Challenges and future of HER2-positive gastric cancer therapy

Ma, Chenzhe; Wang, Xiao; Guo, Jiwu; Yang, Bo; Li, Yumin

doi:10.3389/fonc.2023.1080990

Cited by 9 publications

(11 citation statements)

References 109 publications

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“…In patients with metastatic disease, baseline symptoms may play a greater role in determining OS. Studies have revealed that the prognosis is independent of HER2 expression 27 ; however, HER2+ disease is a predictor of response to anti-HER2 agents in metastatic setting and patients live longer. Other studies suggested that the presence of lung or bone metastases is an independent risk factor for decreased survival.…”

Section: Discussionmentioning

confidence: 99%

Integrating Patient-Reported Outcomes Into Prognostication in Gastroesophageal Cancer: Results of a Population-Based Retrospective Cohort Analysis

Baccili Cury Megid,

Sharma,

Baskurt

et al. 2024

The Oncologist

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Background Patient-reported outcomes measures (PROM) are self-reflections of an individual’s physical functioning and emotional well-being. The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated PRO tool of 10 common symptoms and a patient-reported functional status (PRFS) measure. The prognostic value of this tool is unknown in patients with gastroesophageal cancer (GEC). In this study, we examined the association between the ESAS score and overall survival (OS) in patients with GEC, the prognostication difference between ESAS and Eastern Cooperative Oncology Group (ECOG), and assessed the correlation between PRFS and the physician-reported ECOG performance status (PS). Methods The study was a retrospective cohort study of 211 patients with GEC with localized (stages I-III) and metastatic disease who completed at least one baseline ESAS prior to treatment. Patients were grouped into 3 cohorts based on ESAS score. OS was assessed using the Kaplan-Meier method, and the concordance index (c-index) was calculated for ESAS and physician-reported ECOG. The agreement between PRFS and physician-ECOG was also assessed. Results In total, 211 patients were included. The median age was 60.8 years; 90% of patients were ECOG PS 0-1; 38% of patients were stages I-III, while 62% were de novo metastatic patients. Median OS in low, moderate, high symptom burden (SB) patients’ cohorts was 19.17 m, 16.39 mm, and 12.68 m, respectively (P < .04). The ability to predict death was similar between physician-ECOG and ESAS (c-index 0.56 and 0.5753, respectively) and PRFS and physician-ECOG (c-index of 0.5615 and 0.5545, respectively). The PS agreement between patients and physicians was 50% with a weighted Kappa of 0.27 (95% CI: 0.17-0.38). Conclusion Patient’s SB seems to carry a prognostic significance. ESAS and physician-reported ECOG exhibit comparable prognostic values. Physicians and patients can frequently have divergent opinions on PS. ESAS takes a patient-centered approach and should be encouraged in practice among patients with GEC as an additional tool for prognostication.

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Section: Discussionmentioning

confidence: 99%

Integrating Patient-Reported Outcomes Into Prognostication in Gastroesophageal Cancer: Results of a Population-Based Retrospective Cohort Analysis

Baccili Cury Megid,

Sharma,

Baskurt

et al. 2024

The Oncologist

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“…Tyrosine kinase autophosphorylation and heterodimerization by the HER-2 receptor initiate signal transduction, which prompts downstream pathways, among which are the PI3K-AKT and Ras/MAPK pathways [22]. Upon activation, these pathways can lead to uncontrolled cell growth and tumor progression, as they regulate programmed cell death, proliferation, survival, and differentiation [22,23,27]. The evidence indicates that HER2 can hinder cell apoptosis and facilitate proliferation, making a significant contribution to the survival and aggressiveness of cancer cells but also the development of GC [28].…”

Section: Prevalence and Pathogenesis Of Her2 Overexpression In Gastri...mentioning

confidence: 99%

“…Determining the HER2 status of patients with GC is crucial for devising a treatment plan. There are several techniques to evaluate HER2 status, such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and chromogenic in situ hybridization (CISH) [27]. Considering its low cost and ease of implementation, IHC is the most frequently utilized approach for detecting HER2 overexpression in GC.…”

Section: Diagnosis Of Her2 Overexpression In Gastric Cancermentioning

confidence: 99%

A Clinical Viewpoint on the Use of Targeted Therapy in Advanced Gastric Cancer

Skórzewska,

Gęca,

Polkowski

2023

Cancers

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The development of therapies for advanced gastric cancer (GC) has made significant progress over the past few years. The identification of new molecules and molecular targets is expanding our understanding of the disease’s intricate nature. The end of the classical oncology era, which relied on well-studied chemotherapeutic agents, is giving rise to novel and unexplored challenges, which will cause a significant transformation of the current oncological knowledge in the next few years. The integration of established clinically effective regimens in additional studies will be crucial in managing these innovative aspects of GC. This study aims to present an in-depth and comprehensive review of the clinical advancements in targeted therapy and immunotherapy for advanced GC.

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“…HER2 overexpression occurs in roughly 7.3–20.2% of advanced GC [ 3 ]; and as a result, HER2 targeting has become pivotal in HER2-positive GC treatment. However, unlike the success of various HER2-targeted agents in treating metastatic breast cancer [ 4 , 5 ], only trastuzumab has been established to provide significant efficacy in HER2-positive GC patients, though trastuzumab resistance is increasingly common [ 6 ]. Thus, novel therapeutic strategies are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Elucidating molecular mechanisms and therapeutic synergy: irreversible HER2-TKI plus T-Dxd for enhanced anti-HER2 treatment of gastric cancer

Liu,

Zhu,

Zhao

et al. 2024

Gastric Cancer

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Background HER2-targeted therapies have improved the outcomes of HER2-positive gastric cancer (GC), yet resistance remains a challenge. We sought to explore the effects of reversible and irreversible HER2 tyrosine kinase inhibitors (TKIs) alone or in combination with the HER2-targeting antibody drug conjugate trastuzumab deruxtecan (T-Dxd). Methods The effects of HER2-TKIs on HER2 and downstream signaling were evaluated via Western blotting. Proteasomal inhibitors and co-immunoprecipitation assays were performed to explore the role of proteasomal degradation in HER2 expression modulation, and immunofluorescence assays were employed to explore mechanisms of HER2 internalization. The synergistic potential of the irreversible HER2-TKI pyrotinib in combination with T-Dxd was validated using growth and viability assays in anti-HER2-positive GC cell cultures and tumor growth and immunohistochemical staining assays in a mouse xenograft model. Results Our study revealed that reversible HER2-TKIs elevated HER2 protein levels, whereas irreversible HER2-TKIs decreased them. Pyrotinib triggered HER2 degradation within the proteasome by promoting ubiquitination and dissociation from HSP90. Furthermore, pyrotinib substantially induced HER2 internalization, which led to improved cellular uptake of T-Dxd. The increased T-Dxd uptake was accompanied by greater efficacy in suppressing the growth of GC cells and enhanced anti-tumor effects in an animal model. Conclusion In summary, our research reveals the molecular mechanisms of irreversible HER2-TKIs in regulating HER2 protein expression by promoting HER2 internalization. These findings advance our comprehension of targeted therapy for GC and provide a promising therapeutic combination strategy with enhanced efficacy against HER2-positive GC.

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Challenges and future of HER2-positive gastric cancer therapy

Cited by 9 publications

References 109 publications

Integrating Patient-Reported Outcomes Into Prognostication in Gastroesophageal Cancer: Results of a Population-Based Retrospective Cohort Analysis

Integrating Patient-Reported Outcomes Into Prognostication in Gastroesophageal Cancer: Results of a Population-Based Retrospective Cohort Analysis

A Clinical Viewpoint on the Use of Targeted Therapy in Advanced Gastric Cancer

Elucidating molecular mechanisms and therapeutic synergy: irreversible HER2-TKI plus T-Dxd for enhanced anti-HER2 treatment of gastric cancer

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