Agulnik Mark, da Cunha Santos Gilda, Hedley David, Nicklee Trudey, Dos Reis Patricia Pintor, Ho James, Pond Gregory R, Chen Heidi, Chen Shuo, Shyr Yu, Winquist Eric, Soulieres Denis, Chen Eric X, Squire Jeremy A, Marrano Paula, Kamel-Reid Suzanne, Dancey Janet, Siu Lillian L, Tsao Ming S
Princess Margaret Hospital Phase II Consortium, Toronto, Ontario, Canada.
J Clin Oncol. 2007 Jun 1;25(16):2184-90. doi: 10.1200/JCO.2006.07.6554.
PURPOSE Pharmacodynamic tissue studies were conducted on a phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Levels of epidermal growth factor receptor (EGFR), downstream signaling components, and markers of angiogenesis and apoptosis were evaluated to determine the relationship between correlative end points and clinical outcomes. PATIENTS AND METHODS Pretreatment and during-treatment tumor and skin biopsies, and archival tumor specimens were evaluated for EGFR, phosphorylated (p) -EGFR, extracellular signal-regulated kinase (ERK), p-ERK, Akt, p-Akt, Ki67, p27, p-nuclear factor kappa B (NFkappaB), p-signal transducer and activator of transcription 3 (STAT3), and EGFR gene copy number. Results On 37 archival samples, response to therapy was evident in two of four (50%) patients with high EGFR gene copy number tumors and in four of 27 (15%) patients with low gene copy number tumors. On nine paired tumor biopsies, elevated pretreatment levels of p27 and p-STAT3 predicted for prolonged time to progression (TTP) and overall survival (OS; P < or = .03). With treatment, a decrease in p-EGFR, p-NFkappaB, and p27 correlated with increased TTP, OS, or both TTP and OS, respectively (P < or = .04). Multidimensional scaling (MDS) models revealed clustering profiles of tumor markers by immunofluorescence could predict response. On 32 paired skin biopsies, suppression of p-EGFR with therapy correlated with increased OS (P = .045). CONCLUSION High EGFR gene copy in tumor specimens may predict which patients have an increased likelihood of response to erlotinib, and decreased p-EGFR level in skin biopsies during therapy may represent a potential surrogate marker for improved clinical outcome. MDS represents a novel way to evaluate the relationships between molecular markers and clinical outcome. Additional biomarker studies with larger sample sizes are required to elucidate HNSCC patients who may benefit from this targeted therapy.
对复发或转移性头颈部鳞状细胞癌（HNSCC）患者进行了厄洛替尼和顺铂的I/II期试验的药效组织学研究。评估表皮生长因子受体（EGFR）、下游信号成分以及血管生成和凋亡标志物的水平，以确定相关终点与临床结果之间的关系。
对治疗前和治疗期间的肿瘤及皮肤活检样本，以及存档的肿瘤标本进行评估，检测EGFR、磷酸化（p）-EGFR、细胞外信号调节激酶（ERK）、p-ERK、Akt、p-Akt、Ki67、p27、p-核因子κB（NFκB）、p-信号转导子和转录激活子3（STAT3）以及EGFR基因拷贝数。
在37份存档样本中，EGFR基因拷贝数高的肿瘤患者中有4例中的2例（50%）对治疗有反应，而EGFR基因拷贝数低的肿瘤患者中有27例中的4例（15%）对治疗有反应。在9对肿瘤活检样本中，治疗前p27和p-STAT3水平升高预示着疾病进展时间（TTP）延长和总生存期（OS；P≤0.03）。治疗后，p-EGFR、p-NFκB和p27的降低分别与TTP增加、OS增加或TTP和OS均增加相关（P≤0.04）。多维标度法（MDS）模型显示，通过免疫荧光检测的肿瘤标志物聚类图谱可预测反应。在32对皮肤活检样本中，治疗后p-EGFR的抑制与OS增加相关（P = 0.045）。
肿瘤标本中EGFR基因拷贝数高可能预示哪些患者更有可能对厄洛替尼有反应，治疗期间皮肤活检中p-EGFR水平降低可能是临床结果改善的潜在替代标志物。MDS是评估分子标志物与临床结果之间关系的一种新方法。需要进行更多样本量更大的生物标志物研究，以阐明可能从这种靶向治疗中获益的HNSCC患者。
