PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer
PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer
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DOI：
10.1200/jco.2008.20.2796
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发表时间：
2009-06-01
影响因子：
45.3
通讯作者：
Falcone, Alfredo
中科院分区：
文献类型：
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作者：
Loupakis, Fotios;Pollina, Luca;Falcone, Alfredo
目的PTEN、AKT和KRAS是表皮生长因子受体（EGFR）的下游调节因子。KRAS突变导致西妥昔单抗耐药。这项回顾性研究调查了PTEN的损失，AKT磷酸化，和KRAS突变的西妥昔单抗加伊立替康在转移性结直肠癌（mCRC）患者的活性的作用。患者和MethodsA队列的伊立替康难治性mCRC患者谁是西妥昔单抗加伊立替康治疗的PTEN免疫反应性（即，免疫组织化学; IHC），pAKT IHC和KRAS突变进行了测试。原发性肿瘤和相关转移进行了分析，IHC，突变的结果，和治疗outcomes.Results102例患者之间的关联进行了调查。96例原发性肿瘤、59例转移瘤和53例配对样本可用。49例原发性肿瘤（占可评估样本的58%）具有保留的PTEN表达（PTEN阳性），而35例（占可评估样本的40%）为pAKT阳性。原发肿瘤和转移瘤之间的一致性水平分别为60%，68%和95%的PTEN，pAKT和KRAS。原发肿瘤的PTEN状态和原发肿瘤和转移灶的pAKT状态不能预测缓解或无进展生存期（PFS）。在转移方面，33例PTEN阳性肿瘤患者中有12例（36%）是应答者，而22例PTEN阴性肿瘤患者中有1例（5%）是应答者（P= 0.007）。PTEN阳性转移患者的中位PFS为4.7个月，而PTEN阴性转移患者为3.3个月（风险比[HR]，0.49; P=.005）。与其他患者相比，PTEN阳性转移和KRAS野生型患者的PFS较长（5.5个月vs 3.8个月; HR，0.42; P=.001）。PTEN IHC和KRAS突变分析的组合可以帮助识别具有更高机会从EGFR抑制中获益的mCRC患者亚组。J Clin Oncol 27：2622-2629. (C)2009年美国临床肿瘤学会
PurposePTEN, AKT, and KRAS are epidermal growth factor receptor (EGFR) downstream regulators. KRAS mutations confer resistance to cetuximab. This retrospective study investigated the role of PTEN loss, AKT phosphorylation, and KRAS mutations on the activity of cetuximab plus irinotecan in patients with metastatic colorectal cancer (mCRC).Patients and MethodsA cohort of patients with irinotecan-refractory mCRC who were treated with cetuximab plus irinotecan was tested for PTEN immunoreactivity (ie, immunohistochemistry; IHC), pAKT IHC, and KRAS mutations. Analyses were performed both on primary tumors and on related metastases, and the association among IHC, mutational results, and treatment outcomes was investigated.ResultsOne-hundred two patients were eligible. Ninety-six primary tumors, 59 metastases, and 53 paired samples were available. Forty-nine primary tumors (58% of assessable samples) had a preserved PTEN expression (PTEN-positive), whereas 35 (40% of assessable samples) were pAKT-positive. Levels of concordance between primary tumors and metastases were 60%, 68%, and 95% for PTEN, pAKT, and KRAS, respectively. PTEN status on primary tumors and pAKT status both on primary tumors and on metastases did not predict response or progression-free survival (PFS). On metastases, 12 (36%) of 33 patients with PTEN-positive tumors were responders compared with one (5%) of 22 who had PTEN-negative tumors (P=.007). The median PFS of patients with PTEN-positive metastases was 4.7 months compared with 3.3 months for those with PTEN-negative metastases (hazard ratio [HR], 0.49; P=.005). Patients with PTEN-positive metastases and KRAS wild type had longer PFS compared with other patients (5.5 months v 3.8 months; HR, 0.42; P=.001).ConclusionPTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN IHC and KRAS mutational analyses could help to identify a subgroup of patients with mCRC who have higher chances of benefiting from EGFR inhibition. J Clin Oncol 27: 2622-2629. (C) 2009 by American Society of Clinical Oncology