title: Smad4 loss in esophageal adenocarcinoma is associated with an increased propensity for disease recurrence and poor survival.
abstract: Previously regarded as a rare neoplasm, the incidence of esophageal adenocarcinoma has risen rapidly in recent decades. It is often discovered late in the disease process and has a dismal prognosis. Current prognostic markers including clinical, radiographic, and histopathologic findings have limited utility and do not consider the biology of this deadly disease. Genome-wide analyses have identified SMAD4 inactivation in a subset of tumors. Although Smad4 has been extensively studied in other gastrointestinal malignancies, its role in esophageal adenocarcinoma remains to be defined. Herein, we show, in a large cohort of esophageal adenocarcinomas, Smad4 loss by immunohistochemistry in 21 of 205 (10%) tumors and that Smad4 loss correlated with increased postoperative recurrence (P=0.040). Further, patients whose tumors lacked Smad4 had shorter time to recurrence (TTR) (P=0.007) and poor overall survival (OS) (P=0.011). The median TTR and OS of patients with Smad4-negative tumors was 13 and 16 months, respectively, as compared with 23 and 22 months, respectively, among patients with Smad4-positive tumors. In multivariate analyses, Smad4 loss was a prognostic factor for both TTR and OS, independent of histologic grade, lymphovascular invasion, perineural invasion, tumor stage, and lymph node status. Considering Smad4 loss correlated with postoperative locoregional and/or distant metastases, Smad4 was also assessed in a separate cohort of 5 locoregional recurrences and 43 metastatic esophageal adenocarcinomas. In contrast to primary tumors, a higher prevalence of Smad4 loss was observed in metastatic disease (44% vs. 10%). In summary, loss of Smad4 protein expression is an independent prognostic factor for TTR and OS that correlates with increased propensity for disease recurrence and poor survival in patients with esophageal adenocarcinoma after surgical resection.
authors: Departments of *Pathology †Surgery ‡Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors: Aatur D
authors: AD
authors: Singhi
authors: Tyler J
authors: TJ
authors: Foxwell
authors: Katie
authors: K
authors: Nason
authors: Kristi L
authors: KL
authors: Cressman
authors: Kevin M
authors: KM
authors: McGrath
authors: Weijing
authors: W
authors: Sun
authors: Nathan
authors: N
authors: Bahary
authors: Herbert J
authors: HJ
authors: Zeh
authors: Ryan M
authors: RM
authors: Levy
authors: James D
authors: JD
authors: Luketich
authors: Jon M
authors: JM
authors: Davison
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D051901:Smad4 Protein / Q000032:analysis*; D013997:Time Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C497796:SMAD4 protein, human; D051901:Smad4 Protein
references: Am J Pathol. 2000 Oct;157(4):1105-11
references: 11021814
references: PLoS One. 2014;9(1):e79079
references: 24454681
references: Am J Pathol. 2001 Feb;158(2):537-42
references: 11159190
references: Clin Cancer Res. 2001 Dec;7(12):4115-21
references: 11751510
references: Br J Cancer. 2002 Sep 9;87(6):630-4
references: 12237773
references: N Engl J Med. 2002 Nov 21;347(21):1662-9
references: 12444180
references: Lancet Oncol. 2003 Aug;4(8):481-8
references: 12901962
references: N Engl J Med. 2003 Dec 4;349(23):2241-52
references: 14657432
references: Br J Surg. 2004 Aug;91(8):943-7
references: 15286953
references: JAMA. 1991 Mar 13;265(10):1287-9
references: 1995976
references: Cancer Epidemiol Biomarkers Prev. 1995 Mar;4(2):85-92
references: 7742727
references: Science. 1996 Jan 19;271(5247):350-3
references: 8553070
references: Oncogene. 1999 May 20;18(20):3098-103
references: 10340381
references: J Natl Cancer Inst. 2005 Jan 19;97(2):142-6
references: 15657344
references: J Clin Oncol. 2006 May 10;24(14):2137-50
references: 16682732
references: N Engl J Med. 2006 Jul 6;355(1):11-20
references: 16822992
references: J Clin Oncol. 2009 Apr 10;27(11):1806-13
references: 19273710
references: Clin Cancer Res. 2009 Jul 15;15(14):4674-9
references: 19584151
references: Br J Cancer. 2014 Feb 18;110(4):946-57
references: 24384683
references: J Surg Oncol. 2014 Aug;110(2):171-5
references: 24665063
references: Eur J Biochem. 2000 Dec;267(24):6954-67
references: 11106403
references: Cancer Epidemiol Biomarkers Prev. 2010 Jun;19(6):1468-70
references: 20501776
references: Cancer. 2010 Aug 15;116(16):3763-73
references: 20564099
references: N Engl J Med. 2012 May 31;366(22):2074-84
references: 22646630
references: Ann Surg. 2012 Jul;256(1):95-103
references: 22668811
references: Cancer Res. 2012 Sep 1;72(17):4383-93
references: 22751462
references: Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30
references: 22992590
references: Cancer Discov. 2012 Oct;2(10):899-905
references: 22877736
references: J Clin Oncol. 2013 Apr 20;31(12):1576-82
references: 23509313
references: Nat Genet. 2013 May;45(5):478-86
references: 23525077
references: Nat Rev Gastroenterol Hepatol. 2014 Jan;11(1):19-27
references: 23982683
references: Am J Pathol. 2000 Jan;156(1):37-43
references: 10623651