Adaption and National Validation of a Tool for Predicting Mortality from Other Causes Among Men with Nonmetastatic Prostate Cancer.

BACKGROUND: An electronic health record-based tool could improve accuracy and eliminate bias in provider estimation of the risk of death from other causes among men with nonmetastatic cancer. OBJECTIVE: To recalibrate and validate the Veterans Aging Cohort Study Charlson Comorbidity Index (VACS-CCI) to predict non-prostate cancer mortality (non-PCM) and to compare it with a tool predicting prostate cancer mortality (PCM). DESIGN, SETTING, AND PARTICIPANTS: An observational cohort of men with biopsy-confirmed nonmetastatic prostate cancer, enrolled from 2001 to 2018 in the national US Veterans Health Administration (VA), was divided by the year of diagnosis into the development (2001-2006 and 2008-2018) and validation (2007) sets. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mortality (all cause, non-PCM, and PCM) was evaluated. Accuracy was assessed using calibration curves and C statistic in the development, validation, and combined sets; overall; and by age (<65 and 65+ yr), race (White and Black), Hispanic ethnicity, and treatment groups. RESULTS AND LIMITATIONS: Among 107 370 individuals, we observed 24 977 deaths (86% non-PCM). The median age was 65 yr, 4947 were Black, and 5010 were Hispanic. Compared with CCI and age alone (C statistic 0.67, 95% confidence interval [CI] 0.67-0.68), VACS-CCI demonstrated improved validated discrimination (C statistic 0.75, 95% CI 0.74-0.75 for non-PCM). The prostate cancer mortality tool also discriminated well in validation (C statistic 0.81, 95% CI 0.78-0.83). Both were well calibrated overall and within subgroups. Owing to missing data, 18 009/125 379 (14%) were excluded, and VACS-CCI should be validated outside the VA prior to outside application. CONCLUSIONS: VACS-CCI is ready for implementation within the VA. Electronic health record-assisted calculation is feasible, improves accuracy over age and CCI alone, and could mitigate inaccuracy and bias in provider estimation. PATIENT SUMMARY: Veterans Aging Cohort Study Charlson Comorbidity Index is ready for application within the Veterans Health Administration. Electronic health record-assisted calculation is feasible, improves accuracy over age and Charlson Comorbidity Index alone, and might help mitigate inaccuracy and bias in provider estimation of the risk of non-prostate cancer mortality.

Prostate cancer detection through unbiased capture of methylated cell-free DNA.

Prostate cancer screening using prostate-specific antigen (PSA) has been shown to reduce mortality but with substantial overdiagnosis, leading to unnecessary biopsies. The identification of a highly specific biomarker using liquid biopsies, represents an unmet need in the diagnostic pathway for prostate cancer. In this study, we employed a method that enriches for methylated cell-free DNA fragments coupled with a machine learning algorithm which enabled the detection of metastatic and localized cancers with AUCs of 0.96 and 0.74, respectively. The model also detected 51.8% (14/27) of localized and 88.7% (79/89) of patients with metastatic cancer in an external dataset. Furthermore, we show that the differentially methylated regions reflect epigenetic and transcriptomic changes at the tissue level. Notably, these regions are significantly enriched for biologically relevant pathways associated with the regulation of cellular proliferation and TGF-beta signaling. This demonstrates the potential of circulating tumor DNA methylation for prostate cancer detection and prognostication.

Metabolic imaging across scales reveals distinct prostate cancer phenotypes.

Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer.

Optimising the use of the prostate- specific antigen blood test in asymptomatic men for early prostate cancer detection in primary care: report from a UK clinical consensus.

BACKGROUND: Screening is not recommended for prostate cancer in the UK. Asymptomatic men aged ≥50 years can request a prostate-specific antigen (PSA) test following counselling on potential harms and benefits. There are areas of clinical uncertainty among GPs, resulting in the content and quality of counselling varying. AIM: To produce a consensus that can influence guidelines for UK primary care on the optimal use of the PSA test in asymptomatic men for early prostate cancer detection. DESIGN AND SETTING: Prostate Cancer UK facilitated a RAND/UCLA consensus. METHOD: Statements covering five topics were developed with a subgroup of experts. A panel of 15 experts in prostate cancer scored (round one) statements on a scale of one (strongly disagree) to nine (strongly agree). Panellists met to discuss statements before rescoring (round two). A lived experience panel of seven men scored a subset of statements with outcomes fed into the main panel. RESULTS: Of the initial 94 statements reviewed by the expert panel, a final 48/85 (56%) achieved consensus. In the absence of screening, there was consensus on proactive approaches to initiate discussions about the PSA test with men who were at higher-than-average risk. CONCLUSION: Improvements in the prostate cancer diagnostic pathway may have reduced some of the harms associated with PSA testing; however, several areas of uncertainty remain in relation to screening, including optimal PSA thresholds for referral and intervals for retesting. There is consensus on proactive approaches to testing in higher-than-average risk groups. This should prompt a review of current guidelines.

Diagnostic value of the abnormal digital rectal examination in the modern MRI-based prostate cancer diagnostic pathway.

Objective: Currently the National Institute for Health and Care Excellence (NICE) recommends an abnormal digital rectal examination (DRE) as a standalone referral criterion for suspected prostate cancer. Unlike referrals for a raised prostate-specific antigen (PSA) which are triaged directly to magnetic resonance imaging (MRI), an abnormal DRE requires re-examination in a secondary clinic first. Here, we investigated the ongoing value of the abnormal DRE as a referral criterion. Methods: This study is a retrospective review of patients referred to secondary care for suspected prostate cancer based on an abnormal DRE over a 15-month period at a single UK hospital (n = 158). Age, PSA, primary and repeat DRE findings and eventual diagnosis were collated. Results: A concurrent raised PSA was present in 65/158 (41%). Concordance between primary and secondary care DRE was only 72/158 (46%). The overall and significant cancer detection rate was 26/158 (16%) and 22/158 (14%), respectively. Among men with a concurrent raised PSA, 19/65 (29%) had significant cancer found, whereas with an abnormal primary care DRE and normal PSA (n = 93), only 3/93 (3%) had a significant cancer. Mandating a PSA before referral for an abnormal DRE would have redirected 65/158 (41%) of men to MRI first, negating the need for a repeat DRE (p < 0.0001). This finding was recapitulated in a second prospective validation cohort (n = 30) with 9/30 (30%) redirected to MRI first. Conclusions: This is one of the first studies to investigate the value of the DRE in contemporary practice. We propose that PSA is used to triage men with an abnormal DRE to MRI without needing a repeat DRE. If the PSA is normal, the diagnostic yield is low but may still warrant a repeat DRE to assess the need for further investigations. Additional multicentre studies are required to further validate our findings. Level of evidence: 4.