Department of Pathology and Molecular Pathology, University Hospital Zurich, Zürich, Switzerland.
Department of Oncology, University Hospital Zurich, Zürich, Switzerland.
J Pathol Clin Res. 2024 Mar;10(2):e12362. doi: 10.1002/2056-4538.12362.
Most invasive lobular breast carcinomas (ILBCs) are luminal-type carcinomas with an HER2-negative phenotype (ERBB2 or HER2 un-amplified) and CDH1 mutations. Rare variants include ERBB2-amplified subtypes associated with an unfavorable prognosis and less response to anti-HER2 targeted therapies. We analyzed the clinicopathological and molecular features of ERBB2-amplified ILBC and compared these characteristics with ERBB2-unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin-embedded formalin-fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast-specific markers was tested by immunohistochemistry (IHC). Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent in situ hybridization (FISH) or IHC positive for HER2 amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of ERBB2 amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were ERBB2 amplified. ERBB2-amplified ILBC had higher tumor stage (p < 0.0001), more frequent positive nodal status (p = 0.00022), more distant metastases (p = 0.012), and higher histological grade (p < 0.0001), and were more often hormone receptor negative (p < 0.001) and more often SOX10 positive (p = 0.005). ERBB2 short variant sequence mutations were more often detected in ERBB2-unamplified tumors (6/10, p = 0.027), whereas CDH1 mutations/copy loss were frequently present in both subgroups (9/10 and 7/10, respectively). Amplification of pathogenic genes were more common in HER2-positive ILBC (p = 0.0009). CDK12 gene amplification (≥6 copies) was detected in 7 of 10 ERBB2-amplified ILBC (p = 0.018). There were no CDK12 gene amplifications reported in 44,293 invasive breast carcinomas in the FMI Insights CGP database. ERBB2-amplified ILBC is a distinct molecular subgroup with frequent coamplification of CDK12, whereas ERBB2 sequence mutations occur only in ERBB2-unamplified ILBC. CDK12/ERBB2 co-amplification may explain the poor prognosis and therapy resistance of ERBB2-amplified ILBC.
大多数浸润性小叶乳腺癌（ILBC）是具有 HER2 阴性表型（ERBB2 或 HER2 未扩增）和 CDH1 突变的腔型癌。罕见的变体包括与预后不良和对抗 HER2 靶向治疗反应较差相关的 ERBB2 扩增亚型。我们分析了 ERBB2 扩增型 ILBC 的临床病理和分子特征，并将这些特征与 ERBB2 未扩增型 ILBC 进行了比较。共分析了 253 例 ILBC 患者。其中 250 例患者的石蜡包埋福尔马林固定肿瘤样本被添加到组织微阵列中。通过免疫组织化学（IHC）检测预后、干细胞和乳腺特异性标志物的蛋白表达。对 10 例 ILBC 进行了基于杂交捕获的综合基因组分析（CGP），这些 ILBC 要么是荧光原位杂交（FISH）阳性，要么是 HER2 扩增/过表达的 IHC 阳性，10 例 ILBC 要么是 FISH 阴性，要么是 IHC 阴性。结果与 44,293 例浸润性乳腺癌的 CGP 数据库进行了比较。ERBB2 扩增的 CGP 定义为五个或更多拷贝。在 255 例 ILBC 中，共有 17 例（5%）为 ERBB2 扩增。ERBB2 扩增的 ILBC 具有更高的肿瘤分期（p<0.0001）、更频繁的阳性淋巴结状态（p=0.00022）、更远端转移（p=0.012）和更高的组织学分级（p<0.0001），并且更常为激素受体阴性（p<0.001）和 SOX10 阳性（p=0.005）。在 ERBB2 未扩增的肿瘤中更常检测到 ERBB2 短变体序列突变（6/10，p=0.027），而 CDH1 突变/拷贝缺失在两个亚组中均较常见（9/10 和 7/10）。HER2 阳性 ILBC 中扩增的致病基因更为常见（p=0.0009）。在 10 例 ERBB2 扩增的 ILBC 中，有 7 例检测到 CDK12 基因扩增（≥6 拷贝）（p=0.018）。在 FMI Insights CGP 数据库中，在 44,293 例浸润性乳腺癌中未报告 CDK12 基因扩增。ERBB2 扩增的 ILBC 是一个具有频繁 CDK12 共扩增的独特分子亚群，而 ERBB2 序列突变仅发生在 ERBB2 未扩增的 ILBC 中。CDK12/ERBB2 共扩增可能解释了 ERBB2 扩增的 ILBC 预后不良和治疗耐药性。
