Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
J Cancer Res Clin Oncol. 2013 Mar;139(3):367-78. doi: 10.1007/s00432-012-1340-x. Epub 2012 Oct 26.
Although KRAS mutation has been identified as a negative predictive biomarker of anti-EGFR antibodies in metastatic colorectal cancer (mCRC), the efficacy in mCRC patients with KRAS wild-type status remains limited. Anti-EGFR antibodies work by blocking ligand binding, but the significance of EGFR ligands in mCRC has not been completely described. This study was conducted to identify the correlation between all seven EGFR ligands and clinical outcomes in mCRC treated with anti-EGFR antibodies. Furthermore, we determined an appropriate predictive strategy for anti-EGFR antibodies using these EGFR ligands.
Among 36 mCRC patients who had been treated with cetuximab or panitumumab, we identified 26 mCRC patients with wild-type KRAS status treated properly as the second and further lines and analyzed the relationship between immunoreactivity to seven EGFR ligands and clinical outcomes.
Good clinical outcomes were associated with immunoreactivity against amphiregulin (AR), heparin-binding epidermal growth factor (HB-EGF), transforming growth factor-α (TGF-α), and epiregulin (EREG). Further, patients with immunoreactivity to greater than two of these four ligands (AR, HB-EGF, TGF-α, and EREG) had significantly higher response rate (53.3 vs. 0.0 %, p = 0.004) and disease control rate (93.3 vs. 9.0 %, p = 0.00002) and longer progression-free survival (median PFS: 231 vs. 79 days, p = 0.000008), when compared with patients with immunoreactivity against zero or one ligand.
Immunohistochemical analysis of four EGFR ligands (AR, HB-EGF, TGF-α, and EREG) might be a novel predictive biomarker and may help optimize patient selection for cetuximab and panitumumab therapy in patients with mCRC.
尽管 KRAS 突变已被确定为转移性结直肠癌（mCRC）中抗 EGFR 抗体的阴性预测生物标志物，但 KRAS 野生型状态的 mCRC 患者的疗效仍然有限。抗 EGFR 抗体通过阻断配体结合起作用，但 mCRC 中 EGFR 配体的意义尚未完全描述。本研究旨在确定七种 EGFR 配体与接受抗 EGFR 抗体治疗的 mCRC 患者的临床结局之间的相关性。此外，我们使用这些 EGFR 配体确定了抗 EGFR 抗体的适当预测策略。
在接受西妥昔单抗或帕尼单抗治疗的 36 名 mCRC 患者中，我们确定了 26 名 KRAS 野生型 mCRC 患者，这些患者适当接受二线及进一步治疗，并分析了七种 EGFR 配体的免疫反应与临床结局之间的关系。
良好的临床结局与对 Amphiregulin（AR）、肝素结合表皮生长因子（HB-EGF）、转化生长因子-α（TGF-α）和 Epiregulin（EREG）的免疫反应有关。此外，对这四种配体（AR、HB-EGF、TGF-α和 EREG）中的两种或以上具有免疫反应的患者，其应答率（53.3% vs. 0.0%，p=0.004）和疾病控制率（93.3% vs. 9.0%，p=0.00002）显著更高，无进展生存期更长（中位 PFS：231 天 vs. 79 天，p=0.000008）。
四种 EGFR 配体（AR、HB-EGF、TGF-α和 EREG）的免疫组化分析可能是一种新的预测生物标志物，有助于优化西妥昔单抗和帕尼单抗治疗 mCRC 患者的患者选择。
