Clinical implications of ribonucleotide reductase subunit M1 in patients with pancreatic cancer who undergo curative resection followed by adjuvant chemotherapy with gemcitabine

Abstract

Abstract. To the best of our knowledge, the clinical implications of using ribonucleoside reductase subunit M1 (RRM1) in patients who undergo curative resection and adjuvant chemotherapy have not been established. In the present study, the clinical data from 101 consecutive patients who underwent macroscopically curative resection, and who received adjuvant gemcitabine chemotherapy for pancreatic cancer at the Kanagawa Cancer Centre (Yokohama, Kanagawa, Japan) between April 2005 and December 2014 were retrospectively analyzed. The association between the RRM1 status and survival and clinicopathological features were assessed. Of the 101 patients, 41 patients expressed high levels of RRM1 expression (40.6%). Although a significant difference was observed in lymphatic invasion, there was no difference between the two groups with regard to any other clinicopathological parameters. The median follow-up period was 67.3 months. There was a significant difference between the recurrence-free survival (RFS) rates at 5 years after surgery, which were 12.9 and 0% in the high RRM1 and low RRM1 groups, respectively (P=0.042). Furthermore, there was a significant difference in the 5-year overall survival (OS) rates following surgery, which were 5.1 and 21.5% in the high RRM1 and low RRM1 groups, respectively (P=0.015). The results of the present study indicated that out of the factors assessed, RRM1 was the most important prognostic factor for OS and RFS in patients with pancreatic cancer who underwent curative resection followed by adjuvant chemotherapy with gemcitabine. Adjuvant chemotherapy with gemcitabine alone may be insufficient for the treatment of pancreatic cancer, particularly in patients with relevant risk factors.

Chemoresistance in Pancreatic Cancer

“…Inhibition of RR induced by dFdCDP is the most significant mechanism for the enhancement of gemcitabine activity [20,21]. A recent meta-analysis revealed that patients with high RRM1 expression had largely poorer OS and DFS than those with low RRM1 expression [46,47], suggesting that the expression of RRM1 is an indicator of poor survival in patients with pancreatic cancer accepting gemcitabine chemotherapy [46]. Experiments confirmed that overexpression of RRM1 and RRM2 proteins of the pancreatic cancer cell line can achieve stable genetic gemcitabine resistance [48,49].…”

Effect of ribonucleotide reductase M1 expression on overall survival in patients with pancreatic cancer receiving gemcitabine chemotherapy: A literature‐based meta‐analysis

“…Patients with advanced pancreatic cancer who showed high levels of RRM1 expression were shown to have a low survival rate following gemcitabine treatment, whereas patients with non‐small‐cell lung cancer and with low‐level RRM1 expression had significant benefits from gemcitabine/cisplatin neoadjuvant chemotherapy . There are several studies assessing the prognostic role of RRM1 expression in patients with pancreatic cancer treated by adjuvant chemotherapy with gemcitabine, and no consistent outcomes are reported . To provide a comprehensive assessment of the overall survival prognostic role of RRM1 expression in patients with pancreatic cancer receiving gemcitabine chemotherapy, we performed a meta‐analysis of published studies.…”

RRM1 predicts clinical outcome of high-and intermediate-risk non-muscle-invasive bladder cancer patients treated with intravesical gemcitabine monotherapy

“…The active forms of gemcitabine inhibit DNA synthesis by incorporating into the DNA chain or inhibiting RRM1 activity [8]. Gemcitabine has been widely used for the treatment of several aggressive solid tumour types, including non-small-cell lung cancer (NSCLC), bladder tumours, pancreatic tumours and nasopharyngeal carcinoma [9–12]. There are preclinical and clinical data indicating that high RRM1 protein levels in various cancers are associated with gemcitabine resistance [13, 14].…”