Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection

doi:10.1016/j.surg.2012.10.010

Surgery

Volume 153, Issue 4, April 2013, Pages 565-575

https://doi.org/10.1016/j.surg.2012.10.010 Get rights and content

Background

Although postoperative adjuvant chemotherapy for pancreatic carcinoma improves survival in some patients, its efficacy varies among individuals. The aim of this study was to determine the usefulness of intratumoral expression of human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) as predictive markers of the efficacy of adjuvant gemcitabine-based chemotherapy for pancreatic carcinoma after operative resection.

Methods

The expression of intratumoral hENT1 and RRM1 was examined immunohistochemically in 109 patients with pancreatic carcinoma who received adjuvant gemcitabine-based chemotherapy after operative resection. Relationships between clinicopathologic factors, including hENT1 and RRM1 expression, and disease-free and overall survival (DFS and OS) were evaluated by univariate and multivariate analyses.

Results

The 5-year DFS and OS rates for the 109 patients were 26% and 31%, respectively. In univariate analysis, both hENT1 and RRM1 expression were significantly associated with DFS (hENT1, P = .004; RRM1, P = .011) and OS (hENT1, P = .001; RRM1, P = .040). In multivariate analysis, both were independent factors for DFS (hENT1, P = .001; RRM1, P = .009) and OS (hENT1, P = .001, RRM1, P = .019). Evaluation of the combination analysis of both was also identified as a powerful independent predictor of DFS (P < .001) and OS (P < .001).

Conclusion

Expression of hENT1 and RRM1 is predictive of the efficacy of adjuvant gemcitabine-based chemotherapy for pancreatic carcinoma after operative resection. In addition, their combined analysis has greater predictive value than either factor alone.

Section snippets

Study design

One hundred nine patients with pancreatic adenocarcinoma who received adjuvant gemcitabine-based chemotherapy after curative operative resection (R0 or R1 resection) at the Department of Surgery, Hiroshima University Hospital from January 2002 to May 2011 were enrolled in this study. A diagnosis of pancreatic adenocarcinoma was confirmed histologically in all cases. Other histologic variants, such as pancreatic carcinoma derived from mucinous cystic neoplasms and intraductal papillary-mucinous

Patient demographic and neoplasm characteristics

Of the 109 patients, 52 (48%) were males and 57 (52%) were females with a median age of 67 years (range, 41–83). Pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed for 74 (68%), 30 (28%), and 5 patients (4%), respectively. The pancreatic neoplasm was confined to the head and to the body/tail of the pancreas in 72 patients (66%) and 37 patients (34%), respectively. Twenty-three patients (21%) had undergone R1 resection. Neoplasms were identified as

Discussion

Gemcitabine still plays an important role in adjuvant chemotherapy for patients with resected pancreatic carcinoma, as determined by the results of large randomized phase 3 trials, including the Charite Onkologie 001 (CONKO-001) study⁹ and the European Study Group for Pancreatic Cancer 3 (ESPAC-3) study.¹⁰ However, the efficacy of adjuvant gemcitabine chemotherapy is unsatisfactory, with a median survival time of 22–24 months in these studies,9, 10 because a substantial number of patients are

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Cited by (43)

Precision design of nanomedicines to restore gemcitabine chemosensitivity for personalized pancreatic ductal adenocarcinoma treatment
2018, Biomaterials
Low chemosensitivity considerably restricts the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer treatment. Using immunohistochemical evaluation, we investigated that decreased expression of human equilibrative nucleoside transporter-1 (hENT1, which is the major GEM transporter across cell membranes) and increased expression of ribonucleotide reductase subunit 2 (RRM2, which decreases the cytotoxicity of GEM) was associated with low GEM chemosensitivity. To solve these problems, we employed a nanomedicine-based formulation of cationic liposomes for co-delivery of GEM along with siRNA targeting RRM2. Due to the specific endocytic uptake mechanism of nanocarriers and gene-silencing effect of RRM2 siRNA, this nanomedicine formulation significantly increased GEM chemosensitivity in tumor models of genetically engineered Panc1 cells with low hENT1 or high RRM2 expression. Moreover, in a series of patient-derived cancer cells, we demonstrated that the therapeutic benefits of the nanomedicine formulations were associated with the expression levels of hENT1 and RRM2. In summary, we found that the essential factors of GEM chemosensitivity were the expression levels of hENT1 and RRM2, and synthesized nanoformulations can overcome these problems. This unique design of nanomedicine not only provides a universal platform to enhance chemosensitivity but also contributes to the precision design and personalized treatment in nanomedicine.
Human equilibrative nucleoside transporter 1 expression analysed by the clone SP 120 rabbit antibody is not predictive in patients with pancreatic cancer treated with adjuvant gemcitabine - Results from the CONKO-001 trial
2015, European Journal of Cancer
Citation Excerpt :
Another reason for the differing results could be the different biology and treatment responsiveness between primarily localised/operable tumours and initially metastasised diseases. Differences in other proteins involved in gemcitabine metabolism such as ribonucleotide reductase subunits 1 and 2 may also play a role [18]. Further research should focus on this point.
High expression of human equilibrative nucleoside transporter 1 (hENT1) is considered to predict survival in patients treated with adjuvant gemcitabine for pancreatic cancer. A standard evaluation system for immunohistochemical analysis (antibody, scoring system) has not yet been established.
CONKO-001, a prospective randomised phase III study investigated the role of adjuvant gemcitabine (gem) as compared to observation (obs). Tumour samples of 156 patients were analysed by immunohistochemistry with the rabbit monoclonal antibody SP120 (Ventana Medical Systems) for expression of hENT1. Kaplan–Meier analyses for median disease-free survival (DFS) and overall survival (OS) were performed in dependence of hENT1 expression measured analogously to Farrell et al. 2009 and Poplin et al. 2013.
For the 88 gem and 68 obs patients, median DFS/OS was 12.9/22.7 months and 6.2/19.1 months. High hENT1 expression was not associated with improved median DFS (Farrell: no hENT1 22.2 months, low hENT1 13.7 months, high hENT1 12.1 months, p = 0.248; Poplin: low hENT1 13.2 months versus high hENT1 11.5 months, p = 0.5) or median OS (Farrell: no hENT1 21.7 months, low hENT1 24.7 months, high hENT1 19.5, p = 0.571; Poplin: low hENT1 24.4 months versus high hENT1 19.7 months, p = 0.92;) in the gem group or in the obs group (median DFS Farrell: no hENT1 5.1 months, low hENT1 6.2 months, high hENT1 7.5 months, p = 0.375; Poplin: low hENT1 6.2 months versus high hENT1 5.9 months, p = 0.83; median OS Farrell: no hENT1 20.2 months, low hENT1 17.7 months, high HENT1 19.1 months, p = 0.738; Poplin: low hENT1 17.7 months versus high hENT1 20.4 months, p = 0.65) measured by the Farrell or Poplin Score.
We cannot confirm a predictive role of hENT1 measured by the clone SP120 rabbit antibody in our study population. Reproducible standard procedures are urgently needed prior to the implementation or exclusion of hENT1 as a predictive biomarker in the treatment of pancreatic cancer.
ISRCTN34802808.
Clinical use of biomarkers in the field of cytotoxic nucleoside analogues
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“Open sesame?”: Biomarker status of the human equilibrative nucleoside transporter-1 and molecular mechanisms influencing its expression and activity in the uptake and cytotoxicity of gemcitabine in pancreatic cancer
2020, Cancers
Human equilibrative nucleoside transporter-1 expression is a predictor in patients with resected pancreatic cancer treated with adjuvant S-1 chemotherapy
2020, Cancer Science
HENT1 testing in pancreatic ductal adenocarcinoma: Are we ready? a multimodal evaluation of hENT1 status
2019, Cancers

View all citing articles on Scopus

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Background

Methods

Results

Conclusion

Section snippets

Study design

Patient demographic and neoplasm characteristics

Discussion

Eur J Cancer

J Gastrointest Surg

Am J Surg

J Gastrointest Surg

Gastroenterology

Lung Cancer

Gastroenterology

Cancer statistics, 2012

CA Cancer J Clin

1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience

J Gastrointest Surg

Predicting survival after surgical resection for pancreatic ductal adenocarcinoma

Pancreas

Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma

Br J Surg

Pancreatic cancer: surgery alone is not sufficient

Surg Endosc

Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial

J Clin Oncol

Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial

JAMA

European Study Group for Pancreatic Cancer: adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine followed pancreatic cancer resection: A randomized controlled trial

JAMA

Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non–small-cell lung cancer

J Clin Oncol

Nucleoside transporter profiles in human pancreatic cancer cells: role of hcnt1 in 2′,2′-difluorodeoxycytidine–induced cytotoxicity

Clin Cancer Res

Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines

Cancer Res

Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine

Cancer Res