Alan Paciorek

Physical activity after diagnosis and risk of prostate cancer progression: data from the Cancer of the Prostate Strategic Urologic Research Endeavor

Vigorous activity after diagnosis was recently reported to be inversely associated with prostate cancer-specific mortality. However, men with metastatic disease may decrease their activity due to their disease; thus, a causal interpretation is uncertain. We therefore prospectively examined vigorous activity and brisk walking after diagnosis in relation to risk of prostate cancer progression, an outcome less susceptible to reverse causation, among 1,455 men diagnosed with clinically localized prostate cancer. Cox proportional hazards regression was used to examine vigorous activity, nonvigorous activity, walking duration, and walking pace after diagnosis and risk of prostate cancer progression. We observed 117 events (45 biochemical recurrences, 66 secondary treatments, 3 bone metastases, 3 prostate cancer deaths) during 2,750 person-years. Walking accounted for nearly half of all activity. Men who walked briskly for 3 h/wk or more had a 57% lower rate of progression than men who walked at an easy pace for less than 3 h/wk (HR = 0.43; 95% CI: 0.21-0.91; P = 0.03). Walking pace was associated with decreased risk of progression independent of duration (HR brisk vs. easy pace = 0.52; 95% CI: 0.29-0.91; P(trend) = 0.01). Few men engaged in vigorous activity, but there was a suggestive inverse association (HR ≥3 h/wk vs. none = 0.63; 95% CI: 0.32-1.23; P(trend) = 0.17). Walking duration and total nonvigorous activity were not associated with risk of progression independent of pace or vigorous activity, respectively. Brisk walking after diagnosis may inhibit or delay prostate cancer progression among men diagnosed with clinically localized prostate cancer.

A Model That Predicts the Probability of Positive Imaging in Prostate Cancer Cases With Biochemical Failure After Initial Definitive Local Therapy

PURPOSE Managing biochemical failure in patients following initial treatment of localized prostate cancer is a relatively common clinical problem. Imaging studies to document metastatic disease are frequently obtained but are often uninformative. In this study we identified clinical parameters that were predictive of positive imaging studies. MATERIALS AND METHODS From CaPSURE, a national disease registry, all patients with a detectable prostate specific antigen after definitive therapy with radical prostatectomy or radiation therapy and who had undergone at least 1 imaging study (bone scan, computerized tomography or magnetic resonance imaging of the abdomen and pelvis) were identified. Patient characteristics, trigger prostate specific antigen (prostate specific antigen before the imaging), prostate specific antigen doubling time and velocity prior to imaging for association with a positive imaging test were analyzed. The results were incorporated into a predictive model. RESULTS We identified 292 patients (66% radical prostatectomy and 34% radiation therapy) who had recurrence and had available imaging data, and 31 (11%) patients had a positive imaging study. On multivariate analysis age, imaging type, trigger prostate specific antigen and prostate specific antigen doubling time were significantly associated with imaging results. A multivariate model including age (younger than 60 vs 60 to 69 vs 70 years or older), primary imaging type (bone scan vs computerized tomography vs magnetic resonance imaging), trigger prostate specific antigen (5 or less vs more than 5 ng/ml) and prostate specific antigen doubling time (less than 10 vs 10 or more months) had a concordance index of 84% in predicting positive imaging. CONCLUSIONS Age, imaging type, trigger prostate specific antigen and prostate specific antigen doubling time were significantly associated with imaging results. Imaging studies are unlikely to be useful when trigger prostate specific antigen is 5 or less ng/ml and prostate specific antigen doubling time is 10 or more months.

Intakes of meat, fish, poultry, and eggs and risk of prostate cancer progression

BACKGROUND Processed meat and fish have been shown to be associated with the risk of advanced prostate cancer, but few studies have examined diet after prostate cancer diagnosis and risk of its progression. OBJECTIVE We examined the association between postdiagnostic consumption of processed and unprocessed red meat, fish, poultry, and eggs and the risk of prostate cancer recurrence or progression. DESIGN We conducted a prospective study in 1294 men with prostate cancer, without recurrence or progression as of 2004-2005, who were participating in the Cancer of the Prostate Strategic Urologic Research Endeavor and who were followed for an average of 2 y. RESULTS We observed 127 events (prostate cancer death or metastases, elevated prostate-specific antigen concentration, or secondary treatment) during 2610 person-years. Intakes of processed and unprocessed red meat, fish, total poultry, and skinless poultry were not associated with prostate cancer recurrence or progression. Greater consumption of eggs and poultry with skin was associated with 2-fold increases in risk in a comparison of extreme quantiles: eggs [hazard ratio (HR): 2.02; 95% CI: 1.10, 3.72; P for trend = 0.05] and poultry with skin (HR: 2.26; 95% CI: 1.36, 3.76; P for trend = 0.003). An interaction was observed between prognostic risk at diagnosis and poultry. Men with high prognostic risk and a high poultry intake had a 4-fold increased risk of recurrence or progression compared with men with low/intermediate prognostic risk and a low poultry intake (P for interaction = 0.003). CONCLUSIONS Our results suggest that the postdiagnostic consumption of processed or unprocessed red meat, fish, or skinless poultry is not associated with prostate cancer recurrence or progression, whereas consumption of eggs and poultry with skin may increase the risk.

Impact of radical prostatectomy positive surgical margins on fear of cancer recurrence: results from CaPSURE.

PURPOSE Fear of cancer recurrence (FCR) is a significant source of distress in men with prostate cancer and could affect clinical decision-making, especially in those with positive margins following radical prostatectomy (RP). We examined the influence of positive surgical margin status on fear of cancer recurrence in men undergoing radical prostatectomy. METHODS Five hundred eight-four men underwent RP from 1999 to 2002 in CaPSURE, a prospective, longitudinal, national cohort. All men had both baseline and follow-up assessment of FCR using a validated Kornblith scale. Statistical analysis included chi(2) test, Wald test, and linear as well as repeated measures ANOVA mixed model. RESULTS One hundred sixty (27%) men had positive surgical margins. Baseline FCR and clinical variables did not differ based on margin status. Men with positive margins experienced greater FCR after RP than negative margins (OR, 1.94, 95% CI, 1.22-3.07). Men who had received adjuvant therapy experienced greater FCR (OR, 2.78, 95% CI, 1.21-6.39). Repeated measures analysis showed greater FCR over time (14-month mean follow-up, range 2-31 months) for positive vs. negative margins (P = 0.02). This difference in fear widened over time. There were no significant differences in health-related quality of life scores based on margin status. CONCLUSION Positive surgical margin status is associated with greater fear of cancer recurrence, a difference not alleviated by adjuvant therapy use. Men with positive margins remain more fearful over the course of several years compared with those with negative margins. Clinicians should be aware of the potential stressful impact of positive surgical margins.

Evaluating prostate cancer mortality and competing risks of death in patients with localized prostate cancer using a comprehensive nomogram.

BACKGROUND:The aim of this study was to determine the optimal treatment for a patient with newly diagnosed prostate cancer weighing the individuals risk of disease progression against his risk of non-cancer death.METHODS:We developed a predictive model incorporating clinicopathological tumor variables, patient age, comorbidity status, and primary treatment modality. We identified 6091 patients with clinically-localized prostate cancer managed with radical prostatectomy (n=4117) or radiation therapy (n=1974) from the Cancer of the Prostate Strategic Urologic Research Endeavor database. Fine and Gray competing-risks proportional hazards regression models were used to calculate the risks of prostate cancer-specific mortality (PCSM) and non-prostate cancer death and to generate a nomogram.RESULTS:The median follow-up after treatment was 53 months (interquartile range 30, 80 months). In total, 983 men died during follow-up, including 167 who died of prostate cancer and 816 who died of non-prostate cancer causes. On multivariate analysis, higher Cancer of the Prostate Risk Assessment score and primary treatment with radiation were associated with an increased risk of PCSM, whereas older age, African-American race, and treatment with radiation predicted non-prostate cancer death. The number of comorbidities and receipt of androgen deprivation therapy correlated with an increased risk of non-prostate cancer death, but not PCSM. The resulting nomogram allows quantification and comparison of the 10-year risk of PCSM and non-prostate cancer death.CONCLUSIONS:Integrating clinicopathological variables with comorbid conditions in a competing-risks model affords quantification and comparison of relative probabilities of PCSM and non-prostate cancer death following treatment. Our model thereby facilitates an individualized approach for counseling patients regarding prostate cancer management.

Predictors of clinical metastasis in prostate cancer patients receiving androgen deprivation therapy: results from CaPSURE.

Virtually all patients with prostate cancer who receive androgen deprivation therapy (ADT) will ultimately develop evidence of resistance to treatment. The prognosis for patients who develop metastatic castrate‐resistant disease is reported to be poor, with overall survival historically estimated to be 24 to 36 months. The goal of the current study was to identify predictors of clinical disease progression in patients with prostate cancer who were receiving ADT.

Temporal trends and predictors of salvage cancer treatment after failure following radical prostatectomy or radiation therapy: An analysis from the CaPSURE registry

Prostate cancer treatment after failure of primary therapy by either radical prostatectomy or radiation therapy can vary greatly. This study sought to determine trends and predictors of salvage treatment after failure of primary treatment in a community cohort over the past 10 years.

Postdiagnostic Statin Use and the Risk of Lethal Prostate Cancer in the Health Professionals Follow-up Study

Background: Observational studies suggest potential chemopreventive benefits of statins on prostate cancer outcomes, but data on the impact of postdiagnostic use are sparse. Methods: We examined the association of postdiagnostic statin use and risk of lethal prostate cancer (metastases or prostate cancer death, N = 242) among 3,949 men diagnosed with localized prostate cancer from the Health Professionals Follow-Up Study between 1992 and 2008 and followed through 2010 (33,302 person years). We used Cox proportional hazards regression models to estimate relative risks and 95% confidence intervals (CI), adjusting for age, time period, time from diagnosis to questionnaire, body mass index, vigorous physical activity, smoking, aspirin use, clinical stage, PSA at diagnosis, Gleason score, primary treatment, and comorbidities. Results: We found no statistically significant association between postdiagnostic current use of statins or duration of statin usage and the outcome of lethal prostate cancer [N = 242 cases; multivariate HR = 0.97 (95% CI, 0.72–1.31) for current use yes/no; HR = 0.85 (95% CI, 0.59–1.22) for 1 to 5 years of use, 0.96 (95% CI, 0.66–1.38) for 6+ years of use vs. never use]. Conclusions: We observed little evidence that statin usage after diagnosis of localized prostate cancer reduces risk of progression to metastatic disease or prostate cancer–specific death. Impact: These results do not support statins as a chemopreventive agent for prostate cancer progression. Cancer Epidemiol Biomarkers Prev; 24(10); 1638–40. ©2015 AACR.

Postoperative radiation therapy for patients at high-risk of recurrence after radical prostatectomy: does timing matter?

To evaluate among radical prostatectomy (RP) patients at high‐risk of recurrence whether the timing of postoperative radiation therapy (RT) (adjuvant, early salvage with detectable post‐RP prostate‐specific antigen [PSA], or ‘late’ salvage with a PSA level of >1.0 ng/mL) is significantly associated with overall survival (OS), prostate‐cancer specific survival or metastasis‐free survival, in a longitudinal cohort.

3D: diversity, dynamics, differential testing – a proposed pipeline for analysis of next-generation sequencing T cell repertoire data

BackgroundCancer immunotherapy has demonstrated significant clinical activity in different cancers. T cells represent a crucial component of the adaptive immune system and are thought to mediate anti-tumoral immunity. Antigen-specific recognition by T cells is via the T cell receptor (TCR) which is unique for each T cell. Next generation sequencing (NGS) of the TCRs can be used as a platform to profile the T cell repertoire. Though there are a number of software tools available for processing repertoire data by mapping antigen receptor segments to sequencing reads and assembling the clonotypes, most of them are not designed to track and examine the dynamic nature of the TCR repertoire across multiple time points or between different biologic compartments (e.g., blood and tissue samples) in a clinical context.ResultsWe integrated different diversity measures to assess the T cell repertoire diversity and examined the robustness of the diversity indices. Among those tested, Clonality was identified for its robustness as a key metric for study design and the first choice to measure TCR repertoire diversity. To evaluate the dynamic nature of T cell clonotypes across time, we utilized several binary similarity measures (such as Baroni-Urbani and Buser overlap index), relative clonality and Morisita’s overlap index, as well as the intraclass correlation coefficient, and performed fold change analysis, which was further extended to investigate the transition of clonotypes among different biological compartments. Furthermore, the application of differential testing enabled the detection of clonotypes which were significantly changed across time. By applying the proposed “3D” analysis pipeline to the real example of prostate cancer subjects who received sipuleucel-T, an FDA-approved immunotherapy, we were able to detect changes in TCR sequence frequency and diversity thus demonstrating that sipuleucel-T treatment affected TCR repertoire in blood and in prostate tissue. We also found that the increase in common TCR sequences between tissue and blood after sipuleucel-T treatment supported the hypothesis that treatment-induced T cell migrated into the prostate tissue. In addition, a second example of prostate cancer subjects treated with Ipilimumab and granulocyte macrophage colony stimulating factor (GM-CSF) was presented in the supplementary documents to further illustrate assessing the treatment-associated change in a clinical context by the proposed workflow.ConclusionsOur paper provides guidance to study the diversity and dynamics of NGS-based TCR repertoire profiling in a clinical context to ensure consistency and reproducibility of post-analysis. This analysis pipeline will provide an initial workflow for TCR sequencing data with serial time points and for comparing T cells in multiple compartments for a clinical study.