Elizabeth Humphreys

Background Molecular pathways of proliferation, angiogenesis, neuroendocrine differentiation, apoptosis and alterations in nuclear structure of cancer epithelial cells are important in the pathogenesis of prostate cancer (PCa). Therefore, we evaluated the prognostic value of these parameters in 105 clinically localized PCa tumors with long‐term follow‐up after radical prostatectomy for progression‐free survival (PFS). Method Nuclear roundness variance (NRV) was calculated for tumor nuclei using the graphic tracing DynaCELL system. Immunohistochemistry assessed expression of Ki67, PCNA (proliferation), Chromogranin A (neuroendocrine differentiation), CD31 (angiogenesis), BCL2 (apoptosis), and Her‐2/neu (oncogene) in the tumors. Cox proportional hazards regression, Spearman's rank correlation, and Kaplan–Meier plots were employed to analyze the data. Results Gleason score, focal vs. non‐focal extra‐prostatic extension, organ confined status, NRV, Her‐2/neu, CD‐31 and Ki67 were univariately significant predictors of PFS. NRV was the most significant prognostic indicator with the highest concordance index (0.7) for PFS. Gleason score, NRV and Her‐2/neu were multivariately significant and yielded a concordance index of 0.77. Conclusion Her‐2/neu oncogene and NRV were shown to be significant in the prediction of PFS. The assessment of alterations in nuclear structure using NRV proved to be the most significant factor in the prediction of PFS. Integration of image analysis‐based NRV and molecular biomarkers with pathologic parameters should be considered for validation in the prediction of PFS. Prostate

Abnormal DNA content in tumor cells represents large scale chromosomal alterations and reflects later changes of genetic instability. Her‐2/neu oncogene is amplified in 20–30% of breast and ovarian cancer patients and is associated with poor prognosis. Therefore, we evaluated prognostic value of Her‐2/neu expression and DNA content measurements in 252 clinically localized PCa patients with long‐term follow‐up after radical prostatectomy for progression, metastasis and PCa‐specific death. Her‐2/neu expression was determined by immunohistochemistry and DNA content measurements employed Feulgen‐stained cancer nuclei captured using static image cytometry system. Cox proportional hazard regression and Kaplan‐Meir plots were used to identify significant prognostic factors for progression, metastasis and PCa‐specific death. The proportions of Her‐2/neu positive and high %DNA index tumors significantly increased from nonprogressor to progressors without metastasis to progressors with metastasis (p < 0.0001; p = 0.027; p ≤ 0.001), metastasis (p ≤ 0.01) PCa‐specific death (p ≤ 0.04) in univariate analyses. Multivariately, Her‐2/neu expression and %DNA index were also significant for progression (p = 0.001), metastasis (p = 0.001) and PCa‐specific death (p = 0.02). When all other clinicopathologic information is available, the increment in concordance index by addition of either Her‐2/neu or DNA index was ∼2% and of both biomarkers was ∼3% for progression, metastasis and PCa‐specific death free survival models. Therefore, patients with Her‐2/neu positive and high %DNA index are at a higher risk for disease progression, metastasis and PCa‐specific death. Further, Her‐2/neu expression and %DNA index may be used with clinicopathologic parameters for prediction of long‐term prognosis in PCa.