Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 1/2018

01-01-2018 | Urologic Oncology

Prognostic and Predictive Value of O6-methylguanine Methyltransferase for Chemotherapy in Patients with Muscle-Invasive Bladder Cancer

Authors: Junyu Zhang, MD, Yu Zhu, MD, Yiwei Wang, MD, Qiang Fu, PhD, Huyang Xie, MD, Zheng Liu, MD, Hangcheng Fu, MD, Yifan Cao, MD, Jiejie Xu, MD, PhD, Bo Dai, MD

Published in: Annals of Surgical Oncology | Issue 1/2018

Login to get access

Abstract

Purpose

DNA repair genes are potential biomarkers for chemotherapy in muscle-invasive bladder cancer (MIBC). O6-methylguanine methyltransferase (MGMT) is involved in DNA repair and is found to affect the efficacy of platinum-based chemotherapy. However, the prognostic or predictive value of MGMT expression in chemotherapy for MIBC is unknown.

Materials and Methods

Immunohistochemical staining for MGMT was performed in paraffin-embedded tumor tissue of high-grade MIBC patients who underwent cystectomy in two independent cohorts [n = 74 for Fudan University Shanghai Cancer Center (FUSCC) cohort and n = 115 for Zhongshan Hospital (ZS) cohort]. MGMT messenger RNA (mRNA) analysis was conducted using patients’ clinical and fragments per kilobase of exon model per million mapped fragments mRNA data from The Cancer Genome Atlas (TCGA) database (n = 245).

Results

In our cohorts, high MGMT expression was significantly correlated with shorter overall survival (OS) in patients with platinum-based adjuvant chemotherapy [hazard ratio (HR) 2.386, p = 0.048; HR 2.920, p = 0.007; HR 2.324, p = 0.004, respectively, in FUSCC, ZS, and combination sets], but not in patients without chemotherapy. These findings were corroborated by the TCGA set (HR 1.952 and 0.697 for patients with and without chemotherapy, respectively). The chemotherapy–MGMT interaction for OS was significant in both the surgery set (p = 0.045) and TCGA set (p = 0.034).

Conclusions

We demonstrated that high MGMT expression is an independent poor prognostic factor in MIBC patients with platinum-based adjuvant chemotherapy, but not in patients without chemotherapy. MGMT expression may be a potential predictor for administration of adjuvant chemotherapy.
Appendix
Available only for authorised users
Literature
1.
Alfred Witjes J, Lebret T, Comperat EM, et al. Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur. Urol. 71(3):462–475 (2017).CrossRefPubMed
2.
Cognetti F, Ruggeri EM, Felici A, et al. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann. Oncol. 2012;23(3):695–700.CrossRefPubMed
3.
Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3–pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. The Lancet Oncol. 2015;16(1):76–86.CrossRefPubMed
4.
Galsky MD, Stensland KD, Moshier E, et al. Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer. J. Clin. Oncol. 2016;34(8):825–32.CrossRefPubMed
5.
Ruggeri EM, Fabbri MA, Nelli F. Should we use adjuvant chemotherapy for muscle-invasive bladder cancer after radical cystectomy? J. Clin. Oncol. 2016;34(26):3223.CrossRefPubMed
6.
Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat. Rev. Cancer. 2012;12(12):801–17.CrossRefPubMed
7.
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. 2007;18(3):522–8.CrossRefPubMed
8.
Font A, Taron M, Gago JL, et al. BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer. Ann. Oncol. 2011;22(1):139–44.CrossRefPubMed
9.
Plimack ER, Dunbrack RL, Brennan TA, et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur. Urol. 2015;68(6):959–67.CrossRefPubMedPubMedCentral
10.
Gerson SL. MGMT: its role in cancer aetiology and cancer therapeutics. Nat. Rev. Cancer. 2004;4(4):296–307.CrossRefPubMed
11.
Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 2005;352(10):997–1003.CrossRefPubMed
12.
Arienti C, Tesei A, Verdecchia GM, et al. Peritoneal carcinomatosis from ovarian cancer: chemosensitivity test and tissue markers as predictors of response to chemotherapy. J. Transl. Med. 2011;9:94.CrossRefPubMedPubMedCentral
13.
Liu Z, Liu Y, Xu L, et al. P2X7 receptor predicts postoperative cancer-specific survival of patients with clear-cell renal cell carcinoma. Cancer Sci. 2015;106(9):1224–31.CrossRefPubMedPubMedCentral
14.
Tanaka S, Kobayashi I, Utsuki S, Oka H, Yasui Y, Fujii K. Down-regulation of O6-methylguanine-DNA methyltransferase gene expression in gliomas by platinum compounds. Oncol. Rep. 2005;14(5):1275–80.PubMed
15.
Maki Y, Murakami J, Asaumi J, et al. Role of O6-methylguanine-DNA methyltransferase and effect of O6-benzylguanine on the anti-tumor activity of cis-diaminedichloroplatinum(II) in oral cancer cell lines. Oral Oncol. 2005;41(10):984–93.CrossRefPubMed
16.
Chen SH, Kuo CC, Li CF, et al. O(6)-methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma. Int. J. Cancer. 2015;137(6):1291–305.CrossRefPubMed
17.
Arienti C, Tesei A, Verdecchia GM, et al. Role of conventional chemosensitivity test and tissue biomarker expression in predicting response to treatment of peritoneal carcinomatosis from colon cancer. Clin. Colorectal Cancer. 2013;12(2):122–7.CrossRefPubMed
18.
Braun MS, Richman SD, Quirke P, et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J. Clin. Oncol. 2008;26(16):2690–8.CrossRefPubMed
19.
Konduri SD, Ticku J, Bobustuc GC, et al. Blockade of MGMT expression by O6 benzyl guanine leads to inhibition of pancreatic cancer growth and induction of apoptosis. Clin. Cancer Res. 2009;15(19):6087–95.CrossRefPubMed
20.
Bobustuc GC, Patel A, Thompson M, et al. MGMT inhibition suppresses survivin expression in pancreatic cancer. Pancreas. 2015;44(4):626–35.CrossRefPubMed
21.
Ramakrishnan V, Kushwaha D, Koay DC, et al. Post-transcriptional regulation of O(6)-methylguanine-DNA methyltransferase MGMT in glioblastomas. Cancer Biomark. 2011;10(3–4):185–93.PubMed
Metadata
Title
Prognostic and Predictive Value of O6-methylguanine Methyltransferase for Chemotherapy in Patients with Muscle-Invasive Bladder Cancer
Authors
Junyu Zhang, MD
Yu Zhu, MD
Yiwei Wang, MD
Qiang Fu, PhD
Huyang Xie, MD
Zheng Liu, MD
Hangcheng Fu, MD
Yifan Cao, MD
Jiejie Xu, MD, PhD
Bo Dai, MD
Publication date
01-01-2018
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 1/2018
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-017-6145-3

Other articles of this Issue 1/2018

Annals of Surgical Oncology 1/2018 Go to the issue

Gastrointestinal Oncology

Impact of Proximal Vascular Ligation on Survival of Patients with Colon Cancer

Breast Oncology

Intraoperative Margin Management in Breast-Conserving Surgery: A Systematic Review of the Literature

Endocrine Tumors

Markers of Systemic Inflammatory Response are Prognostic Factors in Patients with Pancreatic Neuroendocrine Tumors (PNETs): A Prospective Analysis

Breast Oncology

Axillary Lymphadenectomy in Sentinel Lymph Node-Positive Breast Cancer

Gastrointestinal Oncology

Short-Term Outcomes Following Minimally Invasive and Open Esophagectomy: A Population-Based Study from Finland and Sweden

Breast Oncology

Pre-operative Axillary Ultrasound-Guided Needle Sampling in Breast Cancer: Comparing the Sensitivity of Fine Needle Aspiration Cytology and Core Needle Biopsy