Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer

Thymidylate synthase (TYMS) plays a role in DNA synthesis and is a target for 5-fluorouracil. In this study TYMS was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. TYMS expression was higher in neoplastic than in normal prostate epithelium and was detectable in 72.9% of 10,223 interpretable cancers. It was considered strong in 21.9%, moderate in 33.4% and weak in 17.6% of tumors. TYMS overexpression was associated with deletions at 5q21 (p < 0.0001), 6q15 (p < 0.0001) and 3p13 (p = 0.0083) and gradually increased with the total number of these deletions present in the respective cancer sample (p < 0.0001). TYMS expression was unrelated to PTEN deletions (p = 0.9535) but tightly linked to high Gleason grade, advanced pathological tumor stage and early PSA recurrence (p < 0.0001). The prognostic value of TYMS was independent from the ERG status and deletions at 3p13, 5q21, and 6q15. In multivariate analyses the prognostic role of TYMS expression was independent of Gleason grade, pT stage, preoperative PSA, pN stage, or resection margins. TYMS expression analysis might result in clinically useful information in prostate cancer. The striking link to some but not all chromosomal aberrations might suggest a mechanistical link with specific types of DNA damage.     

Reduced AZGP1 expression is an independent predictor of early PSA recurrence and associated with ERG‐fusion positive and PTEN deleted prostate cancers

Zinc‐alpha 2‐glycoprotein (AZGP1) is involved in lipid metabolism and was suggested as a candidate prognostic biomarker in prostate cancer. To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, AZGP1 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. Data on ERG status and PTEN, 3p13, 5q21 and 6q15 deletions were available from earlier studies. AZGP1 expression was strong in benign prostatic glands but absent in 38.0% of 8,510 interpretable prostate cancers. Reduced AZGP1 expression was associated with TPMRSS2:ERG fusions, both by FISH and immunohistochemical analysis (p < 0.0001 each). For example, AZGP1 was absent in 54.6% of 2,029 ERG IHC positive but in only 28.1% of 2,398 ERG negative cancers. Irrespective of the ERG status, reduced AZGP1 expression was tightly linked to high Gleason score, advanced pathological tumor stage, positive nodal status and early PSA recurrence (p < 0.0001 each). Reduced AZGP1 expression was also strongly associated with PTEN deletions. AZGP1 immunostaining was lacking in 62.7% of 842 PTEN deleted but in only 37.3% of PTEN non‐deleted cancers but retained strong prognostic influence in both subgroups (p < 0.0001 each). The prognostic role of AZGP1 expression was also independent of Gleason score, pT stage, pN stage, surgical margin status and preoperative PSA, irrespective of whether preoperative or postoperative variables were used for modeling. In conclusion, the results of our study demonstrate that reduced AZGP1 expression is strongly related to adverse prostate cancer prognosis, independently of established clinic‐pathological variables and PTEN deletions.     

Genomic deletion of chromosome 12p is an independent prognostic marker in prostate cancer

Deletion of 12p is a recurrent alteration in prostate cancer, but the prevalence and clinical consequences of this alteration have not been studied in detail. Dual labeling fluorescence in situ hybridization using probes for 12p13 (CDKN1B; p27) and centromere 12 as a reference was used to successfully analyze more than 3700 prostate cancers with clinical follow-up data assembled in a tissue microarray format. CDKN1B was selected as a probe because it is located in the center of the deletion, which spans > 10 Mb and includes > 50 genes in 80% of cancers with 12p deletion. Deletion of 12p was found in 13.7% of cancers and included 13.5% heterozygous and 0.2% homozygous deletions. 12p deletion were linked to advanced tumor stage (p < 0.0001), high Gleason grade (p < 0.0001), rapid tumor cell proliferation (p < 0.0001), lymph node metastasis (p = 0.0004), and biochemical recurrence (p = 0.0027). Multivariate analysis including pT stage (p < 0.0001), Gleason grade (p < 0.0001), pN status (p = 0.0001), preoperative PSA levels (p = 0.0001), and resection margin status (p = 0.0001) revealed an independent prognostic value of 12p deletion (p = 0.0014). Deletion of 12p was unrelated to the ERG fusion status. Deletion of 12p was only marginally linked to reduced p27 expression, which by itself was unrelated to clinical outcome. This argues against p27 as the key target gene of 12p deletions. In summary, the results of our study demonstrate that 12p deletion is frequent in prostate cancer and provides independent prognostic information. 12p deletion analysis alone, or in combination with other prognostic parameters may thus have clinical utility.     

High RNA-binding motif protein 3 expression is an independent prognostic marker in operated prostate cancer and tightly linked to ERG activation and PTEN deletions

BackgroundThe RNA-binding motif protein 3 (RBM3) has recently been suspected as a prognostic biomarker in several cancers.MethodsRBM3 expression was analysed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers.ResultsRBM3 expression was more often detectable in malignant compared to benign prostate. RBM3 immunostaining was found in 64% of the interpretable prostate cancers and was considered strong in 25.6%. High RBM3 expression was linked to advanced tumour stage, high Gleason score, positive nodal involvement and positive surgical margin status (p < 0.0001 each). There was a remarkable accumulation of strong RBM3 expression in v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) positive prostate cancers and tumours harbouring PTEN deletions (p < 0.0001 each). Moreover, RBM3 staining was tightly related to early biochemical recurrence if all tumours or subgroups of ERG negative and ERG positive cancers were analysed (p < 0.0001 each). In multivariate analysis, including RBM3 staining, Gleason grade, pT stage, prostate-specific antigen (PSA), surgical margin status, and nodal status, the prognostic impact of RBM3 staining retained statistically significance (p = 0.0084).ConclusionOur observations indicate that high RBM3 expression is an independent prognostic marker in prostate cancer. The tight link to ERG activation and PTEN deletions suggest interaction with key molecular pathways in prostate cancer.     

High lysophosphatidylcholine acyltransferase 1 expression independently predicts high risk for biochemical recurrence in prostate cancers

Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been suggested to play a role in cancer. To assess its role in prostate cancer, LPCAT1 expression was analyzed on a tissue microarray containing samples from 11,152 prostate cancer patients. In benign prostate glands, LPCAT1 immunostaining was absent or weak. In prostate cancer, LPCAT1 positivity was found in 73.8% of 8786 interpretable tumors including 29.2% with strong expression. Increased LPCAT1 expression was associated with advanced tumor stage (pT3b/T4) (p < 0.0001), high Gleason score (≥4 + 4) (p < 0.0001), positive nodal involvement (p = 0.0002), positive surgical margin (p = 0.0005), and early PSA recurrence (p < 0.0001). High LPCAT1 expression was strongly linked to ERG-fusion type prostate cancer. Strong LPCAT1 staining was detected in 45.3% of ERG positive but in only 16.7% of ERG negative tumors (p < 0.0001). Within ERG negative cancers, LPCAT1 staining was strongly increased within the subgroup of PTEN deleted cancers (p < 0.0001). Further subgroup analyses revealed that associations of high LPCAT1 expression with PSA recurrence and unfavorable tumor phenotype were largely driven by ERG negative cancers (p < 0.0001) while these effects were substantially mitigated in ERG positive cancers (p = 0.0073). The prognostic impact of LPCAT1 expression was independent of histological and clinical parameters. It is concluded, that LPCAT1 measurement, either alone or in combination, may be utilized for better clinical decision-making. These data also highlight the potentially important role of lipid metabolism in prostate cancer biology.     

Loss of pSer2448‐mTOR expression is linked to adverse prognosis and tumor progression in ERG‐fusion‐positive cancers

Prevalence and clinical significance of mammalian target of rapamycin (mTOR) phosphorylation at the serine 2448 is disputed in prostate cancer. A tissue microarray containing 3,261 prostate cancers and 49 normal prostate samples with clinical follow‐up data was analyzed for p^Ser2448‐mTOR expression by immunohistochemistry. Moderate to strong p^Ser2448‐mTOR staining was found in all (n = 49) normal prostate tissues, but was lost in 24% or weak in 29% cancers. Moderate and strong staining was found in 36 and 11% of tumors. Loss of p^Ser2448‐mTOR staining was significantly linked to advanced stage (p = 0.0027), high‐grade (p = 0.0045), nodal positive cancers (p = 0.0483), early tumor recurrence (p < 0.0001, independently from stage and grade, p = 0.0016), lack of Ets‐related gene (ERG) fusion (p < 0.0001), reduced androgen receptor expression (p < 0.0001 each) and increased cell proliferation (p = 0.0092) in all cancers and in the subset of ERG‐fusion‐positive cancers. Loss of p^Ser2448‐mTOR expression was linked to tumor metastasis (p = 0.0275) in ERG‐fusion‐positive cancers only. Molecular subset analysis using pre‐existing phosphatase and tensin homolog (PTEN) deletion data revealed that loss of p^Ser2448‐mTOR expression is of prognostic relevance and defines a subpopulation of PTEN‐deleted and ERG‐fusion‐positive cancers with a particular poor outcome. The results of our study strongly suggest that loss of p^Ser2448‐mTOR expression is a marker for activated AKT/mTOR signaling. Tumors with concomitant PTEN deletion and activated mTOR signaling indicated by loss of p^Ser2448‐mTOR expression characterize a small (4%) but clinically significant subset of prostate cancers that might optimally benefit from anti‐mTOR therapies.     

The prognostic significance of combined ERG and androgen receptor expression in patients with prostate cancer managed by androgen deprivation therapy

ERG and androgen receptor (AR) are known to function cooperatively in prostate cancer (PCa) progression. However, the prognostic value of combined ERG and AR expression and potential pathways are not well characterized. We assessed ERG and AR protein expression by immunohistochemistry in a cohort of 312 men with PCa diagnosed by transurethral resection of the prostate (TURP). Patients were divided into those with no prior hormonal treatment (designated as PCa/AdvPCa) vs. those with castrate-resistant PCa (CRPC) undergoing channel TURP to relieve obstructive symptoms. The expression status was correlated with various clinical-pathological parameters. The Swedish watchful-waiting cohort was used for validation and characterization of potential gene signatures associated with ERG and AR.   Patients with combined ERG-positive/AR high expression profile demonstrated higher rates of PCa-specific mortality (PCSM) compared with patients with ERG-negative/AR low in patients with no prior treatment (n = 90, P = 0.032), but this was attenuated in the overall cohort which included the CRPC subgroup (n = 125, P = 0.096). The prognostic significance to PCSM was validated in the Swedish watchful waiting cohort in univariate (HR: 3.3; 95% CI: 1.9–5.6, P = 4.25E−5) and multivariate analysis (HR: 2; 95% CI: 0.97–4.1, P = 0.057), which included Gleason score. ERG/AR overexpression status characterized 152 genes signatures including WNT, PI3K/AKT and chemokine signaling pathways known to be deregulated in PCa. In conclusion, combined ERG/AR overexpression signifies a class of patients at highest-risk of PCSM with specific key genetic alteration likely responsible for disease progression. The prognostic value of combined ERG/AR overexpression and its associated genes should be further investigated as potential prognostic and therapeutic targets in prostate cancer progression.     

Loss of the adhesion molecule CEACAM1 is associated with early biochemical recurrence in TMPRSS2:ERG fusion-positive prostate cancers

Altered expression of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been linked to adverse tumor features in various cancer types. To better understand the role of CEACAM1 in prostate cancer, we analyzed a tissue microarray containing tumor spots from 17,747 prostate cancer patients by means of immunohistochemistry. Normal prostate glands showed intense membranous CEACAM1 positivity. Immunostaining was interpretable in 13,625 cancers and was considered high in 28%, low in 43% and absent in 29% of tumors. Low and lost CEACAM1 expression was strongly linked to adverse tumor features including high classical and quantitative Gleason grade, lymph node metastasis, advanced tumor stage, positive surgical margin, a high number of genomic deletions and early biochemical recurrence (p < 0.0001 each). Subset analysis of molecularly defined cancer subsets revealed that these associations were strongest in V-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion-positive cancers and that CEACAM1 loss was prognostic even in tumors harboring genomic deletions of the phosphatase and tensin homolog tumor suppressor (p < 0.0001). Multivariate analysis suggested that CEACAM1 analysis can provide independent prognostic information beyond established prognosis parameters at the stage of the initial biopsy when therapy decisions must be taken. In conclusion, loss of CEACAM1 expression predicts poor prognosis in prostate cancer and might provide clinically useful prognostic information particularly in cancers harboring the TMPRSS2:ERG fusion.     

Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer

The deletion of 16q23‐q24 belongs to the most frequent chromosomal changes in prostate cancer, but the clinical consequences of this alteration have not been studied in detail. We performed fluorescence in situ hybridization analysis using a 16q23 probe in more than 7,400 prostate cancers with clinical follow‐up data assembled in a tissue microarray format. Chromosome 16q deletion was found in 21% of cancers, and was linked to advanced tumor stage, high Gleason grade, accelerated cell proliferation, the presence of lymph node metastases (p < 0.0001 each) and positive surgical margin (p = 0.0004). 16q Deletion was more frequent in ERG fusion‐positive (27%) as compared to ERG fusion‐negative cancers (16%, p < 0.0001), and was linked to other ERG‐associated deletions including phosphatase and tensin homolog (PTEN) (p < 0.0001) and 3p13 (p = 0.0303). In univariate analysis, the deletion of 16q was linked to early biochemical recurrence independently from the ERG status (p < 0.0001). Tumors with codeletions of 16q and PTEN had a worse prognosis (p = 0.0199) than those with PTEN or the deletion of 16q alone. Multivariate modeling revealed that the prognostic value of 16q/PTEN deletion patterns was independent from the established prognostic factors. In summary, the results of our study demonstrate that the deletion of 16q and PTEN cooperatively drives prostate cancer progression, and suggests that deletion analysis of 16q and PTEN could be of important clinical value particularly for preoperative risk assessment of the clinically most challenging group of low‐ and intermediated grade prostate cancers.     

A retrospective study of high mobility group protein I(Y) as progression marker for prostate cancer determined by in situ hybridization.

In a previous study using RNA in situ hybridisation (RISH), we found a significant correlation between high mobility group protein I/Y, [HMG-I(Y)] mRNA expression and tumour stage and grade in prostate cancer patients, suggesting that HMG-I(Y) might be a potential prognostic marker in prostate cancer. However, our clinical follow-up was limited because cryopreserved material was used. Assessing the potential prognostic value of this molecule is of importance because the clinical course of prostate cancer patients remains unpredictable. Here we describe our results on paraffin-embedded archival material from a group of 102 patients undergoing radical prostatectomy. These were evaluated for the presence of HMG-I(Y) using RISH, and a follow-up of 12-92 months (average 53 months) was available. In 2 of 14 prostate cancers in which the predominant histological pattern was of Gleason grade 1-2, a high HMG-I(Y) expression was observed, whereas in 19 of 23 Gleason grade 3, and 34 of 35 Gleason grade 4-5 tumours, high HMG-I(Y) mRNA levels were detected (chi-square = 38.78, P < 0.0001). Moreover, of tumours that expressed high HMG-I(Y) levels, 25% were organ confined (T1-2), in contrast to 74.5% of the invading tumours (T3, chi-square = 15.8, P < 0.001). Furthermore, 87% of recurrent tumours showed high HMG-I(Y) expression. However, a multivariate regression analysis including Gleason grade, clinical tumour stage, HMG-I(Y) expression and prostate-specific antigen (PSA) levels showed Gleason grade as the most accurate predictor of progression. High HMG-I(Y) levels measured by RISH were indicative of a worse prognosis, albeit that additional value over the more subjective grading methods was not evident.     

Incidence of high chromogranin A serum levels in patients with non metastatic prostate adenocarcinoma

Background

ChromograninA in prostate carcinoma (PC) indicate NE differentiation. This tumour is more aggressive and resistant to hormone therapy.

Patients and methods

We analyzed the incidence of pre-operative ChromograninA serum levels in non metastatic PC patients. Serum PSA and ChromograninA were analyzed before treatment. Clinicopathological parameters were evaluated in relation to serum ChromograninA. 486 patients were enrolled.

Results

We found 352 pT2 and 134 pT3. 21 patients were N+. 278 patients had Gleason score levels <7; 173 patients had levels = 7 (122 were 3+4 and 51 4+3); and 35 patients with levels >7. Median PSA pre-operative level was 7.61 ng/ml. PSA was significantly associated with pT stage (pT2 with PSA abnormal 23.6% vs pT3 48.5%, p < 0.0001) and with a Gleason score (PSA abnormal 60% in the Gleason score was >7 vs 29.5% in the Gleason score = 7 vs 27.3% in the Gleason score <7, p < 0.0001). In 114 patients pre-operative ChromograninA levels were elevated (23.5%). Serum ChromograninA levels had no significant association with PSA (p = 0.44) and pT stage (p = 0.89). abnormal ChromograninA levels increased from a Gleason score of <7 (25.5%) to >7 (31.4%) (p = 0.12). The serum ChromograninA levels in the two groups of patients were subdivided before and after 2005 on the basis of different used assays, showing no correlation with serum ChromograninA and other parameters.

Conclusions

This study showed that ChromograninA levels correlated to NE differentiation and possible aggressiveness of PC. Pre-operative circulating ChromograninA could complement PSA in selecting more aggressive PC cases, particularly in the presence of a higher Gleason score. Complementary information is provided by the absence of a correlation between serum ChromograninA and PSA levels.     

8p deletion is strongly linked to poor prognosis in breast cancer

Deletions of chromosome 8p occur frequently in breast cancers, but analyses of its clinical relevance have been limited to small patient cohorts and provided controversial results. A tissue microarray with 2,197 breast cancers was thus analyzed by fluorescence in-situ hybridization using an 8p21 probe in combination with a centromere 8 reference probe. 8p deletions were found in 50% of carcinomas with no special type, 67% of papillary, 28% of tubular, 37% of lobular cancers and 56% of cancers with medullary features. Deletions were always heterozygous. 8p deletion was significantly linked to advanced tumor stage (P < 0.0001), high-grade (P < 0.0001), high tumor cell proliferation (Ki67 Labeling Index; P < 0.0001), and shortened overall survival (P < 0.0001). For example, 8p deletion was seen in 32% of 290 grade 1, 43% of 438 grade 2, and 65% of 427 grade 3 cancers. In addition, 8p deletions were strongly linked to amplification of MYC (P < 0.0001), HER2 (P < 0.0001), and CCND1 (p = 0.001), but inversely associated with ER receptor expression (p = 0.0001). Remarkably, 46.5% of 8p-deleted cancers harbored amplification of at least one of the analyzed genes as compared to 27.5% amplifications in 8p-non-deleted cancers (P < 0.0001). In conclusion, 8p deletion characterizes a subset of particularly aggressive breast cancers. As 8p deletions are easy to analyze, this feature appears to be highly suited for future DNA based prognostic breast cancer panels. The strong link of 8p deletion with various gene amplifications raises the possibility of a role for regulating genomic stability.     

An immunohistochemical signature comprising PTEN,MYC, and Ki67 predicts progression in prostate cancer patients receiving adjuvant docetaxel after prostatectomy

BACKGROUND:

Loss of the tumor suppressor PTEN is common in prostate cancer and may have prognostic significance. The authors examined PTEN and additional protein markers in primary tumors from patients with high‐risk, localized prostate cancer who received adjuvant docetaxel in a prospective multicenter trial (TAX2501).

METHODS:

Fifty‐six of 77 patients enrolled in TAX2501 had primary prostatectomy specimens available for immunohistochemical analysis of PTEN, MYC, ERG, tumor protein p53 (p53), antigen KI‐67 (Ki67), and phosphorylated forms of Akt, mammalian target of rapamycin (mTOR), and S6 ribosomal protein. Protocol‐defined progression included a prostate‐specific antigen (PSA) level ≥0.4 ng/mL, radiologic/clinical recurrence, or death. Univariate and multivariable proportional hazards regression analyses were used to investigate the influence of PTEN status (and other protein markers) on progression‐free survival (PFS).

RESULTS:

In this exploratory, post hoc analysis, PTEN protein loss (vs presence) was observed in 61% of patients and was associated with lower preoperative PSA levels, higher clinical stage, lower Ki67 expression, the presence of p53, and the presence of ERG. In univariate analysis, the factors associated with PFS included Gleason sum, seminal vesicle invasion, PTEN status, MYC expression, and Ki67 expression. In multivariable analysis, only 3 variables emerged as independent prognostic factors for PFS: PTEN status (P = .035), MYC expression (P = .001), and Ki67 expression (P < .001). A prognostic model was constructed that incorporated clinical covariates as well as information on PTEN, MYC, and Ki67.

CONCLUSIONS:

The current results indicated that PTEN status, MYC expression, and Ki67 expression in primary tumor samples may predict PFS more accurately than clinical factors alone in men with high‐risk prostate cancer who receive adjuvant docetaxel after prostatectomy. If validated, these hypothesis‐generating findings may have prognostic and therapeutic implications and may aid clinical trial design. Cancer 2012. © 2012 American Cancer Society.     

Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer

Background:

The natural history of prostate cancer is highly variable and difficult to predict. We report on the prognostic value of phosphatase and tensin homologue (PTEN) loss in a cohort of 675 men with conservatively managed prostate cancer diagnosed by transurethral resection of the prostate.

Methods:

The PTEN status was assayed by immunohistochemistry (PTEN IHC) and fluorescent in situ hybridisation (PTEN FISH). The primary end point was death from prostate cancer.

Results:

The PTEN IHC loss was observed in 18% cases. This was significantly associated with prostate cancer death in univariate analysis (hazard ratio (HR)=3.51; 95% CI 2.60–4.73; P=3.1 × 10⁻¹⁴). It was highly predictive of prostate cancer death in the 50% of patients with a low risk score based on Gleason score, PSA, Ki-67 and extent of disease (HR=7.4; 95% CI 2.2–24.6; P=0.012) ), but had no prognostic value in the higher risk patients. The PTEN FISH loss was only weakly associated with PTEN IHC loss (κ=0.5). Both PTEN FISH loss and amplification were univariately predictive of death from prostate cancer, but this was not maintained in the multivariate analyses.

Conclusion:

In low-risk patients, PTEN IHC loss adds prognostic value to Gleason score, PSA, Ki-67 and extent of disease.     

Association between percentage of tumor involvement and Gleason score upgrading in low-risk prostate cancer

To find the predictors of Gleason score upgrading in a cohort of low-risk prostate cancer patients, data were analyzed comprising 1,632 consecutive men with low-risk prostate cancer who underwent radical prostatectomy between 1993 and 2009. Assessment focused on preoperative parameters including patient age, race, diagnostic prostate-specific antigen (PSA) levels, clinical stage and biopsy Gleason score, along with pathological parameters including percentage of tumor involvement (PTI), tumor laterality, pathological stage, extra-capsular extension, seminal vesicle invasion, and surgical margins. These parameters were analyzed using univariate and multivariate methods. Kaplan?CMeier curves compared differences in biochemical disease-free survival in men having cancers with and without Gleason score upgrading. Cases involving pathological Gleason score upgrading were identified in 723 (44.3?%) of 1,632 patients. Kaplan?CMeier PSA recurrence-free survival curves showed a difference in outcome between men with and without Gleason score upgrading (p?<?0.001). Of Gleason score upgraded patients, 35 (4.8?%) men had PTI of <5?%, 237 (32.8?%) had PTI of 5?C9.9?%, 177 (24.5?%) had PTI of 10?C14.9?%, and 274 (37.9?%) had PTI????15?% (p?<?0.001). PTI (p?<?0.001) along with diagnostic PSA, patient age, diagnostic biopsy Gleason score, pathologic stage, and surgical margin status were independent predictors of pathological Gleason score upgrading on multivariate logistic regression. PTI correlates closely with Gleason score upgrading in a low-risk prostate cancer cohort. Low-risk prostate cancer patients with clinical findings suggestive of high PTI or large volume cancers should not benefit from active surveillance strategies.     

ERG expression is associated with increased risk of biochemical relapse following radical prostatectomy in early onset prostate cancer

Purpose

ERG expression has been proposed to signify molecular subtype of PCA. However, its significance in early onset prostate cancer (PCA) is not characterized.

Materials and methods

ERG protein expression was investigated in a cohort of 121 men diagnosed with localized PCA at <50 years of age with a mean follow-up time of 65.7 months. ERG was correlated to patients’ outcome and clinical-pathological parameters using univariate and multivariate analysis.

Results

ERG expression was detected in 76/118 (64.4 %) analyzable patients’ samples and showed interfocal heterogeneity (differences between foci) in 17/118 (14.4 %) patients. There was significant association between ERG expression and Gleason score (p = 0.022), but not with any other clinical-pathologic parameter, including pre-surgical PSA levels, tumor volume, pathological stage, surgical margin or lymph-vascular invasion. ERG had significant effect on the rate of biochemical relapse following radical prostatectomy, with ERG positive patients showing higher relapse rates vs. ERG negative patients (p = 0.007). However, considering time till biochemical relapse post-radical prostatectomy, ERG expression showed positive insignificant trends (p = 0.071). Notably, and of great significance, in this cohort of early onset disease, none of the ERG negative PCA patients exhibited biochemical relapse.

Conclusion

The study results suggest that ERG expression may be of added prognostic value in localized prostate cancer in patients with early onset PCA. However, the issue of ERG interfocal heterogeneity observed may require the evaluation of several tumor foci to assess ERG status per case. Incorporating ERG status into existing nomograms may be of added prognostic value in patients with early onset PCA.     

Hypertension as a predictive biomarker in bevacizumab treatment for colorectal cancer patients

To assess preoperative parameters that may be predictive of pathologic stage T2a (pT2a) and pathologic Gleason score (pGS) ?? 6 disease in low-risk prostate cancer patients considering active surveillance. A cohort of 1,495 men with low-risk prostate cancer between 1993 and 2009 was utilized. Preoperative assessment focused on patient age, race, diagnostic PSA level, clinical stage, diagnostic biopsy Gleason score, and prostate cancer laterality. Kaplan?CMeier curves and a Cox regression model were used for analysis of PSA recurrence. Preoperative parameters were analyzed by univariate and multivariate logistic regression methods. Of 1,495 patients, 187 (12.5 %) were identified with pT2a and pGS ?? 6 disease. Of the 187 men with pT2a and pGS ?? 6 disease, only 6 (3.2 %) cases had PSA recurrence. Kaplan?CMeier PSA recurrence-free survival curves identified a difference between prostate cancers with pT2a and pGS ?? 6 and prostate cancers with >pT2a or pGS ?? 7 disease (p = 0.002). Only biopsy tumor unilaterality (OR, 10.452; p ?? 0.001) and low diagnostic PSA levels (OR, 0.887; p = 0.003) were independent predictors of prostate cancers with pT2a and pGS ?? 6 disease on univariate and multivariate logistic regression. Biopsy tumor unilaterality and low diagnostic PSA levels are the independent predictors of pT2a and pGS ?? 6 disease in low-risk prostate cancer patients. Unilateral cancer by prostate biopsy and low diagnostic PSA level may be the reference to improving the selection of appropriate candidates for active surveillance within a low-risk prostate cancer cohort.     

Korean Prostate Cancer Patients Have Worse Disease Characteristics than their American Counterparts

Background: Although the PSA test has been used in Korea for over 20 years, the incidence of prostatecancer has risen, and the associated mortality has increased about 13-fold over the 20-year period. Also, severalinvestigators have suggested that Asians in America are more likely to present with more advanced prostate cancerthan Caucasians. We compared the characteristics of native Koreans and Americans (Caucasians and African-Americans) undergoing radical prostatectomies in Korea and the US. Materials and Methods: Study subjectscomprised patients at Korean and US hospitals from 2004 to 2012 who had undergone radical prostatectomies.We compared the characteristics of the subjects, including age, preoperative prostate-specific antigen (PSA) levels,body mass index (BMI), Gleason score, and pathological T stage. Results: In total, 1,159 males (502 Koreans, 657Americans) were included. The Korean and American patients had mean ages of 67.1±6.6 and 59.2±6.7 years,respectively. The mean preoperative PSAs were 15.4±17.9 and 6.2±4.6 ng/mL (p=0.0001) and the mean BMIswere 23.6±2.6 and 28.7±4.4 kg/m2 (p=0.0001), respectively. Pathological localized prostate cancer represented71.7% of cases for Koreans and 77.6% for Americans (p=0.07). According to age, Koreans had higher T stagesthan Americans in their 50s (p=0.021) and higher Gleason scores than Americans in all age groups. Accordingto PSA, Koreans had higher Gleason scores than Americans for PSA >10 ng/mL (p<0.05). According to prostatesize and Gleason scores, Koreans had higher PSA values than Americans (p<0.01). Conclusions: These resultsshow that Korean patients have elevated risk of malignant prostate cancers, as indicated by the significantlyhigher Gleason scores and PSAs, suggesting a need for novel prostate cancer treatment strategies in Korea.