Localized PC Research Articles

Real-world treatment patterns and medical costs of prostate cancer patients in Switzerland – A claims data analysis

BackgroundProstate cancer (PC) is the most prevalent cancer in men in Switzerland. However, evidence on the real-world health care use of PC patients is scarce. The aim of this study is to describe health care utilization, treatment patterns, and medical costs in PC patients over a period of five years (2014–2018). MethodWe used routinely collected longitudinal individual-level claims data from a major provider of mandatory health insurance in Switzerland. Due to the lack of diagnostic coding in the claims data, we identified treated PC patients based on the treatments received. We described health care utilization and treatment pathways for patients with localized and metastatic PC. Costs were calculated from a health care system perspective. ResultsA total of 5591 PC patients met the inclusion criteria. Between 2014 and 2018, 1741 patients had outpatient radiotherapy for localized or metastatic PC and 1579 patients underwent radical prostatectomy. 3502 patients had an androgen deprivation therapy (ADT). 9.5% of these patients had a combination therapy with docetaxel, and 11.0% had a combination with abiraterone acetate. Docetaxel was the most commonly used chemotherapy (first-line; n = 413, 78.4% of all patients in chemotherapy). Total medical costs of PC in Switzerland were estimated at CHF 347 m (95% CI 323–372) in 2018. ConclusionMost PC patients in this study were identified based on the use of ADT. Medical costs of PC in Switzerland amounted to 0.45% of total health care spending in 2018. Treatment of metastatic PC accounted for about two thirds of spending.

Evaluatoion of intraoperative histology during nerve-sparing radical prostatectomy

Background. Currently, for patients with localized PC, intact erectile function, and low risk of extracapsular extension radical prostatectomy (RP) with nerve-sparing (NS) technique is indicated. The proven method of intraoperative control for the presence of positive surgical margin is the study of fresh frozen sections.Aim. To evaluate the method of intraoperative histological examination (cito-histology) in NS RP.Materials and methods. A prospective clinical study was conducted to examine fresh frozen sections in laparoscopic NS RP. Between February of 2021 and May of 2022, 90 patients diagnosed with prostate cancer underwent laparoscopic NS RP performed by the same surgeon. The patients were divided into 2 groups: group A (n = 40) included patients who underwent laparoscopic NS RP and intraoperative histology; group B (control group) (n = 50) included patients who underwent standard laparoscopic NS RP. Rapid histological and final histological examinations of all removed samples were carried out at the City Clinical Hospital No. 1 named after N.I. Pirogov by one pathologist. The presence of tumor tissue in a stained resection margin was considered positive surgical margin.Results. Oncological processes in macrosamples obtained by intraoperative histology were observed in 32 (80 %) patients, of which primary positive surgical margin was found in 9 (22.5 %) patients. Conversion of (cito) positive surgical margin status into final negative surgical margin was observed in 4 (10 %) patients. Conversion of the surgical margin status of (cito) negative to positive was observed in 1 (2.5 %) patient due to the targeted examination of the area of interest, and not the entire surface of the prostate. Overall 2-year survival in groups A and B was 100 % and 96 %, respectively; cancer-specific 2-year survival was 100 % and 100 %, respectively. Depending on the pathological group, recurrence-free 2-year survival was: group A (pT2) – 90 %; group B (pT2) – 92 %, group A (pT3) – 91.3 %; group B (pT3) – 77.3 %.Conclusion. The proposed method of intraoperative histological examination allows to determine the presence and location of positive surgical margin, which indicates to the surgeon the necessity of additional tissue removal in the neurovascular bundle area, reduces the technical and economic burden on pathology department compared to other methods of rapid histological examination, and reduces contraindications to performing the NS technique in RP especially in the intermediate-risk group.

Preclinical comparison of [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2 for endoradiotherapy of prostate cancer: biodistribution and dosimetry studies

BackgroundRadiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice.ResultsrhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3–0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6–11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively.ConclusionOur preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).

Prognostic significance of surgery and radiotherapy in elderly patients with localized prostate cancer: establishing and time-based external validation a nomogram from SEER-based study

ObjectiveProstate cancer (PC) is a significant disease affecting men’s health worldwide. More than 60% of patients over 65 years old and more than 80% are diagnosed with localized PC. The current choice of treatment modalities for localized PC and whether overtreatment is controversial. Therefore, we wanted to construct a nomogram to predict the risk factors associated with cancer-specific survival (CSS) and overall survival (OS) in elderly patients with localized PC while assessing the survival differences in surgery and radiotherapy for elderly patients with localized PC.MethodsData of patients with localized PC over 65 years were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression models were used to determine independent risk factors for CSS and OS. Nomograms predicting CSS and OS were built using multivariate Cox regression models. The consistency index (C-index), the area under the subject operating characteristic curve (AUC), and the calibration curve were used to test the accuracy and discrimination of the prediction model. Decision curve analysis (DCA) was used to test the potential clinical value of this model.ResultsA total of 90,434 patients over 65 years and diagnosed with localized PC from 2010 to 2018 were included in the study. All patients were randomly assigned to the training set (n = 63,328) and the validation set (n = 27,106). Univariate and multivariate Cox regression model analysis showed that age, race, marriage, T stage, surgical, radiotherapy, prostate-specific antigen (PSA), and Gleason score (GS) were independent risk factors for predicting CSS in elderly patients with localized PC. Age, race, marriage, surgery, radiotherapy, PSA, and GS were independent risk factors for predicting OS in elderly patients with localized PC. The c-index of the training and validation sets for the predicted CSS is 0.802(95%CI:0.788–0.816) and 0.798(95%CI:0.776–0.820, respectively). The c-index of the training and validation sets for predicting OS is 0.712(95%:0.704–0.720) and 0.724(95%:0.714–0.734). It shows that the nomograms have excellent discriminatory ability. The AUC and the calibration curves also show good accuracy and discriminability.ConclusionWe have developed new nomograms to predict CSS and OS in elderly patients with localized PC. After internal validation and external temporal validation with reasonable accuracy, reliability and potential clinical value, the model can be used for clinically assisted decision-making.

P-MCP treatment in non-metastatic biochemically relapsed prostate cancer (BRPC-M0): Final long-term results of a prospective phase II study.

162 Background: 30% of patients with localized PC will have a biochemical relapse post local therapy. Their optimal treatment remains elusive. While androgen deprivation therapy is effective in reducing PSA level, its long-term benefit remains undefined, and it is toxic. Thus, evaluation of new nontoxic compounds in these patients is warranted. PectaSol-C modified citrus pectin (P-MCP) is an inhibitor of galectin-3 protein, which is involved in prostate cancer pathogenesis. We herein report the final long-term results of a multi-center phase 2 study of P-MCP treatment in BRPC-M0. Methods: Patients with BRPC-M0 were enrolled and treated with P-MCP, 4.8 grams X 3/day, for 6 months (first phase of trial). Patients without PSA progression and/or with improvement of PSA doubling time (PSADT), and with negative scans, were treated for an additional 12 months (second phase of trial). Results: 59 patients were initially enrolled. After initial 6 months of therapy, 46 patients (78%) without disease progression entered the second phase of additional 12 months therapy. Among them, 7 patients withdrew consent and chose to continue therapy out of pocket. Of the remaining 39 patients, after another year of therapy (total of 18 months), 85% (n=33) had an overall long-term response, with a decreased/stable PSA (62 %, n=24), and improvement of PSADT (90 %, n=35), and with negative scans. No patient had grade 3/4 toxicity. Conclusions: P-MCP may have a durable long-term efficacy in patients with BRPC-M0. Clinical trial information: NCT01681823 .

Abstract PR012: Perioperative liver biopsy captures features of the liver pre-metastatic niche and predicts metastatic outcome after pancreatic cancer resection

Abstract Pancreatic cancer (PC) has a high propensity for liver metastasis (LM), a rapidly lethal event, often seen early after resection of the primary tumor. Mounting pre-clinical evidence implicates the establishment of microenvironmental alterations in the liver or other target organs prior to emergence of clinically evident metastases, termed “pre-metastatic niches”, which is a crucial first step in metastatic progression. To determine the translational relevance of these findings, we evaluated liver biopsies from PC patients obtained during pancreatectomy to characterize the cellular, molecular and metabolic features that define the pre-metastatic niche and that may, in turn, be used as biomarkers to stratify the metastatic risk, and as therapeutic targets to interrupt the metastatic cascade. Thus, liver biopsies from 49 patients with localized PC were analyzed by transcriptomics, metabolomics, histopathology, flow cytometry, and in selected patients by single cell RNA sequencing. Patients underwent routine surveillance in a prospective manner to determine which patients developed early (<6 months) or late (>6 months) LM, extrahepatic metastasis, or remained disease-free. Eighteen patients with non-cancerous pancreatic lesions undergoing pancreatectomy were used as controls (non-PC). Single cell transcriptomics analyses and immuno-profiling revealed that, in contrast to non-PC livers, tumor-free, pre-metastatic livers from PC patients exhibited enhanced inflammation evidenced by enrichment of neutrophils, CD11B+ cells, and CD3+ T cells, as well as expansion and activation of a CD11B+ subset of NK cells. Furthermore, immune and metabolic profiling of PC pre-metastatic livers identified features that predicted future patterns of metastasis: high Ki67 proliferation index, neutrophil extracellular trap (NET) formation, and upregulated sortilin-1 gene expression, all of which correlated with earlier LM. Conversely, widespread lobular inflammation, with abundant lobular CD3+ T cells, as well as intact creatine metabolism and steatosis associated with no recurrence, isolated extrahepatic recurrence or later LM. We combined the above variables to develop a decision tree-based prediction model, which performed best for identification of early LM (AUC 0.85). Taken together, these data demonstrate that in patients with apparently localized PC, pre-treatment liver biopsies may confirm the presence of human hepatic pre-metastatic niche and reveal features that correlate with timing and patterns of recurrence (early or late LM, extrahepatic, or no recurrence), after resection of PC. These liver profiles represent novel biomarkers that may be used to provide prognostic information and guide subsequent treatment of PC. Citation Format: Linda Bojmar, Constantinos P. Zambirinis, Jonathan Hernandez, Jayasree Chakraborty, Samer Hanna, Diane Simeone, David Kelsen, Haiying Zhang, Irina R Matei, Per Sandström, Robert Schwartz, William R. Jarnagin, David Lyden. Perioperative liver biopsy captures features of the liver pre-metastatic niche and predicts metastatic outcome after pancreatic cancer resection [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR012.

Cathepsin K regulates the tumor growth and metastasis by IL-17/CTSK/EMT axis and mediates M2 macrophage polarization in castration-resistant prostate cancer

A common stage of advanced prostate cancer is castration-resistant prostate cancer (CRPC), greater understanding of which is required in order to address and solve the clinically difficult challenge. Cathepsin K (CTSK) is a cysteine protease that usually has a strong activity of degrading extracellular matrix and is related to osteoclast-mediated bone destruction. However, the mechanism of CTSK-regulation in CRPC is still unclear to us. The current study aimed to analyze the expression of differentially expressed genes (DEGs) in patient samples (from localized PC and CRPC). Interestingly, we found that CTSK to be significantly up-regulated in CRPC. Through further signal pathway enrichment analysis, we found that the IL-17 signaling pathway to be highly correlated with CTSK. The oncogenic functions of CTSK and IL-17 in CRPC were proven by a series of in vivo and in vitro experiments. Possible downstream molecules of CTSK were investigated, which could serve as control elements to regulate the expression of EMT, thereby facilitating the metastasis and excessive proliferation of PC cells. Expression of CTSK was related to high concentration of M2 tumor-associated macrophages (TAMs) M2 in CRPC. A CTSK-mediated feedback circuit between TAMs and CRPC tissues was indicated in the process of transfer, proving the possibility of CTSK could be use as an available therapeutic target for CRPC.

Boosting the Immune Response-Combining Local and Immune Therapy for Prostate Cancer Treatment.

Due to its slow progression and susceptibility to radical forms of treatment, low-grade PC is associated with high overall survival (OS). With the clinical progression of PC, the therapy is becoming more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by e.g., immune evasion through Treg cells, synthesis of immunosuppressive mediators, and the defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of tumors and eliminate the immunosuppressive properties of the TME. In the settings of PC treatment, this can be commonly achieved with radiation therapy (RT). In addition, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), and irreversible electroporation (IRE) were shown to boost the anti-cancer response. Nevertheless, the present guidelines restrict their application to the context of a clinical trial or a prospective cohort study. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.

Impact of U.S. Preventative Services Task Force grade D recommendation against prostate-specific antigen screening on prostate cancer mortality.

51 Background: The U. S. Preventative Services Task Force (USPSTF) recommendation regarding prostate-specific antigen (PSA) transitioned to a grade D recommendation against PSA screening for adult males in 2012. The impact of this recommendation against PSA screening on prostate cancer-specific mortality (PCSM) in contemporary cohorts is unknown. Our study evaluated PCSM between 1999-2019, comparing mortality rates before and after this change to screening guidelines. Methods: Age-adjusted PCSM rates per 100,000 men were obtained from the National Center for Health Statistics from 1999 – 2019. Trends in PCSM rates from 1999 – 2012 and 2014 – 2019 were estimated using linear regression with year and binary indicator of pre-2013/post-2013 status as interaction terms. Age-adjusted rates of PCSM were calculated for men ≥50 years and by race, ethnicity, urbanization and census region. Similarly, age-adjusted rates of overall cancer mortality (exclusive of PCSM) were calculated. Behavioral Risk Factor Surveillance System was used to establish trends in PSA screening from 2001 – 2018. North American Association of Central Cancer Registries was used to determine age-adjusted incidence of localized and metastatic PC at the time of diagnosis from 1999 – 2017. Results: The age-adjusted PCSM rate in the U.S. decreased linearly at a rate of (-)0.28 per 100,000/year from 1999 – 2012 and subsequently stalled at a rate of no change from 2014 – 2019 (p < 0.001). This effect was particularly striking for men aged 60 – 69, men > 80 years, and Black men. Men aged 60 – 64 had a decreasing rate of (-)0.009 per 100,000/year prior to 2013, followed by a rise of (+)0.001 per 100,000/year (p < 0.001). Among Black men, PCSM rate was decreasing linearly at (-)0.700/100,000/year from 1999-2012 and flattened at a rate of (-)0.091/100,000/year from 2014-2019 (p < 0.001). These changes were seen across races, urbanization and census regions (p < 0.001) and were accompanied by decreases in PSA screening (p = 0.02) together with increases in diagnosis of metastatic disease. These trends were inconsistent with mortality trends observed across all malignancies. Conclusions: Using comprehensive data on PCSM through 2019, this study illustrates decreasing PCSM over time which flattened or increased following the 2012 change in USPSTF guideline, along with a decrease in PSA screening. The change in PCSM was seen in all ages, races, ethnicities, urbanization and census regions, but particularly in men from 60 – 69 and > 80 years old, and Black men. These changes were accompanied by increased diagnosis of metastatic PC and are discordant from trends across other malignancies. These findings suggest that the change in PSA screening guideline may have contributed to the stagnancy of PCSM rates in recent years. The updated 2018 USPSTF guideline supporting shared-decision making may reverse these trends over time.

Five Year Results of Short Course Complete Androgen Blockade With Abiraterone Acetate and LHRH Agonist for Unfavorable Intermediate and Favorable High Risk Prostate Cancer

Purpose/Objective(s)Androgen deprivation therapy (ADT) and radiotherapy (RT) are synergistic, and the combination results in improved survival outcomes for aggressive prostate cancers. However, long-term ADT carries substantial burden of toxicity and morbidity. We hypothesized that a combination of definitive prostate RT and short-term complete androgen blockade (CAB) in men with unfavorable intermediate or favorable high-risk localized PC would provide excellent biochemical control and allow high rates of testosterone recovery. This combination would allow an escalation of therapy for unfavorable intermediate risk and de-escalation for favorable high-risk patients. We tested this hypothesis in a prospective trial of neoadjuvant/concurrent/adjuvant abiraterone acetate, prednisone, and LHRH agonist given for 6 months in conjunction with definitive prostate external beam RT. We now report the mature results of this trial.Materials/Methods37 men were enrolled in an IRB-approved NCT-registered prospective multi-center single arm investigator-initiated trial between January 2014 and August 2016. Eligibility required unfavorable intermediate risk of low volume high risk (NCCN) prostate cancer. All men were treated with 6 months of abiraterone acetate (1000mg daily), prednisone (5mg daily), and depot LHRH agonist initiated 8 weeks prior to standard fractionation RT to prostate/seminal vesicles +/- pelvis. Endpoints included PSA and testosterone (T) kinetics, biochemical progression-free survival (PFS), metastasis-free survival (MFS), overall survival (OS), and patient-reported quality-of-life.ResultsEnrolled patients were low volume (T1-2 disease and PSAs < 20 ng/ml), with Grade Group 1 (11%), 2 (11%), 3 (35%), 4 (27%), and 5 (16%); 43% were high-risk. The median follow-up time among all 37 surviving patients is 58months (range 24-65). Treatment was well tolerated and has been reported previously. In the entire cohort, 5-year BPFS was 92% (95% CI 72-98%). 32 out of 37 men recovered T to at least 150 ng/dl; the median time to T recovery was 9.2 mo (95% CI: 9.0-12.2). In men with T recovery, the 5-year BPFS was also 92% (95% CI: 71-98%). Hormonal/sexual function declined at six months but had improved by 24 mo and remained stable thereafter.ConclusionFor select men with aggressive prostate cancer, short course CAB with abiraterone acetate plus prednisone in combination with definitive prostate RT allows rapid T recovery and can provide excellent biochemical control up to 5 years. Short-course CAB is feasible for favorable high risk prostate cancer and may support optimization of patient quality of life. Prospective randomized trials should be considered. Androgen deprivation therapy (ADT) and radiotherapy (RT) are synergistic, and the combination results in improved survival outcomes for aggressive prostate cancers. However, long-term ADT carries substantial burden of toxicity and morbidity. We hypothesized that a combination of definitive prostate RT and short-term complete androgen blockade (CAB) in men with unfavorable intermediate or favorable high-risk localized PC would provide excellent biochemical control and allow high rates of testosterone recovery. This combination would allow an escalation of therapy for unfavorable intermediate risk and de-escalation for favorable high-risk patients. We tested this hypothesis in a prospective trial of neoadjuvant/concurrent/adjuvant abiraterone acetate, prednisone, and LHRH agonist given for 6 months in conjunction with definitive prostate external beam RT. We now report the mature results of this trial. 37 men were enrolled in an IRB-approved NCT-registered prospective multi-center single arm investigator-initiated trial between January 2014 and August 2016. Eligibility required unfavorable intermediate risk of low volume high risk (NCCN) prostate cancer. All men were treated with 6 months of abiraterone acetate (1000mg daily), prednisone (5mg daily), and depot LHRH agonist initiated 8 weeks prior to standard fractionation RT to prostate/seminal vesicles +/- pelvis. Endpoints included PSA and testosterone (T) kinetics, biochemical progression-free survival (PFS), metastasis-free survival (MFS), overall survival (OS), and patient-reported quality-of-life. Enrolled patients were low volume (T1-2 disease and PSAs < 20 ng/ml), with Grade Group 1 (11%), 2 (11%), 3 (35%), 4 (27%), and 5 (16%); 43% were high-risk. The median follow-up time among all 37 surviving patients is 58months (range 24-65). Treatment was well tolerated and has been reported previously. In the entire cohort, 5-year BPFS was 92% (95% CI 72-98%). 32 out of 37 men recovered T to at least 150 ng/dl; the median time to T recovery was 9.2 mo (95% CI: 9.0-12.2). In men with T recovery, the 5-year BPFS was also 92% (95% CI: 71-98%). Hormonal/sexual function declined at six months but had improved by 24 mo and remained stable thereafter. For select men with aggressive prostate cancer, short course CAB with abiraterone acetate plus prednisone in combination with definitive prostate RT allows rapid T recovery and can provide excellent biochemical control up to 5 years. Short-course CAB is feasible for favorable high risk prostate cancer and may support optimization of patient quality of life. Prospective randomized trials should be considered.

Local resection versus radical surgery for parathyroid carcinoma: A National Cancer Database analysis

IntroductionParathyroid carcinoma (PC) is rare and often diagnosed incidentally after local resection (LR) for other indications. Although recommended treatment has traditionally been radical surgery (RS), more recent guidelines suggest that LR alone may be adequate. We sought to further investigate outcomes of RS versus LR for localized PC. Materials and methodsPC patients from 2004 to 2015 with localized disease were identified from the National Cancer Database, then stratified by surgical therapy: LR or RS. Demographic and clinicopathologic data were compared. Cox proportional hazard models were constructed to estimate associations of variables with overall survival (OS). OS was estimated from time of diagnosis using Kaplan-Meier curves. ResultsA total of 555 patients were included (LR = 522, RS = 33). The groups were comparable aside from LR patients having higher rates of unknown nodal status (66.9% versus 39.4%; p = 0.003). By multivariable analysis, RS did not have a significant association with OS (hazard ratio (HR) = 0.43, 95% confidence interval (95%CI) = 0.10, 1.83; p = 0.255), nor did positive nodal status (HR = 0.66, 95%CI = 0.09, 5.03; p = 0.692) and unknown nodal status (HR = 1.30, 95%CI = 0.78, 2.17; p = 0.311). There was no difference in OS between the LR and RS groups, with median survival not reached by either group at 10 years (median follow-up = 60.4 months; p = 0.20). ConclusionsThere was no difference in OS between LR and RS for localized PC. RS and nodal status may not impact survival as previously identified, and LR should remain a valid initial surgical approach. Future higher-powered studies are necessary to assess the effects of surgical approaches on morbidity and oncologic outcomes.

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial

The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT+ D [OS: hazard ratio (HR) 0.45; P= 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P= 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT+ D (HR 0.41; P= 0.015). This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Understanding racial disparities in survival among U.S. veterans with localized high-risk prostate cancer, 2004-2019.

202 Background: Known racial disparities in prostate cancer outcomes between African-American (AA) and non-Hispanic White (W) men may be ameliorated in the Veterans Health Administration (VA), a large national equal-access health system. We examined factors contributing to racial disparities in mortality among men with high-risk localized prostate cancer diagnosed in the VA. Methods: In this retrospective cohort study, we used linked administrative, survey, and electronic health record data from the Veterans Health Administration (VA) Corporate Data Warehouse to identify AA and W Veterans who were diagnosed with high-risk localized PC, as defined by D’Amico criteria, between January 1, 2004 and December 31, 2013. Patients were followed through December 31, 2019. The primary outcome was all-cause mortality. We used hierarchical Cox regression models, sequentially adjusting for covariates related to social determinants of health (e.g. travel time, marital status), clinical factors at diagnosis (e.g. PSA, Gleason, comorbidity), diagnosing facility, and prostate cancer treatment and adherence to American Cancer Society survivorship care guidelines. Results: Among 21,338 Veterans receiving continuous VA-based care (median age at diagnosis 66 years [interquartile range [IQR] 61-74]), 7,472 (28.7%) were AA, 9,404 (44.1%) died, and median follow-up was 8.4 years (IQR 6.1-11.1). After adjusting for all covariates, AA Veterans (adjusted hazard ratio [aHR] 0.84, 95% confidence interval [CI] 0.83-0.91) had improved overall survival compared to W Veterans. This association persisted in all hierarchical regressions (see Table), was present in all pre-specified subgroups, and was strongest among Veterans living in rural domiciles (aHR 0.70, 95% CI 0.64-0.77). Conclusions: AA Veterans with high-risk localized prostate cancer had improved long-term survival compared to W Veterans, which stands in contrast to prior studies among non-Veterans. Equal access to care may improve racial disparities in prostate cancer, although future studies should clarify mechanisms of improved survival for AA Veterans with prostate cancer in order to provide insights for ameliorating outcome disparities in non-Veterans with prostate cancer. [Table: see text]

Impact of KRAS alterations in localized pancreatic cancer (PC).

431 Background: Patients (pts) with localized PC do not routinely undergo comprehensive genomic profiling (CGP) unless they develop recurrent or metastatic disease. KRAS is the most frequently mutated gene in PC, however, the impact of different KRAS mutations in localized PC has not been well characterized. We interrogated our genomic database to analyze the KRAS status in PC pts who presented with localized disease at diagnosis (Dx). Methods: We identified PC pts at our institution who underwent CGP utilizing the Foundation One CDx assay and had localized disease at initial Dx; these pts were categorized into resectable/borderline resectable PC (LPC) and locally advanced PC (LAPC). All pts with LPC and LAPC underwent neoadjuvant chemotherapy and chemoradiation prior to possible surgery (all intended therapy - AIT). Tissue from metastatic sites was used for CGP in pts who developed recurrent/metastatic disease before or after completion of AIT. The primary tumor was used for CGP in pts who completed AIT without subsequent relapse or in the absence of adequate metastatic tissue. Effect of each gene on response and survival outcomes was estimated using proportional odds and Cox regression analysis, respectively, adjusting for stage. Results: 75 pts were identified, median age at Dx was 65 years, 59% were male, 65% had a primary tumor in the pancreatic head. 38 (86%) pts with LPC completed AIT compared to 21 (68%) pts with LAPC (p&lt;0.001). KRAS mutation was detected in 95% (71/75) of pts– 94% (67/71) in codon 12 and 6% (4/71) in codon 61. The various KRAS mutations and their association with completion of AIT is summarized in the table. The likelihood of completing AIT did not differ based on KRAS wildtype (WT) vs mutated status (p =1.00), the mutated codon (codon 12 vs. codon 61; p =1.00) or the individual KRAS point mutations (p = 0.7); however, all patients with G12A (N= 1), G12C (N=1), G12L (N=1) and G12R (N=11) mutations completed AIT. KRAS status (mutated vs. WT) and the individual KRAS mutations were not associated with overall survival (OS) after adjusting for stage (p= 0.13 and p = 0.26 respectively). Median OS for patients with LPC and LAPC, was 39 months (mos) and 29 mos respectively. Conclusions: KRAS status and individual KRAS mutations did not have an impact on completing AIT or mOS; however, these findings need to be interpreted with caution due to the inherent biases involved in such analyses. The clinical significance and functional relevance of KRAS G12A, G12C, G12L and G12R mutations, though relatively rare, needs further characterization as well as mechanistic elucidation. [Table: see text]

Pathology grade influences competing mortality risks in elderly men with prostate cancer

BackgroundRecent guidelines recommend active management of prostate cancer (CaP), especially high-risk disease, in elderly men. However, descriptive data from a large cohort with extended follow up on the risk of death from CaP in men diagnosed over 70 years of age and its relationship to Gleason score (GS) and serum prostate specific antigen (PSA) level is lacking. Using the Surveillance, Epidemiology, and End Results database, we evaluated the influence of GS and serum PSA levels on the risks of mortality from PC (PCM) and mortality from other causes in localized (LPC) and metastatic (MPC) disease in elderly population. MethodsMen diagnosed with PC over 70 years of age between 2004 and 2016 were divided into LPC and MPC groups, categorized by age: 70–74, 75–79, 80–84, 85–89, and ≥90 years and stratified by GS <7, 7, and >7, and serum PSA level <4, 4–10, 10–20, 20–50, and >50 ng/mL. Competing risk estimates for PCM and mortality from other causes were generated for both groups. ResultsOf the 85,649 men, 85.5 % were LPC at diagnosis. Overall, at a median follow up of 4 years, 15% of the men had died including a third from PC. While <15% of men with GS ≤7 died from PC, the PCM was >30% in men with GS >7 in LPC group, which accounted for almost half of total deaths for age 70–84 years. The GS >7 was also significantly associated with PCM in men with MPC. Furthermore, PCM directly correlated with serum PSA levels, with mortality rates reaching up to 50% and 70% for PSA >50 ng/dl for LPC and MPC, respectively. ConclusionsThere is a substantial risk of dying in men diagnosed with LPC over 70 years of age with GS >7 or a serum PSA >20 ng/mL. Furthermore, the risk for death for MPC directly correlated with GS with PCM increasing from 10%–30% for GS ≤7 to >50% for GS >7. The data, in conjunction with other clinical parameters such as comorbidities could be used to counsel elderly men on management options of PC for both localized and metastatic PC.

Rectum Dose-Volume Histogram (DVH) Parameters And Patient-Reported EPIC-Bowel Domain For Patients Undergoing Radiotherapy (RT) For Prostate Cancer (PC): A Single-Center Prospective Registry Experience

Prostate cancer therapy toxicities can affect QOL. We report one of the first analyses of rectal dose and changes in QOL measured with the EPIC bowel domain in PC patients treated with curative intent RT in a large, single-institution prospective registry. Two hundred fifty-two pts with localized PC were treated with curative intent RT from 2016- 2018 on an IRB approved prospective registry. The Expanded Prostate Cancer Index Composite (EPIC) health-related QOL instrument was administered at baseline, end-of-treatment, 3, 6, 12 months (m), and then annually. A higher EPIC score implies less bowel symptom burden. DVH parameters for the rectal structure were computed, Dx was the dose (Gy) to a % of the rectum and Vx was the % volume receiving a given dose (Gy). Rectal dose was analyzed using BED (alpha/beta = 3), EQD2Gy, and total dose. In order to determine optimal cut-points to find clinically meaningful DVH, we utilized logistic regression and defined the ‘best’ cut-point to be the value that maximized Youden’s Index. Repeated measures mixed models were then implemented to determine the effect of patient, clinical, and treatment factors (including DVH) on patient-reported bowel symptom burden (EPIC-Bowel). Median follow-up was 20mo(range:2.5–40), pre-RT PSA = 6.12(1.3–129), T Stage T1c(T1b–T3b), Gleason Score 7(range 6-10), and 99% N0. The median prescribed dose was 70Gy (38–79.2) in 5 to 44 fractions. Standard fractionation (1.8-2Gy) was used in 120 pts (48.2%), moderate hypofractionation (2.5-3Gy) in 87 pts (35.1%), and extreme hypofractionation (>6Gy) in 42 pts (16.7%). Globally, treatment had minimal effect over EPIC-bowel scores which remained unchanged over time, with a median baseline = (96.4), end-of-treatment = (94.6), 3mo = (95.4), 6mo = (96.4), 12m = (94.6), and 24m = (96.4). However, rectal dose affected QOL with the strongest DVH signals noted for BED V51Gy and EQD2 V22Gy—with an optimal cut-point of 14.4% and 16.4%, respectively. On multivariate modeling BED V51Gy >14.4% was significantly associated with a decline of the epic bowel domain of 2.1 points (p = 0.01), and an EQD2 V22Gy >16.4% was significantly associated with a decline of 2.3 points (p<0.003). Rectal dose, specifically BED V51Gy>14.3% and EQD2 V22Gy>16.4%, are significantly associated with decline in bowel related QOL in patients undergoing definitive RT for localized PC. This is one of the first studies to examine rectal dose and correlate them to patient reported treatment related QOL.

Impact of Neoadjuvant Chemoradiation on Pathologic Response in Patients With Localized Pancreatic Cancer.

Introduction/Background: Multimodal neoadjuvant therapy has resulted in increased rates of histologic response in pancreatic tumors and adjacent lymph nodes. The biologic significance of the collective response in the primary tumor and lymph nodes is not understood.Methods: Patients with localized PC who received neoadjuvant therapy and surgery with histologic assessment of the primary tumor and local-regional lymph nodes were included. Histopathologic response was classified using the modified Ryan score as follows: no viable cancer cells (CR), rare groups of cancer cells (nCR), residual cancer with evident tumor regression (PR), and extensive residual cancer with no evident tumor regression (NR). Nodal status was defined by number of lymph nodes (LN) with tumor metastases: N0 (0 LN), N1 (1–3), N2 (≥4).Results: Of 341 patients with localized PC who received neoadjuvant therapy and surgery, 107 (31%) received chemoradiation alone, 44 (13%) received chemotherapy alone, and 190 (56%) received chemotherapy and chemoradiation. Histopathologic response consisted of 15 (4%) CRs, 59 (17%) nCRs, 188 (55%) PRs, and 79 (23%) NRs. Patients who received chemotherapy alone had the worst responses (n = 21 for NR, 48%) as compared to patients who received chemoradiation alone (n = 25 for NR, 24%) or patients who received both therapies (n = 33 for NR, 17%) (Table 1; p = 0.001). Median overall survival for all 341 patients was 39 months; OS by histopathologic subtype was not reached (CR), 49 months (nCR), 38 months (PR), and 34 months (NR), respectively (p = 0.004). Of the 341 patients, 208 (61%) had N0 disease, 97 (28%) had N1 disease, and 36 (11%) had N2 disease. In an adjusted hazards model, modified Ryan score of PR or NR (HR: 1.71; 95% CI: 1.15–2.54; p = 0.008) and N1 (HR: 1.42; 95% CI: 1.1.02–2.01; p = 0.04), or N2 disease (HR: 2.54, 95% CI: 1.64–3.93; p < 0.001) were associated with increased risk of death.Conclusions: Neoadjuvant chemotherapy alone is associated with lower rates of pathologic response. Patients with CR or nCR have a significantly improved OS as compared to patients with PR or NR. Nodal status is the most important pathologic prognostic factor. Neoadjuvant chemoradiation may be an important driver of pathologic response.

Relationship between Geriatric 8 screening score and treatment selection in patients with prostate cancer.

206 Background: This study aimed to evaluate the geriatric 8 (G8) screening tool for detecting frailty in patients with prostate cancer. Methods: Between January 2017 and June 2019, we prospectively evaluated the G8 in 540 prostate cancer patients, 444 with localized stage M0 and 96 with metastatic stage M1 disease. The primary endpoint was the comparison of G8 scores in patients treated with robot-assisted radical prostatectomy (RARP), radiotherapy, androgen deprivation therapy alone (ADT-alone) for localized disease, and standard care for the M1 disease. Secondary endpoint included the cutoff estimation of G8 score and the influence of G8 on prognosis. Results: The median age was 75 years. G8 scores ≤14 indicating frailty were seen in 36% of RARP (n = 214), 57% of RT (n = 209), 91% of ADT-alone (n = 21), and 70% of M1 disease (n=96). The median G8 score in M0 patients was significantly higher than that in M1 patients (14.5 vs 12.8, respectively). The median G8 score in patients treated with RARP, RT and ADT-alone was 15, 14, and 12, respectively. The patients with RARP had significantly higher G8 score than that of RT or ADT-alone. The optimal G8 cutoff score for patients with M0 and M1 disease was 13.0 (AUC: 0.681). The overall survival was significantly shorter in patients with G8 &lt;13 than that of ≥13. Conclusions: The G8 score of patients with localized and metastatic PC was significantly different. Frailty was significantly associated with treatment selection and prognosis in patients with PC.

Stereotactic body radiation therapy with androgen deprivation therapy for unfavorable-risk prostate cancer.

332 Background: Current ASTRO consensus guidelines do not support routine use of SBRT in higher risk PC. However, the NCCN permits selective use of SBRT with ADT for unfavorable intermediate (UIR) and high (HiR) risk PC in cases where conventional/moderately fractionated radiation therapy (EBRT) present medical or social hardship. How SBRT+ADT compares to EBRT+ADT in UIR and HiR men is unknown. Methods: Men &gt;40 years old with localized PC treated with RT and concomitant ADT for curative intent between 2004-2015 were analyzed from the National Cancer Database. Patients treated with brachytherapy or who lacked ADT or risk stratification data were excluded. A total of 558 men treated with SBRT (5 fractions, ≥7 Gy/fraction) versus 40,797 men treated with moderate or conventional EBRT (dose ≥60 Gy with ≤3 Gy/fraction) were included. Patients were stratified by UIR and HiR using NCCN criteria. Kaplan Meier and Cox proportional hazards were used to compare overall survival (OS) between RT modality, adjusting for age, race, and comorbidity index. Results: With a median follow up of 62 months, there was no difference in 5-year OS between men treated with SBRT versus EBRT regardless of risk group (UIR: 87.2% SBRT versus 87.0% EBRT, p=.40; HiR: 80.4% SBRT versus 80.8% EBRT, p=.21). On multivariable analysis, there was no difference in risk of death for men treated with SBRT compared to EBRT (UIR: adjusted HR 1.09, 95% CI 0.68-1.74, p=.72; HiR: adjusted HR 0.93, 95% CI 0.76-1.14, p=.51). Conclusions: We found no difference in survival between SBRT+ADT and standard of care EBRT+ADT for UIR or HiR PC. Randomized trials of SBRT versus EBRT, with standard concomitant ADT, in these risks groups are needed. If prospectively validated, more widespread use of SBRT for higher risk PC may be warranted, especially in an era of cost-effective care.

Current status and future prospective of focal therapy for localized prostate cancer: development of multiparametric MRI, MRI-TRUS fusion image-guided biopsy, and treatment modalities.

Multiparametric magnetic resonance imaging (mpMRI) has been increasingly used to diagnose clinically significant prostate cancer (csPC) because of its usefulness in combination with anatomic and functional data. MRI-targeted biopsy, such as MRI-transrectal ultrasound (TRUS) fusion image-guided prostate biopsy, has high accuracy in the detection and localization of csPC. This novel diagnostic technique contributes to the development of tailor-made medicine as focal therapy, which cures the csPC while preserving the anatomical structures related to urinary and sexual function. In the early days of focal therapy, TRUS-guided systematic biopsy was used for patient selection, and treatment was performed for patients with low-risk PC. With the introduction of mpMRI and mapping biopsy, the treatment range is now determined based on individualized cancer localization. In recent prospective studies, 87.4% of treated patients had intermediate- and high-risk PC. However, focal therapy has two main limitations. First, a randomized controlled trial would be difficult to design because of the differences in pathological features between patients undergoing focal therapy and radical treatment. Therefore, pair-matched studies and/or historical controlled studies have been performed to compare focal therapy and radical treatment. Second, no long-term (≥ 10-year) follow-up study has been performed. However, recent prospective studies have encouraged the use of focal therapy as a treatment strategy for localized PC because it contributes to high preservation of continence and erectile function.