Kimberly K Leslie1, Virginia L Filiaci2, Adrianne R Mallen3, Kristina W Thiel4, Eric J Devor5, Katherine Moxley6, Debra Richardson7, David Mutch8, Angeles Alvarez Secord9, Krishnansu S Tewari10, Megan E McDonald11, Cara Mathews12, Casey Cosgrove13, Summer Dewdney14, Yovanni Casablanca15, Amanda Jackson16, Peter G Rose17, XunClare Zhou18, Michael McHale19, Heather Lankes20, Douglas A Levine21, Carol Aghajanian22. 1. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA. Electronic address: Kimberly-leslie@uiowa.edu. 2. NRG Oncology, Clinical Trial Development Division, Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. Electronic address: FiliaciV@NRGOncology.org. 3. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. 4. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: kristina-thiel@uiowa.edu. 5. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA. Electronic address: eric-devor@uiowa.edu. 6. Stephenson Cancer Center Gynecologic Cancers Clinic, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA. Electronic address: Katherine-moxley@ouhsc.edu. 7. Stephenson Cancer Center Gynecologic Cancers Clinic, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA. 8. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63108, USA. Electronic address: mutchd@wustl.edu. 9. Duke University Institute, Duke University Health System, Durham, NC 27710, USA. Electronic address: angeles.secord@duke.edu. 10. University of California Irvine Medical Center, Irvine, CA 92868, USA. Electronic address: ktewari@uci.edu. 11. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: megan-e-mcdonald@uiowa.edu. 12. Women and Infants Hospital in Rhode Island/The Warren Alpert Medical School of Brown University, Providence, RI 02905, USA. Electronic address: cmathews@wihri.org. 13. James Cancer Hospital and Solove Research Institute, Obstetrics and Gynecology, Ohio State University Medical Center, Columbus, OH 43210, USA. Electronic address: casey.cosgrove@osumc.edu. 14. Gynecology, Rush University Medical Center, Chicago, IL 60612, USA. Electronic address: Summer_Dewdney@rush.edu. 15. Gynecology, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA. Electronic address: yovanni.casablanca.mil@mail.mil. 16. Gynecologic Oncology Center, University of Cincinnati Cancer Institute, Cincinnati, OH 45219, USA. Electronic address: jacks2a6@uc.mail.uc.edu. 17. Cleveland Clinic Foundation and Case Western Reserve University, Cleveland, OH 44195, USA. Electronic address: rosep@ccf.org. 18. Department of Gynecology, Hospital of Central Connecticut, New Britain, CT 06451, USA. Electronic address: XunClare.Zhou@hhchealth.org. 19. Department of Gynecology, University of California San Diego, La Jolla, CA 92037, USA. Electronic address: mtmchale@health.ucsd.edu. 20. Biopathology Center, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. Electronic address: LankesH@NRGOncology.org. 21. Gynecologic Oncology, NYU Langone Health, 240 E 38th St 19th Floor, New York, NY 10016, USA. Electronic address: Douglas.Levine@nyumc.org. 22. Memorial Sloan Kettering Cancer and Weill Cornell Medical Center, 1275 York Ave, New York, NY 10065, USA. Electronic address: aghajanc@mskcc.org.
Abstract
BACKGROUND: Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P. METHODS: TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P. RESULTS: Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53. CONCLUSIONS: This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.
BACKGROUND: Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P. METHODS: TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P. RESULTS: Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53. CONCLUSIONS: This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.
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