Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era.

OBJECTIVE: Sex steroid hormones are thought to contribute to the growth, differentiation, and progression of prostate cancer. We investigated plasma levels of sex steroid hormones and length of the androgen receptor gene CAG repeat in relation to incident prostate cancer diagnosed in the prostate-specific antigen (PSA) era.METHODS: Using a nested case-control design, we included 460 prostate cancer cases diagnosed after providing a blood specimen in 1993 but before February 1998 among men in the Health Professionals Follow-up Study. Controls were 460 age-matched men without prostate cancer who had a screening PSA test after the date of providing a blood specimen. We measured plasma concentrations of total testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, estradiol, and sex hormone binding globulin (SHBG) and determined the length of the androgen receptor gene CAG repeat. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer.RESULTS: Mean concentrations of the sex steroids adjusted for SHBG, and mean CAG repeat length did not differ significantly between the prostate cancer cases and controls. No significant associations with total prostate cancer were detected for plasma total testosterone concentration (comparing highest versus lowest quartiles: OR, 0.78; 95% CI, 0.48-1.28; P(trend) = 0.73) or the other sex hormones after adjusting for SHBG. However, plasma total testosterone concentration was positively associated with low-grade disease (Gleason sum < 7: OR, 1.91; 95% CI, 0.89-4.07; P(trend) = 0.02) and inversely associated with high-grade disease (Gleason sum > or = 7: OR, 0.26; 95% CI, 0.10-0.66; P(trend) = 0.01). Similar patterns for grade were observed for free testosterone. Short CAG repeat length was not associated with total prostate cancer (< or = 19 versus > or = 24: OR, 0.84; 95% CI, 0.57-1.23; P(trend) = 0.22) or grade of disease. No clear associations with regionally invasive or metastatic (> or = T3b, N1, or M1) were found for any of the hormones or the CAG repeat, although the number of these cases was small.CONCLUSIONS: The overall lack of association of prostate cancer diagnosed in the PSA era with sex steroid hormones and the androgen receptor gene CAG repeat length is consistent with the hypothesis that these factors do not substantially contribute to the development of early prostate cancer in the PSA era. The influence of plasma total and free testosterone concentrations on prostate cancer grade merits further evaluation.     

Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death.

Alpha-methylacyl CoA racemase (AMACR) is overexpressed in prostate cancer relative to benign prostatic tissue. AMACR expression is highest in localized prostate cancer and decreases in metastatic prostate cancer. Herein, we explored the use of AMACR as a biomarker for aggressive prostate cancer. AMACR protein expression was determined by immunohistochemistry using an image analysis system on two localized prostate cancer cohorts consisting of 204 men treated by radical prostatectomy and 188 men followed expectantly. The end points for the cohorts were time to prostate-specific antigen (PSA) failure (i.e., elevation >0.2 ng/mL) and time to prostate cancer death in the watchful waiting cohort. Using a regression tree method, optimal AMACR protein expression cut-points were determined to best differentiate prostate cancer outcome in each of the cohorts separately. Cox proportional hazard models were then employed to examine the effect of the AMACR cut-point on prostate cancer outcome, and adjusted for clinical variables. Lower AMACR tissue expression was associated with worse prostate cancer outcome, independent of clinical variables (hazard ratio, 3.7 for PSA failure; P = 0.018; hazard ratio, 4.1 for prostate cancer death, P = 0.0006). Among those with both low AMACR expression and high Gleason score, the risk of prostate cancer death was 18-fold higher (P = 0.006). The AMACR cut-point developed using prostate cancer-specific death as the end point predicted PSA failures independent of Gleason score, PSA, and margin status. This is the first study to show that AMACR expression is significantly associated with prostate cancer progression and suggests that not all surrogate end points may be optimal to define biomarkers of aggressive prostate cancer.     

Mutations in ribonuclease L gene do not occur at a greater frequency in patients with familial prostate cancer compared with patients with sporadic prostate cancer

Several genetic loci are suspected to be involved in hereditary prostate cancer, including the hereditary prostate cancer 1 (HPC1) locus at chromosome 1q24-25. The ribonuclease L (RNase L) gene has been reported as the putative hereditary prostate cancer gene located at HPC1. If this is the case, mutations of RNase L should be found at a greater frequency in familial cancers than in sporadic prostate cancers. Examination of familial and sporadic cases of prostate cancer by polymerase chain reaction and DNA sequencing resulted in a mutational frequency rate that was not statistically different between the 2 forms of the disease. These results suggest that the mutations examined within this study are rare and may contribute to very few familial prostate cancers.     

A prognostic score for hormone-refractory prostate cancer: analysis of two cancer and leukemia group B studies.

Previously, we have shown that serial measurements of prostate-specific antigen (PSA) in hormone-refractory prostate cancer (HRPC) can be used to calculate an average relative velocity (rva) of PSA. Together, the level of PSA and the rva formed a two-variable model for survival time that worked at any time during the course of HRPC. Here, we have added serial measurements of hemoglobin and weight to test whether they improve the prior model based on PSA alone. Data from two Cancer and Leukemia Group B studies (9181 and 9182) on HRPC were combined to study the relationship between survival and serial measurements of PSA, serum hemoglobin, and patient weight. Altogether, there were 348 patients who could be evaluated. We used the Cox proportional hazard model for survival time with the interval censored method to accommodate time-dependent covariates, and tests for significance were two sided. Log (PSA), rva, log (hemoglobin), and log [weight (in kg)] were all significantly related to survival time during the course of HRPC (P < 3.0 x 10(-5)). Together, they formed a prognostic score based upon the relative hazard. Higher values of this score implied higher probability of death as the next observed event. Serial measurements of PSA, hemoglobin, and weight provide a prognostic score that can be applied continuously during the course of HRPC. Changes in the score may provide a reproducible measure of treatment effect.     

Comparing prostate specific antigen outcomes after different types of radiotherapy management of clinically localized prostate cancer highlights the importance of controlling for established prognostic factors

PURPOSE: We evaluated the impact that the composition of prognostic factors in a patient cohort may have on prostate specific antigen (PSA) outcome following external beam radiation therapy for clinically localized prostate cancer. MATERIALS AND METHODS: The distribution of PSA, biopsy Gleason score and American Joint Committee on Cancer (AJCC) T stage in men with prostate cancer treated with interstitial plus external beam radiation therapy was used to select a matched cohort who underwent 3-dimensional (D) conformal external beam radiation therapy. We compared PSA outcomes after 3-D conformal external beam radiation therapy in the overall and matched cohorts of 766 and 570 patients, respectively. RESULTS: Men treated with interstitial plus external beam radiation therapy had a significantly lower rate of PSA greater than 10 to 20 (p = 0. 02) and greater than 20 ng./ml. (p <0.0001), biopsy Gleason score 7 (p = 0.02) and 8 to 10 (p <0.0001), and AJCC stage T2c disease (p <0. 0001). Likewise, these men also had a significantly higher rate of PSA greater than 4 to 10 ng./ml. (p <0.0001), biopsy Gleason score 5 to 6 (p = 0.0001) and AJCC stage T1 disease (p <0.0001) than those who underwent 3-D conformal external beam radiation therapy. The 5-year estimate of PSA failure-free survival after 3-D conformal external beam radiation therapy was 45% versus 67% (p = 0.0007) for all 766 consecutively treated patients and the matched cohort of 570, respectively. CONCLUSIONS: The composition of prognostic factors in a patient cohort may impact PSA outcome. Therefore, controlling for established prognostic factors is essential when comparing PSA outcome after different forms of radiotherapy for adenocarcinoma of the prostate.     

Chemotherapy for teratoma with malignant transformation.

PURPOSE: Teratoma with malignant transformation (MT) is a well-described entity that refers to the MT of a somatic teratomatous component in a germ cell tumor (GCT) to a histology that is identical to a somatic malignancy (eg, rhabdomyosarcoma [RMS]). Surgical resection has been the mainstay of therapy for localized transformed disease because these tumors are thought to be resistant to standard treatment. We report that chemotherapy has a role in selected patients with MT, determined by cell type. PATIENTS AND METHODS: Chemotherapy was administered to 12 patients with MT of GCT limited to a single cell type (two patients with primitive neuroectodermal tumors, five with undifferentiated RMS, one with anaplastic small-cell tumor, two with adenocarcinoma, and two with leukemia); 10 patients had measurable disease. GCT origin was confirmed by molecular cytogenetics in five patients. Each patient received chemotherapy regimens based on the specific malignant cell observed in the transformed histology. RESULTS: Seven patients with measurable disease achieved a partial response, with the duration of response ranging between 1 month and 7 years. Three of those patients are alive. Three patients did not respond to treatment, and all of those patients died as a result of their disease. CONCLUSION: Chemotherapy for MT limited to a single cell type may result in major responses and long-term survival in selected patients. Local therapy after chemotherapy is an important component of treatment to achieve maximum response.     

Development of an integrated prostate cancer research information system

Background

In this article, we describe the design and implementation of a comprehensive prostate cancer database developed to collect, store, and access clinical, treatment, and outcomes data for research and clinical care.

Patients and Methods

The Prostate Cancer Clinical Research Information System is a relational database. Data are entered from multiple sources, including medical records, institutional laboratory, patient registration, pharmacy systems, and clinician forms. The history, design, and operational characteristics of the database are described. Issues regarding necessary staffing and funding of databases are reviewed.

Results

Four thousand two hundred forty-six patients have information in the Prostate Cancer Clinical Research Information System. Mean age of patients is 62 years, and 89% are white. Seventy-one percent of patients presented at diagnosis with T1 or T2 disease, and 78% had biopsy Gleason scores of ≤ 7, 8-10 in 18%. Median prostatespecific antigen level at diagnosis was 7 ng/mL, and 77% of patients presented with increased prostate-specific antigen as a trigger symptom. Sixty-four percent of patients presented to our clinic having had no previous treatment for prostate cancer. The majority of approached patients provided consent for collection of clinical data, blood, and tissue. Quality control assessments demonstrate high levels of concordance among data entry personnel.

Conclusion

Clinical databases are difficult to implement and maintain; however, they represent a valuable resource, particularly when linked to blood and tissue banks. Elements needed for a successful clinical database include engagement of clinicians, utility for research, and the ability to integrate with legacy systems. As cancer centers develop such databases, lessons learned from each experience should be shared in order to optimize the process.