Histological and molecular markers for pancreatic adenocarcinoma: can they help us define which patients should receive it?

Defining the ability of histological or molecular markers to predict outcome for cancer patients is crucial. Because pancreatic adenocarcinoma is currently associated with such a poor prognosis, understanding the significance of such markers could have a profound effect on patient care, both in predicting prognosis and in guiding therapy. In this issue ofAnnals of Surgical Oncology,White et al. from Duke University take an important first step toward defining the role of histological and molecular markers for patients with pancreatic adenocarcinoma. All of the patients evaluated in this study were treated with neoadjuvant chemoradiotherapy (CRT) followed by surgical resection. Histological evaluation of 54 post-CRT pancreatic tumor specimens was performed to correlate these findings with overall survival. Specifically, tumor fibrosis, tumor load (the percentage of tumor composed of viable tumor cells), and the presence of tumor necrosis were analyzed. Multivariate analysis revealed that in addition to the routine histological prognosticators of lymph node positivity and tumor differentiation, the presence of a large residual tumor load and, paradoxically, the presence of tumor necrosis was associated with a poor prognosis. Although immunohistochemistry was also performed on a subset of these patients to evaluate the significance of epidermal growth factor receptor and p53 expression, there was no correlation between the expression of these markers and overall survival. The unexpected finding of tumor necrosis as a negative predictive factor is difficult to explain, although the authors suggest that this may be a surrogate marker for rapidly dividing tumor. Clearly these findings address an important issue—defining which patients have an improved prognosis after neoadjuvant therapy for pancreatic adenocarcinoma. Other investigators have attempted to characterize the genetic changes that occur in pancreatic cancer tissue, to correlate these findings with prognosis. In various studies, bcl-2, p53, transforming growth factor b, erbB-3, vascular endothelial growth factor, and activators of matrix metalloproteinases present in pancreatic cancer tissue have all been correlated with outcome. Unfortunately, all of these findings are preliminary. Thus, the clinical relevance is still being investigated. Ideally, molecular markers for patients with cancer would enhance our ability to determine prognosis and permit us to individualize therapy. Unfortunately, the paucity of data examining the relevance of molecular markers makes it clear that we are not yet able to make this leap for patients with pancreatic cancer. One of the most frustrating issues for physicians who treat patients with pancreatic cancer is our lack of ability to define the ideal adjuvant or neoadjuvant therapy. The role of adjuvant therapy for patients with pancreatic cancer is difficult to determine according to the limited and flawed data available from randomized prospective trials. Although many investigators are now routinely using neoadjuvant treatment, there are no randomized data evaluating its use. Supporters of neoadjuvant therReceived October 27, 2004; accepted November 19, 2004; published online March 3, 2005. Address correspondence and reprint requests to: Sharon M. Weber, MD; E-mail: webers@surgery.wisc.edu.