Division of Medical Oncology University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Clin Cancer Res. 2010 Nov 15;16(22):5591-602. doi: 10.1158/1078-0432.CCR-10-2092. Epub 2010 Oct 8.
The insulin-like growth factor 1 (IGF1) signaling pathway is an important growth-regulatory pathway, which plays a crucial role in colorectal cancer (CRC) proliferation, differentiation, migration, angiogenesis, and apoptosis. Previous studies showed that hyperactivation of the IGF1 receptor (IGF1R) may result in resistance to anti-epidermal growth factor receptor-targeted treatment. We tested whether germline variations within the IGF1 pathway are associated with clinical outcome in wild-type (wt) KRAS drug-refractory metastatic CRC (mCRC) patients who were treated with cetuximab monotherapy (IMC-0144).
Formalin-fixed, paraffin-embedded (FFPE) tissue samples of 130 drug-refractory mCRC patients enrolled in IMC-0144, a phase II clinical trial of cetuximab monotherapy, were analyzed. gDNA was extracted from dissected FFPE tumor tissue, and KRAS mutation status and six potentially functional IGF1 and IGF1R polymorphisms were analyzed using direct DNA sequencing or PCR-RFLP. Tumor response analysis was based on recursive partitioning, and survival analyses were based on univariate and multivariate hazard regression models.
In univariate and multivariate analyses, five IGF pathway single-nucleotide polymorphisms were significantly associated with progression-free survival (PFS) and/or overall survival (OS). In multivariate combined risk allele analysis, the additive model for PFS and OS was significantly associated with the number of risk alleles in wt KRAS patients (P = 0.001 and P = 0.02, respectively). In addition, wt KRAS patients harboring IGF1 rs2946834 A/A genotype had a 50% objective response rate compared with 0% for A/G genotype.
These results indicate that IGF1 pathway polymorphisms are potential predictive/prognostic molecular markers for cetuximab efficacy in wt KRAS mCRC patients. Prospective biomarker-embedded clinical trials are warranted to validate our findings. Clin Cancer Res; 16(22); 5591-602. ©2010 AACR.
胰岛素样生长因子 1（IGF1）信号通路是一个重要的生长调控通路，在结直肠癌（CRC）的增殖、分化、迁移、血管生成和凋亡中发挥着关键作用。先前的研究表明，IGF1 受体（IGF1R）的过度激活可能导致对表皮生长因子受体靶向治疗的耐药性。我们检测了 IGF1 通路中的种系变异是否与接受西妥昔单抗单药治疗（IMC-0144）的野生型（wt）KRAS 药物难治性转移性 CRC（mCRC）患者的临床结局相关。
对纳入 IMC-0144 Ⅱ期临床试验的 130 例西妥昔单抗耐药 mCRC 患者的福尔马林固定、石蜡包埋（FFPE）组织样本进行分析。从切除的 FFPE 肿瘤组织中提取 gDNA，并使用直接 DNA 测序或 PCR-RFLP 分析 KRAS 突变状态和六个潜在功能的 IGF1 和 IGF1R 多态性。肿瘤反应分析基于递归分区，生存分析基于单变量和多变量风险回归模型。
在单变量和多变量分析中，五个 IGF 通路单核苷酸多态性与无进展生存期（PFS）和/或总生存期（OS）显著相关。在多变量联合风险等位基因分析中，PFS 和 OS 的加性模型与 wtKRAS 患者的风险等位基因数显著相关（P = 0.001 和 P = 0.02）。此外，wtKRAS 患者携带 IGF1 rs2946834 A/A 基因型的客观缓解率为 50%，而 A/G 基因型的客观缓解率为 0%。
这些结果表明，IGF1 通路多态性可能是 wtKRAS mCRC 患者接受西妥昔单抗疗效的潜在预测/预后分子标志物。需要进行前瞻性生物标志物嵌入临床试验来验证我们的发现。Clin Cancer Res; 16(22); 5591-602. ©2010AACR.
