Expression of ribonucleoside reductase subunit M1, but not excision repair cross‑complementation group 1, is predictive in muscle‑invasive bladder cancer treated with chemotherapy and radiation

Shilkrut,Mark; Wu,Angela; Thomas,Dafydd  G.; Hamstra,Daniel  A.

doi:10.3892/mco.2014.264

Expression of ribonucleoside reductase subunit M1, but not excision repair cross‑complementation group 1, is predictive in muscle‑invasive bladder cancer treated with chemotherapy and radiation

Authors:
- Mark Shilkrut
- Angela Wu
- Dafydd G. Thomas
- Daniel A. Hamstra
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Affiliations: Department of Oncology, Rambam Health Care Campus, Haifa 31096, Israel, Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA
Published online on: February 20, 2014 https://doi.org/10.3892/mco.2014.264
Pages: 479-487

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Abstract

The aim of this study was to determine the prognostic and predictive values of ribonucleoside reductase subunit M1 (RRM1) and excision repair cross‑complementation group 1 (ERCC1) expression in patients with muscle‑invasive bladder cancer treated with chemoradiotherapy. the expression of RRM1 and ERCC1 in pretreatment tumor samples of retrospectively identified patients was determined by immunohistochemical analysis. A total of 39 patients were included in this study; 49% were treated with neoadjuvant chemotherapy and 67% with concomitant chemoradiotherapy; 56% were treated with gemcitabine‑based and 51% with platinum‑based chemoradiotherapy. The median follow‑up was 19 months (interquartile range, 11‑50 months). Based on the immunohistochemical analysis, 44 and 32% of the tumors exhibited increased expression of RRM1 and ERCC1, respectively. The complete response (CR) and local recurrence rates following chemoradiotherapy were 79 and 21%, respectively. A low expression of RRM1 was associated with a higher rate of CR to chemoradiotherapy (95 vs. 57%, P=0.012); however, there was no such association with low ERCC1 expression (67 vs. 84%, P=0.39). RRM1 expression predicted an improved CR in patients treated with gemcitabine‑based chemoradiotherapy (57 vs. 100%, P=0.036), but not in those treated with other agents (56 vs. 88%, P=0.29). ERCC1 expression was not found to be correlated with CR (67 vs. 84%, P=0.39), even when restricted to patients treated with platinum agents (71 vs. 75%, P=1.0). In the univariate analysis, RRM1 expression, but not ERCC1 expression, was identified as a prognostic marker for worse cancer‑specific survival in all the patients and in those treated with gemcitabine‑based regimens. No independent prognostic factor was identified in the multivariate model, which included tumor stage, vascular invasion, hydronephrosis and RRM1 status. Although these findings require further validation, they suggest that RRM1 may be a beneficial stratification variable for the selection of chemotherapy regimens for chemoradiotherapy, with patients with low RRM1 expression being considered suitable for gemcitabine treatment.

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1.	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
2.	Milosevic M, Gospodarowicz M, Zietman A, et al: Radiotherapy for bladder cancer. Urology. 69(Suppl 1): 80–92. 2007. View Article : Google Scholar
3.	Efstathiou JA, Bae K, Shipley WU, et al: Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 27:4055–4061. 2009. View Article : Google Scholar : PubMed/NCBI
4.	Efstathiou JA, Spiegel DY, Shipley WU, et al: Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol. 61:705–711. 2012. View Article : Google Scholar
5.	Coppin CM, Gospodarowicz MK, James K, et al: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 14:2901–2907. 1996.
6.	James ND, Hussain SA, Hall E, et al: Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 366:1477–1488. 2012. View Article : Google Scholar : PubMed/NCBI
7.	International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party; European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group; et al: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 29:2171–2177. 2011. View Article : Google Scholar
8.	Sternberg CN, Donat SM, Bellmunt J, et al: Chemotherapy for bladder cancer: treatment guidelines for neoadjuvant chemo-therapy, bladder preservation, adjuvant chemotherapy, and metastatic cancer. Urology. 69(Suppl 1): 62–79. 2007. View Article : Google Scholar
9.	Jordheim LP, Seve P, Tredan O and Dumontet C: The ribo-nucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer. Lancet Oncol. 12:693–702. 2011. View Article : Google Scholar : PubMed/NCBI
10.	Harshman LC, Bepler G, Zheng Z, Higgins JP, Allen GI and Srinivas S: Ribonucleotide reductase subunit M1 expression in resectable, muscle-invasive urothelial cancer correlates with survival in younger patients. BJU Int. 106:1805–1811. 2010. View Article : Google Scholar
11.	Zheng Z, Chen T, Li X, Haura E, Sharma A and Bepler G: DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med. 356:800–808. 2007. View Article : Google Scholar : PubMed/NCBI
12.	Gossage L and Madhusudan S: Current status of excision repair cross complementing-group 1 (ERCC1) in cancer. Cancer Treat Rev. 33:565–577. 2007. View Article : Google Scholar : PubMed/NCBI
13.	Kim KH, Do IG, Kim HS, et al: Excision repair cross-complementation group 1 (ERCC1) expression in advanced urothelial carcinoma patients receiving cisplatin-based chemotherapy. APMIS. 118:941–948. 2010. View Article : Google Scholar
14.	Sun JM, Sung JY, Park SH, et al: ERCC1 as a biomarker for bladder cancer patients likely to benefit from adjuvant chemotherapy. BMC Cancer. 12:1872012. View Article : Google Scholar : PubMed/NCBI
15.	Kawashima A, Nakayama M, Kakuta Y, et al: Excision repair cross-complementing group 1 may predict the efficacy of chemoradiation therapy for muscle-invasive bladder cancer. Clin Cancer Res. 17:2561–2569. 2011. View Article : Google Scholar : PubMed/NCBI
16.	Vilmar A, Garcia-Foncillas J, Huarriz M, Santoni-Rugiu E and Sorensen JB: RT-PCR versus immunohistochemistry for correlation and quantification of ERCC1, BRCA1, TUBB3 and RRM1 in NSCLC. Lung Cancer. 75:306–312. 2012. View Article : Google Scholar : PubMed/NCBI
17.	Ozcan MF, Dizdar O, Dincer N, et al: Low ERCC1 expression is associated with prolonged survival in patients with bladder cancer receiving platinum-based neoadjuvant chemotherapy. Urol Oncol. 31:1709–1715. 2012. View Article : Google Scholar : PubMed/NCBI
18.	Ahmad A, Robinson AR, Duensing A, et al: ERCC1-XPF endonuclease facilitates DNA double-strand break repair. Mol Cell Biol. 28:5082–5092. 2008. View Article : Google Scholar : PubMed/NCBI
19.	Nocito A, Kononen J, Kallioniemi OP and Sauter G: Tissue microarrays (TMAs) for high-throughput molecular pathology research. Int J Cancer. 94:1–5. 2001. View Article : Google Scholar : PubMed/NCBI
20.	Smith DC, Mackler NJ, Dunn RL, et al: Phase II trial of paclitaxel, carboplatin and gemcitabine in patients with locally advanced carcinoma of the bladder. J Urol. 180:2384–2388. 2008. View Article : Google Scholar : PubMed/NCBI
21.	Higano CS, Tangen CM, Sakr WA, et al Southwest Oncology Group Trial 8733: Treatment options for muscle-invasive urothelial cancer for patients who were not eligible for cystectomy or neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin: report of Southwest Oncology Group Trial 8733. Cancer. 112:2181–2187. 2008. View Article : Google Scholar
22.	Kent E, Sandler H, Montie J, et al: Combined-modality therapy with gemcitabine and radiotherapy as a bladder preservation strategy: results of a phase I trial. J Clin Oncol. 22:2540–2545. 2004. View Article : Google Scholar : PubMed/NCBI
23.	Shipley WU, Zietman AL, Kaufman DS, Coen JJ and Sandler HM: Selective bladder preservation by trimodality therapy for patients with muscularis propria-invasive bladder cancer and who are cystectomy candidates - the Massachusetts General Hospital and Radiation Therapy Oncology Group experiences. Semin Radiat Oncol. 15:36–41. 2005. View Article : Google Scholar
24.	Pollack A, Zagars GK, Dinney CP, et al: Preoperative radiotherapy for muscle-invasive bladder carcinoma. Long term follow-up and prognostic factors for 338 patients. Cancer. 74:2819–2827. 1994. View Article : Google Scholar : PubMed/NCBI
25.	No authors listed. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med. 324:1685–1690. 1991. View Article : Google Scholar
26.	Ceppi P, Volante M, Novello S, et al: ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol. 17:1818–1825. 2006. View Article : Google Scholar : PubMed/NCBI
27.	Bellmunt J, Paz-Ares L, Cuello M, et al: Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy. Ann Oncol. 18:522–528. 2007. View Article : Google Scholar : PubMed/NCBI
28.	Kawashima A, Takayama H and Tsujimura A: A review of ERCC1 gene in bladder cancer: implications for carcinogenesis and resistance to chemoradiotherapy. Adv Urol. 2012:8123982012. View Article : Google Scholar : PubMed/NCBI
29.	Simon GR, Schell MJ, Begum M, et al: Preliminary indication of survival benefit from ERCC1 and RRM1-tailored chemo-therapy in patients with advanced nonsmall cell lung cancer: evidence from an individual patient analysis. Cancer. 118:2525–2531. 2012. View Article : Google Scholar
30.	Liu ZG, Chen HY, Cheng JJ, Chen ZP, Li XN and Xia YF: Relationship between methylation status of ERCC1 promoter and radiosensitivity in glioma cell lines. Cell Biol Int. 33:1111–1117. 2009. View Article : Google Scholar : PubMed/NCBI
31.	Friboulet L, Olaussen KA, Pignon JP, et al: ERCC1 isoform expression and DNA repair in non-small-cell lung cancer. N Engl J Med. 368:1101–1110. 2013. View Article : Google Scholar : PubMed/NCBI
32.	Fedeli U, Fedewa SA and Ward EM: Treatment of muscle invasive bladder cancer: evidence from the National Cancer Database, 2003 to 2007. J Urol. 185:72–78. 2011. View Article : Google Scholar : PubMed/NCBI
33.	RTOG 0712 Protocol Information. February 28–2012.http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0712. Accessed December 17, 2013.