Karnes, R. Jeffrey

4657 Background: While active surveillance (AS) is well recognized as an acceptable treatment strategy for low-risk prostate cancer (PC), the extent to which radiation oncologists and urologists perceive AS as effective and routinely recommend it to patients is unknown. Therefore, we sought to assess the attitudes and treatment recommendations for low-risk PC from a national survey of PC specialists. Methods: A mail survey was sent to a population-based sample of 1,439 physicians in the U.S. from late 2011 and early 2012. Physicians were queried about their attitudes regarding AS and treatment recommendations for patients diagnosed with low-risk PC (PSA<10 ng/dl; T1c; Gleason 6 in one of twelve cores). Pearson Chi-square and multivariate logistic regression were used to test for differences in attitudes and treatment recommendations by physician demographics, compensation structure, primary place of employment, and specialty. Results: Overall, 321 radiation oncologists and 322 urologists completed the survey for a 45% response rate. Most physicians reported that AS is effective for low-risk PC (71%) and stated that they were comfortable routinely recommending AS (67%). Urologists were more likely to agree that AS is effective (77% vs. 67%; p=0.005) and were comfortable recommending AS (74% vs. 61%; p=0.001) compared with radiation oncologists. Most physicians recommended radical prostatectomy (47%) or radiation therapy (32%), but fewer endorsed AS (21%) for low-risk disease. After adjusting for physician covariates, radiation oncologists were more likely to recommend radiation therapy (OR: 10.97; p<0.001), while urologists were more likely to recommend surgery (OR: 4.69; p<0.001) and AS (OR: 2.18; p=0.001) for low-risk PC. Conclusions: Although AS is widely viewed as effective by both radiation oncologists and urologists, most urologists continue to recommend surgery, while most radiation oncologists recommend radiation therapy. Our results may explain in part the relatively low contemporary use of AS in the U.S.

4565 Background: The efficient delivery of adjuvant therapy after radical prostatectomy (RP) in patients with prostate cancer is limited by the lack of biomarkers, beyond clinicopathologic factors, that are able to assess the risk of clinically significant disease progression. Previously, routine FFPE patient specimens from the Mayo Clinic Radical Prostatectomy Registry with long term follow-up were selected to develop a genomic classifier (GC) to predict clinical progression. Here, we present the validation of a GC in a cohort of patients at high risk of disease progression. Methods: A case-cohort study of high-risk RP patients from the Mayo Clinic (N=219) was used to validate the genomic classifier (GC) for predicting clinical progression (defined by positive bone or CT scan post-RP). Its performance was compared to a multivariable clinical classifier (CC) and a genomic-clinical classifier (GCC) which combines GC with established clinicopathologic variables. Concordance index, Cox modeling and decision curve analysis were used to compare the different models. Results: GC and GCC were predictive of clinical progression in the high-risk cohort with c-indices of 0.79 and 0.82, respectively, compared to the clinical classifier (0.70). Multivariable survival analysis showed that the majority of prognostic information of GCC came from the GC with a minor contribution from Gleason score. Decision curve analysis showed that GCC had a higher overall net benefit compared to CC over a wide range of ‘decision-to-treat’ thresholds for the risk of progression. Conclusions: In this high-risk cohort, GC and GCC classifiers showed improved performance over CC in prediction of clinical progression. GC is an independent prognostic factor in this cohort and captures the majority of prognostic information. GC and GCC’s prognostic performance and their usefulness in guiding decision-making in the adjuvant setting after RP need further testing in studies of additional prostate cancer risk groups.

483 Background: We evaluate the impact of salvage intravesical therapy on survival in patients with NMIBC previously treated with BCG who ultimately underwent radical cystectomy (RC). Methods: We retrospectively identified patients with NMIBC who received at least 1 complete induction course of BCG and subsequently underwent RC for bladder cancer between 2000-2018. Patients were stratified by receipt of salvage intravesical therapy following BCG prior to RC. Oncologic outcomes were compared using Cox proportional hazards regression analysis and the Kaplan-Meier method. Results: We identified 371 patients who underwent RC after receiving BCG, of whom 55 (15%) received salvage intravesical therapy, most commonly Mitomycin C (n = 26), Valrubicin (n = 8), Gemcitabine (n = 7), and CG0070 (n = 6). Median follow-up among survivors was 1.1 (IQR 0-4.3) years. Patients who received salvage intravesical therapy were more likely to initially present with CIS (27% vs 17%) and less likely to present with T1 disease (33% vs 50%, both p < 0.05). Receipt of salvage intravesical therapy was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (33% vs 41%, p = 0.27). Furthermore, on Kaplan-Meier analysis, receipt of salvage intravesical therapy was not associated with cancer-specific or overall survival. On multivariable Cox proportional hazards regression, clinical stage prior to RC, but not receipt of salvage intravesical therapy, was associated with inferior cancer-specific survival and overall survival. Conclusions: Our results suggest that RC following carefully managed salvage intravesical therapy after BCG is not associated with inferior oncologic outcomes, which can improve patient counseling. [Table: see text]

337 Background: Current risk stratification schema have limited prognostic performance in predicting outcome within National Comprehensive Cancer Network (NCCN) high-risk to very high-risk prostate cancer. Methods: Two multicenter high-risk cohorts were used for training (n = 214) and validation (n = 151) of a novel RNA microarray-based integrated clinical-genomic Classifier Optimized for Outcome in High-risk Prostate cancer (COOHP) to classify patients as COOHP favorable high-risk, standard high-risk, or very high-risk. Cox analysis was used to model metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Model performance was compared to prior sub-classification systems using time-dependent c-indices. Results: Among NCCN high/very high-risk patients in the training cohort, 11% were classified as COOHP favorable high-risk, 70% as COOHP standard high-risk, and 18% as COOHP very high-risk. Patients with COOHP favorable high-risk disease had better rates of 5-year MFS compared to those with COOHP standard high-risk disease (94% vs 76%, hazard ratio [HR] 0.10, p = 0.02), and patients with COOHP very high-risk disease had worse 5-year MFS compared to those with COOHP standard high-risk disease (34% vs 76%, HR 3.5, p < 0.0001). Similarly, patients with COOHP very high-risk disease had worse 10-year PCSS compared to those with COOHP standard high-risk disease (36% vs 82%, HR 4.4, p < 0.0001). The c-indices for 5-year MFS and 10-year PCSS in the training cohort were 0.80 and 0.74, significantly improved compared to prior clinical and clinical-genomic risk stratification systems (0.62-0.69 for 5-year MFS and 0.56-0.63 for 10-year PCSS). These results were consistent in the validation cohort, where 5-year MFS significantly varied among the three COOHP subgroups (100% vs 89% vs 79%, p = 0.020), as did 10-year OS (100% vs 71% vs 53%, p = .040). Conclusions: A clinical-genomic risk stratification system specifically designed to discriminate prognosis in high-risk prostate cancer better identified favorable high-risk and very high-risk subsets of disease compared to prior clinical and clinical-genomic stratification systems.

AbstractBackgroundOptimal sequencing of systemic therapy in the management for metastatic castration resistant prostate cancer (mCRPC) remains poorly elucidated. The CHAARTED and STAMPEDE studies have proven that early chemotherapy in the hormone‐sensitive setting yields a greater net survival advantage than docetaxel for mCRPC. In a retrospective study, we attempt to investigate the two most common treatment sequences for mCRPC and investigate whether earlier chemotherapy for mCRPC is consequential to survival outcomes.MethodsWe identified 112 patients with mCRPC treated at the Mayo Clinic between 2011 and 2017. We identified two cohorts, 80 patients (group A) received full course docetaxel chemotherapy followed by second generation hormone therapy (2nd gen androgen deprivation therapy [ADT]; Abiraterone or Enzalutamide) and 32 patients (group B) treated with 2nd gen ADT followed by docetaxel. The primary endpoint evaluated was 3‐year cancer‐specific survival.ResultsMean prostate specific antigen at initiation of first treatment was 32.0 in group A and 21.7 in group B (P = .4). Bone metastases were more prevalent in group B (87% vs 58%, P = .01). All other clinicopathologic variables were statistically similar between group A and group B. Three‐year cancer‐specific survival was 87.4% vs 64.1% for group A and group B, respectively (P = .016). We report a univariate hazard ratio of 3.61 (95% CI, 1.74‐9.5, 0 P = .01). Three‐year overall survival was 82.4% and 60.8% for group A and group B, P = .01. These results held true when excluding patients with lymph node only metastasi.ConclusionOur data indicates that sequence of systemic therapy may influence outcomes for mCRPC and that docetaxel should be considered before 2nd generation ADT. Our results support the importance of earlier chemotherapy in the castration resistant state.

BackgroundThe progression of prostate cancer is a complex, multistep process that involves molecular alterations in cells of the tumor and the microenvironment, with associated interactions between the stroma and epithelium. Genomic expression analyses of stromal infiltration markers were performed to determine the significance thereof in prostate cancer.MethodsGenome‐wide expression profiles of formalin‐fixed, paraffin‐embedded radical prostatectomy samples were evaluated from a prospective registry cohort (n = 5239) and 3 retrospective institutional cohorts (n = 1135). Two independent stromal gene expression signatures implied stromal infiltration. Cox proportional hazards regression defined the association between stromal infiltration expression and metastasis‐free survival (MFS).ResultsStromal expression scores were correlated with stromal signature genes and with other key stromal markers (CAV1, VIM, and TAGLN), basal activity, and CD3 and CD4 immune biomarkers (r > 0.5 for all). The top decile of stromal expression was associated with high genomic risk scores (Decipher ≥ 0.6) , high Cancer of the Prostate Risk Assessment–Postsurgical scores, Gleason 9 to 10 disease, and a higher risk for metastasis (hazard ratio, 2.35; 95% CI, 1.37‐4.02; P = .001). A higher stromal infiltration score was also associated with decreased expression of DNA repair genes and higher radiation sensitivity genomic scores. Postoperative radiation therapy (RT) was associated with an MFS benefit for patients with high stromal scores, but not for patients with low stromal scores (Pinteraction = .02).ConclusionsExpression of stromal infiltration markers is correlated with prostate cancer aggressiveness/progression and may be predictive of a response to RT. Stromal infiltration markers should be studied and considered for incorporation into clinical prognostication and decision making.