The ability of traditional and newer molecular-based prognostic factors to predict the outcome of prostate cancer is of considerable interest to urologists, pathologists, and patients. In this review, a series of traditional and newer molecular-based prognostic factors are considered, including those that have achieved widespread use, newer tests that are beginning to be used in clinical practice, and emerging molecular markers that have yet to be widely validated in the published literature or clinical trials.

Prognostic factors in prostate cancer.

Tyrosine kinases play central roles in the growth and differentiation of normal and tumor cells. In this study, we have analyzed the general tyrosine kinase expression profile of a prostate carcinoma (PCA) xenograft, CWR22. We describe here an improved reverse transcriptase-PCR approach that permits identification of nearly 40 different kinases in a single screening; several of these kinases are newly cloned kinases and some are novel. According to this, there are 11 receptor kinases, 9 nonreceptor kinases, and at least 7 dual kinases expressed in the xenograft tissue. The receptor kinases include erbB2, erbB3, Ret, platelet-derived growth factor receptor, sky, nyk, eph, htk, sek (eph), ddr, and tkt. The nonreceptor kinases are lck, yes, abl, arg, JakI, tyk2, and etk/bmx. Most of the dual kinases are in the mitogen-activating protein (MAP) kinase-kinase (MKK) family, which includes MKK3, MKK4, MEK5, and a novel one. As a complementary approach, we also analyzed by specific reverse transcriptase-PCR primers the expression profile of erbB/epidermal growth factor receptor family receptors in a variety of PCA specimens, cell lines, and benign prostatic hyperplasia. We found that erbB1, -2, and -3 are often coexpressed in prostate tissues, but not in erbB4. The information established here should provide a base line to study the possible growth and oncogenic signals of PCA.

A tyrosine kinase profile of prostate carcinoma.

BACKGROUND

HER-2/neu gene amplification, established as a prognostic factor in breast carcinoma and other cancers, has not been correlated with outcome in prostate carcinomas (PCs).



METHODS

HER-2/neu gene amplification was determined by automated fluorescence in situ hybridization (FISH) using a unique sequence cosmid probe on 113 formalin fixed, paraffin embedded 4-μm tissue sections and the results compared with tumor grade, DNA ploidy, HER-2/neu protein expression by immunohistochemistry (IHC), serum prostate specific antigen, pathologic stage, and postoperative disease recurrence (mean follow-up of 44 months).



RESULTS

HER-2/neu gene amplification by FISH (41% of PCs) correlated with tumor grade (P = 0.001) and DNA ploidy status (P = 0.0003). HER-2/neu protein overexpression by IHC (29% of PCs) correlated with grade (P = 0.03), but not with DNA ploidy. A trend for similar HER-2/neu status in each PC by IHC and FISH did not reach statistical significance (P = 0.25). On univariate analysis, HER-2/neu amplification by FISH (P = 0.029), tumor grade (P = 0.013), and DNA ploidy (P = 0.016) correlated with postoperative disease recurrence. HER-2/neu expression by IHC did not correlate with outcome. On multivariate analysis, grade (P = 0.0001) and ploidy (P = 0.001) were independent outcome predictors; HER-2/neu amplification by FISH reached near-independent significance (P = 0.125).



CONCLUSIONS

HER-2/neu gene amplification by FISH on archival PCs significantly correlates with grade and DNA ploidy status, is more sensitive than IHC in detecting HER-2/neu gene abnormalities, predicts postoperative disease recurrence, and may prove important in planning therapy for patients with prostate carcinoma. Cancer 1997; 79:2162-70. © 1997 American Cancer Society.

Prognostic significance of HER-2/neu gene amplification status by fluorescence in situ hybridization of prostate carcinoma.

Purpose: The nuclear transcription factor nuclear factor-κB (NFκB) and its inhibitor, IκB, regulate the transcription of various genes involved in cell proliferation, adhesion, and survival. The NFκB transcription factor complex plays a role in cancer development and progression through its influence on apoptosis. More recently, NFκB has been shown to be activated in human and androgen-independent prostate cancer cells. To our knowledge, this is the first study demonstrating the prognostic significance of NFκB immunoreactivity in prostate adenocarcinomas (PACs).

Experimental Design: Using prostatectomy specimens, we performed immunohistochemical staining for NFκB and IκBα (Santa Cruz Biotechnology) on formalin-fixed, paraffin-embedded sections obtained from 136 patients with PAC. Cytoplasmic and nuclear immunoreactivity was scored for intensity and distribution, and results were correlated with preoperative serum prostate-specific antigen, tumor grade, stage, DNA ploidy (Feulgen spectroscopy), and biochemical disease recurrence.

Results: Forty-nine percent of PACs overexpressed cytoplasmic NFκB, and 63% showed decreased IκB expression. Cytoplasmic NFκB overexpression correlated with advanced tumor stage ( P = 0.048), aneuploidy ( P = 0.022), and biochemical disease recurrence ( P = 0.001). When we compared the means for the NFκB-positive and -negative subgroups, NFκB overexpression correlated with preoperative serum prostate-specific antigen ( P = 0.04) and DNA index ( P = 0.05). Fifteen percent of PACs expressed nuclear NFκB, which correlated with high tumor grade ( P = 0.001) and advanced stage ( P = 0.05). Decreased IκBα expression correlated with high tumor grade ( P = 0.015). On multivariate analysis, tumor stage ( P = 0.043) and NFκB overexpression ( P = 0.006) were independent predictors of biochemical recurrence.

Conclusion: These results support a role for NFκB pathway proteins in the tumorigenesis of PACs. The findings are also consistent with reported experimental studies suggesting a new strategy of combined chemotherapy and specific NFκB blockade in decreasing the rate of disease relapse.

https://clincancerres.aacrjournals.org/content/clincanres/10/7/2466.full.pdf

Expression of nuclear factor-κB and IκBα proteins in prostatic adenocarcinomas : Correlation of nuclear factor-κB immunoreactivity with disease recurrence

Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial.

Background. Recent advances in the early detection of prostatic adenocarcinoma have stimulated interest in the development of techniques for determining metastatic potential.



Methods. One hundred cases of adenocarcinoma, including 66 biopsy and radical prostatectomy specimens; 20 biopsies alone; and 14 transurethral resection specimens, were evaluated for Gleason tumor grade, DNA content and HER-2/neu expression. DNA content was determined on Feulgen-stained touch preparations and tissue sections (18 cases) or tissue sections alone. HER-2/neu expression level was determined by image-analysis-assisted quantitative immunocytochemistry.



Results. Tumor grade and ploidy status were independent significant predictors of metastasis. HER-2/neu overexpression was found in 16 (16%) of the 100 cases and significantly correlated with high-tumor grade and aneuploid status, but was not of independent value in the prediction of metastasis.



Conclusions. HER-2/neu overexpression is not uncommon in prostatic adenocarcinoma and is associated with high-tumor grade, abnormal DNA content, and distant metastasis. Tumor grade and DNA ploidy values are of the greatest value in determining the presence of metastasis.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819931115%2972%3A10%3C3020%3A%3AAID-CNCR2820721026%3E3.0.CO%3B2-%23

Contribution of HER-2/neu oncogene expression to tumor grade and DNA content analysis in the prediction of prostatic carcinoma metastasis

Comparative quantitative immunohistochemical and immunoradiometric determinations of cathepsin D in endometrial adenocarcinoma: predictors of tumor aggressiveness.

Background. Recent advances in the early detection of prostatic adenocarcinoma have stimulated interest in the development of techniques for determining metastatic potential. Methods. One hundred cases of adenocarcinoma, including 66 biopsy and radical prostatectomy specimens; 20 biopsies alone; and 14 transurethral resection specimens, were evaluated for Gleason tumor grade, DNA content and HER-2/neu expression. DNA content was determined on Feulgen-stained touch preparations and tissue sections (18 cases) or tissue sections alone. HER-2/ neu expression level was determined by image-analysis-assisted quantitative immunocytochemistry. Results. Tumor grade and ploidy status were independent significant predictors of metastasis

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Contribution of HER-2/neu oncogene expression to tumor grade and DNA content analysis in the prediction of prostatic carcinoma metastasis

Comparative quantitative immunohistochemical and immunoradiometric determinations of cathepsin D in endometrial adenocarcinoma: predictors of tumor aggressiveness.

Contribution of HER-2/neu oncogene expression to tumor grade and DNA content analysis in the prediction of prostatic carcinoma metastasis