Advanced esophageal (EAC), gastroesophageal junction (GEJAC) and gastric (GAC) adenocarcinomas with HER2 amplification or overexpression (HER2+) are routinely treated with trastuzumab. However, it remains unclear if HER2+ is associated with superior overall survival (OS).

The cohort included recurrent or de novo metastatic GAC, GEJAC and EAC from Kaiser Permanente Northern California. We used Cox regression modelling to examine association between HER2+ and OS, adjusting for demographics, performance status, CCI, receipt of chemotherapy and p53 (mutp53), KRAS (mutKRAS), CDKN2A, PIK3CA co-mutations and MYC amplification.

Of 875 total eligible patients, 173 had EAC, 276 had GEJAC and 426 had GAC. HER2+ was associated with better OS among the full cohort (HR = 0.74, 95% CI [0.60-0.93]), among EAC (HR = 0.62; [95% CI, 0.40-0.96]) and GEJAC (HR = 0.59; [95% CI, 0.38-0.87]), but not among GAC (HR = 0.89; [95% CI, 0.59-1.35]) patients. GEJAC had better OS than EAC (HR = 0.68, [95% CI, 0.54-0.86]). Trastuzumab treatment was associated with better OS (HR = 0.40, 95% CI [0.21-0.77]). In addition, HER2+ was associated with better OS across the molecular subgroups except that of KRAS mutation (mutKRAS). Our data also show that GEJAC, EAC and GAC were differentially associated with mutp53, mutKRAS and MYC amplification.

HER2+ and treatment with trastuzumab in HER2+ patients were associated with superior OS in upper gastrointestinal adenocarcinomas across molecular subgroups except that of mutKRAS. These results reaffirm the importance of anti-HER2 treatment in HER2+ patients and provide insight on the prognostic and biological divergence among these anatomically linked upper gastrointestinal adenocarcinomas.

There is a need for novel therapies for patients with previously treated HER2-positive gastroesophageal adenocarcinoma (GEA). This phase 1 (NCT02892123) dose-escalation and expansion trial evaluated zanidatamab (a dual HER2-targeted bispecific antibody) ± chemotherapy in previously treated patients with HER2-expressing, locally advanced/metastatic cancers. Here, we report the outcomes for GEA cohorts receiving zanidatamab monotherapy or with chemotherapy (paclitaxel or capecitabine). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate, progression-free survival, pharmacokinetics, and immunogenicity. Seventy patients were enrolled (n = 29 monotherapy; n = 41 combination therapy); most received prior HER2-targeted agents (monotherapy, 93%; combination therapy, 95%). With monotherapy, 69% of patients had any-grade treatment-related AEs (TRAEs); 17% had grade ≥ 3 TRAEs. The most common any-grade TRAEs were diarrhea (41%) and infusion-related reactions (24%). With combination therapy, 98% of patients had any-grade TRAEs; 51% had grade ≥ 3 TRAEs. The most common any-grade TRAEs were diarrhea (68%) and fatigue (44%). Confirmed ORR was 32.1% (95% confidence interval [CI] 15.9-52.4) with monotherapy and 48.6% (95% CI 31.9-65.6) with combination therapy. In heavily pre-treated patients with HER2-expressing GEA, zanidatamab ± chemotherapy had a manageable safety profile and promising antitumor activity.

The formation of gastric precancerous lesions (GPLs) has been identified as a critical step in tumorigenesis, and patients with GPLs have an increased risk of gastric cancer (GC). Magnolol is the primary biphenolic compound in Magnolia officinalis. It possesses various pharmacological properties, such as cardio- and neuroprotective properties, and inhibits tumor growth. However, its therapeutic effects on GPL treatment and the related mechanisms have not yet been studied. To address this, the mechanisms by which magnolol affects GPLs were elucidated via protein-chemical interaction prediction analysis, molecular docking, molecular dynamics (MD) simulation, and experimental verification. GPL-related targets were obtained from the GeneCards database, whereas magnolol targets were obtained from the STITCH database. The two groups of targets were compared by constructing a Venn diagram, and potential key GPL-related targets of magnolol were identified. Next, the interactions between the active compounds of magnolol and various epithelial-mesenchymal transition (EMT)-related proteins were evaluated via molecular docking. The protein-compound complexes with the optimal binding affinity were analyzed via MD simulation. The efficacy of magnolol in the treatment of GPLs and the related mechanisms was further assessed using in vitro models. In this study, five core GPL-related targets of magnolol were identified. Molecular docking revealed that magnolol and ERBB2 had the strongest binding affinity, suggesting that ERBB2 is a potentially important target for the treatment of GPLs. Similarly, MD simulations revealed a strong affinity between magnolol and ERBB2. Overall, this study showed that magnolol can inhibit the malignant behavior of precancerous lesions in GC cells. Magnolol exerts its pharmacological effects by acting on multiple targets. ERBB2 might be a potential target of magnolol in GPL treatment.

Human epidermal growth factor receptor 2 (HER2) is an important therapeutic target in various types of cancer, although the prognostic value and therapeutic potential of HER2 in cervical adenocarcinoma are still underexplored. The present study aimed to examine the association between HER2 expression levels and prognosis in cervical adenocarcinoma, offering new insights into targeted therapies for HER2-expressing cervical adenocarcinoma. A total of 179 patients with cervical cancer who received surgery were included, and HER2 status in surgical specimens of the included patients were assessed using two classification methods: Immunohistochemistry (IHC) alone and traditional combined IHC/fluorescence in situ hybridization (FISH). IHC alone was used to categorize patients into the HER2 zero expression (IHC 0) and HER2 expression (IHC 1+, 2+ and 3+) groups, while traditional combined IHC/FISH classified the HER2 expression as negative (IHC 0 and 1+ or IHC 2+/FISH-) or positive (IHC 3+ or IHC 2+/FISH+). Kaplan-Meier survival analysis and log-rank tests were used to assess the patients' survival prognosis. A Cox proportional hazards regression model was used to identify independent prognostic factors. The HER2 expression rate was 44.1% (79/179) according to IHC alone, while 5.0% (9/179) were classified as HER2-positive according to the traditional method. HER2 expression was significantly associated with advanced International Federation of Gynecology and Obstetrics stages, higher rates of lymph node metastasis, vascular or perineural invasion, elevated cancer antigen 125 levels and increased recurrence rate (P<0.05). Moreover, HER2 expression was significantly associated with shorter progression-free survival (PFS) time [51.02±2.75 vs. 56.01±2.22 months; hazard ratio (HR), 0.559; 95% confidence interval (CI), 0.313-0.998; P=0.049]. Additionally, programmed death-ligand 1 expression levels were significantly higher in HER2-expressing patients who died (P=0.039). When HER2 status was assessed using the traditional combined IHC/FISH method, HER2 positivity was significantly associated with poorer PFS time (36.44±7.85 vs. 55.17±1.78 months; HR, 0.125; 95% CI, 0.03033-0.5156; P=0.004). In conclusion, classification of HER2 status in patients with cervical adenocarcinoma using IHC alone may provide a promising method for predicting patient outcomes and optimizing therapeutic strategies to improve treatment efficacy.

Advancements in the management of gastric cancer (GC) and innovative therapeutic approaches highlight the significance of the role of biomarkers in GC prognosis. Machine-learning (ML)-based methods can be applied to identify the most important predictors and unravel their interactions to classify patients, which might guide prioritized treatment decisions.

A total of 140 patients with histopathological confirmed GC who underwent surgery between 2011 and 2016 were enrolled in the study. The inspired modification of the partial least squares (SIMPLS)-based model was used to identify the most significant predictors and interactions between variables. Predictive partition analysis was employed to establish the decision tree model to prioritize markers for clinical use. ML models have also been developed to predict TNM stage and different subtypes of GC. Latent class analysis (LCA) and principal component analysis (PCA) were carried out to cluster the GC patients and to find a subgroup of survivors who tended to die.

The findings revealed that the SIMPLS method was able to predict the mortality of GC patients with high predictabilities (Q2 = 0.45-0.70). The analysis identified MMP-7, P53, Ki67, and vimentin as the top predictors. Correlation analysis revealed different patterns of prognostic markers in the non-survivor and survivor cohorts and different GC subtypes. The main prediction models were verified via other ML-based analyses, with a high area under the curve (AUC) (0.84-0.99), specificity (0.82-0.99) and sensitivity (0.87-0.99). Patients were classified into three clusters of mortality risk, which highlighted the most significant mortality predictors. Partition analysis prioritizes the most significant predictors P53 ≥ 6, COX-2 > 2, vimentin > 2, Ki67 ≥ 13 in mortality of patients (AUC = 0.85-0.90).

The present study highlights the importance of considering multiple variables and their interactions to predict the prognosis of mortality and stage in GC patients through ML-based techniques. These findings suggest that the incorporation of molecular biomarkers may enhance patient prognosis compared to relying solely on clinical factors. Furthermore, they demonstrate the potential for personalized medicine in GC treatment by identifying high-risk patients for early intervention and optimizing therapeutic strategies. The partition analysis technique offers a practical tool for identifying cutoffs and prioritizing markers for clinical application. Additionally, providing Clinical Decision Support systems with predictive tools can assist clinicians and pathologists in identifying aggressive cases, thereby improving patient outcomes while minimizing unnecessary treatments. Overall, this study contributes to the ongoing efforts to improve patient outcomes by advancing our comprehension of the intricate nature of GC.

The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.

Talin-1 (TLN1) is crucial in cell migration, metastasis, and cancer development. This study evaluated Talin-1 expression and its clinical significance in gastric cancer (GC), along with human epidermal growth factor receptor-2 (HER-2) expression and its correlation with Talin-1.

Bioinformatics analysis assessed the potential prognostic value of Talin-1 and HER-2 in GC patients. The study included 223 GC patients (Signet Ring Cells and Intestinal subtypes) and 29 non-malignant tissue samples. Immunohistochemistry (IHC) on tissue microarray slides evaluated Talin-1 and HER-2 expression and clinical significance. Receiver operating characteristic (ROC) curves assessed their diagnostic value.

Bioinformatics identified Talin-1 as a potential prognostic factor and HER-2 as an oncogene in GC. Talin-1 and HER-2 expression increased in SRC-type GC samples compared to non-malignant tissues. High cytoplasmic Talin-1 expression inversely correlated with tumor expansion and invasion in SRC-type GC. Increased HER-2 expression positively correlated with metastasis. ROC curves showed significant diagnostic values for both proteins.

Higher cytoplasmic Talin-1 expression is associated with less invasive tumor behavior, while increased membranous HER-2 expression is associated with metastasis in SRC-type GC. These findings suggest potential use in assessing diagnosis and screening high-risk cancer patients, particularly those with SRC-type GC.

Despite the remarkable improvement in gastric adenocarcinoma treatment modalities, the prognosis of gastric adenocarcinoma remains poor. The purpose of this study was to determine the prevalence of HER2 immunohistochemical expression and its association with clinicopathological features of patients with gastric adenocarcinoma.

This was a cross-sectional study which was conducted at the department of pathology. A total of 86 formalin fixed paraffin embedded tissue blocks of the patients who were confirmed histologically with gastric adenocarcinoma from January 2009 to December 2019 were included in the analysis. Laboratory requisition form and patients' files were used to extract the clinical and pathological data of the cases. Immunohistochemistry to assess HER2 overexpression was done using monoclonal (SP3 clone) rabbit anti-HER2/neu (Thermo Fisher Scientific-USA). Chi-square statistical test was used to determine the association of the clinicopathological characteristics with HER2 expression. P <0.05 was considered statistically significant.

Mean age of the patients included in the study was 58.5 ± 14.3 years, and over half 54.7% (n= 47) of the patients were males. Poorly cohesive non-signet ring types contributed most (47.7%) (n= 41) of the cases, and diffuse/mixed histological subtypes were more prevalent (57%) (n= 49) subtypes. Poorly differentiated cases accounted for the majority (66.3%) (n= 57) of the cases. The prevalence of HER2 immunohistochemical expression was 8.1% (n= 7). None of the clinicopathological characteristics were associated with HER2 expression.

This study has shown almost every one in 10 patients with gastric adenocarcinoma may express HER2 when using immunohistochemistry test. However, the HER2 in this study was not associated with age, sex, tumor location, the nature of biopsy, histological subtypes, and tumor grade.

Human epidermal growth factor receptor 2 (HER2) expression is one of the most important pathological characteristics of gastric cancer. The positive rate of HER2 expression in patients with gastric cancer is approximately 20%. The phase III Keynote-811 study revealed that anti-HER2 and anti-PD-1 therapy combined with chemotherapy could significantly improve the objective response rate as first-line treatment in patients with HER2-positive advanced gastric cancer. In the present study, we aimed to evaluate the efficacy of combination therapy with trastuzumab and PD-1 inhibitors in patients with advanced HER2-positive gastric cancer in a real-world setting. Seventy-two HER2-positive gastric cancer patients from three hospitals in China were retrospectively reviewed. These patients were treated with trastuzumab plus one anti-PD-1 agent with or without chemotherapy. The overall response rate, progression-free survival and overall survival were assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). From January 2018 to October 2021, 72 patients with HER2-positive gastric cancer received trastuzumab and a PD-1 inhibitor with or without chemotherapy as neoadjuvant chemotherapy, first-line therapy, second-line therapy or salvage therapy. The ORR was 54.2% for all patients and 79.4% for previously untreated patients. The median PFS and median OS were 10 months (95% CI: 8-13 months) and 26.1 months (95% CI: 18.5-NA months), respectively, for all patients. Grade 3 adverse effects occurred in approximately 25% of patients. Immune-related adverse effects occurred in approximately 12.5% of patients. Trastuzumab and PD-1 inhibitor combination therapy with or without chemotherapy achieved satisfactory survival outcomes in patients with HER2-positive gastric cancer with acceptable safety.

HER2 receptors, overexpressed in certain human cancers, have drawn significant attention in cancer research due to their correlation with poor survival rates. Researchers have developed monoclonal antibodies like Trastuzumab and Pertuzumab against HER2 receptors, which have proven highly beneficial in cancer therapy. Bispecific antibodies like Zanidatamab and antibody-drug conjugates like T-DM1 have been developed to overcome the resistance associated with monotherapy. Small molecules such as Lapatinib, Neratinib, and Pyrotinib were initially developed for treating breast cancer. However, ongoing research is investigating their potential use in other types of cancer, often in combination with other medications. EGFR/HER2 dual-targeted drugs have overcome drug resistance associated with HER2-targeted monotherapy. This comprehensive review covers the structural characteristics of HER2, the HER family signaling pathway mechanism, recent findings regarding HER2 receptor involvement in various cancers, and diverse HER2-targeted therapies. This information provides a comprehensive understanding of HER2-targeted strategies in the evolving field of cancer treatment.

Antibody-drug conjugates (ADCs) represent a crucial component of targeted therapies in gastric cancer, potentially altering traditional treatment paradigms. Many ADCs have entered rigorous clinical trials based on biological theories and preclinical experiments. Modality trials have also been conducted in combination with monoclonal antibody therapies, chemotherapies, immunotherapies, and other treatments to enhance the efficacy of drug coordination effects. However, ADCs exhibit limitations in treating gastric cancer, including resistance triggered by their structure or other factors. Ongoing intensive researches and preclinical experiments are yielding improvements, while enhancements in drug development processes and concomitant diagnostics during the therapeutic period actively boost ADC efficacy. The optimal treatment strategy for gastric cancer patients is continually evolving. This review summarizes the clinical progress of ADCs in treating gastric cancer, analyzes the mechanisms of ADC combination therapies, discusses resistance patterns, and offers a promising outlook for future applications in ADC drug development and companion diagnostics.

The receptor tyrosine-kinase HER2 (also known as ErbB2) is a well-established therapeutic target in patients with breast or gastric cancer selected on the basis of HER2 overexpression on immunohistochemistry and/or ERBB2 amplification on in situ hybridization. With advances in cancer molecular profiling and increased implementation of precision medicine approaches into oncology practice, actionable HER2 alterations in solid tumours have expanded to include ERBB2 mutations in addition to traditional HER2 overexpression and ERBB2 amplification. These various HER2 alterations can be found in solid tumour types beyond breast and gastric cancer, although few HER2-targeted therapeutic options have been established for the other tumour types. Nevertheless, during the 5 years since our previous Review on this topic was published in this journal, obvious and fruitful progress in the development of HER2-targeted therapies has been made, including new disease indications, innovative drugs with diverse mechanisms of action and novel frameworks for approval by regulatory authorities. These advances have culminated in the recent histology-agnostic approval of the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan for patients with HER2-overexpressing solid tumours. In this new Review, we provide an update on the current development landscape of HER2-targeted therapies beyond breast cancer, as well as anticipated future HER2-directed treatment strategies to overcome resistance and thereby improve efficacy and patient outcomes.

Immune checkpoint inhibitors (ICIs) are used as salvage treatments for advanced gastric cancer (AGC) regardless of HER2 status. This study assessed the efficacy of ICIs based on HER2 expression in AGC patients who received pembrolizumab as salvage monotherapy at Samsung Medical Center from November 2017 to March 2023. HER2 status was determined via immunohistochemistry, and tumor response and survival outcomes were compared accordingly. Among the 113 patients analyzed, with a median age of 61 years and 64.6% being male, 12 patients (10.6%) were HER2-positive, and 101 patients (89.4%) were HER2-negative. Of 92 evaluable patients, none had a complete response. However, 50% of HER2-positive patients had a partial response, compared to 4.9% of HER2-negative patients (p < 0.001). The disease control rate was 70% in HER2-positive and 37.8% in HER2-negative patients (p = 0.086). Median progression-free survival was 5.53 months for HER2-positive patients versus 1.81 months for HER2-negative patients (p = 0.037). Pembrolizumab as a salvage chemotherapy for the treatment of AGC demonstrated superior effectiveness in HER2-positive patients compared with HER2-negative patients.

This review critically evaluates the evolution and current status of human epidermal growth factor receptor 2 (HER2)-directed therapies in upper gastrointestinal (GI) malignancies, a timely and relevant inquiry given the dynamic shifts in therapeutic strategies over the past decade. Initial enthusiasm following the Trastuzumab for Gastric Cancer (ToGA) study's demonstration of trastuzumab's efficacy, however, encountered hurdles due to subsequent trials showing limited progress, underscoring the necessity for a reevaluation of therapeutic approaches and the exploration of novel agents.

The review highlights significant breakthroughs in the form of immune checkpoint inhibitors and innovative therapeutic technologies, which have redefined treatment paradigms and shown promising efficacy in HER2-positive cases. Emerging treatments such as trastuzumab deruxtecan (T-DXd), zanidatamab and evorpacept further illustrate the ongoing efforts to leverage unique mechanisms of action for improved HER2-positive antitumor activity.

The advancements in HER2-directed therapies underscore a pivotal era in the management of upper GI malignancies. These developments not only reflect the profound impact of integrating novel therapeutic combinations but also highlight the critical role of ongoing research in overcoming resistance mechanisms and tailoring treatment to individual disease profiles.

The development of trastuzumab is among the most significant cancer drug development projects in the 20th century. Trastuzumab became a gamechanger for the treatment of human epidermal growth receptor 2 (HER2) positive breast cancer, with a significant positive impact on disease recurrence and survival. The development of trastuzumab was the beginning of a new era of cancer drug development, which showed us the importance of understanding the molecular pathophysiology and drug mechanism of action. The drug-diagnostic codevelopment model, in which the drug is developed in parallel with a predictive biomarker assay, has had a significant impact on today's cancer drug development, and we are indebted to trastuzumab when it comes to the clinical enrichment trial design. Trastuzumab is not the only drug developed to target the HER2 protein. Over the past few decades, several new HER2 targeted therapies have been developed, including small-molecule tyrosine kinase inhibitors (TKI), monoclonal antibodies, and antibody-drug conjugates (ADC). In particular, the ADC trastuzumab deruxtecan seems to pave new avenues when it comes to HER2 targeted treatment not only for breast cancer, but also for gastric cancer and non-small cell lung cancer. With the development of trastuzumab as a reference point, this article will provide a brief summary of the efficacy of HER2 targeted therapy, including testing for HER2 positivity, as it has evolved over the past 25 years.

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.

As a result of the high approval dynamics and the growing number of immuno-oncological therapy concepts, the complexity of therapy decisions and control in the area of carcinomas of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD‑1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.

Disitamab Vedotin is a novel antibody-drug conjugate (ADC) drug targeting HER2, which has shown a potential synergistic effect between Disitamab Vedotin and immune checkpoint inhibitors (ICIs). Therefore, we plan to conduct a retrospective real-world study to evaluate the efficacy and safety of Disitamab Vedotin monotherapy or combined with ICIs in the treatment of advanced or metastatic solid tumors.

This retrospective study involved patients with locally advanced or metastatic solid tumors who were treated with Disitamab Vedotin monotherapy or combined with ICIs at West China Hospital of Sichuan University from July 2019 to June 2023. The observation items included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs).

This study included 49 patients, out of which 34 patients were treated with Disitamab Vedotin plus ICIs and 15 patients received Disitamab Vedotin alone. In all patients, the median PFS was 10 months. The 6-month and 1-year OS rates were 91.1% and 82.3%, respectively. Eighteen (36.7%) patients achieved a partial response, and sixteen (32.7%) patients had stable disease. The combination therapy of Disitamab Vedotin plus ICIs showed a higher ORR (44.1% vs. 20.0%) and a longer median PFS (14 vs. 8 months) compared to Disitamab Vedotin alone. The median PFS for patients expressed with HER2 2+/3+ was 10 months and was not reached for patients expressed with HER2 0/1+. Grade 3-4 TRAEs occurred in 14.7% of patients who received the combination treatment and in 26.7% of patients who received Disitamab Vedotin alone.

Our study showed that Disitamab-Vedotin-based treatment, alone or in combination with ICIs, exerted considerable prognosis and good tolerance in patients with locally advanced or metastatic solid tumors, regardless of the HER2 expression levels. Whether combination therapy with ICIs provides greater therapeutic benefits compared to monotherapy needs to be further explored through randomized controlled trials.

As a result of the high approval dynamics and the growing number of immuno-oncological concepts, the complexity of treatment decisions and control in the area of cancers of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD-1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.

Introduction Advanced gastric cancer (GC) has a very poor prognosis, and chemotherapy has been the standard of care. The use of immunotherapy or targeted therapy in the stage 4 setting is dependent on molecular testing of the tumour. There is a paucity of data in the Indian scenario on testing for molecular markers in stage 4 GC. Therefore, in this study, we looked at the prevalence of human epidermal growth factor receptor 2 (HER2/neu) expression/amplification, deficient mismatch repair (d-MMR)/microsatellite instability (MSI) high status, and programmed death ligand 1 (PDL-1) status in stage 4 gastric/gastroesophageal junction (GEJ) adenocarcinoma. Methods A retrospective single-centre observational study was conducted between January 2017 and January 2022 of patients diagnosed with stage 4 GC/GEJ adenocarcinoma. Patient data were collected from stored electronic patient records. Data on stage 4 patients who underwent testing for HER2/neu, mismatch repair (MMR)/MSI, and PDL-1 status were recorded. Treatment received was also noted. Results During the study period, 139 patients were diagnosed with stage 4 GC/GEJ adenocarcinoma. HER2/neu testing was done in 99 stage 4 patients (71.2%), with a positivity rate of 16.16% (n = 16). All patients diagnosed as HER2/neu-positive were treated with trastuzumab. Testing of MMR status was carried out in 91 stage 4 patients (65.4%). d-MMR/MSI high was detected in eight patients (8.8%), of which germline MMR was detected as positive in one patient. Five of these eight patients (62.5%) received immune checkpoint inhibitors. PDL-1 testing was done in 61 of the 139 stage 4 patients (43.9%). Twenty patients (32.7%) had PDL-1 tumour proportion score > 1%/combined positive score > 1. Conclusion Molecular profiling has now become the standard while treating late-stage GC. HER2/neu-positive patients have improved survival due to the use of anti-HER2/neu-targeted therapies. It is important to look at not only PDL-1 but also MMR to identify patients who would be eligible and benefit from immunotherapy.

Gastric cancer is the fifth most common malignancy worldwide and one of the main causes of cancer-related death. While surgical treatment is the only curative option for early disease, many have inoperable or advanced disease at diagnosis. Treatment in this case would be a combination of chemotherapy and immunotherapy. Gastro-esophageal (GEJ) and gastric cancer (GC) genetic profiling with current molecular diagnostic techniques has significantly changed the therapeutic landscape in advanced cancers. The identification of key players in GEJ and GC survival and proliferation, such as human epidermal growth factor 2 (HER2), vascular endothelial growth factor (VEGF), and programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1), has allowed for the individualization of advanced cancer treatment and significant improvement in overall survival and progression-free survival of patients. This review comprehensively examines the current and emerging role of monoclonal antibody-based first-line treatments in advanced GEJ and GC. We explore the impact of monoclonal antibodies targeting HER2, VEGF, PD-1/PD-L1, and Claudin 18.2 (CLDN18.2) on the first-line treatment landscape by talking about key clinical trials. This review emphasizes the importance of biomarker testing for optimal treatment selection and provides practical recommendations based on ASCO guidelines.

PF-06804103 is an anti-HER2 antibody-drug conjugate with auristatin payload. We evaluated its safety, tolerability, and antitumor activity in patients with advanced/unresectable or metastatic breast and gastric cancers. This multicenter, open-label, first-in-human, phase 1 study (NCT03284723) comprised dose escalation (P1) and dose expansion (P2). In P1, adults with HER2+ breast or gastric cancer received PF-06804103 0.15-5.0 mg/kg intravenously once/21 days (Q3W); in P2, patients with HER2+ or HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer received 3.0 or 4.0 mg/kg Q3W. The primary endpoints were dose-limiting toxicities (DLT) and safety (P1), and objective response rate (ORR) assessed using RECIST v1.1 (P2). Ninety-three patients enrolled in P1 (n = 47: HER2+ gastric cancer = 22, HER2+ breast cancer = 25) and P2 [n = 46: HER2+ breast cancer = 19, hormone receptor (HR)+ HER2-low breast cancer = 27] received PF-06804103. Four patients (3.0- and 4.0-mg/kg groups, n = 2 each) had DLTs (mostly Grade 3). Safety and efficacy results showed a dose-response relationship. Adverse events (AE) leading to treatment discontinuation (44/93, 47.3%) included neuropathy (11/93, 11.8%), skin toxicity (9/93, 9.7%), myalgia (5/93, 5.4%), keratitis (3/93, 3.2%), and arthralgia (2/93, 2.2%). Two (2/79, 2.5%) patients (P1, 4.0- and 5.0-mg/kg groups, n = 1 each) achieved complete response; 21 (21/79, 26.6%) achieved partial response. In P2, ORR was higher in HER2+ compared with HR+ HER2-low breast cancer [3.0 mg/kg: 16.7% (2/12) vs. 10.0% (1/10); 4.0 mg/kg: 47.4% (9/19) vs. 27.3% (3/11)]. PF-06804103 demonstrated antitumor activity; however, AEs led to discontinuation in 47.3% of patients. Safety and efficacy were dose-dependent.

Trastuzumab is the only approved target agent for the first-line treatment of human epidermal growth factor receptor-2 (HER-2) positive gastric cancer; however, trastuzumab resistance is a major problem in clinical practice. To comprehend the mechanism of trastuzumab resistance, we focused on the Wnt/β-catenin signaling pathway and its influence on the phenotypes and behavior of trastuzumab-resistant gastric cancer cells.

Trastuzumab-resistant NCI-N87R cells were established in vitro from the human gastric cancer cell line NCI-N87 by dose-escalating repeated trastuzumab treatment. We investigated the phenotypes of NCI-N87R cells, including Wnt signaling pathway activity. Gastric cancer organoid cells were incubated with complete medium and Wnt3a-depletion medium, and their resistance to trastuzumab was compared.

NCI-N87R exhibited stemness and epithelial-mesenchymal transition (EMT)-like phenotypes, along with decreased levels of the epithelial marker E-cadherin and increased levels of the mesenchymal markers Vimentin and Snail along with an increased Wnt signaling pathway activity. When gastric cancer cells were incubated in Wnt3a-conditioned medium. Wnt signaling pathway activity and resistance to trastuzumab increased. Gastric cancer patient-derived organoids incubated in Wnt3a-depletion medium were more susceptible to dose-dependent inhibition of cell viability by trastuzumab than those incubated in complete medium.

Trastuzumab-resistant gastric cancer cells exhibited EMT-like phenotype, and trastuzumab resistance was promoted by the Wnt/β-catenin signaling pathway. The Wnt/β-catenin pathway is a key signaling pathway for trastuzumab resistance in gastric cancer cells.

Many modern anticancer drugs are designed to target specific molecular alterations harbored by the cancer. If a specific drug is able to target these alterations, regardless of the organ or tissue in which the cancer originates, it will often be characterized as a tissue- or tumor agnostic drug. According to the Food and Drug Administration (FDA), a tissue-agnostic drug refers to a drug that targets a specific molecular alteration across multiple cancer types, as defined by organ, tissue, or tumor type.

Over the last 6 years, the FDA has approved seven tissue-agnostic drugs, and more are anticipated in the future. One promising candidate for a tissue-agnostic classification is the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). Currently, T-DXd is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive and HER2-low breast cancer, HER2-positive gastric or gastroesophageal junction adenocarcinoma, and non-small cell lung cancer with activating HER2 mutations. Ongoing clinical research is exploring the potential of T-DXd in various solid tumors that harbor specific HER2 molecular alterations, and encouraging results, including the interim data from the DESTINY-PanTumor02 trial, have been published, which suggest a tissue-agnostic potential.

Published phase I data as well as the interim results from the phase II DESTINY-PanTumor02 trial indicates that patients with different HER2-positive advanced solid tumors may benefit from treatment with T-DXd. Based on the currently available data, it seems likely that T-DXd possesses pantumor activity. However, different clinical trials are ongoing, and it will be necessary to see the results from these trials before drawing a final conclusion. When discussing tissue-agnostic potential, it is important to add that for most of the patients enrolled in the DESTINY-PanTumor02 and other trials, few treatment alternatives seem to exist, and T-DXd might be able to cover an unmet medical need.

Gastric cancer is a highly prevalent and lethal disease worldwide. Given the insidious nature of the presenting symptoms, patients are frequently diagnosed with advanced, unresectable disease. However, many patients will present with locally advanced gastric cancer (LAGC), which is often defined as the primary tumor extending beyond the muscularis propria (cT3-T4) or having nodal metastases (cN+) disease and without distant metastases (cM0). LAGC is typically treated with surgical resection and perioperative chemotherapy. The treatment of LAGC remains a challenge, given the heterogeneity of this disease, and the optimal multimodal treatment regimen may be different for different LAGC subtypes. However, many promising treatments are on the horizon based on knowledge of molecular subtypes and key biomarkers of LAGC, such as microsatellite instability, HER2, Claudin 18.2, FGFR2, and PD-L1. This review will expand upon the discussion of current standard neoadjuvant and adjuvant therapies for LAGC and explore the ongoing and future clinical trials for novel therapies, with information obtained from searches in PubMed and ClinicalTrials.gov.

Gastric cancer is an aggressive disease with increasing global incidence in recent years. Human epidermal growth receptor 2 (HER2) is overexpressed in approximately 10-20% of gastric cancers. The implementation of targeted therapy against HER2 as part of the standard of care treatment in metastatic disease has improved the prognosis of this subset of patients. However, gastric cancer still has high mortality rates and urgently requires new treatment strategies. The combination of immunotherapy with HER2-targeted therapies has shown synergistic effects in preclinical models, this being the rationale behind exploring this combination in clinical trials in locally advanced and metastatic settings. Additionally, the irruption of antibody-drug conjugates and other novel HER2-targeted agents has led to the development of numerous clinical trials showing promising results. This review presents the molecular mechanisms supporting the use of HER2-targeted drugs in combination with immunotherapy and provides an overview of the therapeutic scenario of HER2-positive disease. We focus on the role of immunotherapy but also summarize emerging therapies and combinations under clinical research that may change the standard treatment in HER-2 positive disease in the future.

As the most common type of human papillomavirus-independent endocervical adenocarcinomas (ECAs), gastric-type endocervical adenocarcinomas (GEAs) account for approximately 10% of all ECAs. Although anti-HER2 therapy has been proven effective in many cancers, it has not been used in ECAs, including GEAs, which is at least partly due to the lack of a well-defined guideline. Limited available data regarding HER2 in GEAs and ECAs have considerable variations likely caused by variations in the tumor type selection, testing methods, and scoring criteria. Here, we selected 58 GEA cases to examine the HER2 status using immunohistochemistry and fluorescent in situ hybridization and investigate the prognostic value and their association with other known or potential prognostic factors. When strong complete or lateral/basolateral membranous reactivity in ≥10% tumor cells was used to define HER2 positivity, relatively high prevalence of HER2 overexpression (10/58[17.2%]) and amplification (9/58 [15.5%]), as well as high immunohistochemistry-fluorescent in situ hybridization concordance rate (9/10 [90%]) was found in GEAs. A lateral/basolateral staining pattern ("U-shaped") was observed, at least focally, in most of HER2-positive (3+) and equivocal (2+) tumors. Notably, considerable heterogeneity of HER2 expression was observed in HER2 positive and equivocal cases (80.0% and 83.3%, respectively). HER2 overexpression and amplification were associated with worse progression-free survival (P = .047 and P = .032, respectively). Programmed death-ligand 1 expression was associated with worse progression-free survival (P = .032), whereas mutant-type p53 demonstrated no prognostic significance. Our work laid a solid foundation for the eventual development of a future standard HER2 testing guideline for GEAs.

This study was conducted to evaluate the frequency and clinicopathologic correlates of human epidermal growth factor receptor 2 (HER-2)/neu and betacatenin (BC) oncoproteins in gastric adenocarcinoma and to seek correlation if any between their expression status.

This cross-sectional analytical immunohistochemistry (IHC) study was performed on 50 cases of gastric adenocarcinoma. HER-2/neu immunoexpression was scored as per criteria by Ruschoff et al. as positive (3+), equivocal (2+), and negative (1+, 0). Aberrant BC expression was categorized as nuclear, cytoplasmic, and reduced membranous immunoexpression. Protein expression results of both oncoproteins were correlated with conventional clinicopathological parameters. Correlation between immunoexpression profiles of both proteins was also analyzed. P <0.05 was considered statistically significant.

HER-2/neu positivity (2 + and 3+) was seen in 94% of the cases; almost 60% had strong (3+) expression. All cases showed aberrant BC immunoexpression (any pattern) except 2 cases that revealed negative expression (a form of aberrant immunoexpression) and were removed from analysis due to a very small number. The pattern of BC expression was as follows: nuclear expression (38%), cytoplasmic expression (82%), reduced membranous expression (96%), no staining (4%) cases. HER-2/neu expression correlated with age. No significant correlation was found between any of the 2 oncoprotein immunoexpression and other clinicopathological parameters (P > 0.05). Concordance between protein expression of HER-2/neu and BC was seen in >93% cases, however, the correlation was not significant.

HER-2/neu and BC oncoprotein expression are frequently dysregulated in gastric adenocarcinomas. The significance of pathways involving HER-2/neu and BC in gastric carcinogenesis should be explored.

Positive human epidermal growth factor 2 (HER2) expression and its predictive clinicopathological features remain unclear in Sri Lankan gastric cancer (GC) patients. Here, we aimed to determine GC HER2 status predictors by analyzing associations between clinicopathological features and HER2 expression using immunohistochemistry (IHC) and silver in situ hybridization (SISH).

During this 4-year prospective study, clinicopathological data were collected from participants in the National Hospital of Sri Lanka. HER2 IHC and SISH were performed using commercial reagents. Using chi-square tests, associations of HER2-IHC/SISH with clinicopathological features were analyzed.

Overall, 145 GC patients were included, 69 had gastrectomies and 76 had biopsies. Positive HER2 expression by IHC was associated with age <60 years, high T stage (assessed pathologically in resections and radiologically in biopsies), high nuclear grade, tumor necrosis, mitosis >5/high-power field, with additional perineural invasion and lymphovascular invasion in resections. These features, excluding lymphovascular invasion but including male sex, were associated with HER2 expression by SISH.

Age <60 years, high nuclear grade, tumor necrosis, and perineural invasion are associated factors of HER2 status. These could be used to triage GC patients for HER2 status testing in limited resource settings where IHC/SISH analysis is costly.

Gastric cancer is the fifth most common cancer worldwide, and the treatment of advanced gastric cancer has relatively little progress. With the continuous development of molecularly targeted therapy for tumors, it has been discovered that human epidermal growth factor receptor 2 (HER2) contributes to the poor prognosis and pathogenesis of various cancers. In order to treat HER2-positive advanced gastric cancer, Trastuzumab has emerged as the first first-line targeted medication used in conjunction with chemotherapy. The consequent trastuzumab resistance has become an important issue, and various new HER2-targeted gastric cancer drugs are emerging to address this challenge. This review's primary concern is the drug mechanism of various HER2-positive gastric cancer targeted therapy and fresh techniques of detection.

HER2 overexpression or amplification, which is present in 15% of all cases of biliary tract cancer, has been identified as a druggable molecular target by genomic profiling. In the phase 3 ABC-06 trial, the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen showed a survival benefit compared with active symptom control as second-line therapy for biliary tract cancer. We aimed to evaluate the clinical activity of FOLFOX plus anti-HER2 antibody trastuzumab as a second-line or third-line treatment for HER2-positive biliary tract cancer.

This study was an investigator-initiated, open-label, non-randomised, single-arm, multi institutional, phase 2 trial in participants aged 19 years or older with HER2-positive (defined as immunohistochemistry 3+ or immunohistochemistry 2+ and in-situ hybridisation positive or ERBB2 gene copy number ≥6·0 by next-generation sequencing) biliary tract cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer) who progressed on chemotherapy containing gemcitabine and cisplatin (with one or two previous chemotherapy lines permitted). In cycle one, patients received intravenous trastuzumab-pkrb at 6 mg/kg on day 1, and FOLFOX (consisting of intravenous oxaliplatin [85 mg/m²], intravenous leucovorin [200 mg/m²], and fluorouracil [400 mg/m² bolus] all on day 1, and fluorouracil [2400 mg/m² infusion] on days 1-2. In cycle two onwards, participants were administered intravenous trastuzumab-pkrb at 4 mg/kg and FOLFOX, every 2 weeks, until unacceptable toxic effects or disease progression. The primary endpoint of the study was objective response rate based on RECIST version 1.1, assessed in the participants who completed at least one study cycle. The response rate threshold for a positive objective response rate was 25%. This trial is registered with ClinicalTrials.gov (NCT04722133) and is ongoing.

34 participants were enrolled between June 26, 2020, and Sept 1, 2021. At the time of data cutoff on May 1, 2022, median follow-up was 13·0 months (IQR 11·0-16·9), with three participants remaining on treatment. Ten patients had a partial response and 17 had stable disease; the overall response rate was 29·4% (95% CI 16·7-46·3) and the disease control rate was 79·4% (95% CI 62·9-89·9). Median progression-free survival was 5·1 months (95% CI 3·6-6·7); median overall survival was 10·7 (95%CI 7·9-not reached). The most common treatment-related grade 3 or 4 adverse events were neutropenia (ten [29%] participants with grade 3 and nine [26%] with grade 4), grade 3 anaemia (five [15%] participants), and grade 3 peripheral sensory neuropathy (four [12%] participants). There were no treatment-related cardiac toxic effects or deaths. The overall health assessment (EuroQoL-VAS) score did not change significantly throughout the treatment. Sensory and motor neuropathy symptoms as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy twenty-item scale questionnaire did not change significantly over time.

For HER2-positive biliary tract cancer, second-line or third-line trastuzumab biosimilar plus FOLFOX exhibited promising activity with acceptable toxicity, warranting further investigation.

Boryung Pharmaceutical, Celltrion, National Research Foundation of Korea, National R&D Program for Cancer Control through the National Cancer Center, Yonsei University College of Medicine.

The incidence of intracranial metastatic disease (IMD) in patients with gastrointestinal (GI) cancers is rising. Expression of the erythroblastic oncogene B-2 (ERBB2) is associated with an in increased risk of IMD in patients with breast cancer. The implications of ERBB2 expression for IMD risk in patients with GI cancers is less clear. The objective of this systematic review was to determine the incidence of IMD and OS in patients with ERBB2+ gastrointestinal cancers.

A literature search of MEDLINE, EMBASE, CENTRAL, and grey literature sources was conducted from date of database inception to July 2021. Included studies reported outcomes on patients with IMD secondary to ERBB2 GI cancers.

Fourteen cohort studies met inclusion criteria, of which thirteen were retrospective. Eleven studies reported on gastric, esophageal, or gastroesophageal junction cancers. Three studies directly compared incidence of IMD based on ERBB2 status and among these, ERBB2+ patients had a higher incidence of IMD. One study indicated that ERBB2+ patients had significantly longer OS from the times of primary cancer (P = .015) and IMD diagnosis (P = .01), compared with patients with ERBB2- disease.

In this systematic review, patients with ERBB2+ GI cancer were more likely to develop IMD. Future study is required on the prognostic and predictive value of ERBB2 status in patients with GI cancers.

Accurate evaluation of human epidermal growth factor receptor 2 (HER2) status is very important for appropriate management of advanced gastric cancer (AGC) patients. In this study, we aimed to develop and validate a computed tomography (CT)-based radiomics signature for preoperative prediction of HER2 overexpression and treatment efficacy of trastuzumab in AGC.

We retrospectively enrolled 536 consecutive AGC patients (median age, 59 years; interquartile range, 52-65 years; 377 male, 159 female) and separated them into a training set (n=357) and a testing set (n=179). Radiomic features were extracted from 3 different phase images of contrast-enhanced CT scans, and a radiomics signature was built based on highly reproducible features using the least absolute shrinkage and selection operator (LASSO) method. The predictive performance of the radiomics signature was assessed in the training and testing sets. Univariable and multivariable logistical regression analyses were used to identify independent risk factors of HER2 overexpression. Univariable and multivariable Cox regression analyses were used to identify the risk factors of overall survival (OS) and progression-free survival (PFS). The predictive value of the radiomics signature for treatment efficacy of trastuzumab was also evaluated.

The radiomics signature comprised eight robust features that demonstrated good discrimination ability for HER2 overexpression in the training set [area under the curve (AUC) =0.85] and the testing set (AUC =0.81). Multivariable Cox regression analysis revealed that the radiomics signature was an independent risk factor for OS [hazard ratio (HR) =2.01, P=0.001] and PFS (HR =1.32, P=0.01). The radiomics score of patients who achieved disease control was significantly lower than that of patients with progressive disease (P=0.023).

The proposed radiomics signature showed favorable accuracy for prediction of HER2 overexpression and prognosis in AGC. It has promising potential as a noninvasive approach for selecting patients for target therapy.

The incidence of human epidermal growth factor receptor 2 (HER2) positivity in gastric cancers differs widely across various populations and is unknown in many low-resource settings.

To evaluate the rates of HER2 positivity in gastric and gastroesophageal adenocarcinoma at a national referral hospital in East Africa. We also assessed the association between HER2 overexpression and patient clinicopathologic characteristics.

A retrospective review of cases diagnosed as either gastric or gastroesophageal adenocarcinoma between 2013 and 2017 was performed at Muhimbili National Hospital in Dar es Salaam, Tanzania. Of 1205 specimens meeting inclusion criteria, stratified random sampling was conducted to select 150 cases for HER2 immunohistochemistry and clinicopathologic analysis.

The median age of patients was 56.5 years, with 65.3% (98 of 150) of the cohort composed of male patients, and 34.7% (52 of 150) of female patients. HER2 overexpression was identified in 6.0% (9 of 150) of cases. Approximately half of the tumors (51.3%; 77 of 150) were intestinal-type gastric adenocarcinoma, and 36.0% (54 of 150) were moderately differentiated. Intestinal-type (P = .01) and well-differentiated tumors (P = .001) were associated with HER2 overexpression.

HER2 overexpression was primarily seen in intestinal-type and well-differentiated tumors. Therefore, prioritizing HER2 testing for patients with intestinal-type, well-differentiated, or moderately differentiated gastric and gastroesophageal adenocarcinomas may be appropriate in Tanzania in efforts to allocate testing for patients who are most likely to benefit from trastuzumab therapy.

Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.

Gastric cancer (GC) is one of the most common lethal malignant neoplasms worldwide, with limited treatment options for both locally advanced and/or metastatic conditions, resulting in a dismal prognosis. Although the widely used morphological classifications may be helpful for endoscopic or surgical treatment choices, they are still insufficient to guide precise and/or personalized therapy for individual patients. Recent advances in genomic technology and high-throughput analysis may improve the understanding of molecular pathways associated with GC pathogenesis and aid in the classification of GC at the molecular level. Advances in next-generation sequencing have enabled the identification of several genetic alterations through single experiments. Thus, understanding the driver alterations involved in gastric carcinogenesis has become increasingly important because it can aid in the discovery of potential biomarkers and therapeutic targets. In this article, we review the molecular classifications of GC, focusing on The Cancer Genome Atlas (TCGA) classification. We further describe the currently available biomarker-targeted therapies and potential biomarker-guided therapies. This review will help clinicians by providing an inclusive understanding of the molecular pathology of GC and may assist in selecting the best treatment approaches for patients with GC.

This is a review of the current state of molecular profiling in gastrointestinal (GI) cancers and what to expect from this evolving field in the future. Individualized medicine is moving from broad panel testing of numerous genes or gene products in tumor biopsy samples, identifying biomarkers of prognosis and treatment response, to relatively noninvasive liquid biopsy assays, building on what we have learned in our tumor analysis and growing into its own evolving predictive and prognostic subspecialty. Hence, the field of GI precision oncology is exploding, and this review endeavors to summarize where we are now in preparation for the journey ahead.

Gastric cancer is one of the most common malignancy worldwide with a prognosis less than 1 year in unresectable or metastatic disease. HER2 expression is the main biomarker to lead the addition of trastuzumab to first line systemic chemotherapy improving the overall survival in advanced HER2-positivegastric adenocarcinoma. The inevitable development of resistance to trastuzumab remains a great problem inasmuch several treatment strategies that have proven effective in breast cancer failed to show clinical benefit in advanced gastric cancer. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance toHER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Further, we describe the prognostic value of new non-invasive screening techniques, the current development of novel agents such us HER2 antibody-drug conjugates and bispecific antibodies, and the strategies with antitumor activity on going.

Studies have confirmed the prognostic value of the expression status of human epidermal growth factor receptor 2 (HER2) in advanced gastric cancer. However, its role in early gastric cancer (EGC) remains largely unknown. This study explored the association between HER2 overexpression and clinical outcomes of patients with EGC.

A total of 211 patients who had undergone endoscopic treatment for pN0 EGC were enrolled. The HER2 expression status was assessed using immunohistochemistry (IHC).

The prevalence of HER2 overexpression was 14.2%. HER2 overexpression showed a significant correlation with tumor location (P = 0.033). Multivariate analysis showed that HER2 overexpression was significantly associated with an increased risk of tumor recurrence in pN0 EGC (hazard ratio [HR] = 3.97; 95% confidence interval [CI] 1.30-12.14; P = 0.016) but not overall survival (OS) or disease-specific survival (DSS). Of the included patients, age was associated with OS (HR = 1.11; 95% CI 1.04-1.18; P = 0.002], whereas lymphovascular invasion was significantly associated with poor DSS (HR = 33.66; 95% CI 3.05-371.25; P = 0.004).

This study shows that HER2 overexpression is significantly associated with tumor recurrence in pN0 EGC. Hence, Her2 testing at diagnosis is important and differential treatment and/or follow up strategies for patients with Her2 overexpression may merit future study.

Gastric cancer (GC) or gastroesophageal junction (GEJ) cancer with HER2 overexpression is highly invasive, with a poor prognosis. With the development of new targeted agents, which agents have ideal therapeutic effects must be determined. This network meta-analysis analyzed the effectiveness and tolerability of targeted agents combined with chemotherapy in HER2-positive GC/GEJ cancer.

Public databases were searched from the date of inception to October 22, 2020. Randomized controlled trials (RCTs) on targeted agent-related regimens for HER2-positive advanced GC or GEJ cancer were included. Subgroup analyses based on publication language, first-line treatment, second/third-line treatment, and HER2 staining intensity were performed.

In total, 13 articles were included. The trastuzumabderuxtecan (TraD) and pertuzumab plus trastuzumab and chemotherapy (PerTraChemo) regimens were considered to have high effectiveness but low tolerability. In the subgroup analysis, PerTraChemo still had high effectiveness with low tolerability as the first-line therapy. As the second- or third-line therapy, TraD and lapatinib plus chemotherapy (LapChemo) had high effectiveness and moderate tolerability. In terms of overall survival (OS) time, PerTraChemo had a relative advantage in the immunohistochemistry (IHC) 2+/in situ hybridization (ISH)+ population, whereas TraD, PerTraChemo, and trastuzumab plus chemotherapy (TraChemo) had a relative advantage in the IHC3+ population.

TraD had relative advantages as the second- or third-line therapy and in the IHC3 + population. PerTraChemo is a potential first-line therapy, but it requires further confirmation because the JACOB phase III clinical trial failed to confirm the superiority of PerTraChemo over TraChemo with regard to OS.

Mesothelin (MSLN) is a cell surface protein associated with tumor invasion and metastasis. This study aims to explore the biological function of MSLN in gastric cancer and to evaluate the association of MSLN polymorphism (rs3764247, rs3764246, rs12597489, rs1057147, rs3765319) with the risk and prognosis of gastric cancer. Small interfering RNA (siRNA) transfection and MSLN overexpression were performed in human gastric cancer cell lines, respectively. The proliferation of tumor cells was evaluated by Cell counting kit 8(CCK-8) and colony formation assay. Wound healing assay and transwell assay were used to elucidate gastric cancer cell migration and invasion rates. We conducted a case-control study involving 860 patients with gastric cancer and 870 controls. All mutation sites were genotyped by PCR-LDR sequencing. First, our study revealed the cancer-promoting role of MSLN in gastric cancer. Second, we also demonstrated that rs3764247 and rs3764246 were associated with a reduced risk of gastric cancer (OR = 0.83, p = 0.010; OR = 0.84, p = 0.011; respectively). The clinicopathological analysis further showed that rs3764247 was closely related to T stage, vascular infiltration, and HER2 expression. In addition, in the survival analysis of 392 patients with gastric cancer, patients with rs3764247 CC genotype had poorer survival than patients with AA + AC genotype after adjusting for age, sex, TNM stage, and Lauren classification (HR = 2.07, p = 0.029). Our findings indicated that MSLN could be an oncogene whose polymorphisms were closely related to the risk and prognosis of gastric cancer.