Background:HER2-low breast cancer (HER2 immunohistochemical [IHC] score 1+, or IHC 2+ without HER2 gene amplification) is distinct from HER2-positive and HER2-0 breast cancer (IHC 0), with a differing prognosis and specific therapeutic options. The DESTINY-Breast04 trial demonstrated notable efficacy of the HER2 antibody–drug conjugate trastuzumab deruxtecan over standard chemotherapy in patients with metastatic breast cancer (MBC) defined as HER2-low. More recently, the DESTINY-Breast06 trial confirmed this benefit in hormone receptor-positive and HER2-ultralow (less than 1+, but with ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining) cases, prompting re-evaluation of HER2 diagnostic thresholds and treatment strategies.Methods: Eligible patients were women with HER2-low or HER2-0 MBC evaluated at MD Anderson between January 2006 and January 2019. HER2-low was defined as either (1) IHC 1+ or (2) IHC 2+ and negative on fluorescence in situ hybridization. Multivariate logistic regression was used to evaluate distinct clinicopathologic features of patients with HER2-low status. Overall survival (OS) was estimated by the Kaplan–Meier method. Multivariate Cox proportional hazards regression was applied to assess the effects of covariates of interest on OS across different HER2 groups.Results: We included 3834 women: 2637 (69%) with recurrent and 1197 (31%) with de novo MBC; HER2-low disease was present in 1575 (60%) and 712 (59%), respectively. In de novo cases, higher nuclear grade was associated with HER2-low status (grade 2 vs. 1, OR = 2.02,p= 0.007; grade 3 vs. 1, OR = 1.87,p= 0.015), while recurrent cases were associated with ER-positivity (OR = 1.96,p< 0.001) and prior adjuvant radiotherapy (OR = 0.79,p= 0.007). Median OS was 3.2 years (95% CI 3.0–3.5). In de novo disease, Black race (HR = 1.48), metaplastic (HR = 3.15) or other non-ductal/lobular histologies (HR = 2.36), and grade 3 (HR = 1.67) predicted worse OS, whereas Hispanic ethnicity (HR = 0.74) and Other races (HR = 0.57), higher ER (HR = 0.48–0.41) and PR (HR = 0.72–0.53), and HER2-low status (HR = 0.77) conferred improved outcomes. In recurrent disease, Black race predicted worse OS (HR = 1.21, 95% CI 1.05–1.39), while Other race (HR = 0.78, 95% CI 0.62–0.97), higher ER (HR = 0.69–0.44) and PR (HR = 0.73–0.73), and HER2-low (HR = 0.89) were protective. HER2 discordance between primary and metastatic sites occurred in 38.8% of recurrent and 13.1% of de novo cases.Conclusions: HER2-low status was significantly associated with longer OS compared to HER2-0 status in both recurrent and de novo MBC cases. These real-world data help establish the prevalence of HER2-low status and its distinct outcomes. The discrepancy in HER2-low status between the primary tumor and metastatic sites highlights the potential for changes in HER2 expression over time, exploring the interaction between HER2-low breast cancer and the tumor microenvironment and emphasizing the importance of monitoring and reassessing HER2 status at various stages to guide treatment decisions effectively and the need for more quantitative and reproducible HER assays.
背景：HER2低表达乳腺癌（HER2免疫组化[IHC]评分为1+，或IHC 2+但无HER2基因扩增）与HER2阳性及HER2-0（IHC 0）乳腺癌不同，其预后和治疗选择存在差异。DESTINY-Breast04试验证明，在定义为HER2低表达的转移性乳腺癌患者中，HER2抗体药物偶联物曲妥珠单抗德鲁克汀较标准化疗具有显著疗效。近期，DESTINY-Breast06试验进一步证实该药物在激素受体阳性且HER2超低表达（IHC评分<1+，但≤10%浸润癌细胞呈不完全、微弱/弱膜染色）病例中的益处，这促使学界重新评估HER2诊断阈值和治疗策略。
方法：本研究纳入2006年1月至2019年1月在MD安德森癌症中心评估的HER2低表达或HER2-0转移性乳腺癌女性患者。HER2低表达定义为（1）IHC 1+，或（2）IHC 2+且荧光原位杂交检测阴性。采用多因素逻辑回归分析HER2低表达状态患者的独特临床病理特征。总生存期通过Kaplan-Meier法评估，并使用多因素Cox比例风险回归模型分析不同HER2分组中协变量对总生存期的影响。
结果：共纳入3834例女性患者：2637例（69%）为复发型转移性乳腺癌，1197例（31%）为新发转移性乳腺癌；其中分别有1575例（60%）和712例（59%）为HER2低表达。在新发病例中，较高的核分级与HER2低表达状态相关（2级 vs. 1级，OR=2.02，p=0.007；3级 vs. 1级，OR=1.87，p=0.015），而复发型病例则与雌激素受体阳性（OR=1.96，p<0.001）及既往辅助放疗史（OR=0.79，p=0.007）相关。中位总生存期为3.2年（95%CI 3.0-3.5）。在新发病例中，黑人种族（HR=1.48）、化生性癌（HR=3.15）或其他非导管/小叶组织学类型（HR=2.36）以及3级分化（HR=1.67）预示较差总生存期，而西班牙裔（HR=0.74）与其他种族（HR=0.57）、较高的雌激素受体（HR=0.48-0.41）和孕激素受体水平（HR=0.72-0.53）以及HER2低表达状态（HR=0.77）则与较好的预后相关。在复发型病例中，黑人种族预示较差总生存期（HR=1.21，95%CI 1.05-1.39），而其他种族（HR=0.78，95%CI 0.62-0.97）、较高的雌激素受体（HR=0.69-0.44）和孕激素受体水平（HR=0.73-0.73）以及HER2低表达状态（HR=0.89）具有保护作用。原发灶与转移灶之间HER2状态不一致的发生率在复发型病例中为38.8%，在新发病例中为13.1%。
结论：在复发型和新发转移性乳腺癌病例中，HER2低表达状态相较于HER2-0状态均与更长的总生存期显著相关。这些真实世界数据有助于确立HER2低表达状态的普遍性及其独特的预后特征。原发肿瘤与转移灶之间HER2低表达状态的差异，突显了HER2表达随时间变化的可能性，提示需探索HER2低表达乳腺癌与肿瘤微环境之间的相互作用，强调在不同阶段监测和重新评估HER2状态以有效指导治疗决策的重要性，以及开发更量化、可重复的HER2检测方法的必要性。
Prevalence and Outcomes of HER2-Low Versus HER2-0 Status in Patients with Metastatic Breast Cancer
肿瘤(癌症)患者之家