Martin G. Sanda

18 Background: Prostate cancer practitioners tend to underestimate patients’ treatment-related side effects. We developed the Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) to facilitate patient-reported health-related quality of life (HRQOL) assessment at the point-of-care (Chang P et al, J Urol Sep 2011). We sought to demonstrate the feasibility of EPIC-CP use in routine clinical care, and to compare longitudinal patient-reported and practitioner-reported prostate cancer outcomes. Methods: We reviewed practitioner- and patient-reported HRQOL outcomes in 482 patients who underwent radical prostatectomy at our institution from 2010 to 2014. All EPIC-CP questionnaires were administered and interpreted without research personnel. Practitioner-reported outcomes were assessed using chart review. We used the paired t-test and Wilcoxon signed-rank test to compare pre- and post-treatment EPIC-CP domain scores, and Fisher’s exact test to compare patient-reported and practitioner-reported outcomes. We considered p-values < 0.05 statistically significant. Results: 708 total EPIC-CP questionnaires were completed. Mean urinary incontinence domain scores increased (worsened) significantly from baseline (0.6±0.2) to 3 (3.1±2.3) and 6 months (2.2±2.1) post-treatment, but were not statistically changed from baseline at 12 months (1.6±1.7). Patient-reported incontinence pad-free rates using EPIC-CP at 3, 6, and 12 months were 47%, 76%, and 78%, respectively, which were consistent with practitioner-reported rates. Mean sexual domain scores were significantly worse at 12 months (5.9±3.3) compared to baseline (2.4±2.8). Practitioners significantly overestimated the rate of functional erections compared to patients’ EPIC-CP-reported rates at 3 months (18% vs 12%, p < 0.05) and 12 months (45% vs 23%, p < 0.05). Bowel and vitality/hormonal scores were unchanged, and urinary irritation/obstruction scores improved after surgery. Conclusions: EPIC-CP is feasible to use in the routine clinical care of prostate cancer patients, and can help practitioners more accurately assess patients’ post-treatment symptom severity.

88 Background: Active Surveillance of men with low risk prostate cancer entails uncertainty for the patient and physician in determining risk of progression. While PSA determinations are frequently measured in men on active surveillance, no study thus far has found PSA velocity (PSAV) or PSA doubling times that identify patients at risk for clinical progression. However, based on observations in PASS, we hypothesized that men with negative PSAV might be at decreased risk for progression. Methods: From 723 PASS participants, we identified 396 who had at least 5 PSA values over 12-24 months after their diagnosis and prior to progression or last follow-up. Of the 396 patients, 56 progressed as defined by increase in Gleason score or increase in tumor involvement of the core biopsies to ≥ 34%, or increase in clinical stage while 340 men had no progression. PSAV is the slope of the log(PSA) values over time. ROC analysis was used with PSAV as the predictor of biopsy/clinical progression. Results: PSAV was mildly associated with clinical/biopsy progression with an AUC of 0.62 (95% CI: 0.54-0.70). Interestingly, by thresholding PSAV at 0, 150 of 396 men had negative a PSAV. Subjects with with a negative PSAV had a much lower rate of progression while on active surveillance. PSAV

84 Background: Rectal dose-volume histogram (DVH) parameters and a consensus normal tissue complication probability (NTCP) model predict physician scored toxicity but have not been well studied for patient reported outcomes (PRO) following external beam RT for prostate cancer. Methods: PRO were prospectively collected at baseline and 12 month intervals by expanded prostate cancer index composite (EPIC) for 98 patients from 2004-2009. Linear regression modeling for bowel score at 1 and 2 years was performed using pre-treatment bowel score and DVH parameters [V₈₀ (% of rectal volume >80 Gy), V₇₅, V₇₀, V₅₀, V₂₅, and NTCP]. Results: Median RT dose was 78 Gy with image-guidance in 81%, intensity-modulation in 72%, and pelvic RT in 11%. Rectal DVH parameters are presented in the Table. Pretreatment and 2 year PRO were available for 92% of patients. The mean pretreatment bowel summary score declined from 96.0 (sd 8.0) to 91.8 (13.5) at 2 years. Acute proctitis (grade 1-2) during RT was associated with a decline in 2 year bowel QOL, while acute diarrhea (grade 1-2) was not. At 2 years 63% of patients had a decline dose, NTCP and bowel QOL (Table). Akaike information criterion analysis followed by leave-one-out cross validation, indicated that V₇₅ provided the best predictive model for 2 year bowel QOL followed by NTCP and V₇₀. Conclusions: Most previous studies have highlighted V₇₀ for toxicity (such as rectal bleeding). The association with V₇₅ and rectal QOL has not been previously reported and supports potential changes in how prostate plans are designed to maintain QOL. This is also the first validation of a consensus NTCP model for bowel QOL. [Table: see text]

55 Background: RP, EBRT, and PI for treatment of clinically localized prostate cancer may negatively impact bowel function. Predictions of treatment-related bowel problems from patient-reported, prospective data may be useful in treatment decision-making. Methods: Patient-reported data on treatment-related bowel problems was obtained from 4 prospective, longitudinal, health-related quality-of-life (HRQOL) protocols comprising 2,668 patients treated between 1999 and 2011 by RP (n=1294), EBRT (n=630), and PI (n=744). A single HRQOL instrument was not uniformly used for each study, though all patients were asked if they experienced bother related to bowel problems using a similar 5-point scale. Patient responses were obtained at baseline and at 2 years after treatment. The endpoint of the model was bowel dysfunction, defined as bowel symptoms that were identified as a moderate-to-big problem. Cox proportional hazards regression analysis was used to model the clinical information and follow-up data. Internal validation was performed using bootstrapping. Results: Significant differences in baseline characteristics such as patient age, ethnicity, and disease severity existed between the treatment groups. Overall, 46 patients (2%) with complete data available had bowel dysfunction at baseline, including 11 (1%), 19 (4%), and 16 (3%) patients treated by RP, EBRT, and PI, respectively (p = 0.001). The overall rate of bowel dysfunction at 2 years in those patients with no bowel dysfunction at baseline was 2%, 10%, and 4% for patients treated by RP, EBRT, and PI, respectively (p < 0.001). In multivariable analysis, EBRT (p < 0.001), PI (p < 0.001), baseline bowel symptoms (p < 0.001), and institution (p = 0.04) were associated with bowel dysfunction. A nomogram based on the predictive parameters had a concordance index of 0.73 and predictions were well-calibrated with observed outcome. Conclusions: An externally validated nomogram that predicts 2-year incidence of bowel dysfunction after treatment for localized prostate cancer has been developed and may be useful for patient counseling regarding treatment options.

51 Background: RP, EBRT, and PI for the treatment of clinically localized prostate cancer may negatively impact sexual function. Predictions of treatment-related sexual problems from patient-reported, prospective data may be useful in decision-making. Methods: Patient-reported data on treatment-related sexual problems was obtained from 4 prospective, longitudinal, health-related quality-of-life (HRQOL) protocols comprising 2,668 patients treated between 1999 and 2011 by RP (n = 1,294), EBRT (n = 630), and PI (n = 744). A single HRQOL instrument was not uniformly used for each study, although questions pertaining to the quality and frequency of erections were identical among the studies. Only those patients with quality of erections sufficient for intercourse were included in the model. The endpoint of the model was erections suitable for intercourse on at least half of attempts at 2 years after treatment, with or without the use of oral medications. Cox proportional hazards regression analysis was used to model the clinical information and follow-up data. Internal validation was performed using bootstrapping. Results: Overall, 931 (74%), 249 (42%), and 323 (45%) patients treated by RP, EBRT, and PI were considered to be potent at baseline. Significant differences in baseline characteristics such as patient age, ethnicity, and disease severity existed between the treatment groups. The potency rate at 2 years for 1,215 patients who were potent at baseline and had complete follow-up data was 38%, 51%, and 61% for patients treated by RP, EBRT, and PI, respectively (p < 0.001). In multivariable analysis, age (p < 0.001), baseline frequency of erections (p < 0.001), EBRT (p < 0.001), PI (p < 0.001), PSA (p = 0.001), and institution (p = 0.006), were associated with potency. A nomogram based on the predictive parameters had a concordance index of 0.72 and predictions were well-calibrated with observed outcome. Conclusions: An externally-validated nomogram that predicts 2-year potency after treatment for localized prostate cancer has been developed and may be useful for patient counseling regarding treatment options.

49 Background: RP, EBRT, and PI for the treatment of clinically localized prostate cancer may negatively impact urinary continence. Predictions of treatment-related urinary problems from patient-reported, prospective data may be useful in treatment decision-making. Methods: Patient-reported data on treatment-related urinary incontinence was obtained from four prospective, longitudinal, health-related quality-of-life (HRQOL) protocols comprising 2,668 patients treated between 1999 and 2011 by RP (n = 1,294), EBRT (n = 630), and PI (n = 744). A single HRQOL instrument was not uniformly used for each study, although questions pertaining to the quantity (pad use) and frequency of urinary incontinence (“never” to “more than once per day”) were identical among the studies. Patient responses were obtained at baseline and at two years after treatment. The endpoint of the model was urinary continence defined as no pad use and leakage of urine less than once per day. Cox proportional hazards regression analysis was used to model the clinical information and follow-up data. Internal validation was performed using bootstrapping. Results: Overall, 1,937 (92%) of patients with complete data available were considered to be continent at baseline. Significant differences in baseline characteristics such as patient age, ethnicity, and disease severity existed between the treatment groups. The overall continence rate at two years was 66%, 88%, and 87% for patients treated by RP, EBRT, and PI, respectively (p < 0.001). In multivariable analysis, age (p = 0.001), baseline frequency of incontinence (p < 0.001), EBRT (p < 0.001), PI (p < 0.001), and ethnicity (p < 0.001) were associated with urinary continence. A nomogram based on the predictive parameters had a concordance index of 0.74 and predictions were well-calibrated with observed outcome. Conclusions: An externally-validated nomogram that predicts two-year urinary continence after treatment for localized prostate cancer has been developed and will be useful for patient counseling regarding treatment options.

Recent reports have suggested a possible involvement of Single-minded homolog 2 (SIM2) in human solid cancers, including prostate cancer. However, the exact role of SIM2 in cancer in general, and in prostate cancer in particular, remains largely unknown. This study was designed to elucidate the role of SIM2 in prostate cancer using a shRNA-based approach in the PC3 prostate cancer cell line. Lentiviral shRNAs were used to inhibit SIM2 gene and protein levels in PC3 cells. Quantitative RT-PCR and branched DNA were performed to evaluate transcript expression. SIM2 protein expression level was measured by western blot. Profiling of gene expression spanning the whole genome, as well as polar metabolomics of several major metabolic pathways was performed to identify major pathway dysregulations. SIM2 gene and protein products were significantly downregulated by lenti-shRNA in PC3 cell line. This low expression of SIM2 affected gene expression profile, revealing significant changes in major signaling pathways, networks and functions. In addition, major metabolic pathways were affected. Taken together, our results suggest an involvement of SIM2 in key traits of prostate tumor cell biology and might underlie a contribution of this transcription factor to prostate cancer onset and progression.