A better understanding of the cellular and molecular features of advanced disease will afford new opportunities for investigation, therapeutic intervention and clinical management of patients afflicted with pancreatic cancer. We now provide compelling evidence that advanced pancreatic cancer is not one disease, but instead is composed of distinct morphologic and genetic subtypes with significantly different patterns of metastasis. We acknowledge that our findings are based on a biased population in that they were predominantly white and male compared with the average population, and additional studies will be required using a more representative patient population to verify these findings. Nonetheless, they provide novel insight into the mechanisms of pancreatic cancer metastasis.
There are three clinical implications of these findings. First, contrary to common belief, not all patients with pancreatic cancer die of widespread metastatic disease. Twelve percent of patients had no evidence of metastasis, and this finding was not unique to patients who underwent treatment, nor was it specific to patients initially diagnosed at an early stage. This finding parallels other studies of disease burden at autopsy in pancreatic cancer patients in which 8% to 15% of patients died with locally advanced carcinoma and without metastatic disease, even in the absence of any treatment.23,24
Moreover, among the 88% of patients with metastasis at autopsy, a broad range of metastatic burden was seen that ranged from few metastases (1 to 10) to extensive and widespread metastatic disease (100s to 1,000s), and again this finding did not relate to clinicopathologic features of these patients at initial diagnosis or their treatment history. Overall, in the patients with locally advanced pancreatic cancer in association with no metastases or a limited metastatic disease burden (1 to 10 metastases), the causes of death were often related to complications of locally destructive growth. By contrast, in patients with a primary carcinoma that was relatively confined to the pancreas but with a significant metastatic disease burden (100s to 1,000s of metastases) death was more commonly related to organ failure and cachexia, an observation that has been previously reported.23–25
In one of the few studies to stringently evaluate causes of death related to pancreatic cancer, Nakahashi et al25
found that the number of patients with extensive metastatic disease leading to hepatic dysfunction and death was relatively small, and the presence of isolated hepatic metastases were often clinically insignificant in comparison to the complications that arose from locally destructive growth of the primary carcinoma. Thus, it is important to note that isolated metastases at initial diagnosis are not a harbinger of widespread metastatic disease, nor do they always pose the greatest threat to patient survival compared to that of the primary tumor or other factors such as cachexia.
The second clinical implication of our findings is that the genetic status of a pancreatic carcinoma can be used to predict widespread metastatic failure. For example, locally advanced carcinomas from patients with no documented metastatic disease uncommonly showed loss of Dpc4 expression (22%) as compared with carcinomas from patients with extensive metastatic burden (100s to 1,000s) in which the rates of Dpc4 loss approached 75%. A similar relationship has been found in patients with colon cancer.26
While these findings do not establish that Dpc4 plays a direct role in metastatic ability, an intriguing study by Michor et al27
who applied mathematical modeling to the dynamics of metastasis suppressor gene inactivation found, at a constant rate of cancer cell dissemination, a striking similarity among bi-allelic advantageous mutations in a primary carcinoma and the expected number of metastatic foci (none to > 1,000) that paralleled the metastatic burden seen in this cohort of patients. While more studies are needed to clarify the role of DPC4
and other molecular features of pancreatic cancers in relation to patterns of failure (locally destructive v
distant metastasis), our observations do indicate that fundamental molecular differences exist in a primary pancreatic carcinoma that underlies aggressive behavior or may influence response to treatment.28,29–31
Our findings may also clarify previous findings correlating DPC4
status in surgically resected primary pancreatic cancers with patient outcome. Since loss of Dpc4 immunolabeling reflects an increased likelihood of the patient developing widespread metastasis, it should not be surprising that surgical series have reported a poorer survival in patients with pancreatic cancers with DPC4
Thus, it may be conceivable that patients with DPC4
positive carcinomas would receive a greater clinical benefit from intensive local control by chemoradiotherapy compared to patients with DPC4
negative carcinomas in which systemic chemotherapy alone may be more appropriate.
The third clinical implication of our findings is that advanced pancreatic cancers more commonly have high grade histologic features than those reported for early-stage disease, a finding also reported by Kamisawa et al.24
This finding is reminiscent of epithelial-mesenchymal transition (EMT), a feature well described in a variety of human tumors and in mouse models of pancreatic carcinoma.34,35
High grade features were not correlated with stage at initial diagnosis nor any other clinicopathologic features, and suggest additional events occur in primary carcinomas that lead to dedifferentiation. EMT in pancreatic cancer has been suggested to be mediated by transforming growth factor-β signaling through the PI3K/PTEN pathway.29,31,36
Although functional Dpc4 does not appear necessary for TGF-β-mediated EMT,29
in mouse models of pancreatic cancer functional Dpc4 has been associated with an undifferentiated phenotype.34
However, four of seven patients' carcinomas with anaplastic morphology in this study had loss of Dpc4 immunolabeling, in support of claims that Dpc4 is not specifically required for this phenomenon.
In summary, we now show that information gathered from a rapid autopsy approach has value in identifying novel areas for investigation into pancreatic cancer biology and therapy. These data also suggest that advanced pancreatic cancer may be composed of distinct morphologic and genetic subtypes with different patterns of metastasis. Clinical trials that take into account molecular features such as Dpc4 status of pancreatic cancers may have a role in stratifying patients for different treatment regimens. For example, based on the recent observation that cyclophosphamide given in association with a pancreatic cancer vaccine enhances T-cell responses in pancreatic cancer patients,37
we have an open pancreas cancer study in the neoadjuvant/adjuvant setting using our granulocyte macrophage colony-stimulating factor allogeneic whole cell vaccine in combination with immune modulating doses of Cytoxan and chemoradiotherapy. Immunolabeling will be performed on all resected specimens to determine Dpc4 loss versus retention of protein expression. Should we find a relationship of Dpc4 status and treatment outcome, it is conceivable that a follow-up study could use this information to stratify patients to either chemoradiotherapy when an intact DPC4
gene is found versus systemic chemotherapy alone in the event of DPC4