HER2 低表达、拷贝数变异与 HER2 低转移性乳腺癌患者生存结局的相关性：一项国际多中心队列研究及 TCGA-METABRIC 分析
HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis.
机构信息
Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore.
Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore, Singapore.
出版信息
BMC Med. 2022 Mar 17;20(1):105. doi: 10.1186/s12916-022-02284-6.
BACKGROUND
HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC).
METHODS
Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH-) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH- status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS.
RESULTS
ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82-0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76-0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85-0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79-0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83-0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78-0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH- and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59-0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found.
CONCLUSIONS
HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC.
背景
HER2 低表达乳腺癌（BC）目前是一个活跃的研究领域。本研究评估了 HER2 阴性非转移性乳腺癌（BC）中 HER2 低表达对生存结果的影响。
方法
分析了亚洲乳腺癌合作组（ABCCG）6 个中心的 28280 例 HER2 阴性非转移性 BC 患者。HER2 低表达定义为免疫组化（IHC）1+或 2+且原位杂交非扩增（ISH-），HER2 零表达定义为 IHC 0。主要结局为激素受体状态和 HER2 IHC 0、1+和 2+ISH-状态的无复发生存率（RFS）和总生存率（OS）。还分析了 TCGA-BRCA 和 METABRIC 队列（n=1967），以探讨 HER2 表达、ERBB2 拷贝数变异（CNV）状态与 RFS 的关系。
结果
ABCCG 队列的中位随访时间为 6.6 年；12260 例（43.4%）为 HER2 低表达 BC，16020 例（56.6%）为 HER2 零表达 BC。与 HER2 零表达 BC 相比，HER2 低表达 BC 的结果更好（RFS：中心调整后的危险比（HR）0.88，95%CI 0.82-0.93，P<0.001；OS：中心调整后的 HR 0.82，95%CI 0.76-0.89，P<0.001）。多变量分析显示，HER2 低表达状态具有预后意义（RFS：HR 0.90，95%CI 0.85-0.96，P=0.002；OS：HR 0.86，95%CI 0.79-0.93，P<0.001）。在激素受体阳性肿瘤和激素受体阴性肿瘤的 OS 中，这些差异仍然显著。与 HER2 零表达 BC 相比，HER2 IHC1+BC 具有更好的生存结果（RFS：HR 0.89，95%CI 0.83-0.96，P=0.001；OS：HR 0.85，95%CI 0.78-0.93，P=0.001）。HER2 IHC2+ISH-和 HER2 零表达 BC 之间未见显著差异。在 TCGA-BRCA 和 METABRIC 队列中，ERBB2 CNV 状态是独立的 RFS 预后因素（中性与非中性 HR 0.71，95%CI 0.59-0.86，P<0.001）；未发现 ERBB2 mRNA 表达水平与 RFS 有差异。
结论
与 HER2 零表达 BC 相比，HER2 低表达 BC 在非转移性环境中具有更好的预后，尽管绝对差异较小，主要由 HER2 IHC 1+BC 驱动。ERBB2 CNV 值得在 HER2 阴性 BC 中进一步研究。
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