MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer: RTOG 92-02
Open accessAbstract
PURPOSE MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. PATIENTS AND METHODS Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). Results In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). CONCLUSION Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In prostate cancer, higher Mdm2 levels go together with a greater chance that the cancer will spread.
“Elevated Mdm2 expression is also associated with increased risk of metastasis in prostate cancer [99].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [99]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A Proportional Hazards Model for the Subdistribution of a Competing Risk
Fine, J. P., & Gray, R. J. (1999) · Journal of the American Statistical Association · doi:10.1080/01621459.1999.10474144 · Cited by 14,290 · see citing works
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113 · see citing works
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,447 · see citing works
Mapping of the p53 and mdm-2 Interaction Domains
Chen, J., Maréchal, V., & Levine, A. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.7.4107 · Cited by 689 · see citing works
Hanks, G. E., Pajak, T. F., Porter, A. T., Grignon, D. J., Brereton, H. D., Venkatesan, V., Horwitz, E. M., Lawton, C. A., Rosenthal, S. A., Sandler, H. M., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.11.023 · Cited by 688 · see citing works
Self-citationHorwitz, E. M., Bae, K., Hanks, G. E., Porter, A. T., Grignon, D. J., Brereton, H. D., Venkatesan, V., Lawton, C. A., Rosenthal, S. A., Sandler, H. M., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.9021 · Cited by 687 · see citing works
Self-citationInteraction between the retinoblastoma protein and the oncoprotein MDM2
Xiao, Z.-X., Chen, J., Levine, A. J., Modjtahedi, N., Xing, J. W., Sellers, W. R., & Livingston, D. M. (1995) · Nature · doi:10.1038/375694a0 · Cited by 586 · see citing works
Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein
Martin, K., Trouche, D., Hagemeier, C., Sørensen, T. S., Thangue, N. B. L., & Kouzarides, T. (1995) · Nature · doi:10.1038/375691a0 · Cited by 454 · see citing works
Lin, H.-K., Wang, L., Hu, Y., Altuwaijri, S., & Chang, C. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf406 · Cited by 450 · see citing works
Small Subgroup of Aggressive, Highly Proliferative Prostatic Carcinomas Defined by p53 Accumulation
Visakorpi, T., Kallioniemi, O., Heikkinen, A., et al. (1992) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/84.11.883 · Cited by 312 · see citing works
Agus, D. B., Cordon‐Cardo, C., Fox, W., Drobnjak, M., Koff, A., Golde, D. W., & Scher, H. I. (1999) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/91.21.1869 · Cited by 248 · see citing works
p53 Status and Prognosis of Locally Advanced Prostatic Adenocarcinoma: a Study Based on RTOG 8610
Grignon, D. J., Sarkar, F. H., Forman, J. D., et al. (1997) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/89.2.158 · Cited by 185 · see citing works
Self-citationRegulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation
Gaughan, L. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki141 · Cited by 174 · see citing works
Pollack, A. S., DeSilvio, M., Khor, L. Y., Li, R., Al‐Saleem, T., Hammond, M. E., Venkatesan, V., Lawton, C. A., Roach, M., Shipley, W. U., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.09.150 · Cited by 155 · see citing works
Self-citationCOX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92-02 trial
Khor, L.-Y., Bae, K., Pollack, A. S., et al. (2007) · The Lancet Oncology · doi:10.1016/s1470-2045(07)70280-2 · Cited by 108 · see citing works
Self-citationCronauer, M. V., Schulz, W. A., Burchardt, T., Ackermann, R., & Burchardt, M. (2004) · Oncogene · doi:10.1038/sj.onc.1207346 · Cited by 95 · see citing works
Quinn, D. I., Henshall, S. M., Head, D. R., et al. (2000) · PubMed · Cited by 93 · see citing works
A 60 kd MDM2 isoform is produced by caspase cleavage in non-apoptotic tumor cells
Pochampally, R. R., Fodera, B., Chen, L., Shao, W., Levine, E. A., & Chen, J. (1998) · Oncogene · doi:10.1038/sj.onc.1202206 · Cited by 67 · see citing works
MDM2 as a predictor of prostate carcinoma outcome
Khor, L.-Y., DeSilvio, M., Al‐Saleem, T., Hammond, M. E., Grignon, D. J., Sause, W. T., Pilepich, M. V., Okunieff, P., Sandler, H. M., & Pollack, A. S. (2005) · Cancer · doi:10.1002/cncr.21261 · Cited by 59 · see citing works
Self-citationChakravarti, A., DeSilvio, M., Zhang, M., Grignon, D. J., Rosenthal, S. A., Asbell, S. O., Hanks, G. E., Sandler, H. M., Khor, L.-Y., Pollack, A. S., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.08.4152 · Cited by 52 · see citing works
Self-citationChe, M., DeSilvio, M., Pollack, A. S., et al. (2007) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2007.04.070 · Cited by 43 · see citing works
Self-citationMu, Z., Hachem, P., Agrawal, S., & Pollack, A. S. (2004) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2003.09.029 · Cited by 32 · see citing works
Self-citationMu, Z., Hachem, P., Hensley, H. H., Stoyanova, R. S., Kwon, H. W., Hanlon, A. L., Agrawal, S., & Pollack, A. S. (2008) · The Prostate · doi:10.1002/pros.20731 · Cited by 29 · see citing works
Self-citationHilbe, W., Gächter, A., Duba, H., et al. (2003) · Oncology Reports · doi:10.3892/or.10.1.15 · Cited by 27 · see citing works
Stoyanova, R. S., Hachem, P., Hensley, H. H., Khor, L.-Y., Mu, Z., Hammond, M. E., Agrawal, S., & Pollack, A. S. (2007) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2007.03.047 · Cited by 27 · see citing works
Self-citationThe radiation response of hormone-resistant prostate cancer induced by long-term hormone therapy
Wu, C., Chen, W., Liao, S.-K., Hsu, C.-L., Lee, K., & Chen, M. (2007) · Endocrine Related Cancer · doi:10.1677/erc-07-0073 · Cited by 26 · see citing works
Mu, Z., Hachem, P., Agrawal, S., & Pollack, A. S. (2004) · The Prostate · doi:10.1002/pros.20044 · Cited by 24 · see citing works
Self-citationBrown, R. E., Lun, M., Prichard, J. W., et al. (2004) · PubMed · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
- Authors
- Khor, L.-Y., Bae, K., Paulus, R., Al-Saleem, T., Hammond, M. E., Grignon, D. J., Che, M., Venkatesan, V., Byhardt, R. W., Rotman, M., Hanks, G. E., Sandler, H. M., & Pollack, A.
- Affiliations
- American College of Radiology (US)
- From the Department of Pathology, Drexel University College of Medicine; Department of Statistics, Radiation Therapy Oncology Group, American College of Radiology; and Departments of Pathology and of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA; Department of Pathology, LDS Hospital, Intermountain Health Care, Salt Lake City, UT; Department of Pathology, Indiana University, Indianapolis, IN; Department of Anatomic Pathology, Quest Diagnostics Incorporated, Schaumberg, IL; Radiation...
- Venue
- Journal of Clinical Oncology
- Published
- 2009-07-01
- Volume
- 27
- Issue
- 19
- Pages
- 3177-3184
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC2716939
- OpenAlex
- W2104220131
- Cited by
- 102
- References
- 28
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 8 · 2018: 2 · 2017: 6 · 2016: 13 · 2015: 10 · 2014: 12 · 2013: 8 · 2012: 7
- FWCI
- 7.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pennsylvania Department of Health
- Varian Medical Systems
- National Cancer Institute (R01CA101984, U10CA032115, CA 006927, CA101984, U10CA021661, P30CA006927)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- prostate cancer, MDM2, Ki-67, p53, distant metastasis, all-cause mortality, cause-specific mortality, androgen deprivation therapy, radiotherapy, prognostic factors, risk stratification
- MeSH terms
- Androgen Antagonists, Combined Modality Therapy, Humans, Image Interpretation, Computer-Assisted, Immunohistochemistry, Male, Neoplasm Invasiveness, Prognosis, Prostatic Neoplasms, Radiotherapy, Biomarkers, Tumor, Gene Expression, Tumor Suppressor Protein p53, Treatment Outcome, Antineoplastic Agents, Hormonal, Ki-67 Antigen, Proto-Oncogene Proteins c-mdm2, Kaplan-Meier Estimate
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
