Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
Virchows Arch. 2014 Aug;465(2):145-54. doi: 10.1007/s00428-014-1597-3. Epub 2014 Jun 3.
HER2 protein overexpression and gene amplification are important biomarkers for identifying gastric cancer patients who may respond to HER2-targeted therapy using trastuzumab. The aim of this study was to evaluate the concordance between HER2 protein expression and gene amplification in both surgically resected tumors and matched biopsy specimens of gastric cancer. Formalin-fixed, paraffin-embedded sections of 207 surgically resected tumors and 158 biopsy specimens from 207 cases of invasive intestinal-type gastric cancer were analyzed. Protein expression was assessed using immunohistochemistry and graded by the modified scoring criteria for gastric cancer. Gene amplification was evaluated by fluorescence in situ hybridization (FISH). HER2 overexpression was observed in 17 % of both surgically resected tumors (35/207) and biopsy specimens (26/158). HER2 gene amplification was detected in 31 % (61/200) of surgically resected tumors and 32 % (47/147) of biopsy specimens. Except for immunohistochemistry (IHC) equivocal (2+) cases, the concordance rates between IHC and FISH was 90.9 % in surgically resected tumors and 90.2 % in biopsy specimens. In IHC 2+ cases, the rate of HER2 gene amplification was 56 and 38 % in surgically resected tumors and biopsy specimens, respectively. IHC-FISH discordance was mainly due to intratumoral heterogeneity and low-level gene amplification. The concordance rate of IHC results between surgically resected specimens and the corresponding biopsy specimen was 57.0 % (κ = 0.224), and in discordant cases, HER2 positivity in biopsies and HER2 negativity in surgically resected tumors were most common. The concordance rate of FISH results between surgically resected tumors and biopsy specimens was 72.7 % (κ = 0.313). Polysomy 17 was detected in 5.5 and 7.5 % of surgically resected tumors and biopsy specimens and significantly correlated with IHC score, but polysomy 17 could explain one IHC score 3+ and FISH-negative tumor only. Although high concordance rates between HER2-protein expression and gene amplification were observed in both surgically resected tumors and biopsy specimens, the agreement levels were evaluated to be fair. Polysomy 17 was infrequent and seemed to have limited impact on gastric HER2 testing. Further investigations are required for an appropriate biopsy method to reduce false results of HER2 testing and to clarify the clinical significance of intratumoral heterogeneity in HER2 status.
HER2 蛋白过表达和基因扩增是鉴定可能对曲妥珠单抗的 HER2 靶向治疗有反应的胃癌患者的重要生物标志物。本研究的目的是评估胃癌手术切除肿瘤和匹配活检标本中 HER2 蛋白表达和基因扩增的一致性。对 207 例手术切除的肿瘤和 207 例浸润性肠型胃癌的 158 例活检标本的福尔马林固定、石蜡包埋切片进行了分析。使用免疫组织化学法评估蛋白表达，并根据胃癌改良评分标准进行分级。通过荧光原位杂交（FISH）评估基因扩增。在手术切除的肿瘤（35/207）和活检标本（26/158）中均观察到 17%的 HER2 过表达。在手术切除的肿瘤（61/200）和活检标本（47/147）中检测到 31%的 HER2 基因扩增。除免疫组织化学（IHC）不确定（2+）病例外，手术切除肿瘤和活检标本中 IHC 与 FISH 的一致性率分别为 90.9%和 90.2%。在 IHC 2+病例中，手术切除肿瘤和活检标本中 HER2 基因扩增的比率分别为 56%和 38%。IHC-FISH 不匹配主要是由于肿瘤内异质性和低水平基因扩增。手术切除标本与相应活检标本之间 IHC 结果的一致性率为 57.0%（κ=0.224），在不一致的病例中，活检中 HER2 阳性和手术切除肿瘤中 HER2 阴性最为常见。手术切除肿瘤与活检标本之间 FISH 结果的一致性率为 72.7%（κ=0.313）。多倍体 17 在手术切除的肿瘤和活检标本中分别检测到 5.5%和 7.5%，与 IHC 评分显著相关，但多倍体 17 仅能解释一个 IHC 评分 3+和 FISH 阴性的肿瘤。尽管在手术切除的肿瘤和活检标本中均观察到 HER2 蛋白表达和基因扩增之间具有较高的一致性，但评估一致性水平为中等。多倍体 17 并不常见，似乎对胃 HER2 检测的影响有限。需要进一步研究以确定适当的活检方法，以减少 HER2 检测的假阳性结果，并阐明 HER2 状态肿瘤内异质性的临床意义。
