Local Failure after Prostate SBRT Predominantly Occurs in the PI-RADS 4 or 5 Dominant Intraprostatic Lesion.

BACKGROUND: A positive post-treatment prostate biopsy following definitive radiotherapy carries significant prognostic implications. OBJECTIVE: To determine whether local recurrences after prostate stereotactic body radiation therapy (SBRT) are associated with the presence of and occur more commonly within the region of a PI-RADS 4 or 5 dominant intra-prostatic lesion (DIL) identified on pre-treatment multi-parametric magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: 247 patients with localized prostate cancer treated with SBRT at our institution from 2009-2018 underwent post-treatment biopsies (median time to biopsy: 2.2 years) to evaluate local control. INTERVENTIONS: Prostate SBRT (median 40 Gy in 5 fractions). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: MRIs were read by a single diagnostic radiologist blinded to other patient characteristics and treatment outcomes. The DIL presence, size, location, and extent were then analyzed to determine associations with the post-treatment biopsy outcomes. RESULTS AND LIMITATIONS: Among patients who underwent post-treatment biopsies, 39/247 (15.8%) were positive for Gleason-gradable prostate adenocarcinoma, of which 35/39 (90%) had a DIL initially present and 29/39 (74.4%) had a positive biopsy within the DIL. Factors independently associated with post-treatment biopsy outcomes included the presence of a DIL (OR 6.95; p = 0.001), radiographic T3 disease (OR 5.23, p < 0.001), SBRT dose ≥40 Gy (OR 0.26, p = 0.003), and use of androgen deprivation therapy (ADT; OR 0.28, p = 0.027). Among patients with a DIL (N = 149), the only factors associated with post-treatment biopsy outcomes included ≥50% percent cores positive (OR 2.4, p = 0.037), radiographic T3 disease (OR 4.04, p = 0.001), SBRT dose ≥40 Gy (OR 0.22, p < 0.001), and use of ADT (OR 0.21, p = 0.014). CONCLUSIONS: Our results suggest that men with PI-RADS 4 or 5 DILs have a higher risk of local recurrence after prostate SBRT and that most recurrences are located within the DIL. PATIENT SUMMARY: We found the presence of a dominant tumor on pre-treatment MRI was strongly associated with residual cancer within the prostate after SBRT and that most recurrences were within the dominant tumor.

Brown adipose tissue is not associated with cachexia or increased mortality in a retrospective study of patients with cancer.

Although brown fat is strongly associated with a constellation of cardiometabolic benefits in animal models and humans, it has also been tied to cancer cachexia. In humans, cancer-associated cachexia increases mortality, raising the possibility that brown fat in this context may be associated with increased cancer death. However, the effect of brown fat on cancer-associated cachexia and survival in humans remains unclear. Here, we retrospectively identify patients with and without brown fat on fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET) scans obtained as part of routine cancer care and assemble a cohort to address these questions. We did not find an association between brown fat status and cachexia. Furthermore, we did not observe an association between brown fat and increased mortality in patients with cachexia. Our analyses controlled for confounding factors including age at cancer diagnosis, sex, body mass index, cancer site, cancer stage, outdoor temperature, comorbid conditions (heart failure, type 2 diabetes mellitus, coronary artery disease, hypertension, dyslipidemia, cerebrovascular disease), and ß-blocker use. Taken together, our results suggest that brown fat is not linked to cancer-associated cachexia and does not worsen overall survival in patients with cachexia.NEW & NOTEWORTHY This study finds that brown fat is not linked to cancer-associated cachexia. Moreover, this work shows that brown fat does not worsen overall survival in patients with cachexia.

Associations of Body Fat Distribution and Cardiometabolic Risk of Testicular Cancer Survivors After Cisplatin-Based Chemotherapy.

BACKGROUND: It is unknown how body fat distribution modulates the cardiometabolic risk of testicular cancer survivors after cisplatin-based chemotherapy. METHODS: For 455 patients enrolled in the Platinum Study at Memorial Sloan Kettering Cancer Center, visceral (VAT) and subcutaneous (SAT) adipose tissue was quantified on prechemotherapy computed tomography. The VAT-to-SAT ratio was calculated as a quantitative measure of central adiposity. Endpoints were incidence of new posthemotherapy cardiometabolic disease (new antihypertensive, lipid-lowering, or diabetes medication), and postchemotherapy Framingham risk scores. Cox models and linear regression with interaction terms were applied. Postchemotherapy body fat distribution was analyzed in 108 patients. All statistical tests were 2-sided. RESULTS: The baseline median age was 31 years (interquartile range [IQR] = 26-39 years), body mass index (BMI) was 26 kg/m2 (IQR = 24-29 kg/m2), and the VAT-to-SAT ratio was 0.49 (IQR = 0.31-0.75). The median follow-up was 26 months (IQR = 16-59 months). Higher prechemotherapy VAT-to-SAT ratios inferred a higher likelihood of new cardiometabolic disease among patients with a BMI of 30 kg/m2 or greater (age-adjusted hazard ratio = 3.14, 95% confidence interval = 1.02 to 9.71, P = .047), but not other BMI groups. The prechemotherapy VAT-to-SAT ratio was associated with postchemotherapy Framingham risk scores in univariate regression analysis (exp(ß)-estimate: 2.10, 95% confidence interval = 1.84 to 2.39, P < .001); in a multivariable model, this association was stronger in younger vs older individuals. BMI increased in most patients after chemotherapy and correlated with increases in the VAT-to-SAT ratio (Spearman r = 0.39, P < .001). CONCLUSIONS: In testicular cancer survivors, central adiposity is associated with increased cardiometabolic risk after cisplatin-based chemotherapy, particularly in obese or young men. Weight gain after chemotherapy occurs preferentially in the visceral compartment, providing insight into the pathogenesis of cardiovascular disease in this population.

The Impact of PIK3R1 Mutations and Insulin-PI3K-Glycolytic Pathway Regulation in Prostate Cancer.

PURPOSE: Oncogenic alterations of the PI3K/AKT pathway occur in >40% of patients with metastatic castration-resistant prostate cancer, predominantly via PTEN loss. The significance of other PI3K pathway components in prostate cancer is largely unknown. EXPERIMENTAL DESIGN: Patients in this study underwent tumor sequencing using the MSK-IMPACT clinical assay to capture single-nucleotide variants, insertions, and deletions; copy-number alterations; and structural rearrangements, or were profiled through The Cancer Genome Atlas. The association between PIK3R1 alteration/expression and survival was evaluated using univariable and multivariable Cox proportional-hazards regression models. We used the siRNA-based knockdown of PIK3R1 for functional studies. FDG-PET/CT examinations were performed with a hybrid positron emission tomography (PET)/CT scanner for some prostate cancer patients in the MSK-IMPACT cohort. RESULTS: Analyzing 1,417 human prostate cancers, we found a significant enrichment of PIK3R1 alterations in metastatic cancers compared with primary cancers. PIK3R1 alterations or reduced mRNA expression tended to be associated with worse clinical outcomes in prostate cancer, particularly in primary disease, as well as in breast, gastric, and several other cancers. In prostate cancer cell lines, PIK3R1 knockdown resulted in increased cell proliferation and AKT activity, including insulin-stimulated AKT activity. In cell lines and organoids, PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors. PIK3R1-altered patient prostate tumors had increased uptake of the glucose analogue 18F-fluorodeoxyglucose in PET imaging, suggesting increased glycolysis. CONCLUSIONS: Our findings describe a novel genomic feature in metastatic prostate cancer and suggest that PIK3R1 alteration may be a key event for insulin-PI3K-glycolytic pathway regulation in prostate cancer.

MRI-Detectability of Clinically Significant Prostate Cancer Relates to Oncologic Outcomes After Prostatectomy.

INTRODUCTION/BACKGROUND: Magnetic resonance imaging (MRI) misses a proportion of "clinically significant" prostate cancers (csPC) as defined by histopathology criteria. The aim of this study was to analyze whether long-term oncologic outcomes differ between MRI-detectable and MRI-occult csPC. PATIENTS AND METHODS: Retrospective analysis of 1449 patients with pre-prostatectomy MRI and csPC on prostatectomy specimens (ie, Grade group ≥2 or extraprostatic spread) between 2001-2006. T2-weighted MRIs were classified according to the Prostate Imaging Reporting and Data System into MRI-occult (categories 1, 2), MRI-equivocal (category 3), and MRI-detectable (categories 4, 5). Cumulative incidence of biochemical recurrence (BCR), metastatic disease, and cancer-specific mortality, estimated with competing risk models. The median follow-up in survivors was 11.0 years (IQR: 8.9-13.1). RESULTS: In 188 (13%) cases, csPC was MRI-occult, 435 (30%) MRIs were equivocal, and 826 (57%) csPC were MRI-detectable. The 15-year cumulative incidence [95% CI] of BCR was 8.3% [2.2, 19.5] for MRI-occult cases, 17.4% [11.1, 24.8] for MRI-equivocal cases, and 43.3% [38.7, 47.8] for MRI-detectable cases (P < .001). The cumulative incidences of metastases were 0.61% [0.06, 3.1], 3.5% [1.5, 6.9], and 19.6% [15.4, 24.2] for MRI-occult, MRI-equivocal, and MRI-detectable cases, respectively (P < .001). There were no deaths from prostate cancer observed in patients with MRI-occult csPC, compared to an estimated 1.9% [0.54, 4.9], and 7.1 % [4.5, 10.6] for patients with MRI-equivocal and MRI-detectable cancer, respectively (P < .001). CONCLUSION: Oncologic outcomes after prostatectomy for csPC differ between MRI-occult and MRI-detectable lesions. Judging the clinical significance of a negative prostate MRI based on histopathologic surrogates alone might be misleading. MICROABSTRACT: Among 1449 patients with pre-prostatectomy MRI and clinically significant prostate cancer on prostatectomy histopathology, MRI-occult cancers (n = 188, 13%) were less likely to recur biochemically (8% vs. 43%, P < .001), metastasize (0.6% vs. 20%, P < .001), or lead to prostate cancer mortality (0% vs. 7%, P < .001) than MRI-detectable cancers (n = 826, 57%). MRI-occult cancers constitute a prognostically distinct subgroup among higher-grade prostate cancers.

Correlation Between Imaging-Based Intermediate Endpoints and Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer: Analysis of 28 Randomized Trials Using the Prostate Cancer Clinical Trials Working Group (PCWG2) Criteria in 16,511 Patients.

INTRODUCTION/BACKGROUND: Radiographic progression-free survival (rPFS) based on Prostate Cancer Working Group 2 (PCWG2) has been increasingly used as a meaningful imaging-based intermediate endpoint (IBIE) for overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). In randomized phase III trials, rPFS showed good correlation with OS at the individual trial level. We aimed to assess the correlation between the hazard ratios (HR) of IBIE and OS among PCWG2-based randomized trials. MATERIALS AND METHODS: PubMed and EMBASE databases were systematically searched for randomized trials evaluating systemic treatments on mCRPC using PCWG2 up to April 15, 2020. Hazard ratios for OS and IBIEs were extracted and their correlation was assessed using weighted linear regression. Subgroup analyses were performed according to various clinical settings: prior chemotherapy, drug category, type of IBIE (rPFS vs. composite IBIE, latter defined as progression by imaging and one or a combination of PSA, pain, skeletal-related events, and performance status), and publication year. RESULTS: Twenty-eight phase II-III randomized trials (16,511 patients) were included. Correlation between OS and IBIE was good (R2 = 0.57, 95% confidence interval [CI], 0.35-0.78). Trials using rPFS showed substantially higher correlation than those using a composite IBIE (R2 = 0.58, 95% CI, 0.32-0.82 vs. 0.00, 95% CI, -0.01 to 0.01). Correlations between OS and IBIE in other subgroups were at least moderate in nearly all subgroups (R2 = 0.32-0.91). CONCLUSION: IBIEs in the era of PCWG2 correlate well with OS in randomized trials for systemic drugs in patients with mCRPC. PCWG2-based rPFS should be used instead of a composite IBIE that includes PSA and other clinical variables.

Local Extent of Prostate Cancer at MRI versus Prostatectomy Histopathology: Associations with Long-term Oncologic Outcomes.

Background It is unknown how the imperfect accuracy of MRI for local staging of prostate cancer relates to oncologic outcomes. Purpose To analyze how staging discordances between MRI and histopathologic evaluation relate to recurrence and survival after radical prostatectomy. Materials and Methods Health Insurance Portability and Accountability Act-compliant retrospective analysis of preprostatectomy T2-weighted prostate MRI (January 2001 to December 2006). Extraprostatic extension and seminal vesicle invasion were assessed by using five-point Likert scales; scores of 4 or higher were classified as positive. Biochemical recurrence (BCR), metastases, and prostate cancer-specific mortality rates were estimated with Kaplan-Meier and Cox models. Results A total of 2160 patients (median age, 60 years; interquartile range, 55-64 years) were evaluated. Among patients with histopathologic extraprostatic (pT3) disease (683 of 2160; 32%), those with organ-confined disease at MRI (384 of 683; 56%) experienced better outcomes than those with concordant extraprostatic disease at MRI and pathologic analysis: 15-year risk for BCR, 30% (95% CI: 22, 40) versus 68% (95% CI: 60, 75); risk for metastases, 14% (95% CI: 8.4, 24) versus 32% (95% CI: 26, 39); risk for prostate cancer-specific mortality, 3% (95% CI: 1, 6) versus 15% (95% CI: 9.5, 23) (P < .001 for all comparisons). Among patients with histopathologic organ-confined disease (pT2) (1477 of 2160; 68%), those with extraprostatic disease at MRI (102 of 1477; 7%) were at higher risk for BCR (27% [95% CI: 19, 37] vs 10% [95% CI: 8, 14]; P < .001), metastases (19% [95% CI: 6, 48] vs 3% [95% CI: 1, 6]; P < .001), and prostate cancer-specific mortality (2% [95% CI: 1, 9] vs 1% [95% CI: 0, 5]; P = .009) than those with concordant organ-confined disease at MRI and pathologic analysis. At multivariable analyses, tumor extent at MRI (hazard ratio range, 4.1-5.2) and histopathologic evaluation (hazard ratio range, 3.6-6.7) was associated with the risk for BCR, metastases, and prostate cancer-specific mortality (P < .001 for all analyses). Conclusion The local extent of prostate cancer at MRI is associated with oncologic outcomes after prostatectomy, independent of pathologic tumor stage. This might inform a strategy on how to integrate MRI into a clinical staging algorithm. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Gottlieb in this issue.

Brown adipose tissue is associated with healthier body fat distribution and metabolic benefits independent of regional adiposity.

The association of brown adipose tissue (BAT) and body fat distribution and their combined effects on metabolic health in humans remains unknown. Here, we retrospectively identify individuals with and without BAT on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and assemble a propensity score-matched study cohort to compare body fat distribution and determine its role in mediating the benefits of brown fat. We find that BAT is associated with lower amounts of visceral adipose tissue and higher amounts of subcutaneous adipose tissue, resulting in less central obesity. In addition, BAT is independently associated with lower blood glucose and white blood cell count, improved lipids, lower prevalence of type 2 diabetes mellitus, and decreased liver fat accumulation. These observations are most prominent in individuals with central obesity. Our results support a role of BAT in protection from visceral adiposity and improved metabolic health.

International Multi-Site Initiative to Develop an MRI-Inclusive Nomogram for Side-Specific Prediction of Extraprostatic Extension of Prostate Cancer.

BACKGROUND: To develop an international, multi-site nomogram for side-specific prediction of extraprostatic extension (EPE) of prostate cancer based on clinical, biopsy, and magnetic resonance imaging- (MRI) derived data. METHODS: Ten institutions from the USA and Europe contributed clinical and side-specific biopsy and MRI variables of consecutive patients who underwent prostatectomy. A logistic regression model was used to develop a nomogram for predicting side-specific EPE on prostatectomy specimens. The performance of the statistical model was evaluated by bootstrap resampling and cross validation and compared with the performance of benchmark models that do not incorporate MRI findings. RESULTS: Data from 840 patients were analyzed; pathologic EPE was found in 320/840 (31.8%). The nomogram model included patient age, prostate-specific antigen density, side-specific biopsy data (i.e., Gleason grade group, percent positive cores, tumor extent), and side-specific MRI features (i.e., presence of a PI-RADSv2 4 or 5 lesion, level of suspicion for EPE, length of capsular contact). The area under the receiver operating characteristic curve of the new, MRI-inclusive model (0.828, 95% confidence limits: 0.805, 0.852) was significantly higher than that of any of the benchmark models (p < 0.001 for all). CONCLUSIONS: In an international, multi-site study, we developed an MRI-inclusive nomogram for the side-specific prediction of EPE of prostate cancer that demonstrated significantly greater accuracy than clinical benchmark models.

Concordance between Response Assessment Using Prostate-Specific Membrane Antigen PET and Serum Prostate-Specific Antigen Levels after Systemic Treatment in Patients with Metastatic Castration Resistant Prostate Cancer: A Systematic Review and Meta-Analysis.

Prostate-specific membrane antigen positron emission tomography (PSMA PET) has recently gained interest as a promising tool for treatment response evaluation in metastatic castration-resistant prostate cancer (CRPC). We performed a systematic review and meta-analysis assessing the concordance between response evaluation using PSMA PET and serum prostate-specific antigen (PSA) level after systemic treatment and the association between PSMA PET and overall survival in metastatic CRPC patients. PubMed, Embase, and Cochrane library databases were searched until August 2020. Studies that reported the concordance between PSMA PET and PSA response were included. PSMA PET and PSA response evaluation were dichotomized into response vs. non-response to construct two-by-two contingency tables; an ≥30% increase in PSMA PET according to PET Response Criteria in Solid Tumors 1.0 and as an increase in serum PSA level of ≥25% as per Prostate Cancer Working Group 3 guidelines were defined as non-response. The percent agreement rates were pooled using random-effect model. Ten studies (268 patients) were included. The concordance rates ranged 0.50-0.84 with a pooled proportion of 0.73 (95% confidence interval 0.67-0.79). Patients were treated with 177Lu-PSMA therapy in five, chemotherapy in three, 223Ra in one, and more than one type in one study. Various PET parameters were used: the most widely evaluated was PSMA tumor volume (PSMA-TV). Similar proportions were found across different therapeutic agents, PET response parameters, and regarding directionality of discordance (PSA response/PSMA non-response vs. PSMA response/PSA non-response). Two studies reported that a decrease in PSMA-TV was associated with better overall survival. PSMA PET and PSA response assessments were discordant in nearly a fourth of metastatic CRPC patients. Further studies are warranted to establish the clinical meaning of this discordance and define appropriate management for such clinical situation.

Quantification of Metastatic Prostate Cancer Whole-Body Tumor Burden with 18F-FDG PET Parameters and Associations with Overall Survival After First-Line Abiraterone or Enzalutamide: A Single-Center Retrospective Cohort Study.

New biomarkers for metastatic prostate cancer are needed. The aim of this study was to evaluate the prognostic value of 18F-FDG PET whole-body tumor burden parameters in patients with metastatic prostate cancer who received first-line abiraterone or enzalutamide therapy. Methods: This was a retrospective study of patients with metastatic castration-sensitive prostate cancer (mCSPC, n = 25) and metastatic castration-resistant prostate cancer (mCRPC, n = 71) who underwent 18F-FDG PET/CT within 90 d before first-line treatment with abiraterone or enzalutamide at a tertiary-care academic cancer center. Whole-body tumor burden on PET/CT was quantified as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) and correlated with overall survival (OS) probabilities using Kaplan-Meier curves and Cox models. Results: The median follow-up in survivors was 56.3 mo (interquartile range, 37.7-66.8 mo); the median OSs for patients with mCRPC and mCSPC were 27.8 and 76.1 mo, respectively (P < 0.001). On univariate analysis, the OS probability of mCRPC patients was significantly associated with plasma levels of alkaline phosphatase (hazard ratio [HR], 1.90; P < 0.001), plasma levels of lactate dehydrogenase (HR, 1.01; P < 0.001), hemoglobin levels (HR, 0.80; P = 0.013), whole-body SUVmax (HR, 1.14; P < 0.001), the number of 18F-FDG-avid metastases (HR, 1.08; P < 0.001), whole-body metabolic tumor volume (HR, 1.86; P < 0.001), and TLG (HR, 1.84; P < 0.001). On multivariable analysis with stepwise variable selection, hemoglobin levels (HR, 0.81; P = 0.013) and whole-body TLG (HR, 1.88; P < 0.001) were independently associated with OS. In mCSPC patients, no significant association was observed between these variables and OS. Conclusion: In patients with mCRPC receiving first-line treatment with abiraterone or enzalutamide, 18F-FDG PET WB TLG is independently associated with OS and might be used as a quantitative prognostic imaging biomarker.

Brown adipose tissue is associated with cardiometabolic health.

White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear1,2. Here we retrospectively categorized 134,529 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans from 52,487 patients, by presence or absence of BAT, and used propensity score matching to assemble a study cohort. Scans in the study population were initially conducted for indications related to cancer diagnosis, treatment or surveillance, without previous stimulation. We report that individuals with BAT had lower prevalences of cardiometabolic diseases, and the presence of BAT was independently correlated with lower odds of type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure and hypertension. These findings were supported by improved blood glucose, triglyceride and high-density lipoprotein values. The beneficial effects of BAT were more pronounced in individuals with overweight or obesity, indicating that BAT might play a role in mitigating the deleterious effects of obesity. Taken together, our findings highlight a potential role for BAT in promoting cardiometabolic health.

Oncologic Outcomes after Localized Prostate Cancer Treatment: Associations with Pretreatment Prostate Magnetic Resonance Imaging Findings.

PURPOSE: We investigated whether T2-weighted magnetic resonance imaging findings could improve upon established prognostic indicators of metastatic disease and prostate cancer specific survival. MATERIALS AND METHODS: For a cohort of 3,406 consecutive men who underwent prostate magnetic resonance imaging before prostatectomy (2,160) or radiotherapy (1,246) between 2001 and 2006, T2-weighted magnetic resonance imaging exams were retrospectively interpreted and categorized as I) no focal suspicious lesion, II) organ confined focal lesion, III) focal lesion with extraprostatic extension or IV) focal lesion with seminal vesicle invasion. Clinical risk was recorded based on European Association of Urology (EAU) guidelines and the Cancer of the Prostate Risk Assessment (CAPRA) scoring system. Survival probabilities and c-indices were estimated using Cox models and inverse probability censoring weights, respectively. RESULTS: The median followup was 10.8 years (IQR 8.6-13.0). Higher magnetic resonance imaging categories were associated with a higher likelihood of developing metastases (HR 3.5-18.1, p <0.001 for all magnetic resonance imaging categories) and prostate cancer death (HR 3.1-29.7, p <0.001-0.025); these associations were statistically independent of EAU risk categories, CAPRA scores and treatment type (surgery vs radiation). Combining EAU risk or CAPRA scores with magnetic resonance imaging categories significantly improved prognostication of metastases (c-indices: EAU: 0.798, EAU + magnetic resonance imaging: 0.872; CAPRA: 0.808, CAPRA + magnetic resonance imaging: 0.877) and prostate cancer death (c-indices: EAU 0.813, EAU + magnetic resonance imaging: 0.889; CAPRA: 0.814, CAPRA + magnetic resonance imaging: 0.892; p <0.001 for all). CONCLUSION: Magnetic resonance imaging findings of localized prostate cancer are associated with clinically relevant long-term oncologic outcomes. Combining magnetic resonance imaging and clinicopathological data results in more accurate prognostication, which could facilitate individualized patient management.

Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer.

PURPOSE: The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear. EXPERIMENTAL DESIGN: In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume. RESULTS: Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40-2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28-6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors. CONCLUSIONS: This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.

Prostate-specific membrane antigen positron emission tomography (PSMA-PET) for local staging of prostate cancer: a systematic review and meta-analysis.

PURPOSE: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) has shown promise for detecting nodal and distant prostate cancer (PCa) metastases. However, its performance for local tumor staging is not as well established. The purpose of this study was to review the diagnostic performance of PSMA-PET for determining seminal vesical invasion (SVI) and extraprostatic extension (EPE). METHODS: Pubmed and Embase databases were searched until January 12, 2020. Studies assessing accuracy of PSMA-PET in determining SVI and EPE were included. Study quality was evaluated with the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool. Pooled sensitivity and specificity were calculated using hierarchical summary receiver operating characteristics modeling. Heterogeneity was explored using meta-regression analyses for anatomical imaging component (MRI vs CT) and by testing for a threshold effect. RESULTS: Twelve studies (615 patients) were included. Pooled sensitivity and specificity were 0.68 (95% CI 0.53-0.81) and 0.94 (95% CI 0.90-0.96) for SVI and 0.72 (95% CI 0.56-0.84) and 0.87 (95% CI 0.72-0.94) for EPE. Meta-regression analyses showed that for SVI, PET/MRI demonstrated greater sensitivity than PET/CT (0.87 [95% CI 0.75-0.98] vs 0.60 [95% CI 0.47-0.74]; p = 0.02 for joint model) while specificity was comparable (0.91 [95% CI 0.84-0.97] vs. 0.96 [95% CI 0.93-0.99]) but not for EPE (p = 0.08). A threshold effect was present for studies assessing EPE (correlation coefficient = 0.563 [95% CI, -0.234-0.908] between sensitivity and false-positive rate). CONCLUSION: PSMA-PET has moderate sensitivity and excellent specificity for assessing local tumor extent in patients with PCa. PET/MRI showed potential for greater sensitivity than PET/CT in assessing SVI.

Comparison of Magnetic Resonance Imaging-stratified Clinical Pathways and Systematic Transrectal Ultrasound-guided Biopsy Pathway for the Detection of Clinically Significant Prostate Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

CONTEXT: Recent studies suggested that magnetic resonance imaging (MRI) followed by targeted biopsy ("MRI-stratified pathway") detects more clinically significant prostate cancers (csPCa) than the systematic transrectal ultrasound-guided prostate biopsy (TRUS-Bx) pathway, but controversy persists. Several randomized clinical trials (RCTs) were recently published, enabling generation of higher-level evidence to evaluate this hypothesis. OBJECTIVE: To perform a systematic review and meta-analysis of RCTs comparing the detection rates of csPCa in the MRI-stratified pathway and the systematic TRUS-Bx pathway in patients with a suspicion of prostate cancer (PCa). EVIDENCE ACQUISITION: PubMed, EMBASE, and Cochrane databases were searched up to March 18, 2019. RCTs reporting csPCa detection rates of both pathways in patients with a clinical suspicion of prostate cancer were included. Relative csPCa detection rates of the MRI-stratified pathway were pooled using random-effect model. Study quality was assessed using the Cochrane risk of bias tool for randomized trials. A comparison of detection rates of clinically insignificant PCa (cisPCa) and any PCa was also performed. EVIDENCE SYNTHESIS: Nine RCTs (2908 patients) were included. The MRI-stratified pathway detected more csPCa than the TRUS-Bx pathway (relative detection rate 1.45 [95% confidence interval {CI} 1.09-1.92] for all patients, and 1.42 [95% CI 1.02-1.97] and 1.60 [95% CI 1.01-2.54] for biopsy-naïve and prior negative biopsy patients, respectively). Detection rates were not significantly different between pathways for cisPCa (0.89 [95% CI 0.49-1.62]), but higher in the MRI-stratified pathway for the detection of any PCa (1.39 [95% CI 1.05-1.84]). CONCLUSIONS: The MRI-stratified pathway detected more csPCa than the systematic TRUS-guided biopsy pathway in men with a clinical suspicion of PCa, for both biopsy-naïve patients and those with prior negative biopsy. The detection rate of any PCa was higher in the MRI-stratified pathway, but not significantly different from that of cisPCa. PATIENT SUMMARY: Our meta-analysis of clinical trials shows that the magnetic resonance imaging-stratified pathway detects more clinically significant prostate cancers than the transrectal ultrasound-guided prostate biopsy pathway in men with a suspicion of prostate cancer.

Extracapsular extension on MRI indicates a more aggressive cell cycle progression genotype of prostate cancer.

PURPOSE: To explore associations between magnetic resonance imaging (MRI) features of prostate cancer and expression levels of cell cycle genes, as assessed by the Prolaris® test. MATERIALS AND METHODS: Retrospective analysis of 118 PCa patients with genetic testing of biopsy specimen and prostate MRI from 08/2013 to 11/2015. Associations between the cell cycle risk (CCR) score and MRI features [i.e., PI-RADSv2 score, extracapsular extension (ECE), quantitative metrics] were analyzed with Fisher's exact test, nonparametric tests, and Spearman's correlation coefficient. In 41 patients (34.7%), test results were compared to unfavorable features on prostatectomy specimen (i.e., Gleason group ≥ 3, ECE, lymph node metastases). RESULTS: Fifty-four (45.8%), 60 (50.8%), and 4 (3.4%) patients had low-, intermediate-, and high-risk cancers according to American Urological Association scoring system. Patients with ECE on MRI had significantly higher mean CCR scores (reader 1: 3.9 vs. 3.2, p = 0.015; reader 2: 3.6 vs. 3.2, p = 0.045). PI-RADSv2 scores and quantitative MRI features were not associated with CCR scores. In the prostatectomy subset, ECE on MRI (p = < 0.001-0.001) and CCR scores (p = 0.049) were significantly associated with unfavorable histopathologic features. CONCLUSION: The phenotypic trait of ECE on MRI indicates a more aggressive genotype of prostate cancer.

Trends in oncologic hybrid imaging.

Hybrid imaging plays a central role in the diagnosis and management of a wide range of malignancies at all stages. In this article, we review the most pertinent historical developments, emerging clinical applications of novel radiotracers and imaging technologies, and potential implications for training and practice. This includes an overview of novel tracers for prostate, breast, and neuroendocrine tumors, assessment of tumor heterogeneity, the concept of image-guided 'biologically relevant dosing', and theranostic applications. Recent technological advancements, including time-of-flight PET, PET/MRI, and 'one-minute whole-body PET', are also covered. Finally, we discuss how these rapidly evolving applications might affect current training curricula and how imaging-derived big data could be harnessed to the benefit of our patients.