Biochemical Recurrence In Men Research Articles

FGFR-4 Arg388 Enhances Prostate Cancer Progression via Extracellular Signal–Related Kinase and Serum Response Factor Signaling

Increased expression of FGFR-4 and its ligands have been linked to lethal prostate cancer (PCa). Furthermore, a germ line polymorphism in the FGFR-4 gene, resulting in arginine at codon 388 (Arg³⁸⁸) instead of glycine (Gly³⁸⁸), is associated with aggressive disease. The FGFR-4 Arg³⁸⁸ variant results in increased receptor stability, sustained receptor activation, and increased motility and invasion compared with Gly³⁸⁸. However, the impact of sustained signaling on cellular signal transduction pathways is unknown. Expression microarray analysis of immortalized prostatic epithelial cells lines expressing FGFR-4 Arg³⁸⁸ or Gly³⁸⁸ was used to establish a gene signature associated with FGFR-4 Arg³⁸⁸ expression. Transient transfection of reporters and inhibitors was used to establish the pathways activated by FGFR-4 Arg³⁸⁸ expression. The impact of pathway knockdown in vitro and in an orthotopic model was assessed using inhibitors and/or short hairpin RNA (shRNA). Expression of the FGFR-4 Arg³⁸⁸ protein leads to increased activity of the extracellular signal-related kinase (ERK) pathway, increased activity of serum response factor (SRF) and AP1, and transcription of multiple genes that are correlated with aggressive clinical behavior in PCa. Increased expression of SRF is associated with biochemical recurrence in men undergoing radical prostatectomy. Consistent with these observations, knockdown of FGFR-4 Arg³⁸⁸ in PCa cells decreases proliferation and invasion in vitro and primary tumor growth and metastasis in vivo. These studies define a signal transduction pathway downstream of FGFR-4 Arg³⁸⁸ that acts via ERK and SRF to promote PCa progression.

Tumor volume, surgical margin, and the risk of biochemical recurrence in men with organ-confined prostate cancer

ObjectivesWe proposed to investigate predictors of biochemical recurrence (BCR) in pT2 prostate cancer by identifying the interrelationship between the tumor volume and surgical margin status, and their impact on recurrence. Materials and methodsClinical, pathologic, and follow-up data of 404 consecutive patients who were treated with radical prostatectomy alone and were diagnosed as pT2 prostate cancer in our institution were reviewed. Percent tumor volume (PTV) was estimated from the cancer distribution map, and the surgical margin status was reviewed by a single pathologist (JYR). Clinicopathologic variables were analyzed with respect to the risk of BCR. Results and limitationsRecurrence was observed in 39 (9.7%) patients at a mean of 28.9 (5–47) months. Preoperative PSA, biopsy Gleason score, surgical Gleason score, PTV, and surgical margin status were significantly related to BCR in univariate analysis; in multivariate analysis, PTV (P < 0.001) and surgical Gleason score (P = 0.021) were independent predictors of BCR. PTV was also an independent determinant of positive surgical margin (P = 0.035, HR 1.026, 95% CI 1.002–1.050). By combining the 2 predictors 5-year recurrence-free survivals for PTV ≤ 14.5% and surgical Gleason score ≤ 7, PTV >14.5% or surgical Gleason score > 7, and PTV > 14.5% and surgical Gleason score > 7 were 97.5%, 88.7%, and 44.5%, respectively (log-rank test, P < 0.01). Retrospective study nature, use of PTV instead of actual volume, and intermediate follow-up length are the main limitations of the study. ConclusionsIn men with pT2 prostate cancer, percent tumor volume and the surgical Gleason score were independently prognostic of BCR and by combining the 2 factors, risk of BCR could be significantly stratified. Tumor volume further determined surgical margin status undermining its prognostic value as an independent variable.

Abstract 5569: The association between statin use and risk of biochemical recurrence in men treated with radical prostatectomy in a cohort of men with inherited forms of prostate cancer

Abstract Background: Evidence exists that statin medications are associated with decreased risk of advanced prostate cancer. The risk factors for prostate cancer are increasing age, African-American race and family history of the disease. To date, studies of the association between statin medication and risk of prostate cancer have not considered men with familial or hereditary prostate cancer. Methods: Men enrolled in the University of Michigan Prostate Cancer Genetics Project (PCGP) who had been previously diagnosed with prostate cancer and treated with radical prostatectomy were surveyed as to their past and current statin medication use status, type of statin medication, duration of statin medication use and their incidence of biochemical recurrence. PCGP is a large, family-based study of inherited forms of prostate cancer. The PCGP enrollment criteria included families with two or more living-affected family members in a first-degree or second-degree relationship. The risk of biochemical recurrence (BCR) was modeled using logistic regression models and odds ratios and 95% confidence intervals were calculated. Results: Of 595 unrelated men with past radical prostatectomy surveyed, 91 men experienced BCR. At time of survey, 40% of men were current statin users. Median follow-up time was 67 months for statin users was 75 months for non-statin users. Current statin-use at time of recurrence was associated with a decreased risk of BCR (OR = 0.685; 95% C.I.:0.438 – 1.072; p=0.09); while ever statin-use was not associated with risk of BCR in multivariate models adjusted for age and BMI. Discussion: This represents the only study to date to assess statin medication use and the risk of biochemical recurrence in men with familial and hereditary prostate cancer. Given the importance of family history as a risk factor for prostate cancer, these findings should be confirmed in other studies and may implicate subgroups of men at risk for prostate cancer who may benefit from statin medication use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5569. doi:10.1158/1538-7445.AM2011-5569

459 SMOKING AND ADVERSE OUTCOMES AT RADICAL PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Epidemiology and Natural History1 Apr 2011459 SMOKING AND ADVERSE OUTCOMES AT RADICAL PROSTATECTOMY Tin Ngo, Joy Lee, James Brooks, Rosie Nolley, Michelle Ferrari, and Joseph Presti Tin NgoTin Ngo Stanford, CA More articles by this author , Joy LeeJoy Lee Stanford, CA More articles by this author , James BrooksJames Brooks Stanford, CA More articles by this author , Rosie NolleyRosie Nolley Stanford, CA More articles by this author , Michelle FerrariMichelle Ferrari Stanford, CA More articles by this author , and Joseph PrestiJoseph Presti Stanford, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.552AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Multiple large epidemiologic studies have examined the relationship between smoking and prostate cancer incidence and mortality only to arrive at contradictory results. In this series, we studied the effect of smoking on pathologic outcomes and biochemical recurrence in a cohort of men undergoing radical prostatectomy. METHODS We identified 630 men who underwent radical prostatectomy between 1989–2005 who had detailed smoking histories. There were 321 smokers and 309 nonsmokers. Pathologic outcomes included prostate weight, volume of cancer, volume of high grade cancer, margin status, seminal vesicle involvement, extraprostatic extension, perineural invasion, angiolymphatic invasion, and the presence of nodal metastasis. Biochemical recurrence was defined as a postoperative PSA ≥ 0.2 ng/ml. Univariate analysis and multivariate linear and Cox regression were used to study the impact of smoking on these outcomes. RESULTS The volume of cancer (2.54 vs. 2.16 mL, p=0.016) and the volume of high grade cancer (0.58 vs. 0.28 mL, p=0.004) were greater in smokers compared to nonsmokers. Smoking independently predicted greater volumes of cancer and high grade cancer in multivariate analysis. Heavy smokers (≥20 pack-year history) had a greater risk of biochemical recurrence on univariate survival analysis. Smoking also predicted a greater risk of biochemical recurrence on Cox regression, the magnitude of which was approximately 1% per pack-year smoked. CONCLUSIONS Smoking is associated with adverse pathologic features and a higher risk of biochemical recurrence in men undergoing radical prostatectomy. If confirmed by additional studies, smoking history may need to be included into risk assessment models. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e187 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tin Ngo Stanford, CA More articles by this author Joy Lee Stanford, CA More articles by this author James Brooks Stanford, CA More articles by this author Rosie Nolley Stanford, CA More articles by this author Michelle Ferrari Stanford, CA More articles by this author Joseph Presti Stanford, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Impact of Body Mass Index on Biochemical Recurrence Rates After Radical Prostatectomy: An Analysis Utilizing Propensity Score Matching

To investigate the significance of body mass index (BMI) as an independent predictor of biochemical recurrence in men treated with surgery for clinically localized adenocarcinoma of the prostate. A total of 1877 obese patients who underwent radical prostatectomy were matched to overweight and normal-weight patients in a 1:1 ratio on the basis of propensity scores. This resulted in an overall study population of 5631 men. Clinicopathologic characteristics and biochemical recurrence outcomes after surgery were compared between the three BMI cohorts. Normal-weight patients exhibited lower-grade disease compared with overweight and obese patients (P = 0.021). Lower BMI was also significantly associated with lower rates of positive surgical margins (P <0.001) and extraprostatic extension (P <0.001). Body mass index was not associated with lymph node involvement (P = 0.226) or seminal vesicle invasion (P = 0.142). Body mass index, age, biopsy Gleason score, preoperative prostate-specific antigen level, and clinical tumor stage were independent predictors of biochemical recurrence (P <0.001). Propensity score-based matched analyses indicate that higher BMI is associated with adverse pathologic findings and is a strong independent predictor of biochemical recurrence after radical prostatectomy. These results support the hypothesis that inherent differences may exist in the biological properties of prostate cancer in obese men compared with normal-weight men. Therefore, BMI is an important criterion to consider during subsequent decision making and counseling of patients with prostate cancer.

Risk Stratification for Biochemical Recurrence in Men With Positive Surgical Margins or Extracapsular Disease After Radical Prostatectomy: Results From the SEARCH Database

In men with extracapsular disease or positive surgical margins after radical prostatectomy immediate adjuvant therapy decreases the risk of biochemical recurrence at the cost of increased toxicity. We further stratified these men into a low risk group in which watchful waiting after surgery may be preferred and a high risk cohort in which adjuvant therapy may be preferred. We performed a retrospective analysis of the records of 902 men treated with radical prostatectomy in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database between 1988 and 2007 with positive surgical margins and/or extracapsular disease without seminal vesicle invasion or lymph node metastasis. The significant independent predictors of biochemical recurrence were determined using a multivariate Cox proportional hazards model. Based on the recurrence risk generated from the multivariate Cox proportional hazards regression model we generated tables to estimate the risk of recurrence-free survival 1, 3 and 5 years after surgery. At a median of 3 years of followup 346 patients (39%) had biochemical recurrence. On multivariate analysis the significant predictors of biochemical recurrence were age more than 60 years, prostate specific antigen more than 10 ng/ml, Gleason score 4 + 3 and 8-10, 2 or more sites of positive surgical margins and prostate specimen weight 30 gm or less. As determined by the concordance index, the overall predictive accuracy of the model was 0.67, while it was 0.60 for the postoperative Kattan nomogram in this patient population. We have developed a simple instrument that, once validated, may aid in the postoperative decision making process for men at intermediate risk for recurrence after prostatectomy.

Pathological features of Gleason score 6 prostate cancers in the low and intermediate range of prostate-specific antigen level: is there a difference?

To assess the pathological features of Gleason score 6 prostate cancers after radical prostatectomy in the low (<4 ng/mL) and intermediate range of prostate-specific antigen level (4-10 ng/mL), as such prostate cancers are considered to be well differentiated tumours with a low risk for recurrence after therapy. In all, 1354 patients with T1c prostate cancer and PSA levels of <10.0 ng/mL had a radical retropubic prostatectomy. Patients with Gleason score 6 tumours were divided into two groups, those with PSA levels of <4 and 4.0-10.0 ng/mL. Extracapsular extension, positive surgical margins, biochemical recurrence (BCR) and mean time to BCR were evaluated. Of the 1354 patients, there were 437 (32.3%) with Gleason score 6 prostate cancers. Patients in the low PSA group had less extraprostatic disease than those with a higher level (5.9% vs 14.5%) and both groups had an almost equal proportion of positive surgical margins (9.4% vs 11.0%). In the low PSA group there was statistically significantly shorter BCR than in the high PSA group, with a mean time to BCR of 1.7 vs 3.1 years. These results show a statistically significantly higher rate of extraprostatic disease and earlier BCR in men with a high than a low PSA level even in Gleason score 6 prostate cancer. As the rate of BCR and extracapsular extension are significantly related to prostate cancer mortality, these findings further support the concept of screening using low PSA levels.

The impact of DNA methylation on the identification of recurrent prostate cancer

21086 Purpose: Biochemical (PSA) recurrence of prostate cancer following radical prostatectomy remains a major problem. Better biomarkers are needed to identify high and low-risk patients. DNA methylation of promoter regions leads to gene silencing in many cancers. In this study, we assessed the impact of changes in DNA methylation on biochemical recurrence in men with prostate cancer. Methods: We examined the methylation status of fifteen genes using MSP (Methylation Specific PCR) on tissue samples from 151 patients with clinically localized prostate cancer for whom at least five years of follow-up after prostatectomy was available. Results: In a multivariable logistic regression analysis, extra capsular penetration, high Gleason score, and involvement of the lymph nodes, seminal vesicles, or surgical margin were associated with an increased risk of recurrence. In addition, samples with methylation of 2 specific genes involved in cell-cell adhesion and apoptosis were associated with biochemical recurrence with an odds ratio of 5.64 (95% CI=1.47–21.7, p=0.012) compared to samples without methylation of both of these genes. The methylation status of these 2 genes had a higher sensitivity (72.3%; 95% CI=57–84.4%) for detecting recurrences than all the clinico-pathological variables (p&lt;0.02) except extra-capsular penetration (p=0.346). The methylation status of these 2 genes had a similar negative predictive value (79.0%; 95% CI=66.8–88.3%) as the individual clinico-pathological variables examined. Conclusion: DNA Methylation of specific genes is independently associated with an increased risk of biochemical recurrence after radical prostatectomy even one considers the prognostic clinico-pathologic variables used in the clinic today. Our findings should be validated on another larger group of patients with prostate cancer who have undergone radical prosatetectomies. No significant financial relationships to disclose.

Treatment of PSA only Recurrence of Prostate Cancer After Prior Local Therapy

Prostate cancer recurrence (after prior local treatment) that is detectable only by a rise in serum prostate specific antigen (PSA) level is a very common problem facing clinicians. Given that the majority of contemporary era men with PSA-only or biochemical recurrence are relatively young and otherwise healthy, treatment requires approaches that both improve clinical outcomes and preserve quality of life. Treatment is in one of two broad categories, additional local therapies, termed "salvage" local therapy and systemic therapies. For radical prostatectomy patients, salvage external beam radiotherapy to the prostate bed is commonly employed, being reserved for early biochemical recurrence in men with low risk at distant metastases. For primary radiation patients, salvage radical prostatectomy or cryotherapy can similarly be used for those men felt not to harbor distant metastases. Systemic therapy generally involves hormonal therapy. Traditional hormonal therapy (orchiectomy, luteinizing hormone-releasing hormone agonists or maximum androgen blockade) is the current mainstay of systemic treatment for biochemical recurrence, although non-traditional approaches, such as antiandrogen monotherapy, are increasingly being used. There is a critical need for new pharmaceutical agents to treat this growing stage of prostate cancer. However, it has been difficult to demonstrate efficacy due to the long natural history until death and the survival endpoint currently required by the U.S. Food and Drug Administration. New data show that PSA Doubling time (PSA-DT) during PSA recurrence may be a valid surrogate for death from the disease and may be used to accelerate drug approval. This monograph will attempt to provide a complete balanced discussion of the evaluation and treatment of biochemical recurrence of prostate cancer after prior primary local therapy.

Race as an outcome predictor after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Objectives Whether race is an independent predictor of prostate-specific antigen (PSA) recurrence after RP is controversial. To compare racial differences in clinical and pathologic features and biochemical recurrence in men undergoing radical prostatectomy (RP), we used a newly established multicenter database of patients from four equal-access healthcare centers in California, the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Methods A retrospective survey of 1547 patients treated with RP at four different equal-access medical centers in California between 1988 and 2001 was undertaken. Race was categorized as white (n = 1014), black (n = 338), or nonwhite-nonblack (n = 195). Patients were analyzed for racial differences in preoperative variables (age at surgery, clinical stage, PSA, and biopsy Gleason score) and surgical variables (pathologic stage, surgical Gleason score, incidence of seminal vesicle invasion, positive surgical margins, capsular penetration, and pelvic lymph node involvement). Patients were followed up for PSA recurrence. Multivariate analysis was used to determine whether race was an independent predictor of biochemical failure. Results Significant differences were found among the races in the preoperative factors of clinical stage, age, serum PSA, and biopsy Gleason score, although the absolute differences were small. No differences were found among the races in the pathologic features of the RP specimens, including Gleason score, pathologic stage, and incidence of positive surgical margins, capsular penetration, seminal vesicle invasion, or lymph node involvement. In both univariate and multivariate analyses, only serum PSA ( P <0.001) and biopsy Gleason score ( P <0.001) were significant independent predictors of time to biochemical recurrence. Conclusions In a large multicenter cohort of patients from four equal-access medical care facilities in California, although racial differences were found in clinical stage, age, biopsy Gleason score, and serum PSA level at diagnosis, we found race was not an independent predictor of biochemical recurrence after RP. Race should not be used in models or nomograms predicting PSA failure after RP. The current study represents the largest series of black patients and the first large series of nonwhite-nonblack patients treated with RP reported to date. The Shared Equal Access Regional Cancer Hospital database is a valuable resource for studying patients treated with RP.

DISEASE RECURRENCE AND PROGRESSION IN UNTREATED PATHOLOGIC STAGE T3 PROSTATE CANCER: SELECTING THE PATIENT FOR ADJUVANT THERAPY

Optimal management of pathologic T3 prostate cancer is poorly defined. We conducted a prospective study of untreated pT3 patients to improve understanding of the natural history of this disease and to identify clinical parameters useful in patient selection for adjuvant therapy. Of 583 consecutive patients with clinical stage T1 to 2 disease managed by total prostatectomy, 206 had pT3 disease. Excluding patients requesting immediate adjuvant treatment or neoadjuvant therapy, 156 subjects were eligible for the study, including 34 with pT3a, 80 pT3b, 22 pT3c, and 20 pT3N+ disease. Patients were followed for prostate-specific antigen (PSA) recurrence of greater than 0.2 ng./ml. and biopsy proved local or distant tumor progression demonstrated by imaging studies. After a median of 45 months, PSA recurrence was seen in 29.4% of pT3a (10/34), 30% of pT3b (24/80), 27.3% of pT3c (6/22), and 80% of pT3N+ (16/20 cases). Local or distant progression was seen in 2.9% of pT3a (1), 6.2% of pT3b (5), 9.1% of pT3c (2), and 55% of pT3N+ (11 cases). Recurrence and progression correlated with the number of surgical margins involved by tumor, pathological Gleason score and baseline pre-prostatectomy PSA levels. PSA recurrence was seen in 20.8% (10/48) patients with 1 surgical margin involved, 40.9% (9/22) with 2 margins involved and 50% (5/10) with 3 or more margins involved. PSA recurrence was 20.3% (14/69) with Gleason scores of less than 7, 33.9% (19/56) with a score of 7 and 74.2% (23/31) with scores of greater than 7. Pre-prostatectomy PSA levels less than 10 ng./ml. were associated with a PSA recurrence of 17.3% (14/81) and 45.4% (25/55), with levels greater than 10 ng./ml. Selecting patients for high or low risk based upon the results of these parameters allowed accurate prediction of PSA recurrence; 8.5% (4/47) for low risk patients and 44.8% (30/67) for high risk. Tumor progression was seen in no low risk patient and in 9% (6) with high risk. The difference between the 2 risk groups was highly significant (p <0.0001). The majority of patients with pT3 prostate cancer will not experience recurrent disease for many years if ever. Immediate use of adjuvant treatment should be reserved for those patients with a high risk of recurrent disease.