4.6 Article

Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

Journal

CANCERS
Volume 13, Issue 14, Pages -

Publisher

MDPI
DOI: 10.3390/cancers13143394

Keywords

esophageal adenocarcinoma; chemotherapy; mutation; response; genomics; NAV3

Categories

Funding

  1. Cancer Research UK & Royal College of Surgeons of England Advanced Clinician Scientist Fellowship [A23924]
  2. Wessex Medical Research Innovation Fund [2011 R06, 2014 U10]
  3. Leuka Charity, John Goldman Fellowship [2016/JGF/0003]
  4. Southampton CRUK Centre Development Fund
  5. Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium as part of the International Cancer Genome Consortium
  6. Cancer Research UK [RG81771/84119, RG66287]
  7. Medical Research Council [RG84369]
  8. NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]

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Esophageal adenocarcinoma (EAC) patients receive pre-operative chemotherapy, but a significant portion do not respond to this treatment, exhibiting chromosomal instability and gene copy number alterations. Different genetic profiles, including mutations in the tumor suppressor NAV3, are associated with non-responders, presenting potential drug targets for alternative treatment pathways.
Simple Summary Esophageal 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.

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