Female Sex but Not Oestrogen Receptor Expression Predicts Survival in Advanced Gastroesophageal Adenocarcinoma—A Post-hoc Analysis of the GO2 Trial

Gastroesophageal 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

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma

Background: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. Materials and methods: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). Results: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. Conclusions: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma

BackgroundAn improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA.Materials and methodsTranscriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430).ResultsIn the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME.ConclusionsOur results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours

Fatal attractions? Correlations of CXCL12-CXCR4-CXCR7 expression with disease progression in melanoma and Kaposi sarcoma

No abstract available

Evidence for the asynchronous retreat of large outlet glaciers in southeast Greenland at the end of the last glaciation

Recent rapid changes in the marine-terminating sectors of the Greenland Ice Sheet (GrIS) have prompted concerns about the future stability of the ice sheet. Long-term records of ice sheet behaviour provide valuable context to assess the magnitude of current change and may help resolve the mechanisms driving deglaciation. We report 23 new 10Be exposure ages which constrain the deglacial history of two large fjord systems in southeast (SE) Greenland. We compare our chronologies with existing data from the centre of the sector to examine the timing and style of deglaciation at a regional-scale. Glacial erratic 10Be exposure ages demonstrate that Kangerdlugssuaq Fjord deglaciated at ∼11.8 ka at the end of the Younger Dryas (YD – 12.8–11.6 ka). Retreat at Kangerdlugssuaq Fjord coincided with known incursion of the warm Irminger Current (IC) onto the continental shelf; this is inferred to have initiated retreat. Comparison with recently published results from Sermilik Fjord and new 10Be ages from Bernstorffs Fjord indicates deglaciation occurred ∼1 ka later in the south of the SE region. Sermilik Fjord (∼10.9 ka) and Bernstorffs Fjord (∼10.4 ka) deglaciated later; retreat likely occurred in response to dramatic climatic amelioration at the termination of the YD stadial. We suggest that the disparate timing of deglaciation across the SE region may be primarily explained by the varying influence of the warm IC; glaciers in southern SE Greenland were isolated from warm Atlantic waters during the YD by complex shelf bathymetry. In all fjord settings ice retreat was rapid and persistent, consistent with the absence of geomorphological evidence for stillstand or readvance events. Ice retreat was accompanied by rapid thinning and likely continued to well within present-day ice sheet margins. Glacial erratic 10Be age determinations and geomorphological observations show no evidence for Holocene readvance events prior to the Little Ice Age (LIA)