Narita Yukiya, Mizuno Taro, Ishizuka Yasunobu, Sakakida Tomoki, Masuishi Toshiki, Taniguchi Hiroya, Kadowaki Shigenori, Honda Kazunori, Ando Masashi, Tajika Masahiro, Takahari Daisuke, Muro Kei
Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan.
Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, 484-8681, Japan.
Oncologist. 2025 Jul 4;30(7). doi: 10.1093/oncolo/oyae328.
Human epidermal growth factor receptor 2 (HER2) status is a critical biomarker in advanced gastric cancer (AGC). While the role of HER2-positive tumors in guiding targeted therapies is well-established, the clinical implications of HER2-low expression, defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization-negative (ISH-negative), remain undetermined. The aim of this study was to investigate the prognostic significance and clinicopathological features of HER2-low AGC.
This retrospective analysis involved patients with AGC treated with first-line fluoropyrimidine and platinum-based chemotherapy from 2011 to 2020. Patients were categorized into HER2-zero (HER2 IHC 0), HER2-low (IHC 1+ or 2+/ISH-negative), and HER2-positive (IHC 2+/ISH-positive or 3+) groups.
Among 548 patients analyzed, 33.0%, 45.1%, and 21.8% were classified as HER2-zero, HER2-low, and HER2-positive, respectively. The proportions of male patients, intestinal-type histology, esophagogastric junction/cardia involvement, metastatic disease status, ≥2 metastatic sites, liver metastasis, lymph node metastasis, and high serum carcinoembryonic antigen levels were gradually elevated in the HER2-zero, HER2-low, and HER2-positive groups. Overall survival (median) was 13.8, 13.6, and 23.0 months, respectively, with a non-significant trend favoring HER2-positive over HER2-low (adjusted hazard ratio: 0.80; P = .0672). A delayed separation of Kaplan-Meier curves for overall survival between the HER2-zero and HER2-low groups was observed, without reaching statistical significance (adjusted hazard ratio: 1.12; P = .2568).
Patients with HER2-low status exhibited intermediate and specific clinicopathological features within the HER2-negative category. In terms of prognosis, HER2-low patients showed a worsening trend compared with HER2-positive patients. This evidence implies that HER2-low status represents a distinct clinical subset, bridging the gap between the HER2-zero and HER2-positive profiles.
人表皮生长因子受体2（HER2）状态是晚期胃癌（AGC）的关键生物标志物。虽然HER2阳性肿瘤在指导靶向治疗中的作用已得到充分确立，但HER2低表达（定义为免疫组织化学（IHC）1+或IHC 2+/原位杂交阴性（ISH阴性））的临床意义仍未确定。本研究的目的是探讨HER2低表达AGC的预后意义和临床病理特征。
本回顾性分析纳入了2011年至2020年接受一线氟嘧啶和铂类化疗的AGC患者。患者被分为HER2零表达（HER2 IHC 0）、HER2低表达（IHC 1+或2+/ISH阴性）和HER2阳性（IHC 2+/ISH阳性或3+）组。
在分析的548例患者中，分别有33.0%、45.1%和21.8%被分类为HER2零表达、HER2低表达和HER2阳性。HER2零表达、HER2低表达和HER2阳性组中男性患者、肠型组织学、食管胃交界/贲门受累、转移疾病状态、≥2个转移部位、肝转移、淋巴结转移和高血清癌胚抗原水平的比例逐渐升高。总生存期（中位数）分别为13.8、13.6和23.0个月，HER2阳性组比HER2低表达组有非显著的生存优势趋势（调整后风险比：0.80；P = 0.0672）。观察到HER2零表达和HER2低表达组之间总生存期的Kaplan-Meier曲线分离延迟，但未达到统计学意义（调整后风险比：1.12；P = 0.2568）。
HER2低表达状态的患者在HER2阴性类别中表现出中等程度和特定的临床病理特征。在预后方面，HER2低表达患者与HER2阳性患者相比呈现出恶化趋势。这一证据表明HER2低表达状态代表了一个独特的临床亚组，弥合了HER2零表达和HER2阳性特征之间的差距。
