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Wang, J. ; Sun, N. ; Kunzke, T. ; Shen, J. ; Feuchtinger, A. ; Wang, Q. ; Meixner, R. ; Le Gleut, R. ; Haffner, I.* ; Luber, B.* ; Lordick, F.* ; Walch, A.K.

Metabolic heterogeneity affects trastuzumab response and survival in HER2-positive advanced gastric cancer.

Br. J. Cancer 130, 1036-1045 (2024)

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BACKGROUND: Trastuzumab is the only first-line treatment targeted against the human epidermal growth factor receptor 2 (HER2) approved for patients with HER2-positive advanced gastric cancer. The impact of metabolic heterogeneity on trastuzumab treatment efficacy remains unclear. METHODS: Spatial metabolomics via high mass resolution imaging mass spectrometry was performed in pretherapeutic biopsies of patients with HER2-positive advanced gastric cancer in a prospective multicentre observational study. The mass spectra, representing the metabolic heterogeneity within tumour areas, were grouped by K-means clustering algorithm. Simpson's diversity index was applied to compare the metabolic heterogeneity level of individual patients. RESULTS: Clustering analysis revealed metabolic heterogeneity in HER2-positive gastric cancer patients and uncovered nine tumour subpopulations. High metabolic heterogeneity was shown as a factor indicating sensitivity to trastuzumab (p = 0.008) and favourable prognosis at trend level. Two of the nine tumour subpopulations associated with favourable prognosis and trastuzumab sensitivity, and one subpopulation associated with poor prognosis and trastuzumab resistance. CONCLUSIONS: This work revealed that tumour metabolic heterogeneity associated with prognosis and trastuzumab response based on tissue metabolomics of HER2-positive gastric cancer. Tumour metabolic subpopulations may provide an association with trastuzumab therapy efficacy. CLINICAL TRIAL REGISTRATION: The patient cohort was conducted from a multicentre observational study (VARIANZ;NCT02305043).

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