Reis H, Herold T, Ting S, Worm K, Huber U, Christoph D C, Eberhardt W E, Kostbade K, Kasper S, Stamatis G, Welter S, Darwiche K, Karpf-Wissel R, Theegarten D, Schmid K W, Schuler M, Wiesweg M
Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany; German Cancer Research Center, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
Lung Cancer. 2015 Apr;88(1):34-41. doi: 10.1016/j.lungcan.2015.02.002. Epub 2015 Feb 7.
Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC.
Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS, EGFR, BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH).
HER2-IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2-mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS, EGFR, BRAF and PIK3CA. HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2-IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies.
肺腺癌（ADC）可根据主要致癌驱动因素进行亚组分类。表皮生长因子受体（EGFR）突变定义了一类具有良好预后且对EGFR酪氨酸激酶抑制高度敏感的转移性ADC。相比之下，ADC中其他ERBB家族成员的临床影响尚不明确。为此，我们前瞻性地研究了HER2表达、基因扩增及突变与晚期或转移性ADC患者预后的关系。
对193例连续的III/IV期ADC患者的诊断性肿瘤活检标本进行前瞻性研究，采用免疫组织化学（IHC）检测HER2表达。免疫组化评分2+或3+的病例通过HER2显色原位杂交（CISH）以及HER2第20和23外显子测序进行分析。其他前瞻性确定的生物标志物包括PTEN、cMET、pAKT和pERK表达、KRAS、EGFR、BRAF和PIK3CA突变以及ALK荧光原位杂交（FISH）。
176例（91.2%）病例可行HER2免疫组化检测。53例（30%）免疫组化评分2+/3+的病例中，45例（85%）可进行CISH检测，34例（64%）可进行测序。HER2突变分析数量较少是由于在对KRAS、EGFR、BRAF和PIK3CA进行突变分析后肿瘤组织和DNA耗尽。检测到4例（2.3%）HER2扩增，但未发现突变。HER2表达与pAKT和cMET表达相关。HER2和pAKT表达与IV期疾病的良好总生存期相关。表达HER2的ADC更频繁地携带KRAS突变，而4例BRAF突变病例均未表达HER2。HER2免疫组化不能预测HER2基因扩增或突变，这在对晚期或转移性ADC患者的前瞻性研究中均为罕见事件。HER2和pAKT表达定义了一组具有独特病程的IV期ADC患者，他们可能从特定的量身定制的药物治疗中获益。
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