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. 2024 Mar 20;16(6):1227.
doi: 10.3390/cancers16061227.

HER2 and PD-L1 Expression in Gastric and Gastroesophageal Junction Cancer: Insights for Combinatorial Targeting Approaches

Marta Baptista Freitas  1 , Irene Gullo  2   3   4 , Dina Leitão  3 , Lúcia Águas  1   5 , Carla Oliveira  4   5   6 , António Polónia  4   6   7 , Joana Gomes  4   6 , Fátima Carneiro  2   3   4   6 , Celso Albuquerque Reis  4   5   6   8 , Henrique Oliveira Duarte  4   6
Affiliations

HER2 and PD-L1 Expression in Gastric and Gastroesophageal Junction Cancer: Insights for Combinatorial Targeting Approaches

Marta Baptista Freitas et al. Cancers (Basel). .

Abstract

Gastric and gastroesophageal junction adenocarcinomas (GA/GEJA) are associated with a poor prognosis, primarily due to late disease diagnosis. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression and programmed death-ligand 1 (PD-L1) expression are important biomarkers for treatment selection in locally advanced unresectable and metastatic GA/GEJA, and there is increasing interest in their role in earlier stages of disease. In this study, we aimed to evaluate HER2 and PD-L1 expression in a curative-intent GA/GEJA cohort to describe their expression patterns and analyze the association between HER2 expression and clinicopathological features. HER2 expression was evaluated in surgical and endoscopic submucosal dissection tumor samples, and PD-L1 was evaluated in HER2-positive cases. The clinical cohort included 107 patients, with 8.4% testing positive for HER2 (seven of whom also exhibited a PD-L1 combined positive score of ≥1. HER2 status was not significantly associated with survival outcomes. A pathologist-guided, region-specific analysis revealed that PD-L1 expression rarely overlaps with HER2-positive tumor areas. While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation.

Keywords: Human Epidermal Growth Factor Receptor 2 (HER2); gastric adenocarcinoma; gastroesophageal junction adenocarcinoma; programmed death-ligand 1 (PD-L1); targeted therapy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Gastric adenocarcinoma (GA) tubular solid subtype by WHO ((a): hematoxylin and eosin (H&E) staining, 200× magnification) with overlapping expression of HER2 (IHC 3+) (b): 200× magnification) and PD-L1 (c): 200× magnification; (d): tumoral cell membrane with PD-L1 expression, 400× magnification).
Figure 2
Figure 2
Gastric adenocarcinoma (GA) tubular/papillary subtype by WHO classification ((a): hematoxylin and eosin (H&E) staining, low magnification), with overall HER2 score 0 and a minor component (<10%) showing HER2 expression (2+/3+) ((b): HER2 expression, low magnification; (c): HER2 overexpression, region 1, 200× magnification). PD-L1 expression was observed in tumor areas without HER2 expression ((d): HER2-negative area, region 2, 200× magnification; (e): PD-L1 expression in region 2, low magnification; (f): PD-L1 expression in region 2, 200× magnification).
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