sieber, Oliver M.
影响因子：
45.3
作者：
Van Cutsem, Eric;Kohne, Claus-Henning;Ciardiello, Fortunato
通讯作者：
Ciardiello, Fortunato
用PI3K/AKT/MTOR轴抑制剂治疗的晚期癌症患者的PIK3CA突变。
影响因子：
5.7
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
通讯作者：
Kurzrock R
影响因子：
3.7
作者：
KAPLAN, EL;MEIER, P
通讯作者：
MEIER, P
影响因子：
45.3
作者：
Loupakis, Fotios;Pollina, Luca;Falcone, Alfredo
通讯作者：
Falcone, Alfredo