Unfavourable prognosis associated with K-ras gene mutation in pancreatic cancer surgical margins

Abstract

Background: Despite intent to cure surgery with negative resection margins, locoregional recurrence is common in pancreatic cancer. Aims: To determine whether detection of K-ras gene mutation in the histologically negative surgical margins of pancreatic cancer reflects unrecognised disease. Patients: Seventy patients who underwent curative resection for pancreatic ductal adenocarcinoma were evaluated. Methods: All patients had surgical resection margins (pancreatic transection and retroperitoneal) that were histologically free of invasive cancer. DNA was extracted from these paraffin embedded surgical margins and assessed by quantitative real time polymerase chain reaction to detect the K-ras gene mutation at codon 12. Detection of K-ras mutation was correlated with standard clinicopathological factors. Results: K-ras mutation was detected in histologically negative surgical margins of 37 of 70 (53%) patients. A significant difference in overall survival was demonstrated between patients with margins that were K-ras mutation positive compared with negative (median 15 v 55 months, respectively; p = 0.0008). By univariate and multivariate analyses, detection of K-ras mutation in the margins was a significant prognostic factor for poor survival (hazard ratio (HR) 2.8 (95% confidence interval (CI) 1.5-5.3), p = 0.0009; and HR 2.8 (95% CI 1.4-5.5), p = 0.004, respectively). Conclusions: Detection of cells harbouring K-ras mutation in histologically negative surgical margins of pancreatic cancer may represent unrecognised disease and correlates with poor disease outcome. The study demonstrates that molecular-genetic evaluation of surgical resection margins can improve pathological staging and prognostic evaluation of patients with pancreatic ductal adenocarcinoma.

Molecular markers of pancreatic cancer: development and clinical relevance

“…Following curative surgery, K-ras mutation was detected in histologically free margins of 53% of the patients with a median survival of 15 months only, compared to 55 months survival for patients who did not harbour this mutation [45]. The detection of K-ras mutations in surgical margins was a significant prognostic factor for poor survival.…”

Preoperative CA19-9 Levels and Lymph Node Ratio Are Independent Predictors of Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma

“…Most notably, these include tumour size, nodal involvement (including lymph node 8a status), differentiation and resection margin status. A number of molecular markers have also been shown to be of prognostic value following resection[31,32,33,34,35]; however, these tumour characteristics, whether histological or biological in nature, are invariably only amenable to assessment following surgery.…”

“…Firstly, the role of prognostic molecular markers [31,32,33,34,35] should be properly validated in studies that also include preoperative CA19-9 levels and the lymph node ratio obtained by analysis of the tumour specimen. Secondly, stratification of patients according to both of these variables should be considered in future adjuvant trials [39, 40].…”

Influence of Perineural Invasion on Survival and Recurrence in Patients with Resected Pancreatic Cancer

“…14 of the remaining 35 studies (Kim et al, 2006;Murakami et al, 2008;Balentine et al, 2010;Chu et al, 2010;Kanda et al, 2010;de Jong et al, 2011;Jamieson et al, 2011;Kneuertz et al, 2011;Maithel et al, 2011;Singal et al, 2011;Chatterjee et al, 2012;Watanabe et al, 2012;Xie et al, 2012;Fisher et al, 2013) were excluded because they were reported by the same institutions as other studies. 21 studies (Ozaki et al, 1999;Mitsunaga et al, 2005;Nakagohri et al, 2006;Pawlik et al, 2007;Kazanjian et al, 2008;Kato et al, 2009;Nagai et al, 2009;Sergeant et al, 2009;Ben et al, 2010;Murakami et al, 2010;Bachellier et al, 2011;Kim et al, 2011;Schiffman et al, 2011;Cheng et al, 2012;Jamieson et al, 2012;Lee et al, 2012;Murata et al, 2012;Sahin et al, 2012;Takahashi et al, 2012;Turrini et al, 2013;Xie et al, 2013) were included in the final meta-analysis, comprising one case matched controlled study and 20 retrospective cohort studies (Table 1).…”