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Improving the outcome and management of cancer patients

Kaplan–Meier plots of survival comparing outcomes for patients with 0 of 4, 1–2 of 4, and 3–4 of 4 genes dysregulated for (A) the complete external validation dataset (_2 LR, 13.582; 2 df; P _ 0.001), (B) external validation set patients who were chemotherapy-naive (_2 LR, 4.323; 2 df; P _ .038), and (C) external validation dataset patients who had received neoadjuvant chemotherapy (_2 LR, 5.013; 2 df; P _ .025). Notches represent censored data; P values were calculated using the log-rank (Mantel–Cox) test.
Oesophageal cancer is a disease with a very poor prognosis. Less than 1 in 5 patients diagnosed will still be alive after 5 years. We are interested in finding clinical and molecular markers of prognosis to better enable us to predict how well patients will do, allowing better management decisions to be made. We are doing this via an analysis of both the clinical and molecular features of a large cohort of patients with gastro-oesophageal cancer as part of a multi-centre collaboration called OCCAMS. We have recently generated and validated a four-gene signature that allows us to stratify patients with different outcome (Peters et al., Gastroenterology, 139(6):1995-2004, 2010). We have also identified genes with a potential relevant role in cancer through the analysis of chromosomal abnormalities in these large cohorts of patients (Goh et al., Gut, 2011).  Now with the advent of massively parallel sequencing we are performing whole genome sequencing of oesophageal adenocarcinoma in collaboration with members of OCCAMS through a CRUK funded International Cancer Genome Consortium (ICGC) project. These genome wide analyses are leading to insights into the molecular pathogenesis as well as providing potential therapeutic targets.

With regards to therapy the expression data has enabled us to classify samples into distinct groups with different clinical phenotypes. Knowing the characteristics of each group may identify particular biological pathways which are relevant, and may be targetable with specific drugs. We are currently performing an investigator led Phase 2B clinical trial called LEO to determine the efficacy of Lapatinib (a dual EGFR and HER2 receptor tyrosine kinase inhibitor) in reducing signalling through MAPK pathways in this disease and whether we can predict response to therapy on an individualised basis.