1465P - Potential impact of APC mutation on survival via immune evasion through WNT signaling activation in HER2-positive gastric cancer treated with trastuzumab (tmab), nivolumab (nivo), and chemotherapy

Background

Previous reports have highlighted the clinical relevance of WNT signaling activation in immune evasion, thereby influencing anti-tumor immunity. Our previous study revealed an association between APC mutation and shorter progression-free survival (20.8 vs. 5.6 months; HR 3.47, p=0.018) and a lower response rate (82% vs. 50%) in HER2-positive gastric cancer treated with Tmab and Nivo plus chemotherapy (ESMO 2023). This study aimed to elucidate potential mechanisms of therapeutic resistance through RNA sequencing.

Methods

Patients received initial treatment with S-1 80 mg/m2/day or Capecitabine 2000 mg/m2/day on days 1-14, oxaliplatin 130 mg/m2, Nivo 360mg, and T-mab 8mg/kg, followed by 6 mg/kg on day 1, repeated every 3 weeks (UMIN000034222). Pretreatment primary tumor samples were collected, and whole exome and RNA sequencing was conducted. Pathway analysis targeted WikiPathways to reveal underlying biological functions and mechanisms. Immune and stromal composition estimation was performed using the MCP counter.

Results

Twenty-three patients were included, of whom 6 (26%) had APC-mutated tumors, all of which were truncating mutations. Patients with APC mutations had a median age of 72.5 years, higher than those without APC mutations. Furthermore, all APC-mutated tumors were stomach primary site and exhibited intratumoral HER2 heterogeneity by immunohistochemistry. No significant differences were observed in ERBB2 copy number or tumor mutation burden between the two groups. Pathway analysis revealed upregulation of canonical WNT signaling pathways (adj. p=0.034) and downregulation of type-2 interferon signaling pathways (adj. p=0.005). Additionally, MCP counter analysis demonstrated significantly lower levels of cytotoxic lymphocytes (p=0.024) and T cells (p<0.01) in the APC-mutated tumors compared to those without APC mutations.

Conclusions

Activation of WNT signaling and immune evasion may represent potential resistance mechanisms in APC-mutated tumors undergoing treatment with Tmab and Nivo plus chemotherapy for advanced HER2-positive gastric cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Ono Pharmaceutical Co. Ltd.

Disclosure

H. Shoji: Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd., Zymeworks inc., Astellas; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Institutional, Local PI: Ono Pharmaceutical Co., Ltd., MSD, Astellas, Amgen, Daiichi Sankyo, AbbVie, AstraZeneca, Taiho Pharmaceutical, Elevation Oncology; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co., Ltd., Takeda Pharmaceuticals. I. Nakayama: Financial Interests, Institutional, Local PI: Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, MSD. K. Minashi: Financial Interests, Institutional, Research Grant: Amgen, Taiho Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd., Astellas, Pharmaceutical Co., Ltd. H. Hara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, MSD, Ono, Bayer, Chugai, Lilly, Merck Biopharma, Taiho, Takeda, Yakult, Bristol Myers Squibb, Miyarisan; Financial Interests, Institutional, Coordinating PI: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Chugai, Daiichi Sankyo, Janssen, Merck Biopharma, MSD, Ono, Taiho, ALX Oncology, Jazz Pharmaceuticals. S. Kitano: Financial Interests, Personal, Advisory Board, Scientific Advisor: ImmuniT Research, United Immunity, Sumitomo Pharma; Financial Interests, Personal, Advisory Board, Scientific advisor: Rakuten Medical; Financial Interests, Personal, Other, lecture fee: AstraZeneca; Financial Interests, Personal, Other, Lecture fee: Pfizer, Taiho, Novartis, MSD, Eisai, Bristol Myers Squibb, GSK, Chugai, Takeda, Janssen, Merck KGaA; Financial Interests, Personal, Other, Scientific adviser, Lecture fee: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: PMDA(Pharmaceuticals and Medical Devices Agency); Financial Interests, Personal and Institutional, Local PI, Clinical Trial, Research Grant: Daiichi Sankyo; Financial Interests, Personal and Institutional, Local PI, Clinical Trial: AstraZeneca, Pfizer, MSD, Eisai, Incyte, Takeda, Eli Lilly Japan K.K., Loxo Oncology, AbbVie; Financial Interests, Personal and Institutional, Local PI, Clinical trial, Research Grant: Nippon Boehringer Ingelheim; Financial Interests, Personal and Institutional, Local PI, Clinical trial: Astellas; Financial Interests, Personal and Institutional, Coordinating PI, Clinical trial, Research Grant: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal and Institutional, Local PI, Clinical trial: GSK; Financial Interests, Personal and Institutional, Local PI, Clinical Trial, Research Grant: Chugai; Financial Interests, Personal and Institutional, Research Grant, Research Grant: Takara Bio Inc. N. Boku: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Ono Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd. K. Yamaguchi: Financial Interests, Institutional, Research Funding: Ono Pharmaceutical Co. Ltd. D. Takahari: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb. All other authors have declared no conflicts of interest.