5605 例复发性和转移性乳腺癌中无 ERBB2 基因组扩增：抗 HER2 靶向治疗的新机会。

Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies.

机构信息

Foundation Medicine Inc, Cambridge, Massachusetts.

Department of Pathology, Albany Medical College, Albany, New York.

出版信息

Cancer. 2016 Sep 1;122(17):2654-62. doi: 10.1002/cncr.30102. Epub 2016 Jun 10.

DOI:10.1002/cncr.30102

PMID:27284958

Abstract

BACKGROUND

Activating, nonamplification ERBB2 mutations (ERBB2mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)-targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2mut genomic alterations. Clinical responses to anti-HER2 therapeutics were identified.

METHODS

DNA was extracted from 40 µm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592× mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements.

RESULTS

Of 5605 cases, 698 (12.5%) featured ERBB2 alterations, including 596 (10.6%) ERBB2 amplifications (ERBB2amp) and 138 (2.4%) ERBB2mut; 38 cases (0.7%) had co-occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90%) or extracellular (15 cases; 11%) domains. Both primary BC (52 cases; 38%) and metastatic site biopsies (86 cases; 62%) were found to harbor ERBB2mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50%), invasive ductal carcinoma (IDC) (40 cases; 29%), invasive lobular carcinoma (ILC) (27 cases; 20%), and mucinous mBC (2 cases; 1%). Genes commonly coaltered with ERBB2 were tumor protein 53 (TP53) (49%); phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (42%); cadherin 1, type 1 (CDH1) (37%); MYC (17%); and cyclin D1 protein (CCND1) (16%). CDH1 mutations were enriched in ERBB2mut mBC (P<0.0006) and associated with recurrent mBC. Selected patients with ERBB2mut, without ERBB2amp, who responded to anti-HER2 targeted therapies are presented herein.

CONCLUSIONS

Within this large series, 1.8% of cases harbored ERBB2mut, which are undetectable by standard-of-care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti-HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2654-2662. © 2016 American Cancer Society.

摘要

背景

激活的、非扩增的 ERBB2 突变（ERBB2mut）不能通过免疫组织化学（IHC）或荧光原位杂交（FISH）检测，但可以通过 DNA 测序检测，并且可能预测表皮生长因子受体（HER2）靶向治疗的临床反应。作者对 5605 例晚期/转移性乳腺癌（mBC）进行了查询，以揭示 ERBB2mut 基因组改变的频率。鉴定了对抗 HER2 治疗的临床反应。

方法

从福尔马林固定石蜡包埋（FFPE）切片的 40 μm 中提取 DNA。综合基因组分析（CGP）用于评估多达 315 个基因（平均覆盖率深度 592×）。分析结果以确定碱基取代、短插入缺失、拷贝数变化和选定的重排。

结果

在 5605 例病例中，有 698 例（12.5%）存在 ERBB2 改变，包括 596 例（10.6%）ERBB2 扩增（ERBB2amp）和 138 例（2.4%）ERBB2mut；38 例（0.7%）同时存在 ERBB2amp 和 ERBB2mut。ERBB2mut 主要影响激酶（124 例；90%）或细胞外（15 例；11%）结构域。原发性 BC（52 例；38%）和转移性部位活检（86 例；62%）均发现 ERBB2mut，分布于特定类型的非特指性癌（NOS）（69 例；50%）、浸润性导管癌（IDC）（40 例；29%）、浸润性小叶癌（ILC）（27 例；20%）和黏液性 mBC（2 例；1%）。与 ERBB2 共同发生改变的常见基因有肿瘤蛋白 53（TP53）（49%）；磷脂酰肌醇 3-激酶催化亚单位α（PIK3CA）（42%）；钙黏蛋白 1 型（CDH1）（37%）；MYC（17%）；和周期蛋白 D1 蛋白（CCND1）（16%）。CDH1 突变在 ERBB2mut mBC 中富集（P<0.0006），并与复发性 mBC 相关。本文呈现了一些选择的 ERBB2mut 患者，无 ERBB2amp，对 HER2 靶向治疗有反应。