Date Published: June 5, 2019
Publisher: Public Library of Science
Author(s): Keisuke Taniuchi, Mutsuo Furihata, Seiji Naganuma, Masahiko Sakaguchi, Toshiji Saibara, Yves St-Pierre.
We previously reported that overexpression of PODXL, BCL7B, and ARHGEF4 in pancreatic cancer tissue is correlated with pancreatic cancer-related survival. The aim of this study was to investigate the use of PODXL, BCL7B, ARHGEF4, and the integrin family member ITGB1 as useful markers for the prognosis of postoperative pancreatic cancer patients in comparison with tumor size and the tumor node metastasis (TNM) staging system. Immunohistochemistry was performed using an anti-ITGB1 antibody on 102 samples of pancreatic cancer tissue surgically resected at the University of Kochi Medical School Hospital and the Matsuyama Shimin Hospital. Univariate Cox proportional hazards regression analysis showed that TNM stage and overexpression of PODXL, BCL7B, and ITGB1 were correlated with postoperative survival. However, tumor size was not significantly associated with postoperative prognosis of pancreatic cancer compared to these features. Multivariate Cox proportional hazards regression analysis showed that the overexpression of both PODXL and ITGB1 and overexpression of both BCL7B and ITGB1 increased the hazard ratio (6.27, 95% confidence interval [CI] 2.58–15.21; and 3.93, 95% CI 1.74–8.91, respectively) compared to that of TNM stage (IIA and IIB vs. III and IV; 3.05, 95% CI 1.25–7.42). These results imply that the combination of PODXL with ITGB1 and the combination of BCL7B with ITGB1 accurately predicted the postoperative outcomes of pancreatic cancer patients, and they were superior compared to the TNM staging system. The combination of PODXL with ITGB1 would be particularly useful, as it was the most highly correlated with postoperative outcomes. Importantly, the present results are useful to determine which adjuvant therapy should be selected.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, and the prognosis is poor, with 1- and 5-year survival rates of only 20% and 6%, respectively [1, 2]. Complete tumor resection is the only potential treatment for PDAC that results in a complete cure . Since about half of PDAC patients are diagnosed with end-stage disease, 35% with localized unresectable disease, and 20% with potentially resectable disease, surgery is not always suitable . Neoadjuvant therapies for PDAC patients with borderline resectable and locally-advanced disease have been proposed to achieve tumor down-staging to a subsequent potentially resectable tumor . Additionally, postoperative adjuvant chemotherapies improve both PDAC-related and disease-free survival. A phase III trial (PRODIGE24) recently demonstrated that adjuvant chemotherapy with a modified FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) significantly increases overall survival compared with gemcitabine for 24 weeks after resection of PDAC . However, there are no reliable biomarkers to gauge the response to neoadjuvant and/or adjuvant therapies prior to the initiation of the therapies .
The present study showed that high ITGB1 expression is closely associated with poor prognosis of resected PDAC patients, similar to what has been previously published regarding PODXL and BCL7B [10, 11]. The immunohistochemical scores of ITGB1 were not statistically correlated with the clinicopathological variables, but univariate and multivariate Cox regression analyses revealed that high ITGB1 expression was an independent predictor of worse survival outcomes. Consistent with our results, high ITGB1 expression is significantly associated with poor outcomes as well as progression and metastasis in PDAC [12, 16, 17, 18]. Our results indicate that ITGB1 may be a determinant of poor prognosis of PDAC patients that is functionally associated with cell migration, invasion, and/or metastasis.