Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
J Clin Oncol. 2010 Mar 1;28(7):1181-9. doi: 10.1200/JCO.2009.22.6043. Epub 2010 Jan 25.
This study assessed biomarkers for cetuximab efficacy in tissue samples collected during a phase I dose-escalation study exploring every second week administration of cetuximab as first-line therapy in patients with metastatic colorectal cancer (mCRC).
Sixty-two patients received cetuximab monotherapy for 6 weeks, followed by cetuximab plus infusional fluorouracil, leucovorin, and irinotecan until disease progression. Patients in the control arm received cetuximab as a 400 mg/m(2) initial dose then 250 mg/m(2) per week; patients in the dose-escalation arms received 400 to 700 mg/m(2) every second week. Tumor and skin biopsies were taken for immunohistochemical and microarray expression analyses (tumor only) at baseline and week 4. Plasma was collected for proteomic analysis at baseline and week 4. KRAS tumor mutation status was assessed.
In subsets of paired skin samples from 35 patients, cetuximab treatment was associated with substantial downregulation of phospho(p)-EGFR, p-MAPK and proliferation and substantial upregulation of p27(Kip1) and p-STAT3 levels. No marked difference in these effects was noted for different schedules of administration and dose levels. In the cetuximab monotherapy phase, responses were seen only in patients whose tumors were wild-type for KRAS (eight of 29 v zero of 19 for KRAS mutant tumors; P = .015). Progression-free survival was longer for patients with KRAS wild-type compared with KRAS mutant tumors (log-rank P = .048). Genomics/proteomics analyses (42 and 45 patients, respectively) identified candidate biomarkers associated with response.
Biomarker analysis supported the functional equivalence of weekly and every second week administration of cetuximab and provided further confirmation that patients with KRAS wild-type mCRC were those most likely to benefit from cetuximab treatment.
本研究评估了组织样本中用于西妥昔单抗疗效的生物标志物，这些样本是在一项探索转移性结直肠癌（mCRC）一线治疗每两周一次给予西妥昔单抗的 I 期剂量递增研究中收集的。
62 例患者接受西妥昔单抗单药治疗 6 周，随后给予西妥昔单抗联合氟尿嘧啶、亚叶酸钙和伊立替康，直至疾病进展。对照组患者接受西妥昔单抗初始剂量 400mg/m2，然后每周 250mg/m2；剂量递增组患者每两周给予 400-700mg/m2。在基线和第 4 周时，对肿瘤和皮肤活检进行免疫组织化学和微阵列表达分析（仅肿瘤），在基线和第 4 周时收集血浆进行蛋白质组分析。评估 KRAS 肿瘤突变状态。
在 35 例患者的配对皮肤样本中，西妥昔单抗治疗与磷酸化（p）-表皮生长因子受体（EGFR）、p-MAPK 和增殖的显著下调以及 p27（Kip1）和 p-STAT3 水平的显著上调相关。不同给药方案和剂量水平的这些作用无明显差异。在西妥昔单抗单药治疗阶段，仅在 KRAS 野生型肿瘤患者中观察到应答（29 例中有 8 例，KRAS 突变肿瘤中有 0 例；P =.015）。与 KRAS 突变肿瘤相比，KRAS 野生型肿瘤患者的无进展生存期更长（对数秩检验 P =.048）。基因组/蛋白质组学分析（分别有 42 例和 45 例患者）确定了与应答相关的候选生物标志物。
生物标志物分析支持每周和每两周一次给予西妥昔单抗的功能等效性，并进一步证实 KRAS 野生型 mCRC 患者最有可能从西妥昔单抗治疗中获益。
