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DPC4/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma

From the Cancer Research Program, Garvan Institute of Medical Research, and Division of Surgery and Department of Anatomical Pathology, St Vincent’s Hospital Campus, Darlinghurst, Sydney; Department of Anatomical Pathology, Royal Prince Alfred Hospital, and Department of Pathology, University of Sydney, Camperdown; and Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales, Australia.

Address reprint requests to S.M. Henshall, PhD, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia; email: s.henshall{at}garvan.org.au

PURPOSE: Prognostic indicators in pancreatic cancer (PC) are poorly defined and difficult to quantify preoperatively, hence they may lead to inappropriate patient selection for treatment. We examined the protein expression of key cell-cycle regulatory and cell-signaling molecules that occur at high frequency in PC and assessed their relationship to clinicopathologic parameters, response to operative resection, and outcome.

PATIENTS AND METHODS: We identified 348 patients with pancreatic ductal adenocarcinoma and assessed the influence of reported clinicopathologic prognostic factors and the expression of the cell-cycle regulatory genes p21^WAF1/CIP1 (CDKN1A), cyclin D1 (CCND1), p53, and p16^INK4A (CDKN2) and the cell-signaling molecule DPC4/Smad4 (MADH4) using immunohistochemistry in a subgroup of 129 patients.

RESULTS: Independent prognostic factors in resected patients were tumor size greater than 45 mm (P = .0015), involvement of surgical margins (P < .0001), and perineural invasion (P = .014). Loss of DPC4/Smad4 expression cosegregated with resectability (P < .0001) and was associated with improved survival after resection (P < .0001), whereas resection did not improve survival in patients whose tumor expressed DPC4/Smad4 (P = .5). Aberrant expression of p21^WAF1/CIP1, cyclin D1, p53, or p16^INK4A was not associated with a difference in survival.

CONCLUSION: Tumor size (> 45 mm), resection margin involvement, and perineural invasion were independent prognostic factors. Preoperative assessment of DPC4/Smad4 expression has potential as a prognostic indicator in patients with PC since resection did not benefit those patients whose cancers expressed DPC4/Smad4 and accurate assessment of DPC4/Smad4 expression, unlike tumor size, margin status, and perineural invasion, does not require resection.

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