Reduced genomic tumor heterogeneity after neoadjuvant chemotherapy is related to favorable outcome in patients with esophageal adenocarcinoma.
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.
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, NL.
Askar
A
Obulkasim
Department of Pathology, VU University Medical Center, Amsterdam, NL.
Bauke
B
Ylstra
Department of Pathology, VU University Medical Center, Amsterdam, NL.
Hendrik F
HF
van Essen
Department of Pathology, VU University Medical Center, Amsterdam, NL.
Christian
C
Benner
MRC Clinical Trials Unit at University College London, London, UK.
Sally
S
Stenning
MRC Clinical Trials Unit at University College London, London, UK.
Ruth
R
Langley
Department of Surgery, Royal Marsden NHS Foundation Trust, London, UK.
William
W
Allum
Department of Gastrointestinal Oncology, Royal Marsden NHS Foundation Trust, London and Surrey, UK.
David
D
Cunningham
Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Imran
I
Inam
Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.|Department of Pathology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, NL.
Lindsay C
LC
Hewitt
Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Nicolas P
NP
West
Department of Pathology, VU University Medical Center, Amsterdam, NL.
Gerrit A
GA
Meijer
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, NL.|Department of Mathematics, VU University, Amsterdam, NL.
Mark A
MA
van de Wiel
Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.|Department of Pathology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, NL.
Heike I
HI
Grabsch
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D056915:DNA Copy Number Variations / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D005260:Female; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010865:Pilot Projects; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
array CGH; chemotherapy; esophageal adenocarcinoma; prognosis