HER2-Targeted Therapies in Advanced Gastric Cancer

Human epidermal growth factor receptor 2 (HER2) overexpression or amplification characterises approximately 15–20% of advanced gastric and gastro‐oesophageal junction cancers. The landmark introduction of trastuzumab in combination with chemotherapy established the first targeted standard of care, improving median survival and paving the way for a new era of precision interventions. However, intrinsic and acquired resistance—driven by intratumoral heterogeneity, activation of compensatory pathways, and genetic alterations—limits long‐term benefit. Recent advances centre on novel antibody–drug conjugates (ADCs) that deliver cytotoxic payloads directly to HER2-expressing cells, bispecific antibodies engaging multiple epitopes, and combinations with immune checkpoint inhibitors. Precision biomarker strategies, including circulating tumour DNA and refined immunohistochemical scoring, aim to identify patients most likely to respond and to monitor emergent resistance. Ongoing efforts seek to optimise sequencing of available agents, integrate next‐generation HER2 inhibitors into earlier lines of therapy, and overcome resistance through rational combinations targeting parallel signalling nodes.

Research from Nature Portfolio

Exploratory biomarker analyses from a pivotal phase II trial of trastuzumab deruxtecan revealed that spatial and temporal heterogeneity of HER2 expression in gastric tumours complicates patient selection. Circulating tumour DNA profiling demonstrated that ERBB2 amplification concordance with tissue testing stood at around 64%, while concurrent amplifications in MET, EGFR and FGFR2 correlated with reduced response rates. The findings underscore the need for dynamic biomarker assessment to optimise patient stratification and to understand mechanisms of resistance to ADCs. Earlier foundational work analysed the impact of co-occurring genomic alterations on trastuzumab efficacy, showing that copy-number variations in cell‐cycle regulators such as CCNE1 are associated with shorter progression-free survival, although no single alteration reliably predicts benefit. Complementary preclinical studies established trastuzumab-resistant gastric cancer cell lines and identified down-regulation or mutation of PTEN, activation of the PI3K–AKT axis and up-regulation of IGF-1R signalling as central resistance mechanisms, suggesting that dual inhibition of these pathways may restore sensitivity.

HER2-Targeted Therapies in Advanced Gastric Cancer publication trend

The graph below shows the total number of articles in her2-targeted therapies in advanced gastric cancer across all publications each year (not limited to Nature Index journals).

Technical terms

HER2: A transmembrane tyrosine kinase receptor implicated in tumour cell proliferation and survival when overexpressed or amplified.

Antibody–drug conjugate (ADC): A monoclonal antibody linked to a cytotoxic agent, designed to deliver chemotherapy directly to target cells expressing the antibody’s antigen.

Objective response rate (ORR): The proportion of patients experiencing a predefined magnitude of tumour shrinkage, including complete and partial responses.

Progression-free survival (PFS): The interval from treatment initiation to documented disease progression or death, used to assess efficacy.

Circulating tumour DNA (ctDNA): Tumour-derived fragmented DNA present in the bloodstream, employed as a non-invasive biomarker for molecular profiling.

Intratumoral heterogeneity: Variability in genetic, protein expression or phenotypic characteristics among cancer cells within the same tumour, affecting treatment response.

References

1. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer (2014).
2. Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial. Nature Medicine (2024).
3. Clinical impact of intratumoral HER2 heterogeneity on trastuzumab efficacy in patients with HER2-positive gastric cancer. Journal of Gastroenterology (2018).
4. The Impact of Concomitant Genomic Alterations on Treatment Outcome for Trastuzumab Therapy in HER2-Positive Gastric Cancer. Scientific Reports (2015).
5. Development of trastuzumab-resistant human gastric carcinoma cell lines and mechanisms of drug resistance. Scientific Reports (2015).
6. First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncology (2020).
7. Phase I study of the recombinant humanized anti-HER2 monoclonal antibody–MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors. Gastric Cancer (2021).
8. Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance. Cancers (2020).