MHS, Mayo Clinic Comprehensive Cancer Center, 200 First St SW, Rochester, MN 55905, USA.
J Clin Oncol. 2012 Nov 10;30(32):3932-8. doi: 10.1200/JCO.2012.43.1890. Epub 2012 Sep 17.
There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC).
HER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS).
Overall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023).
Among HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and determination of benefit from HER2-targeted therapy.
人们越来越认识到人类表皮生长因子受体（HER2）的肿瘤内异质性的存在，这影响了 HER2 阳性在临床实践中的解释，并可能对患者的预后和治疗产生影响。我们确定了食管腺癌（EAC）患者中异质性 HER2 基因扩增和 17 号染色体三体的频率和预后影响。
对 675 例外科 EAC 标本进行了 HER2 扩增（荧光原位杂交法）检查。HER2 异质性根据共识指南定义为在超过 5%但少于 50%的癌细胞中存在基因扩增（HER2/CEP17 比值≥2.0）。没有患者接受新辅助或 HER2 靶向治疗。Cox 模型用于评估疾病特异性生存（DSS）和总生存（OS）。
总体而言，117 例 EAC（17%）显示 HER2 扩增，其中 20 例（17%）显示 HER2 异质性。所有 HER2 异质性肿瘤均扩增。在包括转移性淋巴结数量、分级、肿瘤分期和 17 号染色体三体在内的多变量模型中，只有 HER2 异质性和淋巴结数量在 HER2 扩增肿瘤中具有预后意义，异质性显示出更差的 DSS（风险比，2.04；95%CI，1.09 至 3.79；P=0.025）和 OS（P=0.026）。在 HER2 非扩增的 EAC 中，17 号染色体三体与更差的 DSS（P=0.012）和 OS（P=0.023）独立相关。
在 HER2 扩增的 EAC 中，17%显示 HER2 异质性，独立预测癌症特异性死亡的增加。在 HER2 非扩增的 EAC 中，17 号染色体三体与更差的生存独立相关。这些新发现表明在 HER2 扩增和非扩增的 EAC 中有侵袭性亚群，这对 HER2 分析和确定 HER2 靶向治疗的获益具有重要意义。
