Simple SummaryGastroesophageal adenocarcinoma (GOA) is a cancer that has poor survival. Most cases are diagnosed when a cure is not possible, and treatment often has many side effects. It occurs less often and is associated with better outcomes in females. The reason for this is not known. We sought to use samples from a clinical trial in older adults with GOA to investigate whether this observation could be related to oestrogen and its action through oestrogen receptors. We found no clear link between outcome and oestrogen receptor expression but did note improved survival with older age and female sex.AbstractGastroesophageal adenocarcinoma is a disease of older adults that is associated with a very poor prognosis. It is less common and has better outcomes in females. The reason for this is unknown but may relate to signalling via the main oestrogen receptors (ER) α and β. In this study, we sought to investigate this using the GO2 clinical trial patient cohort. GO2 recruited older and/or frail patients with advanced gastroesophageal cancer. Immunohistochemistry was performed on tumour samples from 194 patients. The median age of the population was 76 years (range 52–90), and 25.3% were female. Only one (0.5%) tumour sample was positive for ERα, compared to 70.6% for ERβ expression. There was no survival impact according to ERβ expression level. Female sex and younger age were associated with lower ERβ expression. Female sex was also associated with improved overall survival. To our knowledge, this is the largest study worldwide of ER expression in a cohort of patients with advanced gastroesophageal adenocarcinoma. It is also unique, given the age of the population. We have demonstrated that female sex is associated with better survival outcomes with palliative chemotherapy but that this does not appear to be related to ER IHC expression. The differing ER expression according to age supports the concept of a different disease biology with age.