Institute of Pathology, Hannover Medical School, Hannover, Germany.
West German Study Group, Moenchengladbach, Germany.
Genes Chromosomes Cancer. 2019 Mar;58(3):175-185. doi: 10.1002/gcc.22716. Epub 2019 Jan 7.
HER2-positive breast cancer is defined by amplification or overexpression of the HER2/ERBB2 oncogene and accounts for about 15% of breast cancer cases. Somatic mutation of ERBB2 is an alternative mechanism, by which activation of HER2 signaling can occur. ERBB2 mutation has been associated with invasive lobular breast cancer (ILBC). This study investigates the frequency and phenotype of ILBC harboring mutated ERBB2. The ERBB2 mutation status was determined by next generation sequencing and/or pyrosequencing in n = 106 ILBCs, including n = 86 primary or locally recurrent tumors and n = 20 metastases from visceral organs, soft tissue, or skin. Immunohistochemical characteristics were determined using tissue microarrays. This series was enriched for ILBCs with pleomorphic histology and/or high-risk expression profiles (Oncotype DX, recurrence score RS > 25). Nearly all specimens were E-cadherin-negative (99%), estrogen receptor (ER)-positive (92%), and lacked ERBB2 overexpression (96%). ERBB2 mutations (p.V777L, p.L755S, p.S310F) were identified in 5/106 (5%) cases. ERBB2-mutated cases included 2/86 (2%) primary tumors and 3/20 (15%) metastases (P = 0.045). ERBB2-mutated cases were associated with loss of ER (2/7, 29%, P = 0.035) and histological grade 3 (4/34, 12%, P = 0.023), but not with solid growth (3/31, 10%, P = 0.148) or pleomorphic histology (2/27, 7%, P = 0.599). No ERBB2 mutation was detected in ILBCs with RS > 25 (0/22, 0%). In 10 patients with multiple matched specimens (n = 25), the ERBB2 mutational status was always concordant. In summary, a small subset of ILBCs harbors potentially actionable ERBB2 mutations. In ERBB2-mutated ILBCs, no association with pleomorphic histology was found.
人表皮生长因子受体 2 阳性乳腺癌的定义是 HER2/ERBB2 癌基因扩增或过表达，约占乳腺癌病例的 15%。ERBB2 体细胞突变是一种替代机制，通过这种机制可以激活 HER2 信号。ERBB2 突变与浸润性小叶乳腺癌（ILBC）有关。本研究调查了携带突变 ERBB2 的 ILBC 的频率和表型。通过下一代测序和/或焦磷酸测序，在 n = 106 例 ILBC 中确定了 ERBB2 突变状态，包括 n = 86 例原发性或局部复发性肿瘤和 n = 20 例来自内脏器官、软组织或皮肤的转移灶。使用组织微阵列确定了免疫组织化学特征。该系列富含多形性组织学和/或高危表达谱（Oncotype DX，复发评分 RS>25）的 ILBC。几乎所有标本均为 E-钙黏蛋白阴性（99%），雌激素受体（ER）阳性（92%），且缺乏 ERBB2 过表达（96%）。在 106 例病例中发现 ERBB2 突变（p.V777L、p.L755S、p.S310F），占 5/106（5%）。ERBB2 突变病例包括 2/86（2%）原发性肿瘤和 3/20（15%）转移灶（P = 0.045）。ERBB2 突变病例与 ER 缺失（2/7，29%，P = 0.035）和组织学 3 级（4/34，12%，P = 0.023）相关，但与实性生长（3/31，10%，P = 0.148）或多形性组织学（2/27，7%，P = 0.599）无关。在 RS>25 的 ILBC 中未检测到 ERBB2 突变（0/22，0%）。在 10 例具有多个匹配标本的患者（n = 25）中，ERBB2 突变状态始终一致。总之，一小部分 ILBC 携带潜在可治疗的 ERBB2 突变。在 ERBB2 突变的 ILBC 中，未发现与多形性组织学相关。
