Abstract 4484: HER3 expression after systemic therapy and clinical characteristics in patients with hepatocellular carcinoma
Authors: Okada Mao , Morizane Chigusa , Satake Tomoyuki , Nishioka Mariko , Hiraoka Nobuyoshi , Nara Satoshi , Kakegawa Tomoya , Kobayashi Maki , Koyama Kumiko , Esaki Minoru , Okusaka Takuji 
Published: April 2023

Abstract
Background: In hepatocellular carcinoma (HCC), several standard regimens with angiogenesis inhibitors and immune checkpoint inhibitors have been established; however, novel therapeutic strategies to target key molecules associated with HCC are further required to improve treatment options. ErbB3 (HER3), a member of the HER receptor tyrosine kinase family, has recently emerged as a promising therapeutic target in various cancers. In this study, HER3 expression status after current targeted therapies in HCC was evaluated in order to explore an opportunity for developing anti-HER3 therapy for HCC.
Methods: We collected clinical data and tumor tissue from HCC patients (pts) who received systemic therapy between January 2010 and June 2020 and the tissue samples at post systemic therapy were also obtained. Immunohistochemical staining for HER3 was conducted using HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology) as a primary antibody. IHC scoring (0, 1+, 2+, 3+) of membranous staining intensity was performed according to HER2 IHC gastric scoring guideline.
Results: Seventeen pts were eligible. Eight pts (47%) were HER3 2+/3+, (2+: 7, 3+: 1,), while nine pts (53%) were 0/1+ (0: 4, 1+: 5). For HER3 2+/3+ and HER3 0/1+ groups, median age (range) was 63(43-71)/69(47-78), median alpha-fetoprotein levels were 6071(4-23620)/19.1(1.2-1138) [ng/ml], and median des-gamma-carboxy prothrombin levels were 1351(135-92650)/302(10-10916) [mAU/ml], respectively. The proportions of patients with HER3 2+/3+ were 67% in HCV+ pts, 25% in HBV+ pts, and 43% in other etiologies. Median overall survival of HER3 2+/3+ and 0/1+ pts after start of first line systemic therapy was 32.3 (95% CI: 8.7-51.4) and 12.9 (95% CI: 6.1-20.7) months, respectively (HR: 0.28, 95% CI: 0.09-0.92, p=0.036).Paired pre- and post-treatment samples were available for eight pts. The median number of regimens administered between the pre- and post-treatment samples was 2(1-5). Treatment regimens were sorafenib: 7; lenvatinib: 2; ramucirumab: 1; others: 10, including duplicates. At post-treatment, HER3 was upregulated in 4 pts (1 pt: 0 to 1+, 3 pts: 1+ to 2+) and downregulated in 3 pts (all pts: 1+ to 0). Pts with HER3 upregulation had developed resistance after at least one prior tyrosine kinase inhibitor (TKI) with stable disease or partial response as best response.
Conclusion: In this study, 47% of pts were HER3 2+/3+ at post-treatment. In paired analysis, half of pts upregulated HER3 expression after systemic therapy including TKIs, suggesting HER3 might be one of the factors associated with resistance to systemic therapy.
Citation Format: Mao Okada, Chigusa Morizane, Tomoyuki Satake, Mariko Nishioka, Nobuyoshi Hiraoka, Satoshi Nara, Tomoya Kakegawa, Maki Kobayashi, Kumiko Koyama, Minoru Esaki, Takuji Okusaka. HER3 expression after systemic therapy and clinical characteristics in patients with hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4484.