ArticleGastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association2021
Personalized therapeutic strategies in HER2-driven gastric cancer.
Article in Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 21 citations in OpenAlex.
- Efficacy and safety of KN026, a bispecific anti-HER2 antibody, in combination with KN046, an anti-CTLA4/PD-L1 antibody, in patients with advanced HER2-positive nonbreast cancer: a combined analysis of a phase Ib and a phase II study.Signal transduction and targeted therapy · 2025Trial
- Molecular classification and precision therapy in gastric cancer: Current advances and future perspectives (Review).Oncology reports · 2026Review
- HER2 and urothelial carcinoma: current understanding and future directions.Nature reviews. Urology · 2026Review
- AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer.Cancer research · 2025Article
- PDX models for functional precision oncology and discovery science.Nature reviews. Cancer · 2025Review
- First-line maintenance strategies and later-line options in patients with advanced gastroesophageal adenocarcinoma.Therapeutic advances in medical oncology · 2025Review
- HER2-targeted therapies beyond breast cancer - an update.Nature reviews. Clinical oncology · 2024Review
- Preclinical efficacy of a HER2 synNotch/CEA-CAR combinatorial immunotherapy against colorectal cancer with HER2 amplification.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- IKZF3 amplification predicts worse prognosis especially in intestinal-type gastric cancer.Journal of cancer research and clinical oncology · 2024Article
- Xenograft and organoid models in developing precision medicine for gastric cancer (Review).International journal of oncology · 2024Review
- Negative Hyperselection of Patients with HER2+ and RAS Wild-Type Metastatic Colorectal Cancer Receiving Dual HER2 Blockade: the PRESSING-HER2 Study.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer.Frontiers in molecular biosciences · 2024Review
- Article
- Fatty acid synthase as a new therapeutic target for HER2-positive gastric cancer.Cellular oncology (Dordrecht, Netherlands) · 2023Article
- HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Review
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Authors and funding
43 authors at 10 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTrastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors.
methodsWe undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials.
resultsDespite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting.
conclusionThese preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.
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