HER2-Positive Gastric Cancer: The Role of Immunotherapy and Novel Therapeutic Strategies

Pous, Anna; Notario, L.; Hierro, Cinta; Layos, Laura; Bugés, Cristina

doi:10.3390/ijms241411403

Cited by 11 publications

(6 citation statements)

References 138 publications

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“…In our cohort, seven out of nine (77.8%) HER2-positive tumors were also PD-L1 CPS ≥ 1. Previous studies showed higher and lower rates of PD-L1 CPS ≥ 1 in HER2-positive tumors, which can be related to population heterogeneity or differences in biomarker evaluation, and should be further explored [ 30 , 31 ]. Interestingly, previously proposed molecular classification systems of gastric cancer do not place HER2 and PD-L1 enrichment within the same tumor subtypes [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

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

Freitas,

Gullo,

Leitão

et al. 2024

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

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

Freitas,

Gullo,

Leitão

et al. 2024

Cancers

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“…Indeed, HER2 alteration and, more recently, PD-L1 expression are the only predictive biomarkers of response that can be useful to a clinician in the first-line decision-making process. Based on a strong preclinical rationale, combining immune-checkpoint inhibitors with HER2-directed agents has catalysed the interest of clinical research in the treatment of HER2-positive GEA [88]. The positive results of KEYNOTE-811 have changed the standard of care for HER2-positive/PDL1-positive advanced GEA.…”

Section: Discussionmentioning

confidence: 99%

Targeting HER2 in Gastroesophageal Adenocarcinoma: Molecular Features and Updates in Clinical Practice

Bonomi,

Spada,

Baiocchi

et al. 2024

IJMS

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Gastroesophageal adenocarcinoma (GEA) is one of the principal causes of death related to cancer globally. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor which is found to be overexpressed or amplified in approximately 20% of GEA cases. In GEA, the identification of HER2-positive status is crucial to activate a specific anti-HER2 targeted therapy. The landmark ToGA trial demonstrated the superiority of adding trastuzumab to platinum-based chemotherapy, becoming the first-line standard of treatment. However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions.

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“…A number of studies established that HER2 controls the abnormal expression of PD-L1 in the stomach and the combination of anti-HER2 and anti-PD-1 has proven synergistic anticancer effects in animal models ( 16 , 28 , 29 ). Further studies disclosed that dimerization of the HER2 receptor activates two major intracellular signaling pathways: the mitogen-activated protein kinase (MAPK) (Ras/Raf/MEK/ERK) and phosphatidylinositol 3′-kinase (PI3K)/Akt, inducing cell-cycle progression, proliferation and survival ( 30 – 32 ). PD-L1 is a dynamic marker that can be expressed constitutively (driven by endogenous oncogenic pathways) or in an inducible fashion (motivated by exogenous signals) ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer

Zou,

Wang,

Zhang

et al. 2023

Oncol Lett

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The programmed death receptor 1/programmed death receptor ligand 1 axis (PD-1/PD-L1) is involved in tumor immune escape and is a potential prognostic biomarker and anti-tumor immunotherapy target in patients with gastric cancer (GC). However, the results of studies obtained in recent years have been inconsistent. The present study aimed to determine the possible predictive significance of PD-L1 in conjunction with three proteins linked with PD-L1 regulation in patients with primary GC. In the present study, the PD-L1, human epidermal growth factor receptor 2 (HER2), cluster of differentiation (CD)133 and microphage-associated CD68 expression levels were identified by multiplexed immunohistochemistry and assessed by automated pathological analysis system in 93 GC tumors and neighboring normal tissues arrayed on the same tissue microarray. All four proteins were statistically analyzed in relation to the clinicopathological characteristics. The expression levels of HER2, CD133 and CD68 were considerably higher in cancer tissues compared with neighboring normal tissues (P<0.05), however, the reverse trend was detected for PD-L1 expression (P=0.0577), particularly in tumor nest (TN; P<0.05). There was no significant correlation between the HER2 and CD133 expression levels and clinicopathological factors. However, significant relationships were found between PD-L1 expression and the TNM stage, pathological differentiation and survival status of patients (P<0.05). Moreover, survival time was prolonged in individuals with elevated PD-L1 expression in TN and GC tissues, but no significant correlation was identified (P=0.0881). The CD68 expression level in tumor stroma, but not in TN, was significantly correlated with poor pathological differentiation in patients with GC (P<0.05). However, PD-L1+CD68+ macrophages were strongly related to lower tumor size (diameter <5 cm), early TNM stage (stage I+II), good pathological differentiation and overall survival in TN (P<0.05). In conclusion, PD-L1+CD68+ macrophage infiltration in TN might be a potential indicator of prognosis in patients with primary GC and merits further investigation.

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HER2-Positive Gastric Cancer: The Role of Immunotherapy and Novel Therapeutic Strategies

Cited by 11 publications

References 138 publications

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

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

Targeting HER2 in Gastroesophageal Adenocarcinoma: Molecular Features and Updates in Clinical Practice

Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer

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