Primary Non-metastatic Prostate Cancer Research Articles

Abstract 2745: Sequential tracking of PD-L1 expression on circulating epithelial tumor cells (CETCs) in men with primary non-metastatic prostate cancer

Abstract Background: Radiotherapy (RT) is an essential component of multimodality therapy in the primary or postoperative treatment of prostate cancer with curative intent by preventing local recurrence and distant metastases, indicating its impact on residual occult tumor, such as circulating tumor cells. Immunogenic changes in cancer cells induced by RT can lead to adaptive up-regulation of PD-L1 expression. As immune checkpoint inhibition plays an increasingly important role in prostate cancer, radiogenic PD-L1 upregulation may be of therapeutic importance. The aim of this study was to determine PD-L1 status on CETCs before and during RT. Methods: Peripheral blood samples were collected from 52 primary non-metastatic prostate cancer patients. CETCs were enumerated and analyzed for PDL-L1 expression prior to (baseline), 3 and 6 weeks after the start of RT using fluorescence scanning microscopy. Results: PD-L1 expression was detectable in CETCs and localized in the membrane and/or cytoplasm. We found a correlation between PD-L1 status in CETCs and aggressiveness of cancer disease prior to RT. The frequency of PD-L1 positive CETCs depended on the grading and Gleason score of the primary tumor. Patients with a high Gleason score and G3 tumors had significantly more PD-L1 positive CETCs compared to patients with a low Gleason Score and G1 tumors. Moreover, patients in stage I/II had significantly less PD-L1 positive CETCs compared to patients in stage III/IV (mean 54.25 vs. mean 69.65; p<0.05). A higher number of PD-L1 positive CETCs were detected in patients who had radical prostatectomy before start of RT than in those who had no surgical intervention (mean 66.24 vs. mean 47.46; p<0.01). Interestingly, the fraction of PD-L1 positive CETCs decreased significantly during RT only in patients with G3 tumors and a high Gleason Score. Conclusion: Our results indicated that PD-L1 in CETCs is closely related to the aggressiveness of the primary tumor and may be a co-factor associated with the progression of prostate cancer. PD-1/PD-L1 blockade combined with RT represents a novel and promising treatment strategy that could contribute to improve the treatment efficacy of prostate cancer. Citation Format: Dorothea Schott, Monika Pizon, Ulrich Pachmann, Katharina Pachmann, Matthias Mäurer. Sequential tracking of PD-L1 expression on circulating epithelial tumor cells (CETCs) in men with primary non-metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2745.

2247P Expression of PD-L1 on circulating epithelial tumor cells (CETCs) in men with primary non-metastatic prostate cancer

2247P Expression of PD-L1 on circulating epithelial tumor cells (CETCs) in men with primary non-metastatic prostate cancer

Risk for Second Primary Hematologic Malignancies by Radiotherapy Technique in Prostate Cancer Survivors

<h3>Purpose/Objective(s)</h3> Among the most serious adverse effects after radiotherapy for prostate cancer is the development of second malignant neoplasms. Recent advances in radiotherapy techniques, such as the introduction of intensity-modulated radiation therapy (IMRT) and proton beam radiotherapy (PBRT), have aimed to reduce exposure to adjacent healthy tissues but may lead to greater bone marrow exposure. Risks for developing myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) but not lymphoid malignancies after radiotherapy have been demonstrated. We quantified risks of hematologic malignancies following IMRT and PBRT compared to 3D conformal radiotherapy (CRT) in a large cohort of prostate cancer patients. <h3>Materials/Methods</h3> This retrospective cohort study used the linkage of Surveillance, Epidemiology, and End Results (SEER) cancer registry data with Medicare claims, including men who were diagnosed with first primary non-metastatic prostate cancer at ages 66-84 years from 2002-2014, received external beam radiotherapy (IMRT, PBRT, or CRT) but no chemotherapy in the first year after diagnosis, and survived ≥2 years after diagnosis without a second primary cancer. Using Cox regression, hazard ratios (HR) and corresponding 95% confidence intervals (CI) were computed to estimate risk of second primary hematologic malignancies, classified into subtypes according to the World Health Organization, after IMRT and PBRT vs CRT. Models were adjusted for age at prostate cancer diagnosis, tumor grade, race, Charlson comorbidity score, and receipt of initial prostate cancer therapy. <h3>Results</h3> The cohort (median follow-up=6.8 years) included 69,966 patients, of whom 23,806 received CRT alone, 43,901 received IMRT without PBRT, and 2,259 received PBRT. A total of 387 patients developed a myeloid malignancy, most commonly MDS/AML, N=291), and 739 developed a lymphoid malignancy, most commonly plasma cell neoplasms (N=178) and diffuse large B-cell lymphoma (N=159). Compared to patients who received CRT, neither IMRT nor PBRT was associated with risk of developing myeloid malignancies overall (IMRT: N=211, HR=0.89, 95%CI 0.70-1.13; PBRT: N=13, HR=0.97, 95%CI 0.55-1.74), with similar results for MDS/AML specifically. Similarly, neither IMRT nor PBRT was associated with risk of developing lymphoid malignancies overall (IMRT: N=390, HR=0.93, 95%CI 0.78-1.11; PBRT: N=24, HR=0.94, 95%CI 0.61-1.43) compared to CRT, with similar results for specific lymphoid malignancy subtypes. <h3>Conclusion</h3> This is among the first cohort studies analyzing risk of hematologic malignancies by subtype after prostate cancer radiotherapy. With longer follow-up and larger sample size compared to previous reports, the hypothesized change in risk for MDS/AML with IMRT/PBRT compared to CRT was not observed. As more data accumulates from patients receiving PBRT, we can gain greater insight into the technique's long-term effects.

The value of 18F-PSMA-1007 PET/CT in identifying non-metastatic high-risk prostate cancer

BackgroundClinical management decisions on prostate cancer (PCa) are often based on a determination of risk. 68Ga-prostate-specific membrane antigen (PSMA)-11-positron emission tomography (PET)/computer tomography (CT) is an attractive modality to assess biochemical recurrence of PCa, detect metastatic disease and stage of primary PCa, making it a promising strategy for risk stratification. However, due to some limitation of 68Ga-PSMA-11 the development of alternative tracers is of high interest. In this study, we aimed to investigate the value of 18F-PSMA-1007 in identifying non-metastatic high-risk PCa.MethodsA total of 101 patients with primary non-metastatic PCa who underwent 18F-PSMA-1007 PET/CT were retrospectively analyzed. According to the European Association of Urology guidelines on PCa, patients were classified into intermediate-risk (IR) group or high-risk (HR) group. The maximum standardized uptake values (SUVmax) of the primary prostate tumor were measured on PET/CT images. The diagnostic performance of PET/CT for IR and HR PCa was calculated, and the relationship between the SUVmax of primary prostate tumor, prostate-specific antigen (PSA) level and Gleason score (GS) was analyzed.ResultsOf all 101 patients, 49 patients were classified into IR group and 52 patients were classified into HR group. There was a significant positive correlation between PSA level/GS and SUVmax (r = 0.561, r = 0.496, P < 0.001, respectively). Tumors with GS 6 and 7a showed significantly lower 18F-PSMA-1007 uptake compared to patients with GS 8 and 9 (P < 0.01). SUVmax in patients of HR was significantly higher than those of IR (median SUVmax: 16.85 vs 7.80; P < 0.001). In receiver operating characteristic curve analysis, the optimal cutoff value of the SUVmax for identifying high-risk PCa was set as 9.05 (area under the curve: 0.829; sensitivity: 90.4%; specificity: 65.3%).Conclusion18F-PSMA-1007 PET/CT showed the powerful diagnosis efficacy for high-risk PCa, which can be used as an objective imaging reference index for clinical reference.

917 - Integrating image guided-diagnostics, individualised prognostics and molecular profiling to identify targeted medicine strategies in men with aggressive primary non-metastatic prostate cancer

917 - Integrating image guided-diagnostics, individualised prognostics and molecular profiling to identify targeted medicine strategies in men with aggressive primary non-metastatic prostate cancer

Models predicting survival to guide treatment decision-making in newly diagnosed primary non-metastatic prostate cancer: a systematic review

ObjectivesMen diagnosed with non-metastatic prostate cancer require standardised and robust long-term prognostic information to help them decide on management. Most currently-used tools use short-term and surrogate outcomes. We explored the...

934 - PREDICT: Prostate – a novel prognostic model that estimates individual survival in newly diagnosed primary non-metastatic prostate cancer

934 - PREDICT: Prostate – a novel prognostic model that estimates individual survival in newly diagnosed primary non-metastatic prostate cancer

The Cambridge Prognostic Groups for improved prediction of disease mortality at diagnosis in primary non-metastatic prostate cancer: a validation study

BackgroundThe purpose of this study is to validate a new five-tiered prognostic classification system to better discriminate cancer-specific mortality in men diagnosed with primary non-metastatic prostate cancer.MethodsWe applied a recently described five-strata model, the Cambridge Prognostic Groups (CPGs 1-5), in two international cohorts and tested prognostic performance against the current standard three-strata classification of low-, intermediate- or high-risk disease. Diagnostic clinico-pathological data for men obtained from the Prostate Cancer data Base Sweden (PCBaSe) and the Singapore Health Study were used. The main outcome measure was prostate cancer mortality (PCM) stratified by age group and treatment modality.ResultsThe PCBaSe cohort included 72,337 men, of whom 7162 died of prostate cancer. The CPG model successfully classified men with different risks of PCM with competing risk regression confirming significant intergroup distinction (p < 0.0001). The CPGs were significantly better at stratified prediction of PCM compared to the current three-tiered system (concordance index (C-index) 0.81 vs. 0.77, p < 0.0001). This superiority was maintained for every age group division (p < 0.0001). Also in the ethnically different Singapore cohort of 2550 men with 142 prostate cancer deaths, the CPG model outperformed the three strata categories (C-index 0.79 vs. 0.76, p < 0.0001). The model also retained superior prognostic discrimination in the treatment sub-groups: radical prostatectomy (n = 20,586), C-index 0.77 vs. 074; radiotherapy (n = 11,872), C-index 0.73 vs. 0.69; and conservative management (n = 14,950), C-index 0.74 vs. 0.73. The CPG groups that sub-divided the old intermediate-risk (CPG2 vs. CPG3) and high-risk categories (CPG4 vs. CPG5) significantly discriminated PCM outcomes after radical therapy or conservative management (p < 0.0001).ConclusionsThis validation study of nearly 75,000 men confirms that the CPG five-tiered prognostic model has superior discrimination compared to the three-tiered model in predicting prostate cancer death across different age and treatment groups. Crucially, it identifies distinct sub-groups of men within the old intermediate-risk and high-risk criteria who have very different prognostic outcomes. We therefore propose adoption of the CPG model as a simple-to-use but more accurate prognostic stratification tool to help guide management for men with newly diagnosed prostate cancer.

880 - External validation of a new clinical prognostic grouping to improve prediction of disease mortality at diagnosis in primary non-metastatic prostate cancer

External validation of a new clinical prognostic grouping to improve prediction of disease mortality at diagnosis in primary non-metastatic prostate cancer

876 - Ability of a new clinical prognostic grouping to better predict disease mortality after treatment in primary non-metastatic prostate cancer

876 - Ability of a new clinical prognostic grouping to better predict disease mortality after treatment in primary non-metastatic prostate cancer

Improving Clinical Risk Stratification at Diagnosis in Primary Prostate Cancer: A Prognostic Modelling Study.

IntroductionOver 80% of the nearly 1 million men diagnosed with prostate cancer annually worldwide present with localised or locally advanced non-metastatic disease. Risk stratification is the cornerstone for clinical decision making and treatment selection for these men. The most widely applied stratification systems use presenting prostate-specific antigen (PSA) concentration, biopsy Gleason grade, and clinical stage to classify patients as low, intermediate, or high risk. There is, however, significant heterogeneity in outcomes within these standard groupings. The International Society of Urological Pathology (ISUP) has recently adopted a prognosis-based pathological classification that has yet to be included within a risk stratification system. Here we developed and tested a new stratification system based on the number of individual risk factors and incorporating the new ISUP prognostic score.Methods and FindingsDiagnostic clinicopathological data from 10,139 men with non-metastatic prostate cancer were available for this study from the Public Health England National Cancer Registration Service Eastern Office. This cohort was divided into a training set (n = 6,026; 1,557 total deaths, with 462 from prostate cancer) and a testing set (n = 4,113; 1,053 total deaths, with 327 from prostate cancer). The median follow-up was 6.9 y, and the primary outcome measure was prostate-cancer-specific mortality (PCSM). An external validation cohort (n = 1,706) was also used. Patients were first categorised as low, intermediate, or high risk using the current three-stratum stratification system endorsed by the National Institute for Health and Care Excellence (NICE) guidelines. The variables used to define the groups (PSA concentration, Gleason grading, and clinical stage) were then used to sub-stratify within each risk category by testing the individual and then combined number of risk factors. In addition, we incorporated the new ISUP prognostic score as a discriminator. Using this approach, a new five-stratum risk stratification system was produced, and its prognostic power was compared against the current system, with PCSM as the outcome. The results were analysed using a Cox hazards model, the log-rank test, Kaplan-Meier curves, competing-risks regression, and concordance indices. In the training set, the new risk stratification system identified distinct subgroups with different risks of PCSM in pair-wise comparison (p < 0.0001). Specifically, the new classification identified a very low-risk group (Group 1), a subgroup of intermediate-risk cancers with a low PCSM risk (Group 2, hazard ratio [HR] 1.62 [95% CI 0.96–2.75]), and a subgroup of intermediate-risk cancers with an increased PCSM risk (Group 3, HR 3.35 [95% CI 2.04–5.49]) (p < 0.0001). High-risk cancers were also sub-classified by the new system into subgroups with lower and higher PCSM risk: Group 4 (HR 5.03 [95% CI 3.25–7.80]) and Group 5 (HR 17.28 [95% CI 11.2–26.67]) (p < 0.0001), respectively. These results were recapitulated in the testing set and remained robust after inclusion of competing risks. In comparison to the current risk stratification system, the new system demonstrated improved prognostic performance, with a concordance index of 0.75 (95% CI 0.72–0.77) versus 0.69 (95% CI 0.66–0.71) (p < 0.0001). In an external cohort, the new system achieved a concordance index of 0.79 (95% CI 0.75–0.84) for predicting PCSM versus 0.66 (95% CI 0.63–0.69) (p < 0.0001) for the current NICE risk stratification system. The main limitations of the study were that it was registry based and that follow-up was relatively short.ConclusionsA novel and simple five-stratum risk stratification system outperforms the standard three-stratum risk stratification system in predicting the risk of PCSM at diagnosis in men with primary non-metastatic prostate cancer, even when accounting for competing risks. This model also allows delineation of new clinically relevant subgroups of men who might potentially receive more appropriate therapy for their disease. Future research will seek to validate our results in external datasets and will explore the value of including additional variables in the system in order in improve prognostic performance.

Medium-term Outcomes after Whole-gland High-intensity Focused Ultrasound for the Treatment of Nonmetastatic Prostate Cancer from a Multicentre Registry Cohort

BackgroundHigh-intensity focused ultrasound (HIFU) is a minimally-invasive treatment for nonmetastatic prostate cancer. ObjectiveTo report medium-term outcomes in men receiving primary whole-gland HIFU from a national multi-centre registry cohort. Design, setting, and participantsFive-hundred and sixty-nine patients at eight hospitals were entered into an academic registry. InterventionWhole-gland HIFU (Sonablate 500) for primary nonmetastatic prostate cancer. Redo-HIFU was permitted as part of the intervention. Outcome measurements and statistical analysisOur primary failure-free survival outcome incorporated no transition to any of the following: (1) local salvage therapy (surgery or radiotherapy), (2) systemic therapy, (3) metastases, or (4) prostate cancer-specific mortality. Secondary outcomes included adverse events and genitourinary function. Results and limitationsMean age was 65 yr (47–87 yr). Median prostate-specific antigen was 7.0 ng/ml (interquartile range 4.4–10.2). National Comprehensive Cancer Network low-, intermediate-, and high-risk disease was 161 (28%), 321 (56%), and 81 (14%), respectively. One hundred and sixty three of 569 (29%) required a total of 185 redo-HIFU procedures. Median follow-up was 46 (interquartile range 23–61) mo. Failure-free survival at 5 yr after first HIFU was 70% (95% confidence interval [CI]: 64–74). This was 87% (95% CI: 78–93), 63% (95% CI: 56–70), and 58% (95% CI: 32–77) for National Comprehensive Cancer Network low-, intermediate-, and high-risk groups, respectively. Fifty eight of 754 (7.7%) had one urinary tract infection, 22/574 (2.9%) a recurrent urinary tract infection, 22/754 (3%) epididymo-orchitis, 227/754 (30%) endoscopic interventions, 1/754 (0.13%) recto-urethral fistula, and 1/754 (0.13%) osteitis pubis. Of 206 known to be pad-free pre-HIFU, 183/206 (88%) remained pad free, and of 236 with good baseline erectile function, 91/236 (39%) maintained good function. The main limitation is lack of long-term data. ConclusionsWhole-gland HIFU is a repeatable day-case treatment that confers low rates of urinary incontinence. Disease control at a median of just under 5 yr of follow-up demonstrates its potential as a treatment for nonmetastatic prostate cancer. Endoscopic interventions and erectile dysfunction rates are similar to other whole-gland treatments. Patient summaryIn this report we looked at the 5-yr outcomes following whole-gland high-intensity focused ultrasound treatment for prostate cancer and found that cancer control was acceptable with a low risk of urine leakage. However, risk of erectile dysfunction and further operations was similar to other whole-gland treatments like surgery and radiotherapy.

613 An improved clinical risk stratification system to better predict cancer specific mortality at diagnosis in primary non-metastatic prostate cancer

613 An improved clinical risk stratification system to better predict cancer specific mortality at diagnosis in primary non-metastatic prostate cancer

Trends and outcome from radical therapy for primary non-metastatic prostate cancer in a UK population.

BackgroundIncreasing proportions of men diagnosed with prostate cancer in the UK are presenting with non-metastatic disease. We investigated how treatment trends in this demographic have changed.Patient and MethodsNon-metastatic cancers diagnosed from 2000–2010 in the UK Anglian Cancer network stratified by age and risk group were analysed [n = 10,365]. Radiotherapy [RT] and prostatectomy [RP] cancer specific survival [CSS] were further compared [n = 4755].ResultsOver the decade we observed a fall in uptake of primary androgen deprivation therapy but a rise in conservative management [CM] and radical therapy [p<0.0001]. CM in particular has become the primary management for low-risk disease by the decade end [p<0.0001]. In high-risk disease however both RP and RT uptake increased significantly but in an age dependent manner [p<0.0001]. Principally, increased RP in younger men and increased RT in men ≥ 70y. In multivariate analysis of radically treated men both high-risk disease [HR 8.0 [2.9–22.2], p<0.0001] and use of RT [HR 1.9 [1.0–3.3], p = 0.024] were significant predictors of a poorer CSM. In age-stratified analysis however, the trend to benefit of RP over RT was seen only in younger men [≤ 60 years] with high-risk disease [p = 0.07]. The numbers needed to treat by RP instead of RT to save one cancer death was 19 for this group but 67 for the overall cohort.ConclusionThis study has identified significant shifts in non-metastatic prostate cancer management over the last decade. Low-risk disease is now primarily managed by CM while high-risk disease is increasingly treated radically. Treatment of high-risk younger men by RP is supported by evidence of better CSM but this benefit is not evident in older men.