Loupakis Fotios, Pollina Luca, Stasi Irene, Ruzzo Annamaria, Scartozzi Mario, Santini Daniele, Masi Gianluca, Graziano Francesco, Cremolini Chiara, Rulli Eliana, Canestrari Emanuele, Funel Niccola, Schiavon Gaia, Petrini Iacopo, Magnani Mauro, Tonini Giuseppe, Campani Daniela, Floriani Irene, Cascinu Stefano, Falcone Alfredo
Department of Oncology, Azienda USL 6, Istituto Toscano Tumori, Livorno, Italy.
J Clin Oncol. 2009 Jun 1;27(16):2622-9. doi: 10.1200/JCO.2008.20.2796. Epub 2009 Apr 27.
PTEN, 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).
A 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.
One-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).
PTEN 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.
PTEN、AKT和KRAS是表皮生长因子受体（EGFR）的下游调节因子。KRAS突变会导致对西妥昔单抗产生耐药性。这项回顾性研究调查了PTEN缺失、AKT磷酸化和KRAS突变在转移性结直肠癌（mCRC）患者中对西妥昔单抗联合伊立替康活性的作用。
对一组接受西妥昔单抗联合伊立替康治疗的伊立替康难治性mCRC患者进行PTEN免疫反应性检测（即免疫组织化学；IHC）、pAKT IHC检测和KRAS突变检测。对原发性肿瘤和相关转移灶均进行分析，并研究IHC、突变结果与治疗结果之间的关联。
102例患者符合条件。有96个原发性肿瘤、59个转移灶和53对配对样本。49个原发性肿瘤（占可评估样本的58%）PTEN表达保留（PTEN阳性），而35个（占可评估样本的40%）为pAKT阳性。原发性肿瘤与转移灶之间PTEN、pAKT和KRAS的一致性水平分别为60%、68%和95%。原发性肿瘤的PTEN状态以及原发性肿瘤和转移灶的pAKT状态均不能预测反应或无进展生存期（PFS）。在转移灶方面，33例PTEN阳性肿瘤患者中有12例（36%）有反应，而22例PTEN阴性肿瘤患者中有1例（5%）有反应（P = 0.007）。PTEN阳性转移灶患者的中位PFS为4.7个月，而PTEN阴性转移灶患者为3.3个月（风险比[HR]，0.49；P = 0.005）。与其他患者相比，PTEN阳性转移灶且KRAS野生型的患者PFS更长（5.5个月对3.8个月；HR，0.42；P = 0.001）。
转移灶中PTEN缺失可能预示对西妥昔单抗联合伊立替康耐药。PTEN IHC和KRAS突变分析相结合有助于识别出mCRC患者中更有可能从EGFR抑制中获益的亚组。
