Reduced genomic tumor heterogeneity after neoadjuvant chemotherapy is related to favorable outcome in patients with esophageal adenocarcinoma

// Askar Obulkasim 1 , Bauke Ylstra 2 , Hendrik F. van Essen 2 , Christian Benner 2 , Sally Stenning 3 , Ruth Langley 3 , William Allum 4 , David Cunningham 5 , Imran Inam 6 , Lindsay C. Hewitt 6, 8 , Nicolas P. West 6 , Gerrit A. Meijer 2 , Mark A. van de Wiel 1, 7, * , Heike I. Grabsch 6, 8, * 1 Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, NL 2 Department of Pathology, VU University Medical Center, Amsterdam, NL 3 MRC Clinical Trials Unit at University College London, London, UK 4 Department of Surgery, Royal Marsden NHS Foundation Trust, London, UK 5 Department of Gastrointestinal Oncology, Royal Marsden NHS Foundation Trust, London and Surrey, UK 6 Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK 7 Department of Mathematics, VU University, Amsterdam, NL 8 Department of Pathology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, NL * Both senior authors contributed equally to this study (shared senior authorship) Correspondence to: Heike I. Grabsch, email: H.Grabsch@maastrichtuniversity.nl Keywords: esophageal adenocarcinoma, array CGH, prognosis, chemotherapy Received: March 06, 2016     Accepted: April 29, 2016     Published: June 06, 2016 ABSTRACT Neoadjuvant chemo(radio)therapy followed by surgery is the standard of care for patients with locally advanced resectable esophageal adenocarcinoma (EAC). There is increasing evidence that drug resistance might be related to genomic heterogeneity. We investigated whether genomic tumor heterogeneity is different after cytotoxic chemotherapy and is associated with EAC patient survival. We used arrayCGH and a quantitative assessment of the whole genome DNA copy number aberration patterns (‘DNA copy number entropy’) to establish the level of genomic tumor heterogeneity in 80 EAC treated with neoadjuvant chemotherapy followed by surgery (CS group) or surgery alone (S group). The association between DNA copy number entropy, clinicopathological variables and survival was investigated. DNA copy number entropy was reduced after chemotherapy, even if there was no morphological evidence of response to therapy (p<0.001). Low DNA copy number entropy was associated with improved survival in the CS group (p=0.011) but not in the S group (p=0.396). Our results suggest that cytotoxic chemotherapy reduces DNA copy number entropy, which might be a more sensitive tumor response marker than changes in the morphological tumor phenotype. The use of DNA copy number entropy in clinical practice will require validation of our results in a prospective study.