Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

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...

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Bibliographic Details
Published in:Cancers 2021-07, Vol.13 (14), p.3394
Main Authors: Izadi, Fereshteh, Sharpe, Benjamin P, Breininger, Stella P, Secrier, Maria, Gibson, Jane, Walker, Robert C, Rahman, Saqib, Devonshire, Ginny, Lloyd, Megan A, Walters, Zoë S, Fitzgerald, Rebecca C, Rose-Zerilli, Matthew J J, Underwood, Tim J, On Behalf Of Occams
Format: Article
Language:English
Subjects:
Adenocarcinoma
Biomarkers
c-Myc protein
Cancer therapies
Cell cycle
Chemoradiotherapy
Chemotherapy
Consortia
Copy number
Esophagus
Gene expression
Genomes
Genomic analysis
Genomic instability
Mutation
Myc protein
Patients
Peptides
Surgery
Survival analysis
Therapeutic targets
Tumor suppressor genes
Whole genome sequencing
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Summary: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 ( = 27) and non-responders classified as TRG4-5 ( =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle ( , ), c-Myc ( ), RTK/PIK3 ( , ) and gastrointestinal differentiation ( ) pathway genes being specifically altered in non-responders. Of note, 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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13143394