369. GENOMIC ALTERATIONS AND SURVIVAL AFTER TREATMENT OF EAC BY SURGERY WITHOUT CHEMO- OR RADIOTHERAPY

Abstract

Abstract Prognostic biomarkers for esophageal adenocarcinoma (EAC) remain elusive but may be helpful in treatment planning, as TNM staging often fails to accurately predict survival. Advanced stage patients are treated by peri-operative chemo/radiotherapy; biomarkers associated with survival are thus likely to represent both true prognostic markers as well as markers of response to chemo/radiotherapy. Here we present first-pass genomic findings for a cohort of optimally staged EAC patients treated by surgery alone. DNA was extracted from fresh frozen EAC and matching normal squamous esophageal tissues obtained at esophagectomy from 65 consenting patients who did not receive any neo- or adjuvant chemo- or radiotherapy due to institutional preference at the time of tissue collection. Library preparation and sequencing for a targeted 600 cancer-associated gene panel designed using the Roche/NimbleGen EZ Choice Library NimbleDesign platform were conducted on Illumina-based platforms followed by analysis with an accredited bioinformatics pipeline. The panel design incorporated the entire coding region plus 10 bp of flanking intron of each gene. Mean age 70 yrs; 88% male. All patients underwent an en bloc esophagectomy (mean 35 lymph nodes). TNM (7th ed.) stages were 61% Stage 3, 18% stage 2, 14% stage 1, 6% stage 4. At median 9.5 years follow-up, 20 (31%) patients remained alive. Copy number changes were common, reflecting chromosomal instability. Less than 8% of patients had high tumour mutational burden (>10mut/MB), associated with mutations in DNA repair genes. Commonest somatic mutations included TP53 (HR: 0.43) and LRP1B (HR: 1.7). Pathways implicated included RTK signalling (PIK3CA, EGFR, KRAS), DNA damage (BRCA1, PALB2, MGMT) and histone remodelling (ARID1A, ARID2, KMT2D). Peri-operative treatment means linking genomic changes independent of stage to clinical outcomes is difficult. Neoadjuvant and/or adjuvant treatment is now standard for T2–4 or node positive EAC. This cohort of 65 patients, most of whom had stage 3 disease and all of whom underwent optimal staging with en bloc esophagectomy, represents a unique opportunity to analyze characteristics of EAC without confounding by peri-operative treatment. An EAC-specific DNA sequencing panel approach offers potential for personalized therapy.