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TPS1106 Background: ICB (atezolizumab, anti-PD-L1) is known to improve survival when added to chemo, however only in PD-L1-positive, triple-negative MBC. ICB is less effective in hormone receptor positive (HR+) MBC, or when administered following palliative chemo. Novel approaches are required to broaden clinical benefit of ICB, particularly in PD-L1-negative, HR+, or chemo-experienced MBC. Dual ICB with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) is associated with enhanced activity in melanoma other malignancies, but has not been explored extensively in MBC. Androgen receptor (AR) blockade, in addition to known direct cytostatic effects in AR-expressing MBCs (50% of TNBC, > 75% of HR+ MBC), may also modulate immune response. AR blockade has been shown experimentally to stimulate thymic production of naïve T-cell clones, which in turn can facilitate de novo anti-tumor immune responses. Concurrent ICB can enhance the activity of these T-cell clones by interfering with PD-1-mediated peripheral tolerance. This combination approach is promising in MBC in light of known AR positivity, and the routine use of lymphodepleting chemo regimens in the curative-intent setting. Methods: This is a phase II trial of dual immune checkpoint blockade (nivolumab 240mg IV q2w; ipilimumab 1mg/kg IV q6w) plus AR blockade (bicalutamide, 150mg PO daily, dose reduction allowed) in triple-negative MBC (cohort A: AR-positive [ > 1% by IHC]; cohort B: AR-negative) or HR+ MBC (cohort C) in subjects who received 0/1 prior chemotherapies in the non-curative setting. Objectives include 24-week clinical benefit rate by iRECIST (primary), safety (CTCAE v4.0), and other response measures (RECIST1.1, PFS, OS). Efficacy for each cohort is defined as > 20% improvement in response over historical control (30% per EMBRACE clinical trial) employing a Simon 2-stage design to minimize futility (n = 46/cohort, stage I n = 15). Thymic generation of T-cells will be measured via quantitative deep sequencing of T-cell receptors (TcR, ImmunoSEQ assay) and TcR excision circles (TRECs), as well as real-time flow cytometry using surrogate cell surface markers of recent thymic emigration. Enrollment has commenced, sites: Earle A. Chiles Research Institute (Portland, OR), Memorial Sloan Kettering Cancer Center (New York, NY). Clinical trial information: NCT03650894.

Purpose Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction. Patients and Methods The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Children's Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated. Results SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor–associated protein (GABARAP) gene expression predict decreased survival among all patients. GABAA δ receptor subunit gene expression was predictive of a poor outcome among Evans stage IV-S patients. An index of five coexpressed GABAA receptor subunits was identified (GABAA profile [GAP score]). Patients with a higher GAP score (> −1) had a survival advantage. Multivariate analysis showed that GABARAP and GABAA α2 receptor subunit gene expression levels and GAP score remained predictors of clinical outcome after accounting for current prognostic indicators. Conclusion Dysregulation of the GABAergic system may constitute a fundamental event in the development of NB, and assessment of GABAergic system gene expression could provide improved patient stratification and potential new therapies.

Purpose Adverse events in chemotherapy clinical trials are assessed and reported by clinicians, yet clinician accuracy in assessing symptoms has been questioned. We compared patient reporting of eight symptoms using a validated instrument, the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (QLQ-C30 or QLQ) with physicians' reporting of the same symptoms in the study's adverse events log. Patients and Methods Thirty-seven men with metastatic, androgen-independent prostate cancer enrolled onto a phase II trial of weekly calcitriol and docetaxel completed the QLQ every 4 weeks for up to 28 weeks. A patient-reported symptom was defined as an increase in a QLQ symptom score by at least 10 points (0 to 100 scale), sustained for at least 4 weeks. A physician-reported symptom was considered present if it was ever documented in the adverse event log. Results Forty-nine (new or worsened) symptoms were detected by both physician and QLQ, 48 symptoms were detected by the physician alone, and 55 symptoms were detected by the QLQ alone. They agreed on the absence of a symptom in 102 instances of 254 possible opportunities. Their uncorrected agreement was 59.4%, but Cohen's κ, a coefficient of agreement that corrects for chance, was 0.15, indicating only slight agreement. Using the QLQ as the standard, overall physician sensitivity and specificity was 47% and 68%, respectively, although it varied considerably among symptoms. Conclusion Even in a tightly controlled clinical trial, physician reporting was neither sensitive nor specific in detecting common chemotherapy adverse effects. Tools for collecting patient-reported adverse event data in chemotherapy clinical trials should be developed.

10105 Background: Gynecologic symptoms and sexual dysfunction from endocrine therapy are troublesome side effects for a significant number of patients. This study explored amelioration of vaginal dryness and dyspareunia with fluocinonide cream, a strong topical corticosteroid. Methods: A single-arm, open-label phase II trial of topical fluocinonide 0.05% cream to improve vaginal symptoms in women on endocrine therapy in the adjuvant setting for early stage breast cancer was performed. Patients with vaginal symptoms applied topical vaginal fluocinonide 0.05% cream twice a day for two weeks then once daily for two weeks. Patients were assessed for symptoms by weekly completion of the Mayo/North Central Cancer Treatment Group Patient Pretreatment Questionnaire. The primary outcome was a change from baseline in patient-reported effects of vaginal dryness and dyspareunia on a scale from 0 (no symptoms) to 4 (very severe symptoms) from time of enrollment and at 4 weeks. Secondary outcomes were decrease in vaginal itching and total vaginal index score. Comparisons were made with Wilcoxon sign rank test with 2.5% significance level. Results: Thirty-four women were accrued. At 4 weeks compared with baseline, vaginal dryness improved from a median score of 2 (moderate symptoms) to 0 (no symptoms) ( P < .001) and dyspareunia from 3 (severe symptoms) compared with 1 (mild symptoms) ( P = .002). Percentage of patients who had > 2 point improvement in vaginal dryness and dyspareunia was 69.0% and 75% respectively. Secondary analysis showed decrease in vaginal itching score from 1 to 0 ( P = .001) and vaginal index score of 6 to 1 ( P = .002). Twenty-one patients experienced low-grade toxicities which were mostly limited to skin irritation. Conclusions: Fluocinonide 0.05% cream improves vaginal dryness and dyspareunia experienced by women receiving endocrine therapy and has the potential to improve quality of life of cancer survivors and compliance of endocrine therapy. Clinical trial information: NCT00297011.

PURPOSE Hepatic venoocclusive disease (VOD) is a common complication of cytoreductive therapy for marrow transplantation. Only 25% of patients who develop VOD have severe disease. We tested the hypothesis that early clinical signs of VOD would predict which patients would recover and which would die. PATIENTS AND METHODS We evaluated 355 consecutive patients who had transplants between August 6, 1987 and July 21, 1988 for occurrence of VOD and whether it was reversible within 100 days of transplant. Total serum bilirubin and weight gain from day -7 through day +16 posttransplant were compared among patients with no, severe, or nonsevere VOD. Logistic regression models were developed to estimate probabilities of severe VOD at each of six time intervals. The accuracy of these models was tested by applying them to 392 consecutive patients who underwent transplantation between July 22, 1988 and July 20, 1989. RESULTS As early as day -1, bilirubin and weight gain were significantly different between patients whose VOD proved to be severe and patients with reversible VOD or no disease. Regression models were used to generate coefficients (beta 0, beta 1, beta 2) for the equation P = 1/(1 + e-z), where P is the probability of severe VOD and z = beta 0 + beta 1 (In total serum bilirubin [mg/dL]) + beta 2 (percent weight gain). Application of this equation to the next 392 patients allowed us to calculate sensitivity, specificity, and positive predictive value for a range of probabilities. CONCLUSION The course of VOD after cytoreductive therapy can be predicted by knowing the serum bilirubin and weight gained within 1 to 2 weeks of transplantation. Probability estimates derived from patient data are highly specific and moderately sensitive. Such probability estimates may be useful when considering potentially risky interventions to treat VOD, such as recombinant human tissue plasminogen activator.

5017 Background: Diets high in cruciferous vegetables are strongly associated with lower prostate cancer risk. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on pre-clinical evidence in multiple tumor models. Our own work demonstrates that sulforaphane inhibits HDAC function and suppresses AR signaling in prostate cancer cells (Gibbs, et al PNAS 2009). However, the anti-tumor efficacy and safety of sulforaphane in men with prostate cancer was unknown. Methods: In this single arm study, we treated patients with biochemical (PSA)-recurrence of prostate cancer with 200 µmol of sulforaphane extracts for up to 20 weeks. The primary endpoint was PSA response rate (>50% decline in PSA). Other efficacy endpoints included: maximal PSA decline and percent change in PSA from baseline to end of study. We also analyzed PSA doubling time changes using a mixed effects model. Genotyping for GSTM1 that contributes to sulforaphane metabolism, sulforaphane pharmacokinetics (PK), and pharmacodynamic (PD) measurements of HDAC inhibition in mononuclear cells (MCs) were also performed. Results: Twenty patients were enrolled, and 16/20 (80%) completed the pre-planned 20 weeks of treatment. One patient experienced a PSA decline >50%. Thirty-five percent of patients had lesser PSA declines (3% to 20%), and 15% of patients had a final PSA lower than baseline. There was a significant reduction in PSA doubling time (6 months pre-study vs. 9.4 months on-study, p=.013). Of note, testosterone levels remained non-castrate in all subjects. PK analysis demonstrated that GSTM1 null genotype correlated with longer sulforaphane T1/2 (half-life) (2.6 hours for GSTM1 null vs. 2.1 hours for GSTM1 intact, p=0.04). Sulforaphane treatment also increased histone acetylation in PD assays in MCs. Finally, no grade three adverse events were seen, and only one patient discontinued study treatment for toxicity (grade one GI discomfort). Conclusions: Treatment with 200 µmol per day of sulforaphane is feasible, safe, and inhibits HDAC function. This combined with the preliminary observation of PSA modulation, which may indicate biologic activity, provides the basis for dose escalation studies of sulforaphane in men with prostate cancer. Clinical trial information: NCT01228084.

4667 Background: Exposure to Agent Orange (AO), a defoliate used during the Vietnam War, is a potential risk factor for the development of prostate cancer (PCa). However, it is unknown whether indi...

5007 Background: Prostate biopsy procedures carry a high false-negative rate. However, since Gleason score is strongly associated with cancer-specific mortality; efforts to identify men who harbor high-grade prostate cancer will likely assist in patient selection for repeat biopsies. We sought to identify risk factors for the detection of aggressive prostate cancer (Gleason ≥ 7) on repeat biopsy. Methods: Clinical and pathologic variables collected from subjects undergoing a repeat biopsy included all prostate specific antigen (PSA) values, PSA density (PSAD), PSA doubling time (PSADT). PSADT was examined using PSAs up to the first biopsy, and also in an exploratory analysis using both pre- and post-biopsy PSAs. Predictors of aggressive prostate cancer were identified using recursive partitioning and a stepwise Cox regression model. Results: 511 patients with initial negative biopsies underwent 1,319 biopsy procedures. Median follow-up was 3.7 years. Aggressive cancer was diagnosed in 52 of 511 (10.18%) patients. Recursive partitioning analysis selected PSAD as the sole factor for distinguishing high- and low-risk groups. Based on K-M analysis, a PSAD 0.304 ng/ml/cc carried cancer detection rates of 23% (± 11.9%) and 36% (±15.3%) at 2 and 5 years (p-value = 9.7 (2.565, 1.404 - 4.688), PSAD 0.13 - < 0.19 ng/ml/cc (0.423, 0.179 - 0.999) and volume >= 43.3 cc (0.454, 0.247 - 0.833). PSADT became significant when all PSA data were analyzed: PSADT < 2 years (4.203, 1.894 - 9.325) and PSADT >= 5 years (0.17, 0.89- 0.326). Conclusions: In decision tree analysis, a high PSAD is predictive of aggressive prostate cancer on a repeat biopsy. In addition, high PSA, lower PSAD and prostate volume are predictive of aggressive prostate cancer. However in follow-up using all PSA values, a PSADT < 2 yrs. becomes the most significant predictor of aggressive cancer. Such data may help identify the most appropriate patients for a repeat biopsy and could reduce the rate of unnecessary biopsies and the inherent over-treatment of prostate cancer. No significant financial relationships to disclose.

9021 Background: Physician-reported performance status (PS) is an important prognostic factor in advanced malignancies and is a commonly used stratification variable in cancer clinical trials. However, the extent, predictors, and prognostic importance of disagreement in PS assessment between physicians and patients have not been examined. Methods: Using NCCTG clinical trials from 1987–1990 (J Clin Oncol 19(15):3539–3546, 2001), we analyzed the difference and agreement of PS (ECOG and Karnofsky [KPS]) and nutritional status assessments reported by physicians and patients individually. The degree of disagreement was analyzed using paired t-test. Overall mortality was estimated by Kaplan-Meier method. The effect of disagreement on overall survival was analyzed by Cox regression. Independent predictors of disagreement were identified by logistic regression. Results: 1,636 patients with advanced lung and colorectal cancer had a median survival of 9.8 months (95% CI, 9.4 to 10.4). Percent agreement between patients and physicians about KPS, ECOG PS, and appetite/nutritional status was 32.9%, 43.4% and 42.0% respectively. Physicians were more likely to rate patients better than individual patients were to rate themselves: ECOG (Mean 0.91 vs 1.30, p No significant financial relationships to disclose.

4617 Background: The escalating rate of obesity in the Western world presents a diagnostic challenge when screening for prostate cancer. Increased body-mass index (BMI) disrupts the ability to effectively screen this population due to an associated decrease in serum prostate-specific antigen (PSA) levels and an increase in prostate volume. We therefore sought to understand how BMI impacts the probability of harboring prostate cancer. Methods: Data were collected on 647 referred men with a serum PSA of ≤ 10 ng/ml who underwent an ultrasound-guided prostate biopsy. Variables analyzed included: age, BMI, digital rectal exam (DRE), PSA, PSAD (i.e. PSA ÷ prostate volume), prostate volume, hypoechoic lesions on ultrasound and cancer on biopsy. A one-way ANOVA was performed to determine differences in log2 (PSAD) among BMI groups (2 vs. 25–30 kg/m2 vs. >30 kg/m2). Multivariate logistic regression analysis was performed to estimate the odds-ratio (OR) and 95% confidence intervals (CI). Results: Prostate cancer was detected in 19.2 % of patients. ANOVA showed the mean PSAD to be significantly different in the three BMI groups (F value = 7.1, p = .0009). The mean PSAD significantly decreased as the BMI level increased (p = .0002). Independent pre-biopsy predictors of prostate cancer were tabulated (see below). Conclusions: Obesity was associated with a decrease in PSA density. The multivariate logistic regression revealed that the effect of PSAD on cancer detection was significantly modified by BMI. Specifically, the OR associated with a doubling of PSAD was 1.7 when BMI was 2 vs. 2.1 when BMI was ≥25 kg/m2). This interaction was an independent predictor of prostate cancer risk, along with DRE and ultrasound findings. These data underscore the need to consider BMI as a potential effect modifier of traditional clinical risk factors for prostate cancer. The dramatic rise in obesity in the United States makes this effect modification particularly relevant. [Table: see text] No significant financial relationships to disclose.

4610 Background: Use of PADT as sole therapy for clinically localized PC is rapidly increasing, despite little evidence to support this approach. We examined predictors of overall survival (OS) and cancer-specific survival (CSS) using the data available from the Prostate Cancer Outcome Study (PCOS). Methods: PCOS recruited 5,672 patients between 1994 and 1995, within 6 months of PC diagnosis. Vital status was last updated in 12/02. 276 patients had clinically localized PC and received PADT. We examined the relationship between baseline demographic, socio-economic, and tumor factors and OS and CSS using Kaplan-Meier and Cox regression methods implemented in the SUDAAN software. Results: Of 276 patients, 148 patients have died, 35 from PC. The median age at diagnosis was 75 (50–88). The average follow-up of censored subjects was 7.6 yrs (1.1–8.1). 5-year OS was 66% (95% CI: 69–72), while the 5-year CSS was 91% (95% CI: 86–94). In the multivariate analysis (see Table), age, serum PSA at diagnosis, and Gleason score were the only independent predictors of OS. Abnormal DRE was marginally significant. The Gleason score (≥7) was the only independent predictor of CSS (HR 4.0, p = 0.04); PSA ≥ 20 (HR 2.38, p = 0.09) approached significance. This analysis was limited by a smaller number of deaths due to prostate cancer (n = 35). Conclusions: In an analysis that included a broad range of demographic and socio-economic factors, overall survival of patients with clinically localized prostate cancer treated with PADT was predicted by age and measures of tumor biology (Gleason score) and tumor mass (serum PSA). Thus, cancer remains an important contributor to overall mortality in these patients, particularly those with high Gleason score and high serum PSA. These data can be used to inform patients regarding their individual 5-year survival if they choose PADT for the treatment of their clinically localized prostate cancer. [Table: see text] No significant financial relationships to disclose.

3588 Background: Expression of cyclooxygenase-2 (COX-2), present in most CRC, is associated with a worse prognosis. C, a selective COX-2 inhibitor, has inhibitory effects against CRC which appear at least additive with chemotherapy preclinically. A multi-institutional phase II trial was conducted to evaluate C plus standard IFL as first-line treatment for pts with incurable CRC. Methods: C 400mg po BID starting Day #1; I 125mg/m2 iv weekly starting Day #15; F 500mg/m2 iv bolus weekly starting Day #15; L 20mg/m2 iv weekly bolus starting Day #15. Patients received IFL for 4 weeks followed by a two-week rest. C was continued during the rest. Pts were treated until disease progression or unacceptable toxicity. Primary endpoint was response with planned sample size of 47 patients. Results: 47 pts were consented and treated. Evaluable pt characteristics: Male/female (no.) = 34/13; mean age = 59.7; ECOG PS 0/1/2 (no.) = 31/14/2; cancer stage locally-advanced/distant/unknown (no.) = 10/28/9. Due to concerns of risk of excess cardiovascular (CV) toxicity the protocol was amended halfway through enrollment to exclude pts with PS 2, and to require low-dose aspirin (ASA) for pts at high risk for CV events. Pre-and post-modification (mod) results are shown in the table . In general hematologic toxicity was moderate. Non-hematologic toxicity was mostly gastrointestinal, but 25% experienced cardiac or vascular toxicity (1 cardiac arrest, 1 MI, 1 CHF, 3 arrhythmias, 2 DVT, 2 CVA, 1 hyper- and 1 hypotension). All cardiac events occurred before modification of the protocol. There was 1 treatment-related death from cardiac arrest. Conclusions: C may be given safely with IFL chemotherapy, if pts are carefully selected. Addition of low-dose ASA may reduce cardiac toxicity. Post-mod TTP and survival for C plus IFL appear superior to historical results for IFL, but a phase III study would be required for confirmation. [Table: see text] [Table: see text]

4633 Background: The value of both PSA and DRE for prostate cancer detection have recently been called into question when examined in screening and prostatectomy series (NEJM 350:2239, J Urol 172:1297). The effectiveness of these parameters for detection of clinically significant cancer is not fully characterized. We studied their utility for the detection of aggressive prostate cancer (Gleason Score ≥ 7) in a referral population of men. Methods: Data were collected on 1,699 referred men with a serum PSA of ≤ 10 ng/ml who underwent a prostate biopsy (minimum 6 cores) between 1993 and 2004. Variables analyzed included: age, race, family history, DRE (normal vs. suspicious vs. cancer-likely) and PSA. Thirty percent of the data were randomly reserved for study validation. Logistic regression analysis was performed to estimate the odds ratio and the 95% confidence intervals. Results: Gleason grade ≥ 7 prostate cancer was detected in 157 subjects (9.2%). Using the model building data set (n = 1,184), independent predictors of Gleason ≥ 7 cancer were an elevated PSA and an abnormal DRE only (see table ). Based on these results, a clinically-applicable nomogram was constructed and using the independent validation set (n = 515). The area under the ROC was 0.70 for the model. Conclusions: Although the use of PSA and DRE have recently come under intense scrutiny, they independently predict the presence of aggressive prostate cancer in a contemporary referral population. Improvement in prostate-cancer survival associated with successful treatment of localized disease requires the successful early detection of aggressive prostate cancer. Our results demonstrate that PSA and DRE, currently recommended screening interventions by the ACS and AUA, remain useful for the detection of aggressive prostate cancer in the PSA era. [Table: see text] No significant financial relationships to disclose.

4621 Background: Prostate cancer is characterized by a wide spectrum of biologic heterogeneity that results in divergent clinical outcomes. Thus, not all patients benefit from aggressive therapy. Tumor grade is the most important of the clinicopathologic factors that predict tumor aggressiveness and therefore drive decisions regarding aggressive local therapy vs. observation. The goal of this study was to develop a nomogram for the prediction of high-grade prostate cancer (defined as Gleason ≥ 7) using pre-biopsy factors. Methods: Data were prospectively collected on 1,699 referred men with a serum PSA of ≤ 10 ng/ml who underwent a prostate biopsy (minimum 6 cores). Variables analyzed included: age, race, family history, digital rectal exam (DRE), prostate-specific antigen (PSA), PSA density (PSAD), prostate volume, PSA doubling time (PSADT), and ultrasound (US) findings. Thirty percent of the data were randomly reserved for study validation. Logistic regression analysis was performed to estimate the rela...

4645 Background: PSADT is a strong predictor of adverse outcomes in men with recurrent prostate cancer. Its utility has not been examined, however, for the most common diagnostic challenge: a man r...

4589 Background: Due to a high rate of false negative prostate biopsies, a repeat biopsy is often recommended to men if there is a suspicion of occult carcinoma. We sought to determine the rate of prostate cancer (PC) detection and identify risk factors for cancer detection in men who despite suspicion of PC had a negative biopsy initially and then underwent serial prostate biopsies. Methods: Records of all men undergoing at least one repeat biopsy of the prostate from 1992 to 2003 were reviewed. Variables recorded were: age, race, family history of PC (FH), body mass index, biopsy indication, all PSA values, digital rectal exam (DRE), PSA density (PSAD; i.e. PSA/prostate volume), ultrasound findings, total number of cores obtained at all procedures, and the presence of high-grade PIN on initial biopsy. Outcome was defined as time from the initial biopsy to cancer detection or last follow-up. The data were analyzed by Kaplan-Meier method, log-rank test (univariate analysis), stepwise Cox regression (multi...

4627 Background: Recent studies indicate increasing use of androgen deprivation (AD) as primary therapy for localized prostate cancer. The utility of this approach is not well known; thus, we sought to characterize the outcomes and determine independent predictors of disease progression with this approach. Methods: The records of all patients with cT1–2, N0, M0 adenocarcinoma of the prostate treated with AD as sole initial therapy at the Portland VA between 1993 and 2000 were reviewed. Age, race, Charlson health index (CHI), family history, PSA, PSA density (PSAD, PSA/prostate volume), digital rectal exam findings, Gleason score, and % of positive biopsy cores at diagnosis were recorded. Outcomes included PSA failure (confirmed with 2 rising PSAs), PSA nadir, bone fractures, local failure, distant failure, and overall survival. Kaplan-Meier method and log rank test (univariate analysis) and stepwise Cox regression (multivariate analysis) were used to estimate time to each end point. Results: 81 patients w...

8022 Background: Adverse effects in chemotherapy clinical trials are assessed and reported by physicians, yet physicians' accuracy in assessing symptoms has been questioned. We compared patient rep...