Psyrri Amanda, Lee Ju-Whei, Pectasides Eirini, Vassilakopoulou Maria, Kosmidis Efstratios K, Burtness Barbara A, Rimm David L, Wanebo Harold J, Forastiere Arlene A
Authors' Affiliations: Yale University School of Medicine, New Haven, Connecticut; Dana-Farber Cancer Institute, Boston, Massachusetts; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Landmark Medical Center, Woonsocket, Rhode Island; Johns Hopkins University, Baltimore, Maryland; and Aristotle University of Thessaloniki, Thessaloniki, Greece.
Clin Cancer Res. 2014 Jun 1;20(11):3023-32. doi: 10.1158/1078-0432.CCR-14-0113. Epub 2014 Apr 3.
We sought to evaluate the correlation between tissue biomarker expression (using standardized, quantitative immunofluorescence) and clinical outcome in the E2303 trial.
Sixty-three eligible patients with operable stage III/IV head and neck squamous cell cancer (HNSCC) participated in the Eastern Cooperative Oncology Group (ECOG) 2303 phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel, and carboplatin followed by chemoradiation with the same regimen. A tissue microarray (TMA) was constructed and EGF receptor (EGFR), ERK1/2, Met, Akt, STAT3, β-catenin, E-cadherin, EGFR Variant III, insulin-like growth factor-1 receptor, NF-κB, p53, PI3Kp85, PI3Kp110a, PTEN, NRAS, and pRb protein expression levels were assessed using automated quantitative protein analysis (AQUA). For each dichotomized biomarker, overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were estimated by the Kaplan-Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were used to estimate HRs and test for significance.
Forty-two of 63 patients with TMA data on at least one biomarker were included in the biomarker analysis. Tumor extracellular signal-regulated kinase (ERK)1/2 levels were significantly associated with PFS [HR (low/high), 3.29; P = 0.026] and OS [HR (low/high), 4.34; P = 0.008]. On multivariable Cox regression analysis, ERK1/2 remained significantly associated with OS (P = 0.024) and PFS (P = 0.022) after controlling for primary site (oropharynx vs. non-oropharynx) and disease stage (III vs. IV), respectively. Clustering analysis revealed that clusters indicative of activated RAS/MAPK/ERK and/or PI3K/Akt pathways were associated with inferior OS and/or PFS and maintained significance in multivariable analysis.
These results implicate PI3K/Akt and RAS/MAPK/ERK pathways in resistance to cetuximab-containing chemoradiation in HNSCC. Large prospective studies are required to validate these results.
我们试图评估E2303试验中组织生物标志物表达（使用标准化定量免疫荧光法）与临床结局之间的相关性。
63例符合条件的可手术III/IV期头颈部鳞状细胞癌（HNSCC）患者参加了东部肿瘤协作组（ECOG）2303 II期诱导化疗试验，化疗方案为每周使用西妥昔单抗、紫杉醇和卡铂，随后采用相同方案进行放化疗。构建了组织微阵列（TMA），并使用自动定量蛋白质分析（AQUA）评估表皮生长因子受体（EGFR）、ERK1/2、Met、Akt、STAT3、β-连环蛋白、E-钙黏蛋白、EGFR III型变体、胰岛素样生长因子-1受体、NF-κB、p53、PI3Kp85、PI3Kp110a、PTEN、NRAS和pRb蛋白的表达水平。对于每个二分法生物标志物，采用Kaplan-Meier法估计总生存期（OS）、无进展生存期（PFS）和无事件生存期（EFS），并使用对数秩检验进行比较。采用多变量Cox比例风险模型估计风险比（HR）并检验其显著性。
63例至少有一个生物标志物TMA数据的患者中有42例纳入生物标志物分析。肿瘤细胞外信号调节激酶（ERK）1/2水平与PFS显著相关[HR（低/高），3.29；P = 0.026]和OS[HR（低/高），4.34；P = 0.008]。在多变量Cox回归分析中，分别在控制原发部位（口咽与非口咽）和疾病分期（III期与IV期）后，ERK1/2仍与OS（P = 0.024）和PFS（P = 0.022）显著相关。聚类分析显示，指示RAS/MAPK/ERK和/或PI3K/Akt通路激活的聚类与较差的OS和/或PFS相关，且在多变量分析中保持显著性。
这些结果表明PI3K/Akt和RAS/MAPK/ERK通路参与了HNSCC中含西妥昔单抗放化疗的耐药过程。需要进行大型前瞻性研究来验证这些结果。
