Carvajal-Hausdorf Daniel E, Schalper Kurt A, Bai Yalai, Black Jonathan, Santin Alessandro D, Rimm David L
Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
Department of Pathology, Yale School of Medicine, New Haven, CT, USA; Translational Immuno-oncology Laboratory, Yale Cancer Center, New Haven, CT, USA.
Gynecol Oncol. 2017 Apr;145(1):154-158. doi: 10.1016/j.ygyno.2017.02.002. Epub 2017 Feb 11.
HER2 overexpression/amplification is identified in up to 40% of uterine serous carcinomas (USC) and 10% of ovarian serous carcinomas (OSC). However, clinical trials using various HER2-targeted agents failed to show significant responses. FDA-approved HER2 assays target only the protein's intracellular domain (ICD) and not the extracellular domain (ECD). Previous quantitative studies in breast cancer by our group have shown that ICD of HER2 is expressed in some cases that do not express the HER2 ECD. We measured HER2 ICD and ECD in USC and OSC samples, and determined their relationship with clinico-pathologic characteristics and survival.
We measured HER2 ICD and ECD levels in 2 cohorts of USC and OSC comprising 102 and 175 patients, respectively. HER2 antibodies targeting ICD (CB11) and ECD (SP3) were validated and standardized using the AQUA® method of quantitative immunofluorescence (QIF) and a previously reported HER2 standardization tissue microarray (TMA). Objective, population-based cut-points were used to stratify patients according to HER2 ICD/ECD status.
In USC, 8% of patients with high HER2 ICD had low ECD levels (6/75 patients). In OSC, 42% of patients with high HER2 ICD had low ECD levels (29/69 patients). HER2 ICD/ECD status in USC and OSC was not significantly associated with major clinico-pathological features or survival.
Using objective, domain-specific HER2 measurement, 8% of USC and 42% of OSC patients with high HER2 ICD levels do not show uniform overexpression of the ECD. This may be related to the presence of p95 HER2, an oncogenic fragment generated by full protein cleavage or alternative initiation of translation. These observations raise the possibility that USC/OSCs expressing low ECD despite being HER2-positive by ICD measurement, may benefit from therapies directed against the intracellular domain (e.g. lapatinib or afatinib) alone or in combination with extracellular domain-directed drugs (e.g. trastuzumab, pertuzumab, T-DM1).
在高达40%的子宫浆液性癌（USC）和10%的卵巢浆液性癌（OSC）中可检测到HER2过表达/扩增。然而，使用各种HER2靶向药物的临床试验未能显示出显著疗效。美国食品药品监督管理局（FDA）批准的HER2检测仅针对该蛋白的细胞内结构域（ICD），而非细胞外结构域（ECD）。我们团队之前在乳腺癌中的定量研究表明，在一些不表达HER2 ECD的病例中可检测到HER2的ICD。我们检测了USC和OSC样本中的HER2 ICD和ECD，并确定了它们与临床病理特征及生存率的关系。
我们分别检测了两个队列中USC和OSC患者（分别为102例和175例）的HER2 ICD和ECD水平。使用定量免疫荧光（QIF）的AQUA®方法和先前报道的HER2标准化组织微阵列（TMA）对靶向ICD（CB11）和ECD（SP3）的HER2抗体进行验证和标准化。采用基于人群的客观切点，根据HER2 ICD/ECD状态对患者进行分层。
在USC中，8%的HER2 ICD高表达患者ECD水平较低（75例患者中有6例）。在OSC中，42%的HER2 ICD高表达患者ECD水平较低（69例患者中有29例）。USC和OSC中的HER2 ICD/ECD状态与主要临床病理特征或生存率无显著相关性。
通过客观的、针对特定结构域的HER2检测发现，8%的USC患者和42%的OSC患者HER2 ICD水平高但ECD未呈现一致的过表达。这可能与p95 HER2的存在有关，p95 HER2是由完整蛋白裂解或翻译起始改变产生的致癌片段。这些观察结果提示，尽管通过ICD检测为HER2阳性，但ECD表达低的USC/OSC患者可能单独受益于针对细胞内结构域的治疗（如拉帕替尼或阿法替尼），或与针对细胞外结构域的药物（如曲妥珠单抗、帕妥珠单抗、T-DM1）联合使用。
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