HER2-positive Gastric Cancer Research Articles

The diagnostic value of 68Ga-NOTA-MAL-Cys-MZHER2:342 PET/CT imaging for HER2-positive lung adenocarcinoma.

The human epidermal growth factor receptor 2 gene (HER2) has been identified as a potential therapeutic target in lung adenocarcinoma (LUAD). Non-invasive positron emission tomography (PET) imaging provides a reliable strategy for in vivo determination of HER2 expression through whole-body detection of abnormalities. The PET tracer 68Ga-NOTA-MAL-Cys-MZHER2:342 has shown promising results for HER2-positive breast and gastric cancers. This study aims to evaluate the performance of 68Ga-NOTA-MAL-Cys-MZHER2:342 in vitro and in vivo models and in clinical patients with HER2-positive LUAD. NOTA-MAL-Cys-MZHER2:342 was synthesized and labeled with 68Ga. Cell uptake, cell binding ability, and stability studies of 68Ga-NOTA-MAL-Cys-MZHER2:342 were assessed both in the Calu-3 lung cancer (LC) cell line and normal mice. In vivo assessment in tumor-bearing mice was conducted using microPET imaging and biodistribution experiments. Additionally, preliminary PET/CT imaging analysis was performed on HER2-positive LC patients. 68Ga-NOTA-MAL-Cys-MZHER2:342 was prepared with a radiochemical purity (RCP) exceeding 95%. The tracer demonstrated high cell uptake in HER2-overexpressing Calu-3 cells, with an IC50 of 158.9, an adequate 1.73 nM. Good stability was exhibited both in vitro and in vivo. MicroPET imaging of Calu-3-bearing mice revealed high tumor uptake and notable tumor-to-background ratios. Positive outcomes were also observed in two HER2-positive LUAD patients. 68Ga-NOTA-MAL-Cys-MZHER2:342 demonstrated satisfactory stability, sensitivity, and specificity. These findings suggest that 68Ga-NOTA-MAL-Cys-MZHER2:342 PET/CT imaging provides a novel tool for non-invasive visual assessment of HER2 expression in LUAD patients.

HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis.

Although anti-HER2 therapies have been widely used against gastric carcinoma, the prognostic significance of HER2 overexpression remains unclear. Previous studies failed to provide convincible evidence due to inconsistent HER2 evaluation criteria and heterogeneous clinical characteristics. To figure out the prognostic significance of HER2 expression in gastric cancer, we rigorously designed and conducted this study. Meta-analysis. Record retrieval was performed by searching PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO meeting libraries from inception to November 2022. Cohort studies investigating overall survival comparison between HER2-positive and HER2-negative gastric cancer patients were included. Both resectable and advanced cases were separately collected while HER2 evaluation standards should be consistent across eligible studies. Newcastle-Ottawa Scale was used for quality assessment. Overall survival was the only endpoint and effect size was presented by hazard ratio (HR) with its 95% confidence interval. The pooled calculation was conducted on Review Manager 5.4. Thirty studies were eligible, including 9945 patients. Eligible studies were mostly high quality (n = 31). Regarding resectable cases (n = 22), HER2-positive groups had significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32-1.85, p < 0.00001). For HER2-positive patients with advanced gastric cancer (n = 10), HER2 overexpression was also an unfavorable survival indicator (HR 1.70, 95%CI 1.23-2.35, p = 0.001). Potential heterogeneous studies had been eliminated while outcomes remained stable by sensitivity analysis. Subgroup analysis suggested HER2-positive patients had a poorer prognosis in both East Asian (resectable: HR 1.56; advanced: HR 1.32) and non-East Asian countries (HR 1.58; HR 3.27). As a novel survival biomarker in gastric cancer, HER2 overexpression indicates unfavorable prognosis among both resectable and advanced patients, irrespective of East Asian or non-East Asian populations. PROSPERO (CRD42020168051).

Survival after Trastuzumab Therapy in Patients with Locally Advanced or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Cancer: A Meta-Analysis of Randomized Controlled Trials.

In the Trastuzumab for Gastric Cancer study, it was found that trastuzumab combined with doublet chemotherapy (fluoropyrimidine and platinum) was the gold-standard treatment for gastroesophageal adenocarcinoma (GEA) that was locally advanced, unresectable, or metastatic (HER2+). We performed a meta-analysis of randomized phase II/III studies testing trastuzumab in combination or alone. This meta-analysis's findings involved 2048 patients in total. The treatment arm and hormone receptor status were used to stratify the combined HR. Overall, the PFS (Random model) HR [0.80] and 95% confidence intervals (CI) [0.68-0.95] were significantly higher for regimens containing trastuzumab, fluoropyrimidine, and platinum compared to regimens containing fluoropyrimidine and platinum. The results of this meta-analysis provide additional support for trastuzumab's use in treating HER2-positive GEA, particularly in cases where the disease lacks a HER2+ receptor.

Pembrolizumab Plus Trastuzumab and Chemotherapy for HER2-Positive Gastric or Gastro-oesophageal Junction Adenocarcinoma

he combination of pembrolizumab, and trastuzumab chemotherapy has long been investigated in the treatment of HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. HER2-positive gastric or gastroesophageal junction adenocarcinoma refers to cancers that overexpress the human epidermal growth factor receptor 2 (HER2), which is associated with more aggressive tumor behavior. Pembrolizumab is a monoclonal antibody that targets the programmed cell death protein 1 (PD-1) receptor, a checkpoint protein on immune cells. By blocking PD-1, pembrolizumab helps unleash the immune system to target and attack cancer cells. Trastuzumab is another monoclonal antibody that specifically targets HER2-positive cancer cells. It has been a standard treatment for HER2-positive breast cancer and has been explored in HER2-positive gastric and gastroesophageal junction cancers. Janjigian and colleagues revealed the interim analysis of a randomized, phase 3 KEYNOTE-811 trial which involved 168 medical centers in 20 countries worldwide. They found that compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumors with a PD-L1 combined positive score of 1 or more. They stated that the overall survival follow-up is ongoing and will be reported at the final analysis. Lancet. 2023 Dec 9;402(10418):2197-2208. doi: 10.1016/S0140-6736(23)02033-0.

The tumor immune microenvironment remodeling and response to HER2-targeted therapy in HER2-positive advanced gastric cancer.

Combination therapy with anti-HER2 agents and immunotherapy has demonstrated significant clinical benefits in gastric cancer (GC), but the underlying mechanism remains unclear. In this study, we used multiplex immunohistochemistry to assess the changes of the tumor microenvironment in 47 advanced GC patients receiving anti-HER2 therapy. Additionally, we performed single-cell transcriptional sequencing to investigate potential cell-to-cell communication and molecular mechanisms in four HER2-positive GC baseline samples. We observed that post-treated the infiltration of NK cells, CD8+ T cells, and B lymphocytes were significantly higher in patients who benefited from anti-HER2 treatment than baseline. Further spatial distribution analysis demonstrated that the interaction scores between NK cells and CD8+ T cells, B lymphocytes and M2 macrophages, B lymphocytes and Tregs were also significantly higher in benefited patients. Cell-cell communication analysis from scRNA sequencing showed that NK cells utilized CCL3/CCL4-CCR5 to recruit CD8+ T cell infiltration. B lymphocytes employed CD74-APP/COPA/MIF to interact with M2 macrophages, and utilized TNF-FAS/ICOS/TNFRSR1B to interact with Tregs. These cell-cell interactions contribute to inhibit the immune resistance of M2 macrophages and Tregs. Our research provides potential guidance for the use of anti-HER2 therapy in combination with immune therapy.

Immune checkpoint inhibitors enhanced the antitumor efficacy of disitamab vedotin for patients with HER2-positive or HER2-low advanced or metastatic gastric cancer: a multicenter real-world study

BackgroundNovel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients.MethodsThis was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities.Results45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3–4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively.ConclusionCompared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

Real-world experience with trastuzumab deruxtecan in patients with metastatic HER2-positive breast cancer and HER2-positive gastric cancer: A retrospective study

Aim. To evaluate the effectiveness of trastuzumab deruxtecan in real-world practice in the Russian Federation.&#x0D; Materials and methods. We performed a retrospective analysis of clinical case series related to the use of trastuzumab deruxtecan (N=15) in the setting of a single clinical center, University Headache Clinic (Dr. Laskov's Clinic), as part of the program for the import of an unapproved drug as a life-saving measure. The overall survival, progression-free survival, and objective response rate were assessed, and individual real-world cases of drug efficacy were presented.&#x0D; Results. Objective response rates are comparable to those shown in large randomized trials. The median follow-up was 67 days; the 6-month overall survival was 70.1% (95% confidence interval [CI] 49.4–99.6%), and the 6-month progression-free survival was 52.1% (95% CI 29.9–90.6%). There were no significant complications associated with therapy; in particular, no events of interstitial lung disease were reported.&#x0D; Discussion. The real-world efficacy of trastuzumab deruxtecan was comparable to that in randomized clinical trials. However, at the level of individual clinical cases, slightly lower efficacy was noted in initially frailer patients (ECOG score 3). Also, it should be noted that the study included patients who had the opportunity to purchase an expensive drug and, therefore, had a social status different from the general population, which could affect the results of this study.&#x0D; Conclusion. The use of trastuzumab deruxtecan in real-world settings has demonstrated high efficacy and a good safety profile.

Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis.

Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2. To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment. Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo. The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy. Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors.

PP212 A phase 1B/2 study of trastuzumab, bevacizumab with paclitaxel for HER2-positive gastric cancer in a second-line therapy (TREAZURE)

PP212 A phase 1B/2 study of trastuzumab, bevacizumab with paclitaxel for HER2-positive gastric cancer in a second-line therapy (TREAZURE)

PP61 Cost-Effectiveness Analysis Of Trastuzumab Deruxtecan Versus Chemotherapy For Previously Treated HER2-Positive Gastric Cancer In Singapore

IntroductionThe phase two DESTINY-Gastric-01 trial demonstrated that trastuzumab deruxtecan (T-DXd) improved overall survival in Asian patients with human epidermal growth factor receptor 2 (HER2)-positive, advanced gastric or gastroesophageal adenocarcinoma that had progressed following two or more treatments, compared with chemotherapy (irinotecan or paclitaxel monotherapy). Considering the high cost of T-DXd, we assessed the cost-effectiveness of T-DXd versus chemotherapy from the Singapore healthcare system’s perspective.MethodsA partitioned survival model with three health states (progression-free, progressed disease and death) was developed, with a five-year time horizon. Survival curves from DESTINY-Gastric-01 were extrapolated beyond the trial duration using parametric functions. Health state utilities were obtained from published literature and direct costs were sourced from public healthcare institutions in Singapore. Utility decrements for adverse events such as interstitial lung disease was incorporated into the model for the differences in safety profiles. A discount rate of three percent was applied to costs and outcomes. One-way deterministic sensitivity analyses (OWSA) and scenario analyses were conducted to assess parameter and model uncertainties.ResultsTreatment with T-Dxd, compared to chemotherapy, had a high base case incremental cost-effectiveness ratio (ICER) of over SGD450,000 (USD334,900) per quality-adjusted life-year gained. The cost of T-DXd greatly influenced the results according to OWSA. Seventy-three percent of the total costs accrued in the T-DXd arm was due to the cost of the drug, compared to seven percent in the chemotherapy arm. The ICER was also sensitive to the assumptions around extrapolation of the survival curves, but when tested across all scenario analyses, the results remained unfavorable.ConclusionsAt the current cost, T-DXd does not represent good value compared to chemotherapy for previously treated HER2-positive gastric cancer in Singapore. The findings from our cost-effectiveness analysis, alongside other considerations, will be useful to inform policy makers on funding decisions.

Long noncoding RNA NONHSAT160169.1 promotes resistance via hsa-let-7c-3p/SOX2 axis in gastric cancer

In clinical trials involving patients with HER2 (ERBB2 receptor tyrosine kinase 2) positive gastric cancer, the efficacy of the HER2-targeted drug lapatinib has proven to be disappointingly poor. Under the persistent pressure exerted by targeted drug therapy, a subset of tumor cells exhibit acquired drug resistance through the activation of novel survival signaling cascades, alongside the proliferation of tumor cells that previously harbored mutations conferring resistance to the drug. This study was undertaken with the aim of elucidating in comprehensive detail the intricate mechanisms behind adaptive resistance and identifying novel therapeutic targets that hold promise in the development of effective lapatinib-based therapies for the specific subset of patients afflicted with gastric cancer. We have successfully established a gastric cancer cell line with acquired lapatinib resistance, designated as HGC-27-LR cells. Utilizing comprehensive coding and noncoding transcriptome sequencing analysis, we have identified key factors that regulate lapatinib resistance in HGC-27 cells. We have compellingly validated that among all the lncRNAs identified in HGC-27-LR cells, a novel lncRNA (long noncoding RNA) named NONHSAT160169.1 was found to be most notably upregulated following exposure to lapatinib treatment. The upregulation of NONHSAT160169.1 significantly augmented the migratory, invasive, and stemness capabilities of HGC-27-LR cells. Furthermore, we have delved into the mechanism by which NONHSAT160169.1 regulates lapatinib resistance. The findings have revealed that NONHSAT160169.1, which is induced by the p-STAT3 (signal transducer and activator of transcription 3) nuclear transport pathway, functions as a decoy that competitively interacts with hsa-let-7c-3p and thereby abrogates the inhibitory effect of hsa-let-7c-3p on SOX2 (SRY-box transcription factor 2) expression. Hence, our study has unveiled the NONHSAT160169.1/hsa-let-7c-3p/SOX2 signaling pathway as a novel and pivotal axis for comprehending and surmounting lapatinib resistance in the treatment of HER2-positive gastric cancer.

A case of tongue swelling after S-1, oxaliplatin, and trastuzumab for HER2-positive gastric cancer

BackgroundWe report a case of a patient with HER2-positive gastric cancer with marked tongue swelling during the second cycle of S-1, oxaliplatin, and trastuzumab.Case presentationThe patient was a 74-year-old male, who was taking an angiotensin II receptor blocker (ARB) for pre-existing hypertension, with no history of allergies, diagnosed with HER2-positive gastric cancer, treated with tegafur, gimeracil, and oteracil potassium (S-1) and oxaliplatin for the first cycle, and trastuzumab was added from the second cycle. Three weeks after initiation, during an outpatient visit, grade 2 oral mucositis and significant enlargement of the patient's tongue were observed. Due to the risk of airway obstruction, the patient was referred to an otolaryngologist. After examination, hereditary angioedema was ruled out, and treatment was discontinued in view of ARB-induced angioedema. However, the tongue swelling did not improve markedly. Considering disease progression due to the discontinuation of chemotherapy, it was decided to change S-1 to capecitabine and continue treatment, and chemotherapy was resumed.ConclusionsAngioedema has been reported to be hereditary and drug-related, and angiotensin-converting enzyme (ACE) inhibitors and ARBs have also been reported to lead to drug-related adverse events. Since the patient had oral mucositis at the time of onset and was taking an ARB, it is thought that oxaliplatin and S-1(SOX), and trastuzumab during ARB therapy induced oral mucositis, leading to the development of angioedema.

Multicenter phase I dose escalation and expansion study of pyrotinib in combination with camrelizumab and chemotherapy as first-line treatment for HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma

Pembrolizumab plus trastuzumab and chemotherapy showed remarkable efficacy as first-line therapy for advanced HER2-positive gastric cancer. Pyrotinib is an irreversible pan-HER inhibitor. This single-arm, open-label phase 1 dose-escalation (1a) and expansion (1b) study investigated camrelizumab, an anti-PD-1 antibody, plus pyrotinib and chemotherapy as first-line treatment for advanced HER2-positive gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. Between June 2020 and June 2022, 41 patients with previously untreated HER2-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma were enrolled. In phase 1a, patients underwent a 3+3 escalating dose design, receiving oral pyrotinib (240mg, 320mg, or 400mg daily), intravenous camrelizumab (200mg), and CapeOX (oxaliplatin 130mg/m2 on day 1 and capecitabine 1000mg/m2 twice daily for two weeks) every 3 weeks until progression, intolerable toxicity or consent withdrawal. The recommended phase 2 dose (RP2D) of pyrotinib was determined and used in the phase 1b. The primary endpoints were the safety, maximum tolerated dose (MTD), RP2D, and confirmed objective response rate (ORR). This trial was registered with chictr.org, number ChiCTR2000029717. Among 41 patients, 10 were in phase 1a (3at 240mg, 3at 400mg, and 4at 320mg due to one patient withdrawing consent), and 31 were in phase 1b. In phase 1a, the MTD of pyrotinib was 320mg daily due to dose-limiting toxicities (diarrhea [n=3] and vomiting [n=1]) observed at 400mg. Based on all available data, the RP2D of pyrotinib was set at 320mg. Among 41 patients, 20 patients (48.8%) developed grade ≥3 treatment-emergent adverse events (TEAEs), and four patients (9.8%) had any grade serious adverse events. No deaths occurred due to TEAEs. Among 27 patients who received the RP2D of pyrotinib and had a post-baseline tumor assessment, two patients (7.4%) achieved a confirmed complete response, and 19 patients (70.4%) achieved a confirmed partial response, resulting in a confirmed ORR of 77.8% (95% CI: 57.7-91.4). Pyrotinib plus camrelizumab and chemotherapy showed promising efficacy in the first-line treatment of advanced HER2-positive G/GEJ cancer. The safety profile was consistent with known toxicities of the agents, and no new or unexpected safety signals were identified. This study was funded by the Beijing Xisike Clinical Oncology Research Foundation (Y-HR2019-0377).

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study

BackgroundTrastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate that consists of an anti-human epidermal growth factor receptor 2 (HER2) antibody bound by a cleavable tetrapeptide-based linker to a cytotoxic topoisomerase I inhibitor. Prior to marketing approval in Japan in September 2020, this expanded-access study was conducted to provide T-DXd to previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas.MethodsThis multicenter, open-label, expanded-access study was conducted between March 25 and September 25, 2020 at 17 Japanese sites. Previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas received T-DXd 6.4 mg/kg via intravenous infusions at 3-week intervals. Serious adverse events (SAEs), all potential cases of interstitial lung disease (ILD)/pneumonitis, all liver-related events potentially meeting Hy’s Law criteria, and all cases of overdose were reported on the case report forms.ResultsA total of 64 patients were treated with T-DXd. Among the 17 (26.6%) patients with reported SAEs, 10 (15.6%) had SAEs related to T-DXd treatment. Febrile neutropenia was the most common SAE (n = 6). SAEs led to death in six patients; drug-related SAEs (sepsis and febrile neutropenia) led to death in one patient. Drug-related ILD, as determined by the external Adjudication Committee, occurred in three patients (Grade 1, Grade 2, and Grade 3: all n = 1).ConclusionThis expanded-access study provided T-DXd to a broader population of Japanese patients prior to marketing approval in Japan, bridging the gap between clinical trials and drug approval. No new safety concerns were identified.

Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer: a plain language summary of the DESTINY-Gastric01 study.

This is a summary of the publication about the DESTINY-Gastric01 study, which was published in the New England Journal of Medicine in May 2020. The study included 187 adults in Japan and South Korea with gastric cancer or gastroesophageal junction cancer that had high levels of a protein called HER2 (HER2-positive). All the participants' cancer had spread to nearby or distant parts of the body and had worsened after receiving at least 2 previous cancer treatments or treatment combinations. The researchers wanted to know whether a drug called trastuzumab deruxtecan (T-DXd) could improve participants' cancer more than standard chemotherapy drugs. Researchers in this study found that just over half (51%) of participants who received T-DXd had their cancer shrink significantly or disappear, compared to around 1 out of 7 participants (14%) who received standard chemotherapy. In addition, T-DXd reduced the risk of death by 41% compared to standard chemotherapy. Half of the participants who received T-DXd had died after 12.5months. Half of the participants who received standard chemotherapy had died after 8.4months. Just under half (44%) of participants who received T-DXd had serious medical problems during the study, also called serious adverse events, compared to about a quarter (24%) of participants who received standard chemotherapy. Of the participants who received T-DXd, 1 out of 10 (10%) got interstitial lung disease or pneumonitis that was potentially related to the study treatment. None of the participants who received standard chemotherapy got interstitial lung disease or pneumonitis. T-DXd could be a treatment option for people who have HER2-positive gastric cancer that has been previously treated without success.

1561P APC mutation (mt.), MYC, and GATA6 amplifications (amp.) were associated with worse survival in HER2-positive advanced gastric cancer patients treated with S-1/capecitabine plus oxaliplatin combined with trastuzumab (T-mab) and nivolumab (N-mab)

1561P APC mutation (mt.), MYC, and GATA6 amplifications (amp.) were associated with worse survival in HER2-positive advanced gastric cancer patients treated with S-1/capecitabine plus oxaliplatin combined with trastuzumab (T-mab) and nivolumab (N-mab)

Impact of SMAD2 and MET Expression on Lymph Node Metastasis of HER2-positive Gastric Cancer Cells.

Intra-tumoral heterogeneity, which is frequently found in various types of cancers, has been suggested to play an important role in cancer progression and metastasis. The findings of our previous study suggested that p-SMAD2 and c-MET signaling might play important roles in the progression to lymph node metastasis of HER2-positive gastric cancer. In this study, we confirmed the effect of SMAD2/MET signaling in the progression of HER2-positive gastric cancer in an animal model. NCI-N87 cells over-expressing ERBB2, SMAD2, MET were used. To confirm the role of SMAD2 and MET expression on lymph node metastasis of gastric cancer, we orthotopically injected NCI-N87 cells with or without the knockdown of both SMAD2 and MET into the gastric walls of BALBc nude mice. The number of metastatic lymph nodes was significantly smaller in the knockdown group compared to that in the control group. However, there was no significant difference in gastric tumor size between the two groups. SMAD2 and MET signaling might play important roles specifically in the progression to lymph node metastasis of HER2-positive gastric cancer. c-MET and SMAD2 may be useful targets for preventing lymph node metastasis in patients with HER2-positive gastric cancer.

Self-Assembled Multivalent Aptamer Drug Conjugates: Enhanced Targeting and Cytotoxicity for HER2-Positive Gastric Cancer.

Antibody drug conjugates (ADCs) have shown promise to be the mainstream chemotherapeutics for advanced HER2-positive cancers, yet the issues of poor drug delivery efficiency, limited chemotherapeutic effects, severe immune responses, and drug resistance remain to be addressed before the clinical applications of ADCs. The DNA aptamer-guided drug conjugates (ApDCs) are receiving growing attention for specific tumors due to their excellent tumor affinity and low cost. Therefore, developing a multivalent ApDC nanomedicine by combining anti-HER2 aptamer (HApt), tetrahedral framework nucleic acid (tFNA), and deruxtecan (Dxd) together to form HApt-tFNA@Dxd might help to address these concerns. In this study, the HER2-targeted DNA aptamer modified DNA tetrahedron (HApt-tFNA) was employed as a system for drug delivery, and the adoption of tFNA could effectively enlarge the drug-loading rate compared to aptamer-guided ApDCs previously reported. Compared with free Dxd and tFNA@Dxd, HApt-tFNA@Dxd showed better structural stability, excellent targeted cytotoxicity to HER2-positive gastric cancer, and increased tissue aggregation ability in tumors. These features and superiorities make HApt-tFNA@Dxd a promising chemotherapeutic medicine for HER2-positive tumors. Our work developed a new targeting nanomedicine by combining DNA nanomaterials and chemotherapeutic agents, which represents a critical advance toward developing novel DNA-based nanomaterials and promoting their potential applications for HER2-positive cancer therapy.

Advances in the treatment of gastric cancer: 2022-2023.

To review 2022-2023 studies in gastric cancer. Important studies report the role of laparoscopic surgery in gastric cancer, the activity of immune checkpoint inhibitors in metastatic, locally advanced and adjuvant therapy in gastric cancer, and the effectiveness of zolbetuximab in claudin 18.2-positive metastatic disease. From the Japanese JLSSG0901 Trial, equivalent survival was reported for laparoscopically assisted versus conventional open gastrectomy. Adding nivolumab to adjuvant chemotherapy in resected stage III gastric cancer failed to improve 3-year disease-free survival over chemotherapy alone. Ipilimumab and nivolumab as preoperative therapy in MSI-high gastric cancer resulted in a high rate of pathologic complete response. Trastuzumab added to chemoradiotherapy and surgery in HER2-positive locally advanced esophageal and gastroesophageal junction adenocarcinoma did not improve overall survival over chemoradiotherapy and surgery alone. Adding pembrolizumab to trastuzumab/chemotherapy in metastatic HER2-positive gastric cancer improved antitumor response rate. Addition of zolbetuximab, an antibody targeting claudin 18.2, to first-line chemotherapy in metastatic claudin 18.2-positive gastric cancer improved overall survival. Immune checkpoint inhibition has a role in locally advanced MSI-high and metastatic gastric cancer. Laparoscopic gastrectomy is acceptable in gastric cancer. Zolbetuximab in metastatic gastric cancer will emerge as a new therapy option.

The relationship between brain metastasis and HER2 expression status in gastric cancer.

Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method. There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white,of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30months vs.16.13months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients.