The treatment of metastasized gastroesophageal adenocarcinoma largely depends on molecular profiling based on immunohistochemical procedures. Therefore, the examination of HER2, PD-L1, and dMMR/MSI is recommended by the majority of clinical practice guidelines, as positive expression leads to different treatment approaches. Data from large phase-III trials and consequent approvals in various countries enable physicians to offer their patients several therapy options including immunotherapy, targeted therapy, or both combined with chemotherapy. The introduction of novel therapeutic targets such as CLDN18.2 leads to a more complex decision-making process as a significant number of patients show positive results for the co-expression of other biomarkers besides CLDN18.2. The aim of this review is to summarize the current biomarker landscape of patients with metastatic gastroesophageal tumors, its direct clinical impact on daily decision-making, and to evaluate current findings on biomarker co-expression. Furthermore, possible treatment strategies with multiple biomarker expression are discussed.

Summary: Recent advances in the development of new therapeutic agents and the execution of numerous randomized controlled trials have changed the landscape of systemic therapy approaches in patients with esophageal squamous cell cancer (ESCC). Particularly the inclusion of immunotherapy permits clinicians to improve patient management in multiple settings. This review gives an overview of standard-of-care treatment and sheds light on new therapeutic options, recently approved treatments, and ongoing trials.

Background: History of malignant disease is a common exclusion criterion in clinical cancer trials, yet data on the impact of cancer survivorship on outcome in gastroesophageal cancer patients are scarce. Methods: Retrospective association analyses of self-reported prior or concurrent malignancies with patient characteristics, tumor characteristics, symptoms and overall survival (OS) were performed in 1491 gastroesophageal cancers patients treated between 01/01/2000 and 31/12/2021 at the Medical University of Vienna. Results: Of 1491 patients 255 (18%) had other primary cancer diagnoses, of which 185 (73%) occurred before, 52 (20%) at the same time as and 18 (7%) both before and at the same time as gastroesophageal cancer diagnosis. 205 (80%) patients had one, 43 (17%) had 2 and 7 (3%) had 3 other malignancies. History of other malignancies was associated with older age (p < 0.0001), squamous cell histology (p = 0.018), less aggressive localized tumor stages (p = 0.037) and fewer acid reflux (p = 0.011). There was neither an association between history of other primary malignancies nor the number of other cancer entities and OS (p = 0.47; p = 0.43). Conclusion: Self-reported history of other malignant diseases is frequent in a real-life European gastroesophageal cancer cohort and was not statistically significantly associated with outcome, but rather with older age and squamous cell histology. Our data emphasize that cancer survivors should not be categorically excluded from clinical cancer trials due to fear of dismal prognosis. Prospective research is warranted to improve eligibility for this subgroup.

Since results of the Trastuzumab for Gastric Cancer (ToGA) trial were published in 2010, the addition of trastuzumab to chemotherapy is the standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastroesophageal adenocarcinoma, yet data from European real-world cohorts are scarce. We evaluated baseline characteristics and treatment regimens of gastroesophageal adenocarcinoma patients with advanced and metastatic disease (stage IV) treated at the Medical University of Vienna between 01/01/2010 and 31/12/2023. Log-rank tests were performed to analyse differences in survival. In our cohort of 369 advanced/metastatic gastroesophageal cancer patients, 78 (24%) of tumours with known HER2 status were HER2 positive. First-line chemotherapy with trastuzumab was administered to 60 HER2-positive patients (16% of the overall cohort) and showed statistically significantly improved overall survival compared to patients treated with chemotherapy only (17.3 vs 11.9 months, hazard ratio = 0.62, P =0.0011). Regarding tumour location, 15 (25%) patients had oesophageal cancer, 23 (38%) had cancer of the gastroesophageal junction, and 22 (37%) had gastric cancer. However, no statistically significant survival benefit was observed with the addition of trastuzumab in tumour location subgroups (P = 0.058, P = 0.088, P = 0.07). Our data support the results from the ToGA trial in a real-world cohort and underline the importance of HER2 testing and administration of trastuzumab in clinical routine. Although not included in the initial ToGA trial, oesophageal adenocarcinoma patients express HER2 to a significant extent, and further analyses are needed to investigate the benefit of trastuzumab and other anti-HER2 treatment options in this subgroup.