Oncogenic Alterations in ERBB2/HER2 Represent Potential Therapeutic Targets Across Tumors From Diverse Anatomic Sites of Origin
Oncogenic Alterations in ERBB2/HER2 Represent Potential Therapeutic Targets Across Tumors From Diverse Anatomic Sites of Origin
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DOI：
10.1634/theoncologist.2014-0234
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发表时间：
2015-01-01
期刊：
影响因子：
5.8
通讯作者：
Stephens, Philip J.
中科院分区：
文献类型：
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作者：
Chmielecki, Juliann;Ross, Jeffrey S.;Stephens, Philip J.
背景。靶向ERBB2/HER2抑制剂已被美国食品和药物管理局批准用于治疗HER2/ERBB2过表达或扩增的乳腺癌、胃癌和食管癌，分别通过免疫组织化学（IHC）和荧光原位杂交（FISH）检测。ERBB2的激活突变也有报道，预计会对这些靶向药物产生敏感性。对这些突变的检测没有常规进行，FISH和IHC也没有在这些批准的适应症之外应用。材料与方法。我们通过使用下一代测序技术对7300个实体肿瘤样本进行了全面的基因组分析，探索了激活ERBB2改变的谱。结果分析了碱基替换、插入和删除、选择重排和拷贝数变化。已知的致癌ERBB2改变在27个组织的肿瘤中被发现，在乳腺癌、胃癌和胃食管癌中ERBB2扩增仅占这些改变的30%。131例（32.5%）样本中发现ERBB2激活突变；扩增246份（61%）。两个样本（0.5%）存在ERBB2重排。10份样本（2.5%）携带多个ERBB2突变，但91%的突变病例中突变和扩增是相互排斥的。标准的基于玻片的ERBB2过表达或扩增测试将无法检测到在没有拷贝数变化的情况下绝大多数发生的激活突变。与目前的临床标准相比，对更多样化的肿瘤类型进行全面的基因组分析，可以识别出大约3.5倍于erbb2靶向治疗的患者。
Background. Targeted ERBB2/HER2 inhibitors are approved by the U. S. Food and Drug Administration for the treatment of breast, gastric, and esophageal cancers that overexpress or amplify HER2/ERBB2, as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. Activating mutations in ERBB2 have also been reported and are predicted to confer sensitivity to these targeted agents. Testing for these mutations is not performed routinely, and FISH and IHC are not applied outside of these approved indications.Materials and Methods. We explored the spectrum of activating ERBB2 alterations across a collection of similar to 7,300 solid tumor specimens that underwent comprehensive genomic profiling using next-generation sequencing. Results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes.Results. Known oncogenic ERBB2 alterations were identified in tumors derived from 27 tissues, and ERBB2 amplification in breast, gastric, and gastroesophageal cancers accounted for only 30% of these alterations. Activating mutations in ERBB2 were identified in 131 samples (32.5%); amplification was observed in 246 samples (61%). Two samples (0.5%) harbored an ERBB2 rearrangement. Ten samples (2.5%) harbored multiple ERBB2 mutations, yet mutations and amplifications were mutually exclusive in 91% of mutated cases.Conclusion. Standard slide-based tests for overexpression or amplification of ERBB2 would fail to detect the majority of activating mutations that occur overwhelmingly in the absence of copy number changes. Compared with current clinical standards, comprehensive genomic profiling of a more diverse set of tumor types may identify similar to 3.5 times the number of patients who may benefit from ERBB2-targeted therapy.