Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing due to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrates that this is a heterogeneous cancer dominated by copy number alterations with frequent large scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTKi therapy might be required, as we demonstrate in vitro. However, mutational signatures reveal three distinct molecular subtypes with potential therapeutic relevance, which we verify in an independent cohort (n=87): i) enriched for BRCA signature with prevalent defects in the homologous recombination pathway; ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; iii) C>A/T mutational pattern with evidence of an ageing imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.

Background:Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo.Methods:Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/− Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity.Results:The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules.Conclusions:Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.

In the version of this article initially published online, the mutation signature illustrations for S1 and S2 in Figure 3a were switched. Additionally, in the Online Methods, the text originally stated that structural variants were called using BWA-MEM, when it should have stated that these were called using BWA. These errors have been corrected for the print, PDF and HTML versions of this article.

Oesophageal adenocarcinoma (OAC) has increased dramatically in Western countries, including the UK, over the past 30 years. It usually presents de novo, but is often preceded by Barrett's oesophagus (BO), a premalignant condition whereby the normal squamous epithelium is replaced by columnar lined epithelium with intestinal metaplasia. The main risk factors for BO include male sex, obesity and chronic gastro-oesophageal reflux of acid and bile. The estimated annual risk of BO progression is 0.3%, increasing substantially, up to 30%, when dysplasia is present. Endoscopic surveillance is recommended to detect neoplastic changes at an early stage and considerable evidence supports endoscopic treatment for confirmed low-and high-grade dysplasia, and intramucosal adenocarcinoma. Most OACs are diagnosed at a more advanced stage requiring CT-PET assessment and multi-modal treatment. Surgical treatment is performed in specialist centres, increasingly combined with cytotoxic chemotherapy and radiotherapy, involving close liaison between members of the multidisciplinary team. Molecular targeted therapies, such as HER2 and VEGFR-inhibitors, are beginning to penetrate clinical practice, but high molecular heterogeneity has impeded progress. In view of the overall dismal survival (<20%) for advanced OAC, there is renewed interest in screening techniques for early detection and intervention of dysplastic BO.

Oesophageal adenocarcinoma (OAC) has increased dramatically in Western countries, including the UK, over the past 30 years. It usually presents de novo, but is often preceded by Barrett's oesophagus (BO), a premalignant condition whereby the normal squamous epithelium is replaced by columnar lined epithelium with intestinal metaplasia. The main risk factors for BO include male sex, obesity and chronic gastrooesophageal reflux of acid and bile. The estimated annual risk of BO progression is 0.3%, increasing substantially, up to 30%, when dysplasia is present. Endoscopic surveillance is recommended to detect neoplastic changes at an early stage and considerable evidence supports endoscopic treatment for confirmed low-and high-grade dysplasia, and intramucosal adenocarcinoma. Most OACs are diagnosed at a more advanced stage requiring CT-PET assessment and multi-modal treatment. Surgical treatment is performed in specialist centres, increasingly combined with cytotoxic chemotherapy and radiotherapy, involving close liaison between members of the multidisciplinary team. Molecular targeted therapies, such as HER2 and VEGFR-inhibitors, are beginning to penetrate clinical practice, but high molecular heterogeneity has impeded progress. In view of the overall dismal survival (<20%) for advanced OAC, there is renewed interest in screening techniques for early detection and intervention of dysplastic BO.

No abstract