Tural Deniz, Batur Sebnem, Erdamar Sibel, Akar Emre, Kepil Nuray, Mandel Nil Molinas, Serdengeçti Süheyla
Division of Medical Oncology, Department of Internal Medicine, Akdeniz Medical School, Akdeniz University, 7058, Antalya, Turkey,
Tumour Biol. 2014 Feb;35(2):1041-9. doi: 10.1007/s13277-013-1138-8. Epub 2013 Sep 1.
We investigated predictive values of BRAF, PI3K and PTEN in cetuximab responses in KRAS wild-type (+) chemotherapy refractory, metastatic colorectal cancer (CRC) patients. Primary tumour tissues of 41 KRAS wild-type mCRC patients receiving cetuximab-based chemotherapy were investigated for PI3K, PTEN, KRAS and BRAF mutations. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and the Cox proportional hazards model was used. PTEN and PI3K expressions were 63 and 42 %, respectively. BRAF mutation was observed as 9.8 % among patients. Tumours with BRAF mutation had statistically lower response rates (RR) for cetuximab-based treatment than tumours with BRAF wild type (0 vs. 58 %, p = 0.02). PTEN expressing tumours had statistically higher RR for cetuximab-based treatment than tumours with PTEN loss (42 vs. 12 %, p = 0.04). PI3K expression had worse significant effect on cetuximab RR than PI3K non-expressed tumours (15 vs. 44 %, p = 0.023). Median PFS was significantly longer in patients with PTEN expression (14 months) than in patients with PTEN loss (5 months) (HR, 0.4; p = 0.028). Median PFS was significantly longer in patients with PI3K non-expression (15.2 months) than in patients with PI3K expression (4.1 months) (HR, 0.31; p = 0.001). Significant difference in PFS and OS between patients with BRAF mutated and BRAF wild-type tumours was not detected. However, patients with PTEN expression had significantly longer OS (15.1 months) than patients with PTEN loss tumour (9.9 months) (HR, 0.34; p = 0.008). Patients without PI3K expression had significantly longer OS (18.2 months) than patients with PI3K expression (10.1 months) (HR, 0.27; p = 0.001). Multivariate analyses revealed that PTEN expression (HR, 0.48; p = 0.02) and absence of PI3K expression (HR, 0.2; p = 0.001) were independent prognostic factors for increased PFS. Similarly, PTEN overexpression (HR, 0.62; p = 0.03) and absence of PI3K expression (HR, 0.27; p = 0.005) were independent prognostic factors for increased OS. In PTEN loss, PI3K expression may be used as biomarkers to further select KRAS wild-type patients undergoing anti-epidermal growth factor receptor treatment.
我们研究了BRAF、PI3K和PTEN在KRAS野生型（+）化疗难治性转移性结直肠癌（CRC）患者中对西妥昔单抗反应的预测价值。对41例接受基于西妥昔单抗化疗的KRAS野生型mCRC患者的原发性肿瘤组织进行PI3K、PTEN、KRAS和BRAF突变检测。采用Kaplan-Meier法计算无进展生存期（PFS）和总生存期（OS），并使用Cox比例风险模型。PTEN和PI3K表达率分别为63%和42%。患者中BRAF突变率为9.8%。BRAF突变的肿瘤对基于西妥昔单抗治疗的反应率（RR）在统计学上低于BRAF野生型肿瘤（0%对58%，p = 0.02）。PTEN表达的肿瘤对基于西妥昔单抗治疗的RR在统计学上高于PTEN缺失的肿瘤（42%对12%，p = 0.04）。PI3K表达对西妥昔单抗RR的影响比未表达PI3K的肿瘤更显著（15%对44%，p = 0.023）。PTEN表达患者的中位PFS（14个月）显著长于PTEN缺失患者（5个月）（风险比，0.4；p = 0.028）。PI3K未表达患者的中位PFS（15.2个月）显著长于PI3K表达患者（4.1个月）（风险比，0.31；p = 0.001）。未检测到BRAF突变和BRAF野生型肿瘤患者之间PFS和OS的显著差异。然而，PTEN表达患者的OS（15.1个月）显著长于PTEN缺失肿瘤患者（9.9个月）（风险比，0.34；p = 0.008）。无PI3K表达患者的OS（18.2个月）显著长于PI3K表达患者（10.1个月）（风险比，0.27；p = 0.001）。多因素分析显示，PTEN表达（风险比，0.48；p = 0.02）和无PI3K表达（风险比，0.2；p = 0.001）是PFS延长的独立预后因素。同样，PTEN过表达（风险比，0.62；p = 0.03）和无PI3K表达（风险比，0.27；p = 0.005）是OS延长的独立预后因素。在PTEN缺失的情况下，PI3K表达可用作生物标志物，以进一步筛选接受抗表皮生长因子受体治疗的KRAS野生型患者。
