Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90089, USA.
Clin Cancer Res. 2011 Aug 1;17(15):5161-9. doi: 10.1158/1078-0432.CCR-10-2666. Epub 2011 Jun 14.
Cetuximab has shown significant clinical activity in metastatic colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response in locally advanced rectal cancer patients in recent phase I/II trials. We evaluated functional germline polymorphisms of genes involved in epidermal growth factor receptor pathway, angiogenesis, antibody-dependent cell-mediated cytotoxicity, DNA repair, and drug metabolism, for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation.
130 patients (74 men and 56 women) with locally advanced rectal cancer (4 with stage II, 109 with stage III, and 15 with stage IV, 2 unknown) who were enrolled in phase I/II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was done by using PCR-RFLP assays. Fisher's exact test was used to examine associations between polymorphisms and complete pathologic response (pCR) that was determined by a modified Dworak classification system (grade III vs. grade IV: complete response).
Patients with the epidermal growth factor (EGF) 61 G/G genotype had pCR of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) in patients homozygous for the A/A allele (P < 0.001). In addition, this association between EGF 61 G allele and pCR remained significant (P = 0.019) in the 59 patients with wild-type KRAS.
This study suggested EGF A+61G polymorphism to be a predictive marker for pCR, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer.
西妥昔单抗在转移性结直肠癌中显示出显著的临床活性。然而，在最近的 I/II 期试验中，含西妥昔单抗的新辅助放化疗并未改善局部晚期直肠癌患者的肿瘤反应。我们评估了参与表皮生长因子受体途径、血管生成、抗体依赖性细胞介导的细胞毒性、DNA 修复和药物代谢的基因的功能性种系多态性，以评估其作为接受术前西妥昔单抗为基础的放化疗的局部晚期直肠癌患者临床结局的潜在分子预测因子的作用。
130 名（74 名男性和 56 名女性）局部晚期直肠癌患者（4 名 II 期，109 名 III 期，15 名 IV 期，2 名未知期）被纳入欧洲癌症中心的 I/II 期临床试验，接受西妥昔单抗为基础的放化疗。从福尔马林固定石蜡包埋的肿瘤样本中提取基因组 DNA，并通过 PCR-RFLP 检测进行基因分型。Fisher 确切检验用于检查多态性与完全病理缓解（pCR）之间的关联，pCR 由改良的 Dworak 分类系统（III 级与 IV 级：完全缓解）确定。
表皮生长因子（EGF）61 G/G 基因型患者的 pCR 为 45%（5/11），杂合子患者为 21%（11/53），纯合子患者为 2%（1/54）（P<0.001）。此外，在 59 名 KRAS 野生型患者中，EGF 61 G 等位基因与 pCR 之间的这种关联仍然显著（P=0.019）。
这项研究表明，EGF A+61G 多态性是预测接受西妥昔单抗为基础的新辅助放化疗的局部晚期直肠癌患者 pCR 的标志物，独立于 KRAS 突变状态。
