Researchers at the Fisher Biomarker Biorepository Laboratory (FBBL) have been studying nuclear morphometry to characterize tissue biomarkers that predict prostate cancer (PCa) metastasis, PCa-specific death, and PCa progression to biochemical recurrence. Using digital image analysis, we have assessed the nuclear size and shape, DNA content, and chromatin texture of cancer cells and benign epithelial cells adjacent to cancer. The reasons for assessing these important nuclear structural features of the prostate cancer cell were summarized in two key manuscripts that clearly identified metastatic prostate cancers. (1-4)

The FBBL has evaluated several biomarkers in PCa cells from men with long-term follow-up after radical prostatectomy, including biomarkers for cell proliferation (Ki67), apoptosis (Bcl2), angiogenesis (CD34 for blood vessel formation), neuroendocrine differentiation (Chromogranin), oncogene activation (Her2/neu), DNA content, and nuclear roundness.(1-7) Several of these biomarkers significantly correlated with PCa metastasis and PCa-specific death; however, when we ranked the pathological and molecular biomarker variables, nuclear roundness variance (NRV) proved to be the most predictive marker for both PCa metastasis and PCa-specific death. (1-2, 6-7)

Recently, we followed up on the measurement of nuclear shape using tracing methodology in long-term studies on PCa patients. Our laboratory and others previously showed that alterations in nuclear shape can result from activation of certain chromatin-remodeling genes and oncogenes. We therefore evaluated the prognostic value of NRV for PCa metastasis-, PCa progression-, and PCa-specific death-free survivals in a cohort of 116 PCa patients that underwent radical prostatectomy (RP) at JHH. Approximately 18 years ago, in collaboration with the JHH group, Dr. Alan Partin captured a total of ~150 intact nuclei from a single Dr. Epstein selected section of primary RP per patient. Dr. Partin utilized the DynaCELL Motility Morphometry Measurement workstation (JAW Associates, Inc., Annapolis, MD) for image analysis. Median patient follow-up time after RP was 19.0 years (range: 1-25 years, mean: 17.43 years), with approximately 92% (107/116), 71% (82/116), and 47% (55/116) of patients having ≥10, 15, and 20 years of follow-up, respectively.

In this study, NRV was the most significant parameter (Cox proportional hazards regression analysis) for prediction of all three outcomes, and its concordance-index (C-Index) increased from progression-free (0.7080) to metastasis-free (0.7332) to PCa-specific death-free (0.8090) survival predictions. The NRV C-Index was significantly higher than the Gleason Score C-Index for both metastasis-free (0.7332 vs. 0.6046; p = 0.027) and PCa-specific death-free (0.8090 vs. 0.6336; p = 0.004) survival predictions. The NRV and Gleason Score C-Indices for progression-free survival prediction, however, were not significantly different (0.7080 vs. 0.6463; p = 0.106). The Kaplan-Meier results (Figure 1) are summarized below and published in The Prostate, 2010; 70(12): 1333-9. Our team's conclusions should spark renewed interest in NRV as a valuable prognostic marker for assessing PCa aggression. The FBBL is attempting to identify a commercial partner while continuing to validate the use of NRV as a prognostic factor.

To accomplish all of these translational studies, we required PCa tissue samples with well-documented long-term patient follow-up in formatted and audited databases that could be quickly and easily accessed. The keys to our success were Dr. Partin's Department of Urology biorepository and associated PCa databases, which contain over 17,000 cases, and have about 1,000 new RP patients added annually. Further, the JHH Department of Pathology has developed and maintains numerous unique tissue microarrays for PCa progression for study and the program is directed by Dr. Angelo Demarzo. These valuable and unique biorepository resources have made our studies possible.

References:

1. Epstein JI, Berry SJ, Jewett HJ, Eggleston JC, and Coffey DC. A new method to assess metastatic potential of human prostate cancer: relative nuclear roundness. J Urology, 1982; 128: 729-34.

2. Epstein JI, Berry SJ, Jewett HJ, Eggleston JC. Nuclear roundness factor: A predictor of progression in untreated Stage A2 prostate cancer. Cancer, 1984; 54: 1666-71.

3. Veltri RW, Ph.D., Miller MC, Isharwal S, Marlow C, BS., Makarov DV M.D., B.S and Partin AW, M.D., PhD. Prediction of PSA Recurrence in Men with 12 years Post-prostatectomy Follow-up. Cancer Epidemiology Biomarkers Prev, 2008; 17(1):102- 110.

4. Isharwal S, Miller MC, B.S., Epstein JI, Mangold LA., Humphreys E, Partin AW, Veltri RW. Nuclear DNA Ploidy Measurements as a Surrogate to Biopsy Gleason Score for Preoperative Pathologic Stage Prediction. Submitted: Urology, 2009; 73(5):1092-7.

5. Isharwal S, Miller MC, B.S., Epstein JI, Mangold LA., Humphreys E, Partin AW, Veltri RW. Prognostic value of Her-2/neu and %DNA Index for Progression, Metastasis and Prostate Cancer-specific Death in Men with Long-Term Follow-up after Radical Prostatectomy. Int. J Cancer, 2008; 123, 2636-2643.

6. Veltri RW, Isharwal S, Miller MC, Epstein JI, Mangold, LA, Humphreys E, and Partin AW. Long-Term Assessment of Prostate Cancer Progression Free Survival: Evaluation of Pathological Parameters, Nuclear Shape and Molecular Biomarkers of Pathogenesis. The Prostate, 2008; 68:1806-1815.

7. Veltri RW, Isharwal S, Miller MC, Epstein JI, and Partin AW. Nuclear Roundness Variance predicts Prostate Cancer Progression, Metastasis and Death: A prospective evaluation with up to 25 years of Follow-up after Radical Prostatectomy. The Prostate, 2010; PROS-10-024.R1 (Accepted and In Press 2-22-10).

Robert Veltri, PhD as part of Beyond the Abstract on UroToday. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations, etc., of their research by referencing the published abstract.

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