Free Prostate-specific Antigen Research Articles

Use of IsoPSA with prostate MRI PIRADS score in biopsy decision making in patients with elevated PSA.

388 Background: IsoPSA is prospectively validated to be superior to PSA and percent free PSA in predicting prostate cancer (PCa) as well as clinically significant prostate cancer. We sought to evaluate the use of IsoPSA in combination with prostate magnetic resonance imaging (MRI) and the prostate imaging reporting and data systems (PIRADS) on predicting either benign/indolent or csPCA at biopsy. Methods: This was a single center retrospective review of prospectively collected patient data that included all patients who underwent IsoPSA testing, preoperative prostate MRI and prostate biopsy from 2019-2021. Chi Squared analysis was used to assess for associations between a binary classification of low (<6) or elevated (>6) IsoPSA index, in combination with PIRADS scores in predicting either indolent/benign or csPCa at biopsy. Logistic regression was used to explore independent predictors of csPCa. Receiver Operating Curve (ROC) analysis was completed with areas under the curve (AUC) for IsoPSA and PIRADS scores, both alone and in combination. Predictive probabilities were assessed using combinations of IsoPSA thresholds and PIRADS scores. Results: 207 patients met inclusion criteria. Among patients with a negative MRI, low IsoPSA index was associated with a lower chance of csPCa compared to those with elevated IsoPSA (2% vs 15%, p<0.018). For those with a PIRADS 4-5 lesion, elevated IsoPSA index was associated with a higher chance of csPCa at biopsy compared to a low IsoPSA index (49% vs 19%, p=0.05). On multivariate analysis, elevated IsoPSA and PIRADS 4-5 were independent predictors of csPCa (p<0.001). Similarly, low IsoPSA index and negative MRI were independent predictors of benign/indolent disease at biopsy (p<0.001). Using predictive probabilities, the combination of PIRADS 4-5 with elevated IsoPSA was associated with the highest risk of csPCa (48%) and the highest AUC (0.83) for predicting csPCa. This AUC value was superior to either marker alone (0.76, 0.76) and total PSA alone (0.57) (p<0.001). Conclusions: The combination of elevated IsoPSA with adverse PIRADS score (4-5) is associated with a 48% predicted probability of csPCa at biopsy with an AUC of 0.83, which was more accurate than either marker alone. A low IsoPSA in combination with a negative MRI resulted in a 98% chance of benign/indolent disease at biopsy. These findings may prove useful for the practicing Urologist and may help guide discussions regarding the need for biopsy when interpreting various IsoPSA/PIRADS combinations. [Table: see text]

Combination of [68Ga]Ga-PSMA PET/CT and [18F]FDG PET/CT in demonstrating dedifferentiation in castration-resistant prostate cancer

Aim of the studyIn this study, we aimed to determine the factors affecting increased glucose metabolism, which is one of the dedifferentiation mechanisms, by using [18F]FDG and [68Ga]Ga-PSMA PET/CT in patients with castration-resistant prostate cancer (CRPC). Materials and methodNinety-three patients with CRPC were included in the study. Gleason score (GS), and total PSA and free PSA levels of the patients were recorded. Patient- and organ-based evaluations were performed according to the lesion uptakes as follows: score 0: PSMA (-) FDG (-), score 1: PSMA (+) FDG (-), score 2: PSMA (+) FDG (+) (FDG < PSMA), score 3: PSMA (+) FDG (+) (FDG = PSMA), score 4: PSMA (+) FDG (+) (FDG > PSMA), and score 5: PSMA (-) FDG (+). scores 1 and 2 were classified as group 1, and scores 3 to 5 were classified as group 2. ResultsThe median age of our patients was 70 (51–88) years. Eighty-eight patients (94.6%) were PSMA-positive, 78 patients (83.8%) were FDG-positive, and 89 patients (95.6%) were or PSMA or FDG positive. When the two groups were compared in terms of patient-based parameters, the median age and GS were found to be significantly higher in group 2. ROC analyses revealed that age and GS were significant in predicting group 2. ConclusionSince glucose metabolism can increase in CRPC patients with advanced age and high GS, we recommend combining [18F]FDG PET/CT with [68Ga]Ga-PSMA PET/CT in routine clinical practice in order to identify this patient subset and refer them to additional therapies.

Immuno-analytical characteristics of PSA and derived biomarkers (total PSA, free PSA, p2PSA)

Prostate-specific antigen (PSA) is the recommended tumor marker for individual screening and follow-up of prostate cancer. This paper reviews main structural and physiological data about prostate specific antigen isoforms: total PSA, free PSA, [-2]proPSA (also named p2PSA). It describes the pre-, per- and post-analytical conditions for these different parameters. It presents the interpretation of results and derived calculated indices (free/total PSA ratio, Prostate Health Index or PHI) for the management of prostate cancer (initial diagnosis and follow-up).

Consistency and diagnostic accuracy of 4 assays in the detection of the total and free prostate-specific antigen.

The lack of interchangeability among prostate-specific antigen (PSA) assays causes difficulties in clinical interpretation. The currently available mainstream assays for PSA were based on Western populations, but it is not clear whether these assays yield different results in prostate cancer (PCa) screening in Chinese populations. A total of 163 men with a total PSA (tPSA) level of 2-10 µg/L scheduled for prostate biopsy were enrolled in this study. The levels of the tPSA and free PSA (fPSA) were detected by the Beckman (using the Hybritech calibration), Roche, Abbott, and Mindray (using the World Health Organization's calibration). Methodological comparison were performed according to EP9-A3 of the Clinical and Laboratory Standards Institute, USA. With pathological diagnosis as the gold standard, the predictive accuracy of the biomarkers was quantified as the area under the receiver operating characteristic curve (AUC) for each of the four methods. A total of 32 PCa patients and 131 patients with benign prostate disease were included in this study. The tPSA levels detected by the Roche, Abbott, and Mindray showed good consistency with Beckman but not of the fPSA levels. Compared to the Beckman tPSA values, the measured values were 1.1% higher for Roche, 2.1% higher for Abbott, and 6.7% higher for Mindray. The fPSA levels measured by Roche, Abbott, and Mindray were 5.4% lower, 22.1% higher, and 4.6% higher than Beckman, respectively. When the tPSA was 4 ng/mL, the diagnostic performance (sensitivity, specificity, positive predictive value, negative predictive value, and missed diagnosis rate) was similar among these 4 assays. When the %fPSA was 16%, Abbott had the highest missed diagnosis rate (37.50%), while Mindray had a sensitivity of 81.25%, the highest negative predictive value (93.88%), and the lowest missed diagnosis rate (18.75%). When the tPSA level is 2-10 ng/mL, the Mindray, like the Roche and Abbott, has good consistency with the Beckman in detecting tPSA, which makes it possible to relieve the pressure of clinical interpretation. However, 4 assays using the same %fPSA cut-off may lead to diverse missed diagnosis rates for PCa screening in China.

Price transparency of prostate cancer care in the United States: An analysis of pricing and disclosure following the centers for medicare and medicaid mandate.

Starting January 1, 2021, Centers for Medicare and Medicaid Services required United States hospitals to publicly disclose prices of their services provided. We analyzed publicly-disclosed prices of prostate cancer-related services. All United States hospitals were queried for publicly-disclosed prices of total and free prostate-specific antigen, prostate magnetic resonance imaging, prostate biopsy, radical prostatectomy, and intensity-modulated radiation therapy as of May 2022. Prices were adjusted by regional price parity. Hospitals disclosing prices were compared with non-disclosing hospitals. Of 6013 hospitals, 3840 (64%) disclosed pricing for at least one prostate cancer-related service. Compared to non-disclosing hospitals, disclosing hospitals had higher median gross annual revenue ($318,502,426 vs. $62,930,436, p < 0.001) and were more likely to be non-profit (56% vs. 30%, p < 0.001), academic-affiliated (46% vs. 13%, p < 0.001), and in neighborhoods with low hospital density (68% vs 62%, p < 0.001). Self-pay prices were higher than insurance-negotiated prices for all services (p < 0.001) other than prostate biopsy. The range of pricing was widest for self-pay prostatectomy, with a 32-fold difference from 90th to 10th percentile ($47,445 to $1476). Self-pay prices of total prostate-specific antigen, magnetic resonance imaging, biopsy, intensity-modulated radiation therapy, and prostatectomy were higher at academic vs. non-academic, for-profit vs. non-profit hospitals, and hospitals in the top quartile of gross annual revenue vs. the third and fourth quartiles (p < 0.01). Self-pay prices of prostate biopsy and prostatectomy were higher in urban vs. rural neighborhoods and neighborhoods with high vs. low hospital density (p < 0.001). Self-pay prices of prostate cancer services were generally higher than insurance-negotiated prices and were higher at for-profit hospitals, academic hospitals, and hospitals in the highest quartile of gross annual revenue. Higher neighborhood hospital density was not associated with higher likelihood of price disclosure nor lower pricing of services, suggesting that local competition does not lead to lower prices and may disincentivize disclosure of prices.

Comparison of low PSA results in a commutable EQA program

The RCPAQAP provides a Liquid Serum Chemistry Program sourced from consenting male and female haemochromatosis patients presenting for therapeutic venesection. Where possible, serum from individual male and female patients are pooled over successive collections. The option to report PSA and Free PSA was introduced in the 2022 program. Here we report on the performance at low PSA levels across 6 instruments from 4 vendors.

The Role of Free Prostate-Specific Antigen in the Diagnosis of Prostate Carcinoma: A Cross-Sectional Study in Rajshahi, Bangladesh

The prevalence of prostatic carcinoma is the outcome of several factors including improved awareness the general population of the significance of carcinoma of the prostate and progresses in diagnostic approaches. The PSA is a probable prostate cancer tumor marker, although it cannot distinguish prostate cancer from BPH solely. To assess the usefulness of free, total, and free/total PSA ratios in differentiating BPH and prostate cancer has been studied under this research work. The work was carried out at RMCH during April 2021 to March 2022, 350 purposively selected urology outpatients and inpatients at RMCH were studied cross-sectional study. Trans-rectal ultrasound (TRUS) and serum PSA levels were analyzed along with Digital rectal examination (DRE). A digital guided prostatic biopsy using a monopty biopsy gun confirmed the diagnosis. Data analysis was done in SPSS 26 software program. Prostatic cancer was more prevalent in men aged 70-80, whereas BPH was more common in men aged 60-70 (p = 0.00032). Histopathology revealed 95 prostate cancer patients, 82 with PSA &gt;4 ng/ml and 85 patients had f/t PSA ratio&gt;0.16. BPH was found in 255 individuals. 139 BPH patients had total PSA &gt;4 ng/ml and 245 BPH patients had f/t PSA ratio ≤0.16. Total PSA had sensitivity and specificity of 86.32% and 45.49%, respectively, lower than f/t ratio. The (Positive predictive value) PPV and accuracy was significantly higher in f/t ratio than total PSA. Along with total PSA, free and free/total PSA ratio may help detect prostate cancer early and distinguish BPH from prostate cancer. J Bio-Sci. 30(1): 79-89, 2022 (June)

Amide Proton Transfer-weighted MRI combined with serum prostate-specific antigen levels for differentiating malignant prostate lesions from benign prostate lesions: a retrospective cohort study

BackgroundEarly diagnosis of prostate cancer improves its prognosis, while it is essential to upgrade screening tools. This study aimed to explore the value of a novel functional magnetic resonance imaging (MRI) technique, namely amide proton transfer (APT)-weighted MRI, combined with serum prostate-specific antigen (PSA) levels to differentiate malignant prostate lesions from benign prostate lesions.MethodsData of patients who underwent prostate examinations at Chongqing University Cancer Hospital between July 2019 and March 2022 were retrospectively analyzed. All patients underwent T2-weighted imaging (T2WI), APT, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) MRI. Two radiologists analyzed the images independently. The ability of the quantitative parameters alone or in different combinations in differentiating malignant prostate lesions from benign prostate lesions were compared by using receiver operating characteristic (ROC) curves. According to the DeLong test, the combined parameters were significantly different from the corresponding single parameter (P < 0.05).ResultsA total of 79 patients were finally enrolled, including 52 patients in the malignant group and 27 patients in the benign group. The separate assessment of indexes revealed that APTmax, APTmean, mean apparent diffusion coefficient (ADCmean), ADCmax, ADCmin, tPAD, free prostate-specific antigen (FPSA), FPSA/total prostate-specific antigen (tPSA), and PSA density (PSAD) were significantly different between the two groups (P < 0.05), while APTmin was not significantly different between the two groups (P > 0.05). APTmax and APTmean had the high values of area under the ROC curve (AUC), which were 0.780 and 0.710, respectively. APTmax had a high sensitivity, and APTmean had a high specificity. The combination of APTmax, APTmean, ADCmean, and PSAD had the highest AUC value (AUC: 0.880, sensitivity: 86.540, specificity: 78.260).ConclusionAPTmax, APTmean, ADCmean, ADCmin, tPAD, FPSA, and PSAD showed to have a high value in differentiating malignant prostate lesions from benign prostate lesions in the separate assessment of indexes. The combination of APTmax, APTmean, ADCmean, and PSAD had the highest diagnostic value.

Human Kallikrein-2 and Free Prostate Specific Antigen as Biomarkers for Early Detection of Prostate Cancer, Sudan: A Case-Control Study

Background: Prostate cancer (PCa) is considered one of the major health threats facing males in Sudan. Prostate-specific antigen (PSA) test is the most important laboratory test used in the diagnosis of prostate cancer, the main disadvantage of PSA is its limited specificity, which triggered a lot of interest in development, more research on other markers such as serum human kallikrein-2 (KLK-2) and free prostate specific antigen (fPSA). Objectives: To evaluate the validity of serum kallikrein-2 (KLK-2) and free prostate specific antigen (fPSA) in the early detection of prostate cancer among Sudanese patients. Method: In this study seventy men were considered as a case subject, who were diagnosed as cancer prostate at Gezira Hospital for Renal Disease and Surgery (GHRDS), Sudan during the period February 2018 to July 2019. Randomly selected sixty patients of BPH patients and forty-five apparently healthy men as control subject. KLK-2, fPSA and PSA estimations were performed from serum samples using the principle of Enzyme Linked Immunosorbent Assay (ELISA). Results: The results revealed a highly significant difference between the serum levels individual biomarkers (KLK-2, fPSA, PSA) and multiple biomarkers (fPSA/PSA, KLK-2/fPSA, KLK-2/PSA) for patients with prostate cancer when compared with the control groups. Furthermore, the fPSA/PSA ratio was lower in the patients with prostate cancer (P value = 0.00) than in the control group, the fPSA/PSA ratio showed that best accuracy to differentiate prostate cancer from control group, fPSA cut-off value was found to be more than (18 ng/ml), with sensitivity (93%), specificity (80%), and odds ratio (55). Conclusions: The use of multiple biomarkers rather than individual biomarkers especially fPSA/PSA ratio improves the specificity as well as maintenance of higher sensitivity for early diagnosis of the prostate cancer.

Observation of Serological Index and Efficacy of Abiraterone Hydrochloride Tablets Combined with Endocrine Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer.

This study reviewed and analysed the serological indexes, clinical efficacy and common clinical indexes of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with combination of abiraterone hydrochloride tablets and endocrine therapy. This study is a retrospective analysis. A total of 133 mCRPC patients who were admitted to our hospital from January 2019 to December 2021 were selected as the study subjects. The patients were categorised into the experimental group (n = 51) and control group (n = 82) according to their treatment method. The control group was treated with docetaxel combined with endocrine therapy, whilst the experimental group was treated with combination therapy with abiraterone hydrochloride tablets. Subsequently, the clinical data of the two groups, including serum insulin-like growth factor-1 (IGF-1), human glandular kallikrein 2 (hK2), prostate specific antigen (PSA), vascular endothelial growth factor (VEGF) and serum carcinoembryonic antigen (CEA), were analysed. The overall response rate of the experimental group (84.3%) was higher than that of the control group (72.0%). The serum levels of CEA, total prostate specific antigen, free prostate specific antigen, testosterone and androgen receptor splice variant 7 in both groups were lower than those of before treatment, and the values obtained by the experimental group were lower than those of the control group (p < 0.05). After treatment, the levels of CD3+, CD4+ and CD4+/CD8+ in both groups were higher than those before treatment, and the levels of CD8+, IGF-1, hK2, PSA and VEGF in the two groups decreased after treatment (p < 0.05). The use of abiraterone hydrochloride tablet combined with endocrine therapy for patients with mCRPC is effective and can improve clinical symptoms and serum cytokine levels.

A retrospective study on significance of total and free Prostate specific antigen (PSA) level with their ratio in diagnosis of prostatic lesions at a tertiary care centre

A retrospective study on significance of total and free Prostate specific antigen (PSA) level with their ratio in diagnosis of prostatic lesions at a tertiary care centre

The prevalence and risk factors of upgrading of Gleason grade group between transrectal ultrasound prostate biopsy and prostatectomy specimens

The risk stratification of prostate cancer using Gleason grade group (GG), serum prostate-specific antigen (PSA), and T staging has an important role for appropriate treatment. In fact, the GG of biopsy was not the same as the prostatectomy specimen. The upgrading of GG has a significant risk of delay treatment. The study aims to evaluate the concordance of GG between biopsy and prostatectomy specimens and the factors of upgrading GG. Retrospectively reviewed data from January 2010 to December 2019, 137 patients underwent prostate biopsy and followed by prostatectomy. Patients' data include pathological reports, imaging reports, serum PSA, PSA density (PSAD), and free PSA were analyzed by univariate and multivariate analysis. The concordance between the pathology was found in 54 specimens (39.4%) with the upgrading of GG in the prostatectomy was 57 specimens (41.6%). Furthermore, the downgrading was 26 specimens (18.9%). Serum PSA >10 ng/ml (P 0.003), PSAD >0.2 ng/ml/cm3 (P 0.002), free/total PSA ratio (P 0.003), margin positive for malignancy (P 0.033), and extraprostatic involvement (P 0.039) were significantly related with upgrading at the univariate analysis. Only a PSAD >0.2 (P 0.014) was found to be an independent factor that is predictive of upstaging in multivariate analysis. The prevalence of upgrading of GG from prostate biopsy to radical prostatectomy is as high as the other study. The factor that related to upstaging of GG was PSAD. Therefore, additional tools for biopsy were required to enhance the accurate diagnosis and staging of prostate cancer.

Free PSA performs better than total PSA in predicting prostate volume in Chinese men with PSA levels of 2.5-9.9 ng ml-1.

This study investigated whether free prostate-specific antigen (fPSA) performs better than total PSA (tPSA) in predicting prostate volume (PV) in Chinese men with different PSA levels. A total of 5463 men with PSA levels of <10 ng ml-1 and without prostate cancer diagnosis were included in this study. Patients were classified into four groups: PSA <2.5 ng ml-1, 2.5-3.9 ng ml-1, 4.0-9.9 ng ml-1, and 2.5-9.9 ng ml-1. Pearson/Spearman's correlation coefficient (r) and receiver operating characteristic (ROC) curves were used to evaluate the ability of tPSA and fPSA to predict PV. The correlation coefficient between tPSA and PV in the PSA <2.5 ng ml-1 cohort (r = 0.422; P < 0.001) was markedly higher than those of the cohorts with PSA levels of 2.5-3.9 ng ml-1, 4.0-9.9 ng ml-1, and 2.5-9.9 ng ml-1 (r = 0.114, 0.167, and 0.264, respectively; all P ≤ 0.001), while fPSA levels did not differ significantly among different PSA groups. Area under ROC curve (AUC) analyses revealed that the performance of fPSA in predicting PV ≥40 ml (AUC: 0.694, 0.714, and 0.727) was better than that of tPSA (AUC = 0.545, 0.561, and 0.611) in men with PSA levels of 2.5-3.9 ng ml-1, 4.0-9.9 ng ml-1, and 2.5-9.9 ng ml-1, respectively, but not at PSA levels of <2.5 ng ml-1 (AUC: 0.713 vs 0.720). These findings suggest that the relationship between tPSA and PV may vary with PSA level and that fPSA is more powerful at predicting PV only in the ''gray zone'' (PSA levels of 2.5-9.9 ng ml-1), but its performance was similar to that of tPSA at PSA levels of <2.5 ng ml-1.

A prospective study of the prostate health index density and multiparametric magnetic resonance imaging in diagnosing clinically significant prostate cancer.

To evaluate the predictive performance of the prostate health index (PHI) and PHI density (PHID), for clinically significant prostate cancer (csPCa) in patients with a PI-RADS score ≤3. Patients tested for total prostate-specific antigen (tPSA, ≤100 ng/mL), free PSA (fPSA), and p2PSA at Peking University First Hospital were prospectively enrolled. Possible predictive factors of csPCa were analyzed using the receiver operating characteristic (ROC) curve. Results were expressed as area under the curve (AUC) with 95% confidence intervals (CI). The cutoff values of PHI and PHID were determined. We enrolled 222 patients in this study. The prevalence of csPCa in the PI-RADS ≤3 subgroup (n=89) was 22.47% (20/89). Age, tPSA, F/T, prostate volume, PSA density, PHI, PHID, and PI-RADS score were significantly associated with csPCa. PHID (AUC: 0.829 [95% CI: 0.717-0.941]) was the best predictor of csPCa. PHID >0.956 was set as the threshold of suspicious csPCa with a sensitivity of 85.00% and a specificity of 73.91%, avoiding 94.44% of unnecessary biopsies but missing 15.00% csPCa. A threshold of PHI ≥52.83 showed the same sensitivity but a rather lower specificity of 65.22% that avoided 93.75% of unnecessary biopsies. PHI and PHID have the best predictive performance of csPCa in patients with PI-RADS score ≤3. A threshold value of PHID ≥0.956 may be used as the criterion for biopsy in these patients.

Abstract IA023: Improved sensitivity of a multi-analyte early detection test based on mutation, methylation, aneuploidy, and protein biomarkers

Abstract Background: A multi-analyte blood test has the potential to maximize performance for early detection across different cancer stages and types. Improvements in early-stage cancer detection might be achieved using multi-component tests with high sensitivities and specificities. We recently performed a large feasibility study to assess the performance of 4 biomarkers (aneuploidy, methylation, mutation, and protein) for the detection of cancers from up to 15 organ sites. Specifically, a training and validation set was tested for 3 biomarkers (aneuploidy, methylation, and protein) and the performance was subsequently confirmed in an independent testing set. Methods: We have now further improved the performance of a 4-marker cancer detection blood test by fine-tuning the respective marker calling models and thresholds, exploring prostate-specific antigen (PSA) for prostate cancer detection, and developing an overarching Machine Learning (ML) cancer classifier. To improve the mutation detection, we tested (in triplicate) 200 plasma and buffy samples from young, non-cancer subjects and mutant DNA from cell lines to develop an ML-based mutation calling algorithm. This caller was validated on 186 samples and tested on an independent set of 1388 cancer and non-cancer samples. The calling of cancer-associated DNA methylation events was refined by performing training, validation, and testing across different studies. We also explored models for methylation detection based solely on distribution of methylation signal observed in non-cancer samples. Free and total PSA were investigated as markers for prostate cancer detection by including clinically relevant Gleason scores in the development of the protein-based cancer calling algorithm. Results: In the previous analysis the combination of mutation, aneuploidy, methylation, and protein biomarkers resulted in an overall sensitivity of 61.0% (95% CI: 56.9%-65.0) at a specificity of 98.2% (95% CI: 97.1 – 99.4%). We will present the added performance benefit of ML-based mutation variant calling. PSA derived features were evaluated with the goal of increasing the detectability of high-grade prostate cancers while minimizing the detection of indolent cancers. Lastly, we compared the Boolean logic-based 4-biomarker combination algorithm used in the previous analysis with an ML-based cancer classifier. The results of the modeling, applied to the testing set, will be shared. Conclusions: In summary, improvements in cancer detection performance may be achieved by optimizing each biomarker calling algorithm as well as overarching cancer classifier. When combining these improvements, we believe that a single blood test will provide robust sensitivity for the detection of several cancer types, particularly for earlier-stage disease in real world settings. Citation Format: Vladimir Gianullin, Leonardo Hagmann, Kevin Arvai, Amira Djebbari, Christopher L. Nobles, Larson Hogstrom, Mael Manesse, Vuna Fa, Fanglei Zhuang, Xi Chen, Viatcheslav E. Katerov, Jorge Garces, Hatim T. Allawi, Abigail McElhinny, Frank Diehl, Gustavo C Cerqueira. Improved sensitivity of a multi-analyte early detection test based on mutation, methylation, aneuploidy, and protein biomarkers. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA023.

Abstract P041: Improved sensitivity of a multi-analyte early detection test based on mutation, methylation, aneuploidy, and protein biomarkers

Abstract Background: A multi-analyte blood test has the potential to maximize performance for early detection across different cancer stages and types. Improvements in early-stage cancer detection might be achieved using multi-component tests with high sensitivities and specificities. We recently performed a large feasibility study to assess the performance of 4 biomarkers (aneuploidy, methylation, mutation, and protein) for the detection of cancers from up to 15 organ sites. Specifically, a training and validation set was tested for 3 biomarkers (aneuploidy, methylation, and protein) and the performance was subsequently confirmed in an independent testing set. Methods: We have now further improved the performance of a 4-marker cancer detection blood test by fine-tuning the respective marker calling models and thresholds, exploring prostate-specific antigen (PSA) for prostate cancer detection, and developing an overarching Machine Learning (ML) cancer classifier. To improve the mutation detection, we tested (in triplicate) 200 plasma and buffy samples from young, non-cancer subjects and mutant DNA from cell lines to develop an ML-based mutation calling algorithm. This caller was validated on 186 samples and tested on an independent set of 1388 cancer and non-cancer samples. The calling of cancer-associated DNA methylation events was refined by performing training, validation, and testing across different studies. We also explored models for methylation detection based solely on distribution of methylation signal observed in non-cancer samples. Free and total PSA were investigated as markers for prostate cancer detection by including clinically relevant Gleason scores in the development of the protein-based cancer calling algorithm. Results: In the previous analysis the combination of mutation, aneuploidy, methylation, and protein biomarkers resulted in an overall sensitivity of 61.0% (95% CI: 56.9%-65.0) at a specificity of 98.2% (95% CI: 97.1 – 99.4%). We will present the added performance benefit of ML-based mutation variant calling. PSA derived features were evaluated with the goal of increasing the detectability of high-grade prostate cancers while minimizing the detection of indolent cancers. Lastly, we compared the Boolean logic-based 4-biomarker combination algorithm used in the previous analysis with an ML-based cancer classifier. The results of the modeling, applied to the testing set, will be shared. Conclusions: In summary, improvements in cancer detection performance may be achieved by optimizing each biomarker calling algorithm as well as overarching cancer classifier. When combining these improvements, we believe that a single blood test will provide robust sensitivity for the detection of several cancer types, particularly for earlier-stage disease in real world settings. Citation Format: Vladimir Gianullin, Leonardo Hagmann, Kevin Arvai, Amira Djebbari, Christopher L. Nobles, Larson Hogstrom, Mael Manesse, Vuna Fa, Fanglei Zhuang, Xi Chen, Viatcheslav E. Katerov, Jorge Garces, Hatim T. Allawi, Abigail McElhinny, Frank Diehl, Gustavo C Cerqueira. Improved sensitivity of a multi-analyte early detection test based on mutation, methylation, aneuploidy, and protein biomarkers. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P041.

Screening for Prostate Cancer: Role of Free Psa, Psad with Prostate Biopsy Findings and Digital Rectal Examination

Background and Aim The incidence of various cancers including the prostate, is on the rise globally. Prostate cancer is one of the most frequently reported cancer in men worldwide. This study was done to study the correlation of free PSA, percentage free PSA, and PSAD, with prostate biopsy findings, and the role of DRE in screening for carcinoma prostate. Methods The cross-sectional, correlational study was conducted at a tertiary care hospital in Coastal Kerala, over a period of 18 months in a sample size of 100 patients. The following was the study outline followed; Results The prevalence of prostate cancer was found to be 41%, maximum number of patients were in the age group of 50 -70 years of age. Percentage free PSA (%fPSA) and prostate volume were found to vary significantly between patients with Benign Prostate Hyperplasia and prostate cancer. At a cut off of 0.15, PSA density was seen to significantly vary between patients with BPH and prostate cancer. At a cut off of 15% (chosen based on prior studies), %fPSA was seen to significantly vary between patients with BPH and prostate cancer. The sensitivity and specificity of %fPSA were 73.17% and 93.22% respectively. Digital rectal examination varied significantly between patients with benign enlargement and those with malignancy. However, false positive rate with DRE alone was 44.06%. Conclusion DRE continues to be a useful screening technique as a part of clinical examination to identify patients who should undergo further screening for prostate cancer such as PSA estimation, free PSA estimation, and if required, a prostate biopsy, but DRE alone cannot be used to make accurate clinical decision owing to the false positives. Percentage fPSA could be a useful tool that can be used to avoid unnecessary biopsies in patients with a PSA range between 4.0 – 10.0 ng/ml.

Prospective of 18-Core TRUS Biopsy and Detection Rate of Prostate Cancer

Background: A systematic 12-core transrectal ultrasound (TRUS)-guided prostate biopsy is currently recommended for prostate malignancy detection modalities. However, there is limited data about the diagnostic yield of increasing the core number to 18. Objective: To assess the effectiveness of cancer detection and clinical advantages between 12- and 18-core TRUS biopsies. Materials and Methods: The authors conducted a prospective, single-group trial of TRUS biopsies specifically for patients with prostate-specific antigen (PSA) levels between 4.0 and 20.0 ng/mL. Sixty-two consecutive patients were enrolled and received a 12- or an 18-core TRUS biopsy under local anaesthesia. The patients and prostate cancer characteristics, such as serum PSA, free PSA, prostate volume, PSA density, D’Amico risk classification, and Gleason grade group were recorded and analysed. Results: The prostate cancer detection rate using 12 cores for the initial TRUS biopsy was 22.6% (14 patients), while using 18 cores was 24.2% (15 patients). The results were not statistically different (p=0.83). Postoperative complications were two cases of gross haematuria and two case of acute urinary retention, which did not require admission. Infection occurred in two patients and no serious morbidities or mortalities. Conclusion: The present study did not find any significant benefit in increasing the number of biopsy cores from 12 to 18 for the diagnosis of prostate cancer in men with serum PSA levels between 4.0 and 20.0 ng/mL. Keywords: Transrectal prostate biopsy; 12-core; 18-core; Prostate cancer; Cancer detection

Development of a novel nomogram for predicting clinically significant prostate cancer with the prostate health index and multiparametric MRI.

On prostate biopsy, multiparametric magnetic resonance imaging (mpMRI) and the Prostate Health Index (PHI) have allowed prediction of clinically significant prostate cancer (csPCa). To predict the likelihood of csPCa, we created a nomogram based on a multivariate model that included PHI and mpMRI. We assessed 315 males who were scheduled for prostate biopsies. We used the Prostate Imaging Reporting and Data System version 2 (PI-RADS V2) to assess mpMRI and optimize PHI testing prior to biopsy. Univariate analysis showed that csPCa may be identified by PHI with a cut-off value of 77.77, PHID with 2.36, and PI-RADS with 3 as the best threshold. Multivariable logistic models for predicting csPCa were developed using PI-RADS, free PSA (fPSA), PHI, and prostate volume. A multivariate model that included PI-RADS, fPSA, PHI, and prostate volume had the best accuracy (AUC: 0.882). Decision curve analysis (DCA), which was carried out to verify the nomogram's clinical applicability, showed an ideal advantage (13.35% higher than the model that include PI-RADS only). In conclusion, the nomogram based on PHI and mpMRI is a valuable tool for predicting csPCa while avoiding unnecessary biopsy as much as possible.

Kinetic Analysis of Prostate-Specific Antigen Interaction with Monoclonal Antibodies for Development of a Magnetic Immunoassay Based on Nontransparent Fiber Structures.

Prostate cancer is the second most common cancer diagnosed in men worldwide. Measuring the prostate-specific antigen (PSA) is regarded as essential during prostate cancer screening. Early diagnosis of this disease relapse after radical prostatectomy requires extremely sensitive methods. This research presents an approach to development of an ultrasensitive magnetic sandwich immunoassay, which demonstrates the limit of PSA detection in human serum of 19 pg/mL at a dynamic range exceeding 3.5 orders of concentration. Such attractive performance stems, inter alia, from the kinetic analysis of monoclonal antibodies (mAbs) against free PSA to select the mAbs exhibiting best kinetic characteristics and specificity. The analysis is carried out with a label-free multiplex spectral-correlation interferometry compatible with inexpensive single-use glass sensor chips. The high sensitivity of developed PSA immunoassay is due to electronic quantification of magnetic nanolabels functionalized by the selected mAbs and three-dimension porous filters used as an extended solid phase. The assay is promising for PSA monitoring after radical prostatectomy. The proposed versatile approach can be applied for the rational design of highly sensitive tests for detection of other analytes in many fields, including in vitro diagnostics, veterinary, food safety, etc.