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Ribonucleotide Reductase Expression in Cervical Cancer: A Radiation Therapy Oncology Group Translational Science Analysis
  1. Charles A. Kunos, MD, PhD*,
  2. Kathryn Winter, MS,
  3. Adam P. Dicker, MD, PhD,
  4. William Small, MD§,
  5. Fadi W. Abdul-Karim, MD,
  6. Dawn Dawson, MD*,
  7. Anuja Jhingran, MD,
  8. Richard Valicenti, MD#,
  9. Joanne B. Weidhaas, MD, PhD** and
  10. David K. Gaffney, MD, PhD††
  1. *University Hospitals of Cleveland, Cleveland, OH;
  2. RTOG Statistical Center, Philadelphia, PA;
  3. Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA;
  4. §Northwestern University Hospital, Chicago, IL;
  5. Cleveland Clinic, Cleveland, OH;
  6. University of Texas M.D. Anderson Cancer Center, Houston, TX;
  7. #University of California Davis Medical Center, Sacramento, CA;
  8. **Yale University of School of Medicine, New Haven, CT; and
  9. ††University of Utah Health Sciences Center, Salt Lake City, UT.
  1. Address correspondence and reprint requests to Charles Kunos, MD, PhD, Department of Radiation Oncology, University Hospitals of Cleveland, 11100 Euclid Ave, LTR 6068, Cleveland, OH 44106. E-mail:


Objective To evaluate pretherapy ribonucleotide reductase (RNR) expression and its effect on radiochemotherapeutic outcome in women with cervical cancer.

Methods/Materials Pretherapy RNR M1, M2, and M2b immunohistochemistry was done on cervical cancer specimens retrieved from women treated on Radiation Therapy Oncology Group (RTOG) 0116 and 0128 clinical trials. Enrollees of RTOG 0116 (node-positive stages IA–IVA) received weekly cisplatin (40 mg/m2) with amifostine (500 mg) and extended-field radiation then brachytherapy (85 Gy). Enrollees of RTOG 0128 (node-positive or bulky ≥5 cm, stages IB-IIA or stages IIB-IVA) received cisplatin (75 mg/m2) on days 1, 23, and 43 and 5-FU (1 g/m2 for 4 days) during pelvic radiation then brachytherapy (85 Gy), plus celecoxib (400 mg twice daily, day 1 through 1 year). Disease-free survival (DFS) was estimated univariately by the Kaplan-Meier method. Cox proportional hazards models evaluated the impact of RNR immunoreactivity on DFS.

Results Fifty-one tissue samples were analyzed: 13 from RTOG 0116 and 38 from RTOG 0128. M1, M2, and M2b overexpression (3+) frequencies were 2%, 80%, and 47%, respectively. Low-level (0–1+, n = 44/51) expression of the regulatory subunit M1 did not associate with DFS (P = 0.38). High (3+) M2 expression occurred in most (n = 41/51) but without impact alone on DFS (hazard ratio, 0.54; 95% confidence interval, 0.2–1.4; P = 0.20). After adjusting for M2b status, pelvic node–positive women had increased hazard for relapse or death (hazard ratio, 5.5; 95% confidence interval, 2.2–13.8; P = 0.0003).

Conclusions These results suggest that RNR subunit expression may discriminate cervical cancer phenotype and radiochemotherapy outcome. Future RNR biomarker studies are warranted.

  • Ribonucleotide reductase
  • Radiosensitivity
  • Cervical cancer

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  • This project was supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and RTOG Biospecimen Resource grant U24 CA114734 from the National Cancer Institute (NCI) and 2010 Pennsylvania Department of Health Formula Grant 4100054841.

  • This manuscript’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

  • The authors declare no conflicts of interest.

  • This manuscript has been seen, read, and agreed upon in its content by all designated authors. This manuscript has not been submitted or published elsewhere.