Citations

152 Background: Plasma cfDNA ARcopy number variations (CNV) have been suggested to have prognostic significance in mCRPC stage. We compared plasma AR amplification ( ARamp) with CTC counts (the only FDA approved prognostic marker in mCRPC stage) in a prospective trial of patients (pts) progressing on androgen deprivation therapy. Methods: Plasma and CTC counts were obtained concurrently as part of a prospective clinical trial in mCRPC stage pts initiating abiraterone acetate (NCT# 01953640). Plasma cfDNA was purified using DNA Blood Mini Kit (Qiagen, Valencia, CA) and AR CNVs were detected using QuantStudio3D digital PCR system (Life Technologies, Carlsbad, CA, USA). CTC enumeration was performed using the FDA cleared CellSearch platform. The distributions of overall survival (OS) time based on ARamp status and CTC counts ( < 5 vs ≥ 5 cells) were estimated using the Kaplan-Meier method. Log-rank tests were used to test association of ARamp status and CTC counts with overall survival (OS). Univariate and multivariate logistic regression models and ROC evaluated association of OS at 24 months by ARamp status and CTCs ≥ 5. Results: Between 05/2013 and 09/2015, 92 pts were enrolled of which complete CTC, plasma and outcome data was available for 70 pts. Median age of the cohort (range) was 72 yrs (39-91); Median PSA–16.2 ng/ml (range: 0.9-2026.0); Median CTC count was 2.0 (range: 0-372); 58/70 pts had bone metastases; 38/70 had high volume and 32/70 had low volume metastatic disease at the time of sample collection. The median (range) follow up time at the time of this analysis was: 26.5 (7.9-37.0) months at which time 28/70 patients had died. ARamp was present in 19/70 pts while 51/70 did not have amplification. 24/70 had CTCs ≥ 5. A significant association of increased ARamp status with OS (p < 0.0001, log-rank test; AUC: 0.66) as well as with CTC counts ≥ 5 (p = 0.001, log-rank test; AUC: 0.67) was observed. Combining CTC status and plasma ARamp status the AUC was 0.75. Conclusions: Plasma cfDNA ARamp status and CTC counts have comparable and clinically meaningful prognostic marker value in mCRPC stage patients.

142 Background: Despite documented oncological benefit, postoperative adjuvant radiotherapy (aRT) utilization in prostate cancer (PCa) patients is still limited in the US. We aimed to develop and internally validate a risk stratification tool incorporating the Decipher score, along with routinely available clinicopathologic features, to identify patients who would benefit the most from aRT. Methods: Our cohort included a total of 512 PCa patients treated with RP at one of four US academic centers between 1990-2010. All patients had ≥ pT3a disease, positive margins, and/or pathologic lymph node invasion (LNI). Multivariable Cox regression analysis (MVA) tested the relationship between available predictors (including Decipher score) and clinical recurrence (CR), which were then used to develop a novel risk stratification tool. Our study adhered to the TRIPOD guidelines for development of prognostic models. Results: Overall, 21.9% patients received aRT. Median follow-up in censored patients was 8.3 years. The 10-year CR rate was 4.9% vs. 17.4% in patients treated with aRT vs. initial observation (p < 0.001). Pathological T3b/T4 stage, Gleason score 8-10, LNI and Decipher score > 0.6 were independent predictors of CR (all p < 0.01) Cumulative number of risk factors was 0, 1, 2, and 3-4 in respectively 46.5, 28.9, 17.2, and 7.4% of patients. Adjuvant RT was associated with decreased CR rate in patients with ≥ 2 risk factors (10-year CR rate 10.1% in aRT vs. 42.1% in initial observation, p = 0.008), but not in those with < 2 risk factors (p = 0.23). Conclusions: Utilizing the novel model to indicate aRT might reduce overtreatment, decrease unnecessary side effects, and reduce risk of CR in the subset of patients (~25% of all patients with aggressive pathological disease) who really benefit from this therapy.

137 Background: Prior work from SWOG 9346 revealed that PSA ≤ 0.2 ng/dL at 7 months (mo) is prognostic for longer OS with ADT alone. We sought to evaluate if this optimal decline remained predictive of better OS when D was added to ADT for initial mHSPC treatment. Methods: We performed a landmark survival analysis at 7 mo using the E3805 database (NCT00309985). Inclusion required at least 7 mo of followup and PSA levels at 7 mo from ADT initiation. Survival was defined from ADT start or randomization to death. SWOG 9346 PSA nadirs of ≤ 0.2, > 0.2-4 and > 4 were used as classifiers. Results: 719 patients were eligible for analysis: 358 treated with ADT plus D and 361 with ADT alone. Median follow-up was 23.1 mo. On multivariable analysis (MVA), achieving a PSA ≤ 0.2 at 7 mo was more likely if the patient received D and had lower volume disease, prior local therapy, and lower baseline PSAs (all p ≤ 0.01). Across all patients, median OS was significantly longer if PSA at 7 mo reached ≤ 0.2 compared to > 4 (p < 0.0001) (Table). On MVA, PSA ≤ 0.2 at 7 mo and low volume disease were prognostic of longer OS (all p < 0.01). On ADT, 28.8% achieved a PSA ≤ 0.2 at 7 mo vs. 45.3% on ADT+D. Patients on ADT alone who achieved a PSA nadir ≤ 0.2 had the best survival. These patients were more likely to have low volume disease (56.7%) compared to the ADT + D pts (46.3%). Conclusions: Achieving PSA ≤ 0.2 at 7 mo remains prognostic for longer OS with ADT for mHSPC, whether administered alone or with D. Adding D to ADT increased the likelihood of a lower PSA and improved survival. Partial support and drug supply by Sanofi. Clinical trial information: NCT00309985. [Table: see text]

136 Background: Patients with a low burden of metastatic disease and who relapse after localized therapy with curative intent have a longer overall survival. It is unclear whether these patients benefit from early docetaxel (D). Methods: Patients in GETUG-AFU15 (N = 385, median follow-up 84 mo) and CHAARTED (N = 790, median follow up 54 mo) were randomized to ADT alone or ADT + D and outcomes described using the same definition of high volume (HV) and low volume (LV) disease. (HV: visceral metastases and/or 4 or more bone metastases with at least one outside the axis) and whether the patients had prior local therapy or not. Results: Table 1 details across both studies that de novo HV group treated with ADT alone has the shortest overall survival and D has a consistent effect in improving OS. In contrast, in both studies patients with LV disease had a much longer OS with no evidence that D improved OS. Conclusions: There was no apparent survival benefit in CHAARTED and GETUG-15 studies with D for LV whether patients had prior local treatment or not. Across both studies, early D had a consistent effect and improved OS in HV pts especially those with no prior local therapy. Partial Support and drug supply by Sanofi. Clinical trial information: NCT00104715, NCT00309985. [Table: see text]

133 Background: The genomic classifier, Decipher, has been validated to predict risk of metastasis after radical prostatectomy (RP). However, the cohort size and event rate in the previous studies did not allow for a thorough investigation into performance within individual clinicopathologic or treatment subgroups. In this study, we present the first meta-analysis of the performance of the 22-marker genomic classifier in men with prostate cancer (PCa) post-RP. Methods: MEDLINE, EMBASE, and the Decipher genomic resource information database were searched for published reports of men with PCa treated by RP between 2010 and 2016 where the benefit of the Decipher genomic classifier test was assessed. The primary end point was the ability of Decipher to independently improve prognostication of regional or distant metastasis over routine clinicopathologic factors. Meta-analysis was performed with random-effects modeling, and extent of heterogeneity between studies was determined with the I2 test. Results: Five studies (975 total patients, and 855 with individual patient genomic and clinicopathologic data) were eligible for analysis. The median follow-up was 8 years. All patients had clinical high-risk disease, yet 60.9%, 22.6%, and 16.5% of patients were classified as low, intermediate, and high-risk, respectively by Decipher and had 10-year cumulative incidence rates of metastases of 5.5%, 15.0% and 26.7% (p < 0.001), respectively. Adjusting for standard clinicopathologic variables, on multivariable analysis Decipher remained a statistically significant predictor of metastasis (hazard ratio [HR] 1.30 per 0.1 unit, 95% confidence interval [CI] 1.14-1.47, p < 0.001), and the summary HR for metastasis of Decipher across the 5 studies was 1.52 (95% CI 1.39-1.67) per 0.1 unit. Conclusions: The genomic classifier test, Decipher, has the ability to independently improve prognostication of men post-RP, as well as within nearly all clinicopathologic and treatment subgroups. Strong consideration should be given to incorporating the use of genomic testing in clinical decision making and clinical trials to better individualize treatment.

106 Background: Pharmacoepidemiologic studies suggest prognostic benefits of aspirin in prostate cancer. We hypothesized that prostate cancer tissue from regular aspirin users at cancer diagnosis compared to nonusers is characterized by specific transcriptional changes. Methods: We analyzed tumor whole-transcriptome data from men diagnosed with prostate cancer during prospective follow up of the Physicians Health Study 1 (PHS1, n1 = 150), initially a randomized-controlled trial of aspirin for prevention of cardiovascular disease and cancer. We compared the expression of putative aspirin target genes ( PTGS2, CTNNB1, MYC, AXIN2, PTGER3) between regular aspirin users ( ≥ 3 x 324 mg/week) and non-users at cancer diagnosis. We used Gene Set Enrichment Analysis to identify Gene Ontology biological process gene sets (total, 3609) associated with aspirin use. Leading edge genes of ≥ 3 functionally related gene sets were summarized in a meta-gene score. Results were validated among prostate cancer patients from the Health-Professionals Follow-up Study (HPFS, n2 = 254; aspirin use, ≥ 2 x/week). Results: Regular aspirin use was common (65% in PHS1; 45% in HPFS) and not associated with age, stage, and Gleason grade. In PHS1, none of the predefined genes were associated with aspirin use (all p > 0.05). 26 gene sets were downregulated in aspirin users at a false discovery rate (FDR) < 0.25 (9 at FDR < 0.05). 11 gene sets were clustered functionally around ribosome function and protein translation. A “ribosome” score of 96 genes was higher in aspirin users compared to nonusers (difference, 35.5 standard deviations [SD]; p = 0.0001). There was no dose-dependency for cumulative duration of aspirin use before cancer diagnosis ( ptrend = 0.17) or time since stopping use among non-users at diagnosis ( p = 0.32). In HPFS, neither the pre-defined target genes (all p > 0.18) nor the score were associated with aspirin use (difference, –9.8 SD; p = 0.18). Conclusions: Although RNA acetylation and resulting intratumoral gene expression changes due to aspirin use may be biologically plausible, we were unable to corroborate this association in two-long term prospective studies. Short-term trials might assess if aspirin has direct effects on tumor gene expression.

101 Background: Diabetes mellitus (DM) has been associated with an increased risk of mortality among patients with many types of cancers. The aim of this case-control study was to determine the impact of DM on short-term overall survival in prostate cancer patients, and to examine the impact of prostate cancer on glycemic control in DM. Methods: 276 patients with newly diagnosed prostate cancer from 2007-2014 with DM were identified from the Institutional Cancer Registry and matched to 276 prostate cancer patients without DM according to age and year of prostate cancer diagnosis. The file was linked to the electronic medical record to obtain information on DM and cancer therapies, and laboratory results. Results: The mean age of the entire prostate cancer cohort was 72 years, most (93%) were white, the most common Gleason score (in 52%) was 7, and the majority (56%) were tumor stage 2. No differences in age, race/ethnicity, Gleason score, or tumor stage were detected between patients with and without DM, although DM patients had higher body mass index (P = .031). Among those with DM the mean hemoglobin A1c (HbA1c) was 6.7%. In Kaplan-Meier survival analysis (median follow-up time of 43.7 months), 5-year overall survival was estimated at 88% for DM patients versus 93% in non-DM patients. Hazard ratio (for matched pairs) was 1.64 (95% CI: 0.77-3.46, P = .20). Moreover, mean HbA1c and glucose values among DM cases did not significantly change over 1 year (P ≥ .13). Mean glucose among DM patients was significantly (p < 0.01) higher compared to non-DM patients. Conclusions: DM did not adversely impact survival in prostate cancer patients. In addition, prostate cancer or its treatment does not appear to affect glycemic control. Both patients and their providers can be reassured that the two concurrent diagnoses do not adversely interact to worsen short term outcomes.

Abstract We describe a series of 102 patients diagnosed from January 1, 1990 to December 31, 2015 with Type 1 monoclonal cryoglobulinemia (MoC). Symptoms were seen in 89 (87%) patients, including: cutaneous symptoms in 64 (63%) patients, with purpura (n = 43, 42%) and ulcers/gangrene (n = 35, 34%) being most common; neurological findings in 33 (32%) patients, most frequently sensory neuropathy (n = 24, 24%); vasomotor symptoms, mainly Raynaud's phenomenon in 25 (25%); arthralgias in 24 (24%); and renal manifestations, primarily glomerulonephritis in 14 (14%) patients. An underlying lymphoproliferative disorder was identified in 94 (92%) subjects; MGUS—39, myeloma—20, lymphoplasmacytic lymphoma—21 and others—14. Treatment was initiated in 73 (72%) patients, primarily for cryoglobulinemia‐related symptoms in 57. Treatment regimens consisted of: steroids ± alkylating agents in 29 (40%), novel myeloma therapies in 16 (22%), rituximab with alkylating agents in 12 (16%) and rituximab ± steroids in 11 (15%) patients; 22 patients received plasmapheresis. Six patients underwent autologous stem cell transplant. Cryocrit at treatment initiation, change in cryocrit and time to nadir cryocrit were predictive of symptom improvement. Treatment directed toward the underlying clonal disorder resulted in improvement (n = 47) or stabilization (n = 16) of symptoms in the majority of patients and disappearance of cryoglobulin in over one‐half.

Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics for treating C9ORF72 -associated amyotrophic lateral sclerosis.