Abstract
Simple SummaryEsophageal adenocarcinoma (EAC) is a cancer with very poor survival outcomes. Patients are treated with pre-operative chemotherapy or chemoradiotherapy before surgery. However, four out of every five patients do not respond to pre-operative therapy and these patients (non-responders) have significantly worse outcomes. Identifying non-responders prior to therapy would allow alternative treatment pathways to be offered to these patients. In this study, we analyze whole genome sequences of pre-treatment biopsies from 65 patients and find that non-responders display chromosomal instability and increased gene copy number alterations. We report a distinct profile of copy number alterations in non-responders compared to responders, predominantly in genes involved in cell cycle control and RTK/Ras signaling. Mutations in the tumor suppressor NAV3 are also found exclusively in non-responders. These genetic profiles present potential drug targets for investigation in EAC patients who would not respond to pre-operative chemotherapy.Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.
Highlights
Esophageal adenocarcinoma (EAC) is a cancer of unmet clinical need
We evaluated the CIN70 signature in matched RNA-Seq data, a gene signature whose expression was consistently correlated with total functional aneuploidy across multiple cancer types [51]
We investigated whether copy number changes in driver genes were co-occurrent and found that GATA6 and EGFR
Summary
Esophageal adenocarcinoma (EAC) is a cancer of unmet clinical need. Patients with locally advanced EAC suitable for curative treatment receive neo-adjuvant chemoradiotherapy or neo-adjuvant chemotherapy (NAC) with or without adjuvant chemotherapy as standard of care. Randomized trials of NAC have consistently shown survival benefits for patients [1,2,3,4,5]. This survival advantage (9% at five years) [6] is not due to an incremental improvement in outcome for all patients, but instead driven by a very good response in less than 20% of patients treated with the ECX regimen [7,8,9,10,11], or in. A Mandard TRG score of 1 corresponds to complete regression of the tumor leaving only fibrosis; TRG 2 is defined by fibrosis and scattered residual tumor cells; TRG 3 and 4 display progressively less tumor regression; and TRG
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