DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.
OBJECTIVE
Contrary to the extensive data accumulated regarding pancreatic carcinogenesis, the clinical and molecular features characteristic of advanced stage (stage III and IV) disease are unknown. A comprehensive study of pancreatic cancers from patients who have succumbed to their disease has the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for intervention.


METHODS
Rapid autopsies were performed on 76 patients with documented pancreatic cancer. The histologic features of end stage disease were determined and correlated to the stage at initial diagnosis, patterns of failure (locally destructive v metastatic disease) and the status of the KRAS2, TP53, and DPC4 genes.


RESULTS
At autopsy, 30% of patients died with locally destructive pancreatic cancer, and 70% died with widespread metastatic disease. These divergent patterns of failure found at autopsy (locally destructive v metastatic) were unrelated to clinical stage at initial presentation, treatment history, or histopathologic features. However, Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy, a sensitive marker of DPC4 genetic status, was highly correlated with the presence of widespread metastasis but not with locally destructive tumors (P = .007).


CONCLUSIONS
Pancreatic cancers are represented by distinct genetic subtypes with significantly different patterns of failure. Determinations of DPC4 status at initial diagnosis may be of value in stratifying patients into treatment regimens related to local control versus systemic therapy.
Iacobuzio-Donahue
Christine A
CA
Department of Pathology, Surgery, and Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. ciacobu@jhmi.edu
Fu
Baojin
B
Yachida
Shinichi
S
Luo
Mingde
M
Abe
Hisashi
H
Henderson
Clark M
CM
Vilardell
Felip
F
Wang
Zheng
Z
Keller
Jesse W
JW
Banerjee
Priya
P
Herman
Joseph M
JM
Cameron
John L
JL
Yeo
Charles J
CJ
Halushka
Marc K
MK
Eshleman
James R
JR
Raben
Marian
M
Klein
Alison P
AP
Hruban
Ralph H
RH
Hidalgo
Manuel
M
Laheru
Daniel
D
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D001344:Autopsy; D018196:Carcinoma, Adenosquamous / Q000235:genetics* / Q000473:pathology; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D051901:Smad4 Protein / Q000235:genetics*; D016019:Survival Analysis; D017211:Treatment Failure; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins