KRAS、BRAF、PIK3CA 突变、PTEN、AREG、EREG 表达及皮疹对≥2 线基于西妥昔单抗治疗的结直肠癌患者的影响。

Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥ 2 line cetuximab-based therapy of colorectal cancer patients.

机构信息

Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.

出版信息

PLoS One. 2011 Jan 20;6(1):e15980. doi: 10.1371/journal.pone.0015980.

BACKGROUND

To investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC) patients treated with cetuximab containing salvage chemotherapy.

METHODS

Primary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded.

RESULTS

KRAS, BRAF and PIK3CA mutations were present in 37 (33%), 8 (7.2%) and 11 (9.8%) cases, respectively, PTEN was lost in 21 (19.8%) cases, AREG and EREG were overexpressed in 48 (45%) and 51 (49%) cases. In the whole study population, time to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with KRAS (p = 0.001 and p = 0.026, respectively) or BRAF (p = 0.001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.018 and p = 0.013, respectively) or EREG (p = 0.002 and p = 0.004, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p = 0.0001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively) or EREG (p = 0.0001 and p<0.0001, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). TTP was significantly lower in patients with PIK3CA mutations (p = 0.01) or lost PTEN (p = 0.002). Multivariate analysis revealed KRAS (Hazard Ratio [HR] 4.3, p<0.0001), BRAF mutation (HR: 5.1, p<0.0001), EREG low expression (HR: 1.6, p = 0.021) and absence of severe/moderate skin rash (HR: 4.0, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p = 0.01), BRAF mutation (HR: 3.0, p = 0.001), EREG low expression (HR: 1.7, p = 0.021), absence of severe/moderate skin rash (HR: 3.7, p<0.0001) and the presence of undifferantited tumours (HR: 2.2, p = 0.001) were revealed as independent prognostic factors for decreased OS.

CONCLUSIONS

These results underscore that KRAS-BRAF mutations and EREG expression can be used as biomarkers to further select patients undergoing anti-EGFR treatment.

背景

研究 KRAS、BRAF、PIK3CA 基因突变状态、AREG-EREG mRNA 表达、PTEN 蛋白表达和皮疹在接受西妥昔单抗联合挽救化疗的转移性结直肠癌（mCRC）患者中的预测意义。

方法

分析了 112 例 mCRC 患者的原发肿瘤。记录治疗过程中最严重的皮肤毒性。

结果

分别有 37（33%）、8（7.2%）和 11（9.8%）例患者存在 KRAS、BRAF 和 PIK3CA 突变，21（19.8%）例患者 PTEN 缺失，48（45%）和 51（49%）例患者 AREG 和 EREG 过表达。在整个研究人群中，KRAS（p=0.001 和 p=0.026）或 BRAF（p=0.001 和 p<0.0001）突变肿瘤患者的肿瘤进展时间（TTP）和总生存期（OS）明显降低，AREG（p=0.018 和 p=0.013）或 EREG（p=0.002 和 p=0.004）下调和 0-1 级皮疹（p<0.0001 和 p<0.0001）。在 KRASwt 患者中，KRAS（p=0.0001 和 p<0.0001）突变肿瘤、AREG（p=0.021 和 p=0.004）或 EREG（p=0.0001 和 p<0.0001）下调和 0-1 级皮疹（p<0.0001 和 p<0.0001）患者的 TTP 和 OS 明显降低。PIK3CA 突变（p=0.01）或 PTEN 缺失（p=0.002）患者的 TTP 明显降低。多因素分析显示 KRAS（风险比[HR]4.3，p<0.0001）、BRAF 突变（HR：5.1，p<0.0001）、低表达 EREG（HR：1.6，p=0.021）和无严重/中度皮疹（HR：4.0，p<0.0001）为 TTP 降低的独立预后因素。同样，KRAS（HR 2.9，p=0.01）、BRAF 突变（HR：3.0，p=0.001）、低表达 EREG（HR：1.7，p=0.021）、无严重/中度皮疹（HR：3.7，p<0.0001）和未分化肿瘤（HR：2.2，p=0.001）为 OS 降低的独立预后因素。