DPC4 Gene Status of the Primary Carcinoma Correlates With Patterns of Failure in Patients With Pancreatic Cancer

Abstract

A B S T R A C T PurposeContrary 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. Materials and MethodsRapid 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. ResultsAt 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 ϭ .007). ConclusionPancreatic 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.

Targeting TGF-β Signaling for Therapeutic Gain

“…In colon cancer with microsatellite instability (MIS), TGFBR2 is a mutational hotspot for genetic inactivation caused by the possession of a 10-bp polyadenine repeat within its coding sequence (Parsons et al 1995). However, loss of a single component of the pathway, such as SMAD4/DPC4 in pancreatic cancer (Iacobuzio-Donahue et al 2009), does not necessarily ablate all TGF-b responses. Tumor cells are highly plastic, and can rewire signaling networks independently of Smad4 (Hocevar et al 1999;Giehl et al 2007;Descargues et al 2008).…”

Improving Survival of Pancreatic Cancer. What Have We Learnt?

“…The same authors also showed that SMAD4 status correlates with patterns of failure in pancreatic cancer [112]. Also, mutations that abolish TP53 gene expression promote widespread metastatic failure independently of SMAD4 loss in some patients.…”

The genetic classification of pancreatic neoplasia

“…They found that loss of SMAD4 in a pancreatic cancer was associated with a shorter overall survival (11.5 months compared with 14.2 months in patients whose tumors had intact SMAD4). Taking these findings one step further, Iacobuzio-Donahue et al [60] showed that PDAs with inactivated SMAD4 are more likely to metastasize widely than are PDAs with intact SMAD4. Taken together, these findings suggest that SMAD4 status could guide therapeutic approaches in patients with borderline resectable PDA.…”