Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Clin Colorectal Cancer. 2017 Sep;16(3):e147-e152. doi: 10.1016/j.clcc.2017.01.005. Epub 2017 Jan 25.
Cetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harboring wild-type RAS. Human epidermal growth factor receptor 2 (HER2) amplification may be a mechanism of cetuximab resistance. We evaluated the association between HER2 amplification and cetuximab efficacy in patients with mCRC harboring wild-type RAS and BRAF.
Between December 2003 and June 2013, we identified 142 patients with mCRC whose tumors harbored both wild-type exons 2, 3, and 4 in KRAS and NRAS, and wild-type exon 15 in BRAF using high throughput sequencing (OncoMap version 4.0). All patients received cetuximab after oxaliplatin, irinotecan, and fluoropyrimidine failure. HER2 status was determined using immunohistochemistry and silver in situ hybridization (SISH) and correlated with cetuximab efficacy.
Of 142 RAS and BRAF wild-type tumors, we observed 7 cases (4.9%) of HER2 amplification by SISH. After a median follow-up of 13.2 months (range, 1.4-78.1 months), median progression-free survival (PFS) was significantly different according to HER2 status: 3.1 months in patients with HER2 amplification compared with 5.6 months in those with non-amplified HER2 (hazard ratio, 2.73; 95% confidence interval, 1.18-6.31; P = .019). Overall survival (OS) was not significantly different between groups, although there was a tendency towards shorter OS in patients with HER2-amplified tumors (hazard ratio, 1.31; 95% confidence interval, 0.61-2.82; 10.1 vs. 13.5 months; P = .488).
HER2 amplification is predictive of shorter PFS after cetuximab treatment in patients with mCRC harboring wild-type RAS and BRAF. Further study is warranted for this patient population.
西妥昔单抗在携带野生型 RAS 的转移性结直肠癌（mCRC）患者中显示出临床获益。人表皮生长因子受体 2（HER2）扩增可能是西妥昔单抗耐药的机制。我们评估了 HER2 扩增与携带野生型 RAS 和 BRAF 的 mCRC 患者中西妥昔单抗疗效之间的关系。
2003 年 12 月至 2013 年 6 月，我们使用高通量测序（OncoMap 版本 4.0）鉴定了 142 名 mCRC 患者，这些患者的肿瘤同时携带 KRAS 和 NRAS 外显子 2、3 和 4 以及 BRAF 外显子 15 的野生型。所有患者在奥沙利铂、伊立替康和氟嘧啶治疗失败后均接受西妥昔单抗治疗。HER2 状态通过免疫组化和银原位杂交（SISH）确定，并与西妥昔单抗疗效相关。
在 142 例 RAS 和 BRAF 野生型肿瘤中，我们通过 SISH 观察到 7 例（4.9%）HER2 扩增。在中位随访 13.2 个月（范围，1.4-78.1 个月）后，根据 HER2 状态，中位无进展生存期（PFS）差异有统计学意义：HER2 扩增患者为 3.1 个月，而非扩增 HER2 患者为 5.6 个月（风险比，2.73；95%置信区间，1.18-6.31；P=0.019）。尽管 HER2 扩增肿瘤患者的总生存期（OS）无显著差异，但 OS 有缩短趋势（风险比，1.31；95%置信区间，0.61-2.82；10.1 个月与 13.5 个月；P=0.488）。
在携带野生型 RAS 和 BRAF 的 mCRC 患者中，HER2 扩增预示着西妥昔单抗治疗后 PFS 较短。对于这部分患者人群，需要进一步研究。
