Oesophageal adenocarcinoma (OAC) has a poor prognosis and the fastest increasing incidence of any malignancy in Western populations. Neoadjuvant chemoradiation therapy (neo-CRT) followed by surgery, is increasingly the standard of care for locally advanced OAC. Evidence demonstrates that the tumour response to neo-CRT is the best predictor of disease-free and overall survival, with 5-year survival rates increased to 60% for patients achieving a complete pathological response (pCR). However, only ~30% of patients achieve a pCR following neo-CRT. The remaining patients (70%) are subject to therapy-associated toxicities without benefit and their prognosis may be worsened by delay to surgery. There are currently no alternative treatment strategies for these patients.
This innovative project will address an unmet global healthcare challenge in OAC, to identify, prior to treatment, those patients who will derive a benefit from neo-CRT, for improved stratification. In pilot studies, we demonstrate for the first time, that activation of the ‘complement system’, an important regulator of immunity, is altered in vitro in a novel OAC radioresistance model and in vivo, in pre-treatment sera and tumour biopsies from OAC patients who are resistant to neo-CRT. This novel study will prospectively validate key complement components in pre-treatment tumour tissue and sera, as predictors of response to neo-CRT in OAC patients enrolled in a phase III clinical trial at a national and international hospital site. We will also determine the cellular compartment that these alterations are associated with and will determine the relationship between complement and macrophages in the tumour microenvironment to identify novel combination immunotherapy and neo-CRT approaches for the 70% of patients who are resistant to the current standard of care. The findings of this study will aid clinicians in treatment stratification and planning, leading to tangible impact on patient treatment, quality of life and survival, worldwide.
