Background

The prognostic value and molecular landscape of human epidermal growth factor receptor 2 (HER2) low-expressing (HER2-L) metastatic colorectal cancer (mCRC) remain unclear.

Patients and Methods

This study enrolled patients with mCRC who had undergone surgical resection of primary tumor. Using the specimen, we evaluated HER2 expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 positivity was defined as follows: HER2 positivity (HER2-Pos) as IHC 3 + or IHC 2+/FISH positive, HER2-L as IHC 2+/FISH negative or IHC 1+, and HER2 negativity (HER2-Neg) as IHC 0+. Gene alterations were determined by next-generation sequencing.

Results

Between 2005 and 2015, a total of 370 patients were analyzed, comprising 15 patients (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg disease. The clinicopathologic characteristics among groups had no differences. HER2-L had a significantly higher proportion of coaltered RAS mutation than HER2-Pos (P = .037). With a median follow-up of 101.8 months, HER2-L had a significantly better median overall survival than HER2-Pos (P = .029) (18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 patients harboring wild-type RAS and receiving anti-EGFR antibody therapy, HER2-L had a better median progression-free survival tendency than HER2-Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.1 in HER2-Neg (P = .036).

Conclusion

HER2-L mCRC showed a better prognosis than HER2-Pos mCRC, and it is similar to HER2-Neg mCRC. Hence, HER2-L mCRC might have different biologic behavior in terms of prognostic value and molecular landscape of mCRC, suggesting the possibility of implementation of HER2-guided clinical development against HER2-expressing mCRC.

中文翻译：

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HER2 低表达转移性结直肠癌的预后价值和分子景观

背景

人表皮生长因子受体 2 (HER2) 低表达 (HER2-L) 转移性结直肠癌 (mCRC) 的预后价值和分子景观仍不清楚。

患者和方法

该研究招募了接受原发肿瘤手术切除的 mCRC 患者。使用标本，我们通过免疫组织化学 (IHC) 和荧光原位杂交 (FISH) 评估了 HER2 表达。HER2 阳性定义如下：HER2 阳性 (HER2-Pos) 为 IHC 3 + 或 IHC 2+/FISH 阳性，HER2-L 为 IHC 2+/FISH 阴性或 IHC 1+，HER2 阴性 (HER2-Neg) 为IHC 0+。通过下一代测序确定基因改变。

结果

2005 年至 2015 年间，共分析了 370 名患者，其中 15 名患者 (4%) 患有 HER2-Pos，21 名 (6%) 患有 HER2-L，334 名 (90%) 患有 HER2-Neg 疾病。各组间临床病理特征无差异。HER2-L 的RAS突变比例显着高于HER2-Pos ( P  = .037)。中位随访时间为 101.8 个月，HER2-L 的中位总生存期明显优于 HER2-Pos（P  = .029）（HER2-Pos 为 18.2 个月，HER2-L 为 33.3 个月，HER2-L 为 27.9 个月）否定）。在 58 名携带野生型RAS 的患者中接受抗 EGFR 抗体治疗后，HER2-L 的中位无进展生存趋势优于 HER2-Pos，HER2-Pos 为 2.2 个月，HER2-L 为 7.8 个月，HER2-Neg 为 5.1 个月（P  = .036 ）。

结论

HER2-L mCRC 的预后优于 HER2-Pos mCRC，与 HER2-Neg mCRC 相似。因此，就 mCRC 的预后价值和分子景观而言，HER2-L mCRC 可能具有不同的生物学行为，这表明针对表达 HER2 的 mCRC 实施 HER2 指导的临床开发的可能性。