Association between HER2 heterogeneity and clinical outcomes of HER2-positive gastric cancer patients treated with trastuzumab

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 25; no. 4; pp. 794 - 803
• Main Authors: Bang, Kyunghye, Cheon, Jaekyung, Park, Young Soo, Kim, Hyung-Don, Ryu, Min-Hee, Park, Yangsoon, Moon, Meesun, Lee, Hyungeun, Kang, Yoon-Koo
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01-07-2022; Springer Nature B.V
• Subjects: Abdominal Surgery; Biopsy; Cancer Research; Chemotherapy; Clinical outcomes; ErbB-2 protein; Gastric cancer; Gastroenterology; Hybridization; Immunohistochemistry; Medicine; Medicine & Public Health; Monoclonal antibodies; Oncology; Original Article; Patients; Surgical Oncology; Survival; Targeted cancer therapy; Trastuzumab; H-score; Gastric cancer; HER2 heterogeneity; Trastuzumab; Rescued HER2-positivity
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-022-01298-6

Background
The GASTHER1 study showed that re-evaluation of HER2 status rescued 8% of HER2-positive gastric cancer (GC) patients with initially HER2-negative GC. Since rescued HER2 positivity represents HER2 heterogeneity, we aimed to investigate this in a larger cohort with longer follow-up duration.
Methods
Data of 153 HER2-positive advanced GC patients who received first-line trastuzumab-based chemotherapy were analyzed. Repeat endoscopic biopsy was performed in patients with initially HER2-negative GC. Survival outcomes were analyzed according to the immunohistochemistry (IHC) score (IHC 2+ /in situ hybridization [ISH] + vs IHC 3+), HER2 status (initially vs rescued HER2 positive), and H-score.
Results
IHC 2+ /ISH + patients showed worse progression-free survival (PFS) and overall survival (OS) than those with IHC 3+ (
p
 < 0.05). Rescued HER2-positive patients showed worse PFS and OS than initially HER2-positive patients (
p
 < 0.05). Although survival outcomes were comparable according to HER2 status in IHC 2+ /ISH + patients, initially HER2-positive patients showed more favorable PFS and OS than rescued HER2-positive patients (
p
 < 0.05) among those with IHC 3+ . Among the subgroups determined by HER2 status and IHC score, the initially IHC 3+ subgroup had the highest H-score. The low H-score group (H-score ≤ 210) had significantly worse survival outcomes than the high H-score group (H-score > 210) (
p
 < 0.05). An H-score of ≤ 210 was independently associated with shorter OS (HR = 1.54, 95% CI 1.02–2.31,
p
 = 0.04).
Conclusions
Rescued HER2-positive patients showed worse clinical outcomes than initially HER2-positive patients, especially those with IHC 3+ . This finding highlights the impact of HER2 heterogeneity, which can be quantified indirectly as an H-score.