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251 Background: The heterogeneity of individual sites of disease in prostate cancer is well recognized and increases over time as the therapies administered promote divergent evolution. In clinical practice, this is often depicted in radiology reports as a mixed response, wherein some lesions improve and others progress or emerge, for which individualizing management is challenging. The problem is exacerbated in patients with high volume disease by the inability to concisely and effectively assess overall disease status which may mask the presence of emerging resistance that could benefit from early intervention and/or a change in therapy. Methods: Thirty-one sets of serial baseline and on-treatment FDG-PET/CT images done for the clinical management of patients with progressing mCRPC were analyzed using TRAQinform IQ software (AIQ Solutions). Individual regions of interest (ROI) identified and tracked across imaging time-points were analyzed for a range of features. The univariate prognostic weight of each feature was assessed with Cox regression models. Imaging features from single timepoints, heterogeneity of response features, and PSA values/dynamics were input into the separate TRAQinform Profile software, which was calculated to predict either time on treatment or overall survival using 3-fold cross-validation of a random survival forest. Individual case reviews were performed on select patients including TRAQinform IQ analytics, PSA trends, radiology reports, and physician notes to evaluate the potential additive benefit of the TRAQinform IQ output. Results: In general, imaging features were more strongly correlated with overall survival than PSA dynamics. After iterative feature selection, only imaging features were selected for TRAQinform Profile scores. In the case of predicting OS, the most important features were baseline total lesion glycolysis (TLG), and the number of new/progressing lesions. Patients with high TRAQinform Profile scores had shorter median survival times than those with low scores (630 vs 1326 days, p

PURPOSE To determine if radiomic measures of tumor heterogeneity derived from baseline contrast-enhanced computed tomography (CE-CT) are associated with durable clinical benefit and time to off-treatment in patients with recurrent ovarian cancer (OC) enrolled in prospective immunotherapeutic trials. MATERIALS AND METHODS This retrospective study included 75 patients with recurrent OC who were enrolled in prospective immunotherapeutic trials (n = 74) or treated off-label (n = 1) and had baseline CE-CT scans. Disease burden (total tumor volume, number of disease sites), radiomic measures of intertumor heterogeneity (cluster-site entropy, cluster-site dissimilarity), and intratumor heterogeneity of the largest lesion (Haralick texture features) were computed. Associations of clinical, conventional imaging, and radiomic measures with durable clinical benefit and time to off-treatment were examined. RESULTS In univariable analysis, fewer disease sites, lower intertumor heterogeneity (lower cluster-site entropy, lower cluster-site dissimilarity), and lower intratumor heterogeneity of the largest lesion (higher energy) were significantly associated with durable clinical benefit ( P ≤ .031). More disease sites, presence of pleural disease and/or distant metastases, higher intertumor heterogeneity (higher cluster-site entropy, higher cluster-site dissimilarity), and higher intratumor heterogeneity of the largest lesion (higher Contrastlargest-lesion) were significantly associated with shorter time to off-treatment ( P ≤ .034). In multivariable analysis, higher Energylargest-lesion (indicator of lower intratumor heterogeneity; P = .006; odds ratio, 1.41) and fewer disease sites ( P = .003; odds ratio, 1.64) remained significant indicators of durable clinical benefit (multivariable model C-index, 0.821). Higher cluster-site dissimilarity (indicator of higher intertumor heterogeneity) was a modest but single independent indicator of shorter time to off-treatment ( P = .004; hazard ratio, 1.19; C-index, 0.6). CONCLUSION Fewer disease sites and lower intra- and intertumor heterogeneity modeled from the baseline CE-CT may indicate better response of OC to immunotherapy.

440 Background: Neoadjuvant chemotherapy (NAC) has proven survival benefits for invasive urothelial carcinoma of the bladder, yet its role in upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a phase II multicenter trial of NAC with gemcitabine and cisplatin (GC) in patients with high-risk UTUC prior to extirpative surgery to evaluate major outcomes of response, survival, and tolerability. Methods: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of GC prior to surgical resection and lymph node dissection. The primary study endpoint was pathologic response rate (defined as < pT2N0). Patients with progressive disease prior or unable to proceed to surgery were considered treatment failures. Secondary endpoints included time to disease progression (PFS), overall survival (OS), and safety and tolerability. Results: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response, meeting the primary endpoint of the study. A complete response was noted in 11 patients (19%), defined as pT0N0. Forty patients (70%) tolerated all four cycles of GC, and all patients proceeded to surgery. The 90-day ≥ grade 3 surgical complication rate was 7.0%. With a median follow up of 42.3 months among survivors, six patients succumbed to disease. Two and five-year PFS were 76% (95% CI 66, 89) and 61% (95% CI 47, 78). Two and five-year OS were 93% (95% CI 86, 100) and 79% (95% CI 67, 94). Patients demonstrating pathologic response had improved PFS and OS compared to those who did not (two-year PFS 91% vs 52%, log-rank p < 0.001, two-year OS 100% vs 80%, log-rank p < 0.001). Conclusions: NAC for high-risk UTUC demonstrates outcomes of favorable pathologic response, is well tolerated requiring minimal delay to surgery without significant perioperative complication risk, and thus should be considered a new standard of care option for patients with high-risk UTUC. Better survival outcomes in patients with favorable pathologic features after NAC indicate a potential clinical benefit to this approach. Clinical trial information: NCT01261728.

Purpose A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in this disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic noncastrate, and metastatic castration-resistant prostate cancer. Patients and Methods Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was used to identify single-nucleotide variations, small insertions and deletions, copy number alterations, and structural rearrangements in more than 300 cancer-related genes in tumors and matched normal blood. Results We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase pathways. Twenty-seven percent of patients harbored a germline or a somatic alteration in a DNA damage repair gene that may predict for response to poly (ADP-ribose) polymerase inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, whereas ATM alterations were specifically enriched in castration-resistant prostate cancer. Conclusion Through genomic profiling of prostate tumors that represent the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis, and castration resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.

5019 Background: Preferential fat accumulation in the visceral compartment (i.e. central adiposity) increases cardiovascular risk in the general population independent of body mass index (BMI). We investigated how body fat distribution modulates the cardiometabolic risk of male germ cell tumor (GCT) survivors after cisplatin-based chemotherapy. Methods: For 456 patients in The Platinum Study enrolled at Memorial Sloan Kettering Cancer Center, visceral (VAT) and subcutaneous (SAT) adipose tissue compartments were quantified on pre-chemotherapy computed tomography (CT) scans (median time between CT and chemotherapy: 13 days, range: 0-56). The VAT/SAT ratio was calculated as a quantitative indicator of central adiposity. Endpoints were (I) post-chemotherapy cardiovascular risk as per the office-based Framingham risk calculator, and (II) incidence of post-chemotherapy cardiometabolic disease defined as need for new anti-hypertensive drugs, or lipid-lowering drugs, or medication used to treat diabetes. Changes in fat distribution after chemotherapy were analyzed in a subgroup with post-chemotherapy CTs (n = 108; median interval from chemotherapy start: 18 months, range: 7-185). Linear regression with interaction terms (endpoint 1, subgroup analysis) and Cox proportional hazard regression (endpoint 2) were applied. Results: For all 456 patients, median age at chemotherapy initiation was 31 years and median follow-up was 27 months (range: 7, 207). At baseline (pre-chemotherapy), the median BMI was 26.2 kg/m2, and 102 patients (22.4%) had a BMI of ≥30 kg/m2. The median VAT/SAT ratio at baseline CT was 0.49, and positively associated with higher post-chemotherapy Framingham risk scores after adjustment for age, BMI, and blood pressure measurements at chemotherapy start, as well as post-therapy follow-up time (adjusted β-estimate: 1.36, 95% CI: 1.15, 1.59, p < 0.001). A higher VAT/SAT ratio also inferred a higher likelihood of new onset cardiometabolic disease in patients with BMI ≥30 kg/m2 (age-adjusted HR: 3.11, 95%CI: 1.01, 9.62, p = 0.048), but not in those with BMI < 30 kg/m2. In the subgroup analysis, we observed a significant increase of BMI after chemotherapy (mean: +1.1 kg/m2, 95% CI: +0.58, +1.54; p < 0.001). Changes in BMI were positively associated with changes of the VAT/SAT ratio (β-estimate: 3.0, 95% CI: 2.23, 4.04; p < 0.001), meaning that weight gain occurred preferentially in the VAT compartment, while weight loss tended to be paralleled by an improved body fat distribution. Conclusions: In male GCT patients, central adiposity at baseline increases cardiometabolic risk after cisplatin-based chemotherapy, particularly for obese individuals. Quantification of an individual’s body fat distribution on pre-chemotherapy CT could potentially help to identify high risk individuals who may benefit from intensified risk-modulating interventions.

522 Background: Neoadjuvant chemotherapy (NAC) has established survival benefits prior to radical cystectomy for bladder cancer, yet its role in upper tract urothelial carcinoma (UTUC) prior to nephroureterectomy (NU) is less clear. We performed a phase II clinical trial of NAC with gemcitabine and cisplatin (GC) in patients with UTUC to evaluate pathologic response. We investigated if radiographic responses could predict pathologic response. Methods: Patients with high-risk localized UTUC (high grade on biopsy and/or radiographic evidence of cT2-4 disease with positive select cytology) were recruited to receive 4 cycles of GC prior to NU with the primary objective of the phase 2 study being pathologic response rate, defined as ≤pT1N0. All patients underwent CT imaging at before and after chemotherapy. All baseline imaging studies were categorized as: (i) no abnormality, (ii) focal mass or (iii) thickening without discrete mass. Post-chemotherapy imaging studies were categorized as: (i) stable disease, (ii) progression of disease, (iii) partial response or (iv) complete response. Radiographic responses were correlated with final pathologic staging. Results: 43 patients (pT0N0 = 9, ≤pT1N0 = 18 and >pT1N0 = 16) had CT performed pre- and post-chemotherapy. All patients had a visible lesion seen (mass = 34 and thickening = 9). The median pre-chemotherapy mass size was 3.1cm (IQR 1.8, 4.1). Approximately 60.5% of patients (N = 26) had evidence of hydronephrosis prior to chemotherapy. Following chemotherapy, 10 patients had a complete response, 20 had a partial response and 13 had stable disease. No patients progressed radiographically while on chemotherapy. Patients who had a complete radiographic response were more likely to have a pathologic response (≤pT1N0 = 90%), compared to a partial response (90% vs 65%, P = 0.21) and stable disease (90% vs 38%, P = 0.01). Conclusions: Radiographic response following NAC for UTUC appears to be correlated with pathologic response at time of surgery. Radiographic response, in addition to other pre-operative predictors, may play a useful role in counselling and optimizing management of patients with UTUC.

e16606 Background: To study the role of mpMRI and PSA density in predicting the likelihood of disease reclassification on re-biopsy and on final pathology among men with low-risk prostate cancer (PCa) enrolled in active surveillance (AS) protocol. Methods: In this IRB-approved prospective study, consecutive patients on AS for low-risk PCa (clinical stage cT1–T2a, Gleason score ≤6, serum PSA < 10 ng/mL, no more than 3 positive cores on biopsy, and all biopsy cores with < 50% of tumor involvement) from March 2015 to August 2017 were selected. The exclusion criteria were previous PCa treatment, contraindication to mpMRI or transrectal ultrasound-guided (TRUS) biopsy. All patients underwent mpMRI ≥3 months from initial biopsy and MRI-targeted TRUS-guided re-biopsy within 6-12 months. One experienced radiologist evaluated all mpMRI studies using the PI-RADS v2. The performance of mpMRI and PSA density for the prediction of reclassification on re-biopsy and final pathology was assessed. A single genitourinary pathologist reviewed all the final specimens who was blinded to the initial biopsy results. Results: A total of 154 patients were included in the final analysis. Among patients classified as PI-RADS ≤3, 11/69 (15.9%) were upgraded on re-biopsy whereas 65/85 (76.5%) were upgraded among those with PI-RADS 4 or 5 lesions. With regards to prostatectomy 7/49 (14.2%) patients classified as PI-RADS ≤3 were upgraded, while 42/49 (85.7%) were upgraded among those with PI-RADS 4 or 5. mpMRI sensitivity was 85.5% and specificity 74.4% on re-biopsy and 85.7% and in predicting upgrade on reclassification. Patients with PI-RADS 4 or 5 and PSA density > 0.15 ng/mL/cm3 had 94.6% of chance of having clinically significant PCa, while patients with PI-RADS 1, 2 or 3 and PSA density ≤ 0.08 ng/mL/cm3 had only 4.2% probability. Conclusions: mpMRI and PSA density are significant tools for predicting severity reclassification on re-biopsy and final pathology among patients under active surveillance. Reclassification was low among patients with PI-RADS ≤3 and low PSA density. Overall, patients with PI-RADS 4 or 5 and PSA density > 0.15 were almost invariably found to harbor significant prostate cancer.

5012 Background: Accurate detection of prostate cancer is imperative to patient management, yet standard imaging methods perform poorly in accurately detecting mPC. 18F-DCFPyL is a novel PET imaging agent that selectively binds to prostate-specific membrane antigen, a recognized target for prostate cancer. OSPREY was a prospective, multicenter study in pts with either newly diagnosed high-risk prostate cancer (cohort A), or known or suspected mPC (cohort B). Here we focus on Cohort B. Methods: 117 men planned for biopsy of recurrent or mPC received 18F-DCFPyL. Pts underwent image-guided biopsy. Sensitivity, positive predictive value (PPV), and safety of 18F-DCFPyL PET/CT were the key endpoints for Cohort B. 18F-DCFPyL PET/CT scans were evaluated by three independent, blinded central readers; and results were compared to histopathology as the truth standard. Results: The sensitivity and PPV of 18F-DCFPyL PET/CT as compared to histopathology ranged from 92.9-98.6% (lower bound of 95% CI: 84.0-91.6%) and 81.2-87.8%, respectively. Diagnostic performance by anatomic location showed high sensitivity and high PPV in all sites of disease (Table). Only two (1.7%) cohort B pts experienced ≥1 drug-related AE (dysgeusia and generalized rash), both were mild (Grade 1) in severity. Conclusions: 18F-DCFPyL PET/CT was well tolerated and demonstrated high sensitivity and PPV in accurately detecting nodal, bone, and visceral/soft tissue metastases. A positive 18F-DCFPyL PET/CT scan is highly likely to represent pathologically proven distant disease, demonstrating the potential of 18F-DCFPyL as a PET imaging agent to favorably influence treatment planning. Clinical trial information: NCT02981368. [Table: see text]

482 Background: Quantitative imaging descriptors derived from CT and MRI can be integrated with genomic data that may be used as non-invasive prognostic or predictive biomarkers. We report an integrated radiogenomics project designed to develop subjective and objective parameters extracted from cross-sectional imaging of MIBC from studies archived in the TCIA and linked to the TCGA project. Methods: We reported comprehensive integrated genomic analysis of 412 tumors (Cell 2017). 7 of 33 tissue source sites submitted CT scans to the TCIA (n=106). We developed 17 features describing tumor size/location, metastases sites, and tumor morphology; 9 GU radiologists reviewed the scans in a blinded manner. EH analyzed the data independent of the radiologists. We computed kappa statistics for categorical features and coverage probabilities for quantitative features (Lin et al 2002). The tumor was segmented on an axial image and the segmented image analyzed using a radiomics panel (radiomicslab.usc.edu). Associations between individual features and subtypes were assessed (Fisher’s Exact Test) for categorical features and Kruskal-Wallis Test for quantitative features. Results: Substantial agreement (k≥ 0.6) was observed in 4 features: tumor laterality, tumor within bladder diverticulum, right and left UVJ involvement and hydroureter. We observed weak agreement (95% CI

5084 Background: The current selection criteria to AS is critical and it becomes even more relevant in Latin America, given the higher proportion of high risk cancers. The objective of this study is to analyze the accuracy of mpMRI using PI-RADS v2 in predicting the risk of upgrading on re-biopsy (UR) in men with low-risk PCa on AS. Methods: In this Institutional Review Board approved prospective study, patients with low-grade PCa selected for AS at our institution underwent mpMRI at least 6 weeks after the baseline 12-core random prostate biopsy (BSB), from March 2014 to March 2016. One blinded abdominal radiologist evaluated the exams regarding presence of dominant lesion and assigned the PI-RADS v2 score. MRI-target transrectal ultrasound-guided re-biopsies were performed in all patients within 6-12 months after the BSB. Standardized 12-core biopsy was performed and additional cores were taken from suspicious areas on mpMRI. Results: One hundred and nine patients were included, 93 (85.3%) patients had a dominant lesion on MRI. mpMRI were classified as PI-RADS 1, 2 or 3 in 67 (61.5%) patients, and as PI-RADS 4 or 5 in 42 (38.5%) patients. UR occurred in 42 (38.5%) patients. Out of these, 39 (92.8%) had radical prostatectomy, 6 (15.4%) T2a, 24 (61.5%) T2b, and 9 (23.1%) T3a. The diagnostic performance of mpMRI for PCa upgrading after re-biopsy was summarized in table 1. Patients assigned as PI-RADS 4 or 5 presented a significantly higher risk for UR compared with patients with PI-RADS 1, 2 or 3 (73.8% vs 16.4%, p < 0.001). Logistic regression analyses demonstrated that PI-RADS 4 or 5 remained a significant predictor of UR (OR: 37.366, p < 0.0001). Conclusions: We demonstrated in our population that mpMRI using PI-RADS v2 is a significant predictor for upgrading on re-biopsy in patients on AS and could be used to guide TRUS biopsy, increasing the accuracy of current clinical criteria for AS. [Table: see text]

187 Background: The paradigm of first testing systemic treatments in advanced disease followed by development in earlier disease states and finally large-scale trials evaluating whether the approach, in combination with local therapy, can prevent or delay the time-to-event measures of disease progression or death in patients with “high-risk” tumors is no longer practical now that 6 life-prolonging systemic therapies in metastatic castration-resistant prostate cancer are available. New strategies are needed to rapidly evaluate and prioritize regimens for large-scale phase 3 testing. Methods: We conducted a pilot study of twenty men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis. All sites of disease were treated using a multimodal approach that included androgen deprivation (ADT), radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease and/or the primary site. ADT was discontinued in responding patients. Outcomes of each treatment were assessed sequentially. The primary endpoint of “no evidence of disease” (NED) was defined by an undetectable PSA with noncastrate levels of testosterone at 20 months. Results: Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after ADT alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval 3-38%) achieved the primary endpoint, which persisted for 5, 6, 27+, and 46+ months. All patients meeting the primary endpoint had been classified with M1b disease at presentation. Conclusions: Treatment directed at all sites can eliminate detectable disease in selected patients with metastatic prostate cancer. A multimodal treatment strategy inclusive of the NED endpoint for patients who present with disease that is beyond the limits of curability by any single modality should be considered to enable the evaluation of new approaches in order to prioritize large-scale testing in early stages of advanced disease.

105 Background: Our objective was to evaluate the impact of MRI and systematic biopsy characteristics to identify the index lesion for salvage partial gland ablation using tumor maps from whole mount slides of salvage radical prostatectomy (sRP) specimen. Methods: We identified 225 patients who underwent sRP between 2000 and 2014 and a tumor map was created from whole-mount slides in 77 patients. Among these patients, we selected men with a priori pre-treatment criteria considered eligible for PGA, including, biopsy proven unilateral disease concordant with a region of interest (ROI) on MRI, and excluding men with imaging suspicious for extra-capsular extension (ECE), seminal vesicle Invasion (SVI) or lymph node involvement (LNI). We describe the correlation between pre-treatment clinical characteristics and final radical prostatectomy whole mount specimen to select men eligible for PGA defined as hemi-gland ablation. Results: Among 77 patients with a tumor map of entirely-submitted and whole-mounted specimens, 15 patients were determined to be eligible for partial gland ablation based on pre-treatment clinical characteristics. The mean age was 60 years and median time from primary RT was 48 months. The median (IQR) tumor volume of the index lesion was 0.3 (0.4) cc. The location of the index lesion was determined to be the apex, mid-gland and base in 77%, 100% and 15% of patients, respectively. The median distance of the index tumor to the urethra was 0.5 (0.2) cm. The index tumor was confined to one lobe and concordant to the biopsy pathology and MRI data in all 15 patients (100%). There was no ECE, LNI or SVI identified in the sRP specimens. To account for those patients who did not have a tumor map of the whole-mount specimen, a sensitivity analysis was performed and determined that the clinical characteristics of the 77 patients with tumor maps were comparable to the entire 225 sRP cohort. Conclusions: Clinical characteristics guided by biopsy findings and MRI data can be used to select men for PGA with recurrent localized prostate cancer after radiation therapy and based on tumor maps from sRP specimen, we propose that salvage hemi-gland ablation including periurethral tissue is feasible.

5073 Background: Cabo is a multitargeted kinase inhibitor that has demonstrated complete and partial responses in mCRPC as assessed byTc-99 MDP bone scintigraphy. FDG and FDHT PET/CT demonstrate glucose metabolism and androgen receptor binding, respectively. We are exploring these tracers as response biomarkers in mCRPC treated with cabo. Methods: Patients (pts) treated with cabo were scanned with FDHT and FDG PET at baseline and after 6, 12, and 24 weeks (wks) of treatment. 5 index lesions were selected at baseline for each PET modality. The hottest slices from each were averaged (SUVmaxavg) and measured on post-treatment scans. The concordance of the post-treatment alterations of the two tracers (rise vs. decline) was examined, as were PSA alterations. Results: All 16 pts had FDG avid and 15 had FDHT avid disease. Baseline median FDHTmaxavg was 10.84 (3.52 – 18.52) and FDGmaxavg was 6.26 (2.74 – 14.7). Post-treatment alterations are described (Table). Conclusions: Most pts with mCRPC demonstrate diminution of FDHT uptake after 6 and 12 wks of treatment with cabo. These declines are matched by FDG 50-60% of the time, and correlate with PSA declines even less frequently. The etiology of the extent and degree of FDHT declines, and lack of concordance with post-treatment PSA changes, warrant further investigation, and correlation with other imaging modalities and clinical outcomes. Clinical trial information: NCT00588185. [Table: see text]