{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:27:44Z","timestamp":1785432464635,"version":"3.56.0"},"reference-count":105,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FOCUS: Training and Guidance for UMFST Researchers in Health","award":["100455\/29.08.2025"],"award-info":[{"award-number":["100455\/29.08.2025"]}]},{"name":"FOCUS: Training and Guidance for UMFST Researchers in Health","award":["SMIS 350717"],"award-info":[{"award-number":["SMIS 350717"]}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["PS\/688\/PS_P3\/OP4\/ESO4.7\/PS_P3_ESO4.7_A6"],"award-info":[{"award-number":["PS\/688\/PS_P3\/OP4\/ESO4.7\/PS_P3_ESO4.7_A6"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"award":["PS\/688\/PS_P3\/OP4\/ESO4.7\/PS_P3_ESO4.7_A6"],"award-info":[{"award-number":["PS\/688\/PS_P3\/OP4\/ESO4.7\/PS_P3_ESO4.7_A6"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human epidermal growth factor receptor 2 (HER2) dysregulation contributes to tumorigenesis in gastric and gastroesophageal junction adenocarcinomas (GC\/GEJ). HER2 overexpression has been associated in multiple cohorts with aggressive behavior and poor outcomes. While HER2 amplification has long guided therapy in HER2-positive disease, antibody\u2013drug conjugates (ADCs) have shifted attention toward the HER2-low category, typically defined as immunohistochemistry (IHC) 1+ or IHC 2+ with negative in situ hybridization (ISH). This narrative review integrates evidence from the peer-reviewed literature, current testing recommendations, and registered clinical trials. It clarifies practical issues in HER2-low assessment and maps the evolving therapeutic landscape of HER2-targeted ADCs including rational combination strategies that may extend benefit beyond conventionally HER2-positive tumors. A cross-tumor perspective contrasts GC\/GEJ testing and biology with the breast cancer paradigm and summarizes the importance of HER2-low expression in non-gastric malignancies. Finally, we discuss the therapeutic strategies in HER2-low GC\/GEJ and highlight key safety and monitoring considerations for HER2-directed ADCs.<\/jats:p>","DOI":"10.3390\/ijms27114673","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T12:14:52Z","timestamp":1779452092000},"page":"4673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["HER2-Low Gastric and Gastroesophageal Junction Adenocarcinoma: From Assessment to Treatment Strategies"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8851-6789","authenticated-orcid":false,"given":"Alexandra Georgiana","family":"Scurtu","sequence":"first","affiliation":[{"name":"Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540139 Targu Mures, Romania"},{"name":"2nd Clinic of Surgery, Mure\u0219 County Emergency Clinical Hospital, 540136 Targu Mures, Romania"},{"name":"Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540139 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Tatiana","family":"Sala","sequence":"additional","affiliation":[{"name":"2nd Clinic of Surgery, Mure\u0219 County Emergency Clinical Hospital, 540136 Targu Mures, Romania"},{"name":"Department of Surgery, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540139 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioan","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540139 Targu Mures, Romania"},{"name":"Romanian Academy of Medical Sciences, 030167 Bucuresti, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tivadar","family":"Bara","sequence":"additional","affiliation":[{"name":"2nd Clinic of Surgery, Mure\u0219 County Emergency Clinical Hospital, 540136 Targu Mures, Romania"},{"name":"Department of Surgery, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540139 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radu Mircea","family":"Neagoe","sequence":"additional","affiliation":[{"name":"2nd Clinic of Surgery, Mure\u0219 County Emergency Clinical Hospital, 540136 Targu Mures, Romania"},{"name":"Department of Surgery, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540139 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0854-5617","authenticated-orcid":false,"given":"Zsolt Zolt\u00e1n","family":"F\u00fcl\u00f6p","sequence":"additional","affiliation":[{"name":"Szegedi Tudom\u00e1nyegyetem, Szent-Gy\u00f6rgyi Albert Klinikai K\u00f6zpont, Seb\u00e9szeti Klinika, 6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3968-5118","authenticated-orcid":false,"given":"Simona","family":"Gurzu","sequence":"additional","affiliation":[{"name":"Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 540139 Targu Mures, Romania"},{"name":"Romanian Academy of Medical Sciences, 030167 Bucuresti, Romania"},{"name":"Research Center of Oncopathology and Translational Medicine (CCOMT), 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","unstructured":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1994). Schistosomes, Liver Flukes and Helicobacter pylori, International Agency for Research on Cancer."},{"key":"ref_2","first-page":"19","article-title":"Helicobacter pylori antibiotic sensitivity by microdilution","volume":"25","author":"Rivas","year":"2000","journal-title":"Rev. Med. Panama"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.canlet.2020.09.019","article-title":"Epstein\u2013Barr Virus-Associated Gastric Cancer: A Distinct Subtype","volume":"495","author":"Yang","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13053-022-00239-9","article-title":"Attitudes toward Preimplantation Genetic Testing and Quality of Life among Individuals with Hereditary Diffuse Gastric Cancer Syndrome","volume":"20","author":"Shah","year":"2022","journal-title":"Hered. Cancer Clin. Pract."},{"key":"ref_5","unstructured":"National Cancer Institute (2026, January 20). Stomach (Gastric) Cancer Causes and Risk Factors: Patient Version, Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK66033\/."},{"key":"ref_6","unstructured":"International Agency for Research on Cancer (2025, June 22). Global Cancer Observatory: Cancer Today. Available online: https:\/\/gco.iarc.who.int\/today."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1097\/CEJ.0000000000000982","article-title":"Impact of HER2 and Microsatellite Instability Status on Response to Neoadjuvant\/Conversion Therapy and Survival in Patients with Gastric Cancer","volume":"35","author":"Piccioni","year":"2026","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.1007\/s12094-025-03865-6","article-title":"Biomarkers in Gastroesophageal Cancer 2025: An Updated Consensus Statement by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP)","volume":"27","author":"Cuatrecasas","year":"2025","journal-title":"Clin. Transl. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"993","DOI":"10.5858\/arpa.2023-0950-SA","article-title":"Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer","volume":"147","author":"Wolff","year":"2023","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2203690","article-title":"Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer","volume":"387","author":"Modi","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/apm.1965.64.1.31","article-title":"The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma: An Attempt at a Histo-Clinical Classification","volume":"64","year":"1965","journal-title":"Acta Pathol. Microbiol. Scand."},{"key":"ref_12","unstructured":"Organisation Mondiale de la Sant\u00e9, Centre International de Recherche sur le Cancer (2010). WHO Classification of Tumours of the Digestive System, International Agency for Research on Cancer. [4th ed.]. WHO Classification of Tumours."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"D\u00edaz Del Arco, C., Fern\u00e1ndez Ace\u00f1ero, M.J., and Ortega Medina, L. (2024). Molecular Classifications in Gastric Cancer: A Call for Interdisciplinary Collaboration. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052649"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"The Cancer Genome Atlas Research Network (2014). Comprehensive Molecular Characterization of Gastric Adenocarcinoma. Nature, 513, 202\u2013209.","DOI":"10.1038\/nature13480"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/nm.3850","article-title":"Molecular Analysis of Gastric Cancer Identifies Subtypes Associated with Distinct Clinical Outcomes","volume":"21","author":"Cristescu","year":"2015","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"153797","DOI":"10.1016\/j.prp.2022.153797","article-title":"Molecular Subtyping of Gastric Cancer According to ACRG Using Immunohistochemistry\u2014Correlation with Clinical Parameters","volume":"231","author":"Pretzsch","year":"2022","journal-title":"Pathol.\u2014Res. Pract."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Brodkin, J., Kaprio, T., Hagstr\u00f6m, J., Lepp\u00e4, A., Kokkola, A., Haglund, C., and B\u00f6ckelman, C. (2024). Prognostic Effect of Immunohistochemically Determined Molecular Subtypes in Gastric Cancer. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-13236-z"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"688","DOI":"10.5306\/wjco.v12.i8.688","article-title":"Gastric Cancer Molecular Classification Based on Immunohistochemistry and In Situ Hybridization: Analysis in Western Patients after Curative-Intent Surgery","volume":"12","author":"Ramos","year":"2021","journal-title":"World J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Yoon, J.-Y., Sy, K., Brezden-Masley, C., and Streutker, C.J. (2019). Histo- and Immunohistochemistry-Based Estimation of the TCGA and ACRG Molecular Subtypes for Gastric Carcinoma and Their Prognostic Significance: A Single-Institution Study. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0224812"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"473","DOI":"10.47102\/annals-acadmedsg.V33N4p473","article-title":"The HercepTest and Routine C-erbB2 Immunohistochemistry in Breast Cancer: Any Difference?","volume":"33","author":"Selvarajan","year":"2004","journal-title":"Ann. Acad. Med. Singap."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cheng, X. (2024). A Comprehensive Review of HER2 in Cancer Biology and Therapeutics. Genes, 15.","DOI":"10.20944\/preprints202406.0515.v1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.jtho.2015.10.025","article-title":"HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers","volume":"11","author":"Li","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.18.00226","article-title":"Validation of HER2 Amplification as a Predictive Biomarker for Anti-Epidermal Growth Factor Receptor Antibody Therapy in Metastatic Colorectal Cancer","volume":"3","author":"Raghav","year":"2019","journal-title":"JCO Precis. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1016\/S0140-6736(16)32417-5","article-title":"HER2-Positive Breast Cancer","volume":"389","author":"Loibl","year":"2017","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0140-6736(10)61121-X","article-title":"Trastuzumab in Combination with Chemotherapy versus Chemotherapy Alone for Treatment of HER2-Positive Advanced Gastric or Gastro-Oesophageal Junction Cancer (ToGA): A Phase 3, Open-Label, Randomised Controlled Trial","volume":"376","author":"Bang","year":"2010","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s40364-024-00565-1","article-title":"HER2-Targeted Therapies in Cancer: A Systematic Review","volume":"12","author":"Zhu","year":"2024","journal-title":"Biomark. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Riaz, A. (2025). HER2: Biology, Definition, Diagnosis, and Its Role in Cancers. Role of HER2\u2014From Molecular Mechanisms to Targeted Therapies, IntechOpen.","DOI":"10.5772\/intechopen.1006255"},{"key":"ref_28","unstructured":"European Society for Medical Oncology (ESMO) (2025, June 22). HER2 in Gastric Cancer: ESMO Biomarker Factsheet. Available online: https:\/\/oncologypro.esmo.org\/education-library\/factsheets-on-biomarkers\/her2-in-gastric-cancer."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1200\/JCO.2016.69.4836","article-title":"HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology","volume":"35","author":"Bartley","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_30","unstructured":"Numbere, N., and Huber, A.R. (2026, January 27). HER2 Stomach\/GE Junction. PathologyOutlines.com. Available online: https:\/\/www.pathologyoutlines.com\/topic\/stainsher2GI.html."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s00428-010-0952-2","article-title":"HER2 Diagnostics in Gastric Cancer\u2014Guideline Validation and Development of Standardized Immunohistochemical Testing","volume":"457","author":"Dietel","year":"2010","journal-title":"Virchows Arch."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/modpathol.2011.198","article-title":"HER2 Testing in Gastric Cancer: A Practical Approach","volume":"25","author":"Hanna","year":"2012","journal-title":"Mod. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1111\/j.1365-2559.2008.03028.x","article-title":"Assessment of a HER2 Scoring System for Gastric Cancer: Results from a Validation Study","volume":"52","author":"Hofmann","year":"2008","journal-title":"Histopathology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/PAP.0b013e3182026d72","article-title":"HER2 Testing in Gastric Cancer","volume":"18","author":"Albarello","year":"2011","journal-title":"Adv. Anat. Pathol."},{"key":"ref_35","first-page":"397","article-title":"Are Biopsy Specimens Predictive of HER2 Status in Gastric Cancer Patients?","volume":"58","author":"Pirrelli","year":"2013","journal-title":"Dig. Dis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8860174","DOI":"10.1155\/2020\/8860174","article-title":"HER2 Heterogeneity in Gastric Cancer: A Comparative Study, Using Two Commercial Antibodies","volume":"2020","author":"Satala","year":"2020","journal-title":"J. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.12998\/wjcc.v7.i15.1964","article-title":"HER2 Heterogeneity Is a Poor Prognosticator for HER2-Positive Gastric Cancer","volume":"7","author":"Kaito","year":"2019","journal-title":"World J. Clin. Cases"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"34","DOI":"10.4132\/jptm.2019.11.03","article-title":"HER2 Status in Breast Cancer: Changes in Guidelines and Complicating Factors for Interpretation","volume":"54","author":"Ahn","year":"2020","journal-title":"J. Pathol. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41523-020-00208-2","article-title":"Clinical, Pathological, and PAM50 Gene Expression Features of HER2-Low Breast Cancer","volume":"7","author":"Schettini","year":"2021","journal-title":"npj Breast Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"oyae328","DOI":"10.1093\/oncolo\/oyae328","article-title":"Clinicopathological and Prognostic Significance of HER2-Low Expression in Advanced Gastric Cancer: A Retrospective Observational Study","volume":"30","author":"Narita","year":"2025","journal-title":"Oncologist"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s12957-026-04323-5","article-title":"Clinicopathological Features and Prognosis of HER2-Low Gastric Cancer: A Real-World Retrospective Cohort Study","volume":"24","author":"Zhang","year":"2026","journal-title":"World J. Surg. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Yang, T., Xu, R., You, J., Li, F., Yan, B., and Cheng, J.-N. (2022). Prognostic and Clinical Significance of HER-2 Low Expression in Early-Stage Gastric Cancer. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-10262-7"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s40364-022-00416-x","article-title":"HER2-Targeted Advanced Metastatic Gastric\/Gastroesophageal Junction Adenocarcinoma: Treatment Landscape and Future Perspectives","volume":"10","author":"Li","year":"2022","journal-title":"Biomark. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"26787","DOI":"10.18632\/oncotarget.25507","article-title":"The Dynamics of HER2 Status in Esophageal Adenocarcinoma","volume":"9","author":"Creemers","year":"2018","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1136\/jcp-2023-208767","article-title":"HER2-Low in Gastro-Oesophageal Adenocarcinoma: A Real-World Pathological Perspective","volume":"76","author":"Angerilli","year":"2023","journal-title":"J. Clin. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100925","DOI":"10.1016\/j.modpat.2025.100925","article-title":"International Expert Consensus Recommendations for HER2 Reporting in Breast Cancer: Focus on HER2-Low and Ultralow Categories","volume":"39","author":"Rakha","year":"2026","journal-title":"Mod. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/s41698-025-00881-1","article-title":"Evolution of HER2-Low Expression from Primary to Paired Metastatic Gastric Cancer Lesions","volume":"9","author":"He","year":"2025","journal-title":"npj Precis. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/modpathol.2012.228","article-title":"HER2 in Gastric Cancer: A Digital Image Analysis in Pre-Neoplastic, Primary and Metastatic Lesions","volume":"26","author":"Fusco","year":"2013","journal-title":"Mod. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1056\/NEJMoa2407086","article-title":"Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer","volume":"391","author":"Bardia","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1038\/s41591-023-02478-2","article-title":"Trastuzumab Deruxtecan in Metastatic Breast Cancer with Variable HER2 Expression: The Phase 2 DAISY Trial","volume":"29","author":"Mosele","year":"2023","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"100637","DOI":"10.1016\/j.medj.2025.100637","article-title":"Efficacy and Safety of DV in HER2-Negative and HER2-Low Locally Advanced or Metastatic Urothelial Carcinoma: Results of a Phase 2 Study","volume":"6","author":"Yan","year":"2025","journal-title":"Med"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1200\/JCO.22.02558","article-title":"Trastuzumab Deruxtecan for Human Epidermal Growth Factor Receptor 2-Expressing Advanced or Recurrent Uterine Carcinosarcoma (NCCH1615): The STATICE Trial","volume":"41","author":"Nishikawa","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.3802\/jgo.2025.36.e14","article-title":"HER2-Negative or Low Expression as an Unfavorable Prognostic Factor in Patients with Stage I\/II Uterine Carcinosarcoma","volume":"36","author":"Mizoguchi","year":"2025","journal-title":"J. Gynecol. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"101311","DOI":"10.1016\/j.gore.2023.101311","article-title":"Response of Low HER2-Expressing Ovarian Carcinosarcoma to Trastuzumab Deruxtecan, a Case Report","volume":"50","author":"Rose","year":"2023","journal-title":"Gynecol. Oncol. Rep."},{"key":"ref_55","unstructured":"ClinicalTrials.gov (2025, December 27). Study of Trastuzumab Deruxtecan with Bevacizumab Versus Bevacizumab Monotherapy for First-Line Maintenance in HER2-Expressing Ovarian Cancer (DESTINY-Ovarian01), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06819007."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1056\/NEJMoa2112431","article-title":"Trastuzumab Deruxtecan in HER2-Mutant Non\u2013Small-Cell Lung Cancer","volume":"386","author":"Li","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Uy, N.F., Merkhofer, C.M., and Baik, C.S. (2022). HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies. Cancers, 14.","DOI":"10.3390\/cancers14174155"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S1470-2045(24)00064-0","article-title":"Trastuzumab Deruxtecan in Patients with Metastatic Non-Small-Cell Lung Cancer (DESTINY-Lung01): Primary Results of the HER2-Overexpressing Cohorts from a Single-Arm, Phase 2 Trial","volume":"25","author":"Smit","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Han, S.-H., Ryu, K.H., and Kwon, A.-Y. (2021). The Prognostic Impact of HER2 Genetic and Protein Expression in Pancreatic Carcinoma-HER2 Protein and Gene in Pancreatic Cancer. Diagnostics, 11.","DOI":"10.3390\/diagnostics11040653"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1200\/JCO.23.02005","article-title":"Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial","volume":"42","author":"Makker","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4090","DOI":"10.1200\/JCO.2024.42.16_suppl.4090","article-title":"Trastuzumab Deruxtecan (T-DXd) in Patients with HER2-Expressing Biliary Tract Cancer (BTC) and Pancreatic Cancer (PC): Outcomes from DESTINY-PanTumor02 (DP-02)","volume":"42","author":"Oh","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"103679","DOI":"10.1016\/j.esmoop.2024.103679","article-title":"HER2-Low Gastric Cancer: Is the Subgroup Targetable?","volume":"9","author":"Shimozaki","year":"2024","journal-title":"ESMO Open"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1097\/PAI.0000000000000463","article-title":"Digital Image Analysis of HER2 Immunostained Gastric and Gastroesophageal Junction Adenocarcinomas","volume":"25","author":"Nielsen","year":"2017","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"105563","DOI":"10.1016\/j.esmoop.2025.105563","article-title":"HER2DX ERBB2 Score in Advanced HER2-Positive Gastric Cancer Treated with Trastuzumab and Chemotherapy","volume":"10","author":"Pascual","year":"2025","journal-title":"ESMO Open"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Ichikawa, H., Usui, K., Aizawa, M., Shimada, Y., Muneoka, Y., Kano, Y., Sugai, M., Moro, K., Hirose, Y., and Miura, K. (2024). Clinical Application of Targeted Tumour Sequencing Tests for Detecting ERBB2 Amplification and Optimizing Anti-HER2 Therapy in Gastric Cancer. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-12482-5"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.jmoldx.2019.02.007","article-title":"Tumor Heterogeneity Index to Detect Human Epidermal Growth Factor Receptor 2 Amplification by Next-Generation Sequencing: A Direct Comparison Study with Immunohistochemistry","volume":"21","author":"Choi","year":"2019","journal-title":"J. Mol. Diagn."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"56","DOI":"10.21037\/tgh.2020.01.09","article-title":"Next Generation Sequencing in Gastric or Gastroesophageal Adenocarcinoma","volume":"5","author":"Ku","year":"2020","journal-title":"Transl. Gastroenterol. Hepatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s40265-020-01272-5","article-title":"Human Epidermal Growth Factor Receptor 2 (HER2) in Advanced Gastric Cancer: Current Knowledge and Future Perspectives","volume":"80","author":"Palle","year":"2020","journal-title":"Drugs"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"102415","DOI":"10.1016\/j.eclinm.2023.102415","article-title":"Disitamab Vedotin (RC48) plus Toripalimab for HER2-Expressing Advanced Gastric or Gastroesophageal Junction and Other Solid Tumours: A Multicentre, Open Label, Dose Escalation and Expansion Phase 1 Trial","volume":"68","author":"Wang","year":"2024","journal-title":"eClinicalMedicine"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1200\/JCO.22.00575","article-title":"Trastuzumab Deruxtecan in Anti\u2013Human Epidermal Growth Factor Receptor 2 Treatment\u2013Naive Patients With Human Epidermal Growth Factor Receptor 2\u2013Low Gastric or Gastroesophageal Junction Adenocarcinoma: Exploratory Cohort Results in a Phase II Trial","volume":"41","author":"Yamaguchi","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1002\/cac2.12214","article-title":"Efficacy and Safety of a Novel anti-HER2 Therapeutic Antibody RC48 in Patients with HER2-overexpressing, Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer: A Single-arm Phase II Study","volume":"41","author":"Peng","year":"2021","journal-title":"Cancer Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1007\/s10120-021-01168-7","article-title":"Phase I Study of the Recombinant Humanized Anti-HER2 Monoclonal Antibody\u2013MMAE Conjugate RC48-ADC in Patients with HER2-Positive Advanced Solid Tumors","volume":"24","author":"Xu","year":"2021","journal-title":"Gastric Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"S478","DOI":"10.1016\/j.annonc.2023.09.1870","article-title":"684P: Phase I Trial of SHR-A1811 in HER2-Expressing Advanced Gastric Cancer (GC) or Gastroesophageal Junction Adenocarcinoma (GEJ) and Colorectal Cancer (CRC)","volume":"34","author":"Li","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1158\/1535-7163.MCT-17-0749","article-title":"A HER2-Targeting Antibody\u2013Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model","volume":"17","author":"Iwata","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Nie, C., Xu, W., Guo, Y., Gao, X., Lv, H., Chen, B., Wang, J., Liu, Y., Zhao, J., and Wang, S. (2023). 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. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-11735-z"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"100207","DOI":"10.1016\/j.esmogo.2025.100207","article-title":"An Open-Label Phase Ib\/II Study of Trastuzumab Deruxtecan Combined with Nivolumab and CAPOX for HER2-Low Gastroesophageal Adenocarcinoma","volume":"9","author":"Aoki","year":"2025","journal-title":"ESMO Gastrointest. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"S199","DOI":"10.1016\/j.annonc.2024.05.412","article-title":"500TiP: An Open Label Phase Ib\/II Study of Trastuzumab Deruxtecan (T-DXd) in Combination with Nivolumab and CAPOX for Patients with HER2-Low Expressing Gastroesophageal Adenocarcinoma (EPOC2203)","volume":"35","author":"Aoki","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_78","unstructured":"ClinicalTrials.gov (2026, January 08). A Study of RC48-ADC Combine with Toripalimab and Chemotherapy or RC48-ADC Combine with Toripalimab and Trastuzumab as First-Line Treatment in Local Advanced or Metastatic Gastric Cancer with the HER2 Expression or Non-Expression, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05980481."},{"key":"ref_79","unstructured":"ClinicalTrials.gov (2026, January 15). An Open Label, Single-Arm, Multicenter Phase Ib\/II Study to Evaluate the Safety and Efficacy of T-Dxd in Combination with Ramucirumab as a 2nd Line in Patients with HER2 Low Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma, Available online: https:\/\/www.clinicaltrials.gov\/study\/NCT05894824."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejca.2022.10.004","article-title":"KN026 (Anti-HER2 Bispecific Antibody) in Patients with Previously Treated, Advanced HER2-Expressing Gastric or Gastroesophageal Junction Cancer","volume":"178","author":"Xu","year":"2023","journal-title":"Eur. J. Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41392-025-02195-x","article-title":"Efficacy and Safety of KN026, a Bispecific Anti-HER2 Antibody, in Combination with KN046, an Anti-CTLA4\/PD-L1 Antibody, in Patients with Advanced HER2-Positive Nonbreast Cancer: A Combined Analysis of a Phase Ib and a Phase II Study","volume":"10","author":"Liu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1158\/1078-0432.CCR-24-4295","article-title":"Phase Ib\/II Study of Zanidatamab in Combination with Tislelizumab and Chemotherapy in First-Line HER2-Positive Gastric\/Gastroesophageal Junction Adenocarcinoma","volume":"32","author":"Lee","year":"2026","journal-title":"Clin. Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1056\/NEJMoa2004413","article-title":"Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer","volume":"382","author":"Shitara","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1038\/s41591-024-02992-x","article-title":"Trastuzumab Deruxtecan in HER2-Positive Advanced Gastric Cancer: Exploratory Biomarker Analysis of the Randomized, Phase 2 DESTINY-Gastric01 Trial","volume":"30","author":"Shitara","year":"2024","journal-title":"Nat. Med."},{"key":"ref_85","unstructured":"ClinicalTrials.gov (2026, January 23). A Phase 1b\/2 Multicenter, Open-Label, Dose-Escalation and Dose-Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of Trastuzumab Deruxtecan (T-DXd) Monotherapy and Combinations in Adult Participants With HER2-Expressing Gastric Cancer (DESTINY-Gastric-03), Available online: https:\/\/www.clinicaltrials.gov\/study\/NCT04379596."},{"key":"ref_86","unstructured":"Japan Registry of Clinical Trials (jRCT) (2026, January 06). An Open Label Phase 1b\/2 Study to Evaluate Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd) plus Nivolumab plus Capecitabin plus Oxaliplatin for Patients with HER2 Low Gastric and Gastroesophageal Junction Adenocarcinoma (T-DXd_HER2Low). Available online: https:\/\/jrct.mhlw.go.jp\/en-latest-detail\/jRCT2031230477."},{"key":"ref_87","unstructured":"ClinicalTrials.gov (2026, January 09). Phase 2 Study of Trastuzumab Deruxtecan in the Neoadjuvant Treatment, or Trastuzumab Deruxtecan plus Capecitabine plus Durvalumab (MEDI4736) in the Preoperative and Postoperative Adjuvant Treatment for Patients with HER2 Positive Gastric and Gastroesophageal Junction Adenocarcinoma, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05034887."},{"key":"ref_88","unstructured":"ClinicalTrials.gov (2026, January 23). A Phase I, Open-Label, Dose Escalation Clinical Trial to Assess the Safety, Efficacy, Tolerability and Pharmacokinetics of the Recombinant Humanized Anti-PD1 Monoclonal Antibody (JS001) in Combination with Recombinant Humanized Anti-HER2 Monoclonal Antibody-MMAE Conjugate (RC48-ADC) in Treatment of HER2-Positive Advanced Malignant Solid Tumors, Available online: https:\/\/clinicaltrials.gov\/study\/NCT04280341."},{"key":"ref_89","unstructured":"ClinicalTrials.gov (2026, January 28). Efficacy and Safety of Disitamab Vedotin Combined With PD-1 in Posterior Line Therapy of Advanced HER2-Low Expressing Gastric Cancer, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06078982."},{"key":"ref_90","unstructured":"ClinicalTrials.gov (2026, January 23). Ph 1\/2 Study of Trastuzumab Deruxtecan (T-DXd) and Afatinib Combination in HER2-Low Advanced Gastric Cancer (VIKTORY-2), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06085755."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"107778","DOI":"10.1016\/j.isci.2023.107778","article-title":"Peripheral Neuropathy Associated with Monomethyl Auristatin E-Based Antibody-Drug Conjugates","volume":"26","author":"Fu","year":"2023","journal-title":"iScience"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1056\/NEJMoa2503119","article-title":"Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer","volume":"393","author":"Shitara","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/S1470-2045(23)00215-2","article-title":"Trastuzumab Deruxtecan in Patients in the USA and Europe with HER2-Positive Advanced Gastric or Gastroesophageal Junction Cancer with Disease Progression on or after a Trastuzumab-Containing Regimen (DESTINY-Gastric02): Primary and Updated Analyses from a Single-Arm, Phase 2 Study","volume":"24","author":"Smyth","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_94","unstructured":"Daiichi Sankyo, Inc., and AstraZeneca Pharmaceuticals LP (2026, January 14). ENHERTU (Fam-Trastuzumab Deruxtecan-Nxki) for Injection, for Intravenous Use: US Prescribing Information. Available online: https:\/\/daiichisankyo.us\/prescribing-information-portlet\/getPIContent?productName=Enhertu&inline=true."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"102418","DOI":"10.1016\/j.ctrv.2022.102418","article-title":"Resistance Mechanisms to HER2-Targeted Therapy in Gastroesophageal Adenocarcinoma: A Systematic Review","volume":"108","author":"Stroes","year":"2022","journal-title":"Cancer Treat. Rev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5600","DOI":"10.4049\/jimmunol.1202364","article-title":"Catecholamine-Induced \u03922-Adrenergic Receptor Activation Mediates Desensitization of Gastric Cancer Cells to Trastuzumab by Upregulating MUC4 Expression","volume":"190","author":"Shi","year":"2013","journal-title":"J. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.critrevonc.2019.05.001","article-title":"Resistance Mechanisms to Anti-HER2 Therapies in HER2-Positive Breast Cancer: Current Knowledge, New Research Directions and Therapeutic Perspectives","volume":"139","author":"Vernieri","year":"2019","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1158\/2159-8290.CD-18-0598","article-title":"EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer","volume":"9","author":"Hechtman","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1136\/gutjnl-2018-316522","article-title":"Liquid Biopsies to Track Trastuzumab Resistance in Metastatic HER2-Positive Gastric Cancer","volume":"68","author":"Wang","year":"2019","journal-title":"Gut"},{"key":"ref_100","first-page":"59","article-title":"Mechanisms of Resistance to Antibody-Drug Conjugates in Cancer Therapy: Molecular Basis and Therapeutic Strategies","volume":"8","author":"Hao","year":"2025","journal-title":"Cancer Drug Resist."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.apsb.2024.12.036","article-title":"Resistance to Antibody-Drug Conjugates: A Review","volume":"15","author":"Li","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"152697","DOI":"10.1016\/j.prp.2019.152697","article-title":"Gastrointestinal mixed adenoneuroendocrine carcinoma (MANEC): An immunohistochemistry study of 13 microsatellite stable cases","volume":"215","author":"Gurzu","year":"2019","journal-title":"Pathol. Res. Pract."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.3748\/wjg.v21.i4.1329","article-title":"Mixed adenoneuroendocrine carcinoma of gastrointestinal tract: Report of two cases","volume":"21","author":"Gurzu","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.12998\/wjcc.v7.i14.1837","article-title":"Primary gastric choriocarcinoma\u2014A rare and aggressive tumor with multilineage differentiation: A case report","volume":"7","author":"Gurzu","year":"2019","journal-title":"World J. Clin. Case"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"118","DOI":"10.2174\/2212798409666171101121108","article-title":"The epithelial-mesenchymal transition pathway in two cases with gastric metastasis originating from breast carcinoma, one with a metachronous primary gastric cancer","volume":"13","author":"Gurzu","year":"2018","journal-title":"Recent Pat. Anti-Cancer Drug Discov."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4673\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T04:11:22Z","timestamp":1779595882000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4673"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":105,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114673"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114673","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]}}}