Inferior Cancer Survival for Men with Localized High-grade Prostate Cancer but Low Prostate-specific Antigen.
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ABSTRACT:
SUBMITTER: Fankhauser CD
PROVIDER: S-EPMC8411278 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe consequences of low prostate-specific antigen (PSA) in high-grade (Gleason 8-10) prostate cancer are unknown.ObjectiveTo evaluate the clinical implications and genomic features of low-PSA, high-grade disease.Design, setting, and participantsThis was a retrospective study of clinical data for 494 793 patients from the National Cancer Data Base and 136 113 patients from the Surveillance, Epidemiology, and End Results program with cT1-4N0M0 prostate cancer (median follow-up 48.9 and 25.0 mo, respectively), and genomic data for 4960 patients from the Decipher Genomic Resource Information Database. Data were collected for 2004-2017.Outcome measurements and statistical analysisMultivariable Fine-Gray and Cox regressions were used to analyze prostate cancer-specific mortality (PCSM) and all-cause mortality, respectively.Results and limitationsFor Gleason 8-10 disease, using PSA 4.1-10.0ng/ml (n=38 719) as referent, the distribution of PCSM by PSA was U-shaped, with an adjusted hazard ratio (AHR) of 2.70 for PSA ≤2.5ng/ml (n=3862, p<0.001) versus 1.97, 1.36, and 2.56 for PSA of 2.6-4.0 (n=4199), 10.1-20.0 (n=17 372), and >20.0ng/ml (n=16 114), respectively. By contrast, the distribution of PCSM by PSA was linear for Gleason ≤7 (using PSA 4.1-10.0ng/ml as the referent, n=359 898), with an AHR of 0.41 (p=0.13) for PSA ≤2.5ng/ml (n=37 812) versus 1.38, 2.28, and 4.61 for PSA of 2.6-4.0 (n=54 152), 10.1-20.0 (n=63 319), and >20.0ng/ml (n=35 459), respectively (pinteraction<0.001). Gleason 8-10, PSA ≤2.5ng/ml disease had a significantly higher PCSM than standard high-risk/very high-risk disease with PSA >2.5ng/ml (AHR 2.15, p=0.002; 47-mo PCSM 14% vs 4.9%). Among Gleason 8-10 patients treated with radiotherapy, androgen deprivation therapy was associated with a survival benefit for PSA >2.5ng/ml (AHR 0.87; p<0.001) but not ≤2.5ng/ml (AHR 1.36; p=0.084; pinteraction=0.021). For Gleason 8-10 tumors, PSA ≤2.5ng/ml was associated with higher expression of neuroendocrine/small-cell markers compared to >2.5ng/ml (p=0.046), with no such relationship for Gleason ≤7 disease.ConclusionsLow-PSA, high-grade prostate cancer has very high risk for PCSM, potentially responds poorly to androgen deprivation therapy, and is associated with neuroendocrine genomic features.Patient summaryIn this study, we found that low-prostate-specific antigen, high-grade prostate cancer has a very high risk for prostate cancer death, may not respond well to androgen deprivation therapy, and is associated with neuroendocrine genomic features. These findings suggest that current nomograms and treatment paradigms may need modification.
| S-EPMC6615042 | biostudies-literature
Project description:The Nutritional Prevention of Cancer trial showed a 52% lower incidence of prostate cancer in men supplemented with selenium. As a result, our study was designed to assess whether selenium supplementation attenuates the progression of prostate cancer. A phase 2 randomized, double-blind, placebo-controlled clinical trial was conducted in men with localized nonmetastatic prostate cancer who had elected to forgo active treatment and be followed by active surveillance. A total of 140 men were randomized to placebo (n = 46), 200 microg/d (n = 47), or 800 microg/d (n = 47) selenium p.o. (as selenized yeast) and followed every 3 months for up to 5 years. Prostate-specific antigen (PSA) velocity was used as a marker of prostate cancer progression and was estimated using mixed-effects regression. Adjusting for age, body mass index, baseline selenium, smoking, baseline PSA, race, PSA method, and Gleason score, PSA velocities for the 200 microg/d and 800 microg/d treatment groups were not statistically significantly different from placebo (P = 0.32 and P = 0.61, respectively). In the highest quartile of baseline selenium, men supplemented with 800 microg selenium showed statistically significantly higher PSA velocity as compared with placebo (P = 0.018). Selenium supplementation did not show a protective effect on PSA velocity in subjects with localized prostate cancer. On the contrary, supplementation with high-dose selenium was observed to be a risk factor for increased PSA velocity in men with high baseline plasma selenium concentrations.
| S-EPMC4533875 | biostudies-literature
Project description:Prostate specific antigen velocity is an unreliable predictor of adverse pathology findings in patients on active surveillance for low risk prostate cancer. However, to our knowledge a new concept called prostate specific antigen velocity risk count, recently validated in a screening cohort, has not been investigated in an active surveillance cohort.We evaluated a cohort of men from 1995 to 2012 with prostate cancer on active surveillance. They had stage T1c disease, prostate specific antigen density less than 0.15 ng/ml, Gleason score 6 or less, 2 or fewer biopsy cores and 50% or less involvement of any core with cancer. The men were observed by semiannual prostate specific antigen measurements, digital rectal examinations and an annual surveillance biopsy. Treatment was recommended for biopsy reclassification. Patients with 30 months or greater of followup and 3 serial prostate specific antigen velocity measurements were used in primary analysis by logistic regression, Cox proportional hazards, Kaplan-Meier analysis and performance parameters, including the AUC of the ROC curve.Primary analysis included 275 of 668 men who met very low risk inclusion criteria, of whom 83 (30.2%) were reclassified at a median of 57.1 months. Reclassification risk increased with risk count, that is a risk count of 3 (HR 4.63, 95% CI 1.54-13.87) and 2 (HR 3.73, 95% CI 1.75-7.97) compared to zero. Results were similar for Gleason score reclassification (HR 7.45, 95% CI 1.60-34.71 and 3.96, 95% CI 1.35-11.62, respectively). On secondary analysis the negative predictive value (risk count 1 or less) was 91.5% for reclassification in the next year. Adding the prostate specific antigen velocity risk count improved the AUC in a model including baseline prostate specific antigen density (0.7423 vs 0.6818, p = 0.025) and it outperformed the addition of overall prostate specific antigen velocity (0.7423 vs 0.6960, p = 0.037).Prostate specific antigen velocity risk count may be useful for monitoring patients on active surveillance and decreasing the frequency of biopsies needed in the long term.
| S-EPMC4711358 | biostudies-other
Project description:Thymidine kinase 1 (TK1) is an intracellular enzyme involved in DNA-precursor synthesis. Increased serum TK1 levels are used as a biomarker in various malignancies. We combined serum TK1 with PSA and evaluated its capacity to predict overall survival (OS) in 175 men with prostate cancer (PCa), detected by screening in 1988-1989 (n = 52) and during follow-up (median 22.6 years) (n = 123). TK1 was measured in frozen serum, age was stratified into four groups, and dates of PCa diagnosis and dates of death were obtained from Swedish population-based registries. The median concentration of TK1 and PSA was 0.25 and 3.8 ng/ml. TK1 was an independent variable of OS. In the multivariate analysis, PSA was not statistically significant in combination with age whereas the significance remained for TK1 + PSA. Measured once, TK1 + PSA predicted a difference of up to 10 years (depending on patient subgroup) in OS at a median of 9 years before PCa diagnosis. The TK1 concentration in 193 controls without malignancies did not differ from that of the PCa patients, hence TK1 was likely not released from incidental PCa. Thus, TK1 in the blood circulation may indicate the release of TK1 from sources other than cancers, nonetheless associated with OS.
| S-EPMC10049218 | biostudies-literature
Project description:ContextDespite a lack of data, increasing numbers of patients are receiving primary androgen deprivation therapy (PADT) as an alternative to surgery, radiation, or conservative management for the treatment of localized prostate cancer.ObjectiveTo evaluate the association between PADT and survival in elderly men with localized prostate cancer.Design, setting, and patientsA population-based cohort study of 19,271 men aged 66 years or older receiving Medicare who did not receive definitive local therapy for clinical stage T1-T2 prostate cancer. These patients were diagnosed in 1992-2002 within predefined US geographical areas, with follow-up through December 31, 2006, for all-cause mortality and through December 31, 2004, for prostate cancer-specific mortality. Instrumental variable analysis was used to address potential biases associated with unmeasured confounding variables.Main outcome measuresProstate cancer-specific survival and overall survival.ResultsAmong patients with localized prostate cancer (median age, 77 years), 7867 (41%) received PADT, and 11,404 were treated with conservative management, not including PADT. During the follow-up period, there were 1560 prostate cancer deaths and 11,045 deaths from all causes. Primary androgen deprivation therapy was associated with lower 10-year prostate cancer-specific survival (80.1% vs 82.6%; hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.03-1.33) and no increase in 10-year overall survival (30.2% vs 30.3%; HR, 1.00; 95% CI, 0.96-1.05) compared with conservative management. However, in a prespecified subset analysis, PADT use in men with poorly differentiated cancer was associated with improved prostate cancer-specific survival (59.8% vs 54.3%; HR, 0.84; 95% CI, 0.70-1.00; P = .049) but not overall survival (17.3% vs 15.3%; HR, 0.92; 95% CI, 0.84-1.01).ConclusionPrimary androgen deprivation therapy is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management.
| S-EPMC2645653 | biostudies-literature
Project description:Objective: This study compared survival of prostate cancer patients with low prostate specific antigen level (PSA ≤ 10 ng/ml) and high-grades of Gleason score (GS) of 8-10 with different treatment options (i.e., radical prostatectomy [RP], external beam radiotherapy [EBRT], or external beam radiotherapy with brachytherapy [EBRT+BT]). Materials and Methods: The Surveillance, Epidemiology and End Results (SEER) database data (2004-2013), and overall survival (OS) and prostate cancer-specific mortality (PCSM), were evaluated using the Cox proportional hazards regression model and Fine and Gray competing risk model. Results: The SEER data contained 9,114 patients, 4,175 of whom received RP, 4,114 received EBRT, and 825 received EBRT+BT with a median follow-up duration of 47 months. RP patients had significantly better OS than patients with EBRT and EBRT+BT (adjusted HR [AHR]: 3.36, 95% CI: 2.43-4.64, P < 0.001; AHR: 2.15, 95% CI: 1.32-3.48, P = 0.002; respectively). There was no statistical difference in PCSM between RP and EBRT+BT (AHR: 1.31, 95% CI: 0.61-2.80, P = 0.485), while EBRT had worse OS (P < 0.05). The subgroup analysis revealed that there was no statistical difference in prognosis of patients with age of >70 years old, or PSA levels of ≤ 2.5 ng/ml between RP and EBRT+BT (P > 0.05). Conclusion: RP patients with low PSA levels and high GS had better OS compared to either EBRT or EBRT+BT, while RP and EBRT+BT resulted in significantly lower PCSM, compared to EBRT. Moreover, EBRT+BT and RP were associated with similar survival of patients with age of > 70 years old, or PSA levels of ≤ 2.5 ng/ml.
| S-EPMC6659440 | biostudies-literature
Project description:BACKGROUND:Prostate-specific antigen (PSA) measurement in midlife predicts long-term prostate cancer (PCa) mortality among white men. OBJECTIVE:To determine whether baseline PSA level during midlife predicts risk of aggressive PCa in black men. DESIGN, SETTING, AND PARTICIPANTS:Nested case-control study among black men in the Southern Community Cohort Study recruited between 2002 and 2009. A prospective cohort in the southeastern USA with recruitment from community health centers. A total of 197 incident PCa patients aged 40-64 yr at study entry and 569 controls matched on age, date of blood draw, and site of enrollment. Total PSA was measured in blood collected and stored at enrollment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Total and aggressive PCa (91 aggressive: Gleason ?7, American Joint Committee on Cancer stage III/IV, or PCa-specific death). Exact conditional logistic regression estimated odds ratios (ORs) with 95% confidence intervals (CIs) for PCa by category of baseline PSA. RESULTS AND LIMITATIONS:Median PSA among controls was 0.72, 0.80, 0.94, and 1.03ng/ml for age groups 40-49, 50-54, 55-59, and 60-64 yr, respectively; 90th percentile levels were 1.68, 1.85, 2.73, and 3.33ng/ml. Furthermore, 95% of total and 97% of aggressive cases had baseline PSA above the age-specific median. Median follow-up was 9 yr. The OR for total PCa comparing PSA >90th percentile versus ?median was 83.6 (95% CI, 21.2-539) for 40-54 yr and 71.7 (95% CI, 23.3-288) for 55-64 yr. For aggressive cancer, ORs were 174 (95% CI, 32.3-infinity) for 40-54 yr and 51.8 (95% CI, 11.0-519) for 55-64 yr. A composite endpoint of aggressive PCa based on stage, grade, and mortality was used and is a limitation. CONCLUSIONS:PSA levels in midlife strongly predicted total and aggressive PCa among black men. PSA levels among controls were similar to those among white controls in prior studies. PATIENT SUMMARY:Prostate-specific antigen (PSA) level during midlife strongly predicted future development of aggressive prostate cancer among black men. Targeted screening based on a midlife PSA might identify men at high risk while minimizing screening in those men at low risk.
| S-EPMC6390280 | biostudies-literature
Project description:Combined molecular and morphologic imaging modalities have emerged in recent years as an alternative to conventional imaging in prostate cancer (PC). In particular, novel prostate-specific membrane antigen (PSMA) radiotracers have demonstrated increased sensitivity and specificity for the initial staging of men with clinically localized PC, as well as for PC detection in the setting of biochemical recurrence (BCR). Molecular imaging is increasingly used to guide treatment decisions in these patients-though its impact on survival has yet to be established. Improved PC detection in men with BCR has also helped to identify a subset of patients with oligometastatic disease. The optimal management of oligometastatic PC and the role of metastasis-directed therapies (MDT) are the subjects of ongoing studies. In comparison to clinically localized or biochemically recurrent PC, the role of molecular imaging in men with advanced disease is less established. In metastatic castration-resistant PC (mCRPC), PSMA-based imaging has primarily been investigated as a companion diagnostic tool to predict and monitor response to PSMA-targeted radioligand therapy (RLT). More recent efforts have focused on using molecular imaging to monitor treatment response to conventional chemohormonal therapies. However, despite promising early results, several barriers remain to the widespread use of PSMA-based imaging in metastatic PC: temporary flares in PSMA uptake have been described in a subset of patients after initiation of therapy, and the underlying mechanism and clinical implications of this phenomenon are still poorly understood. Furthermore, whereas PSMA is invariably expressed in hormone-sensitive PC, loss of PSMA expression is increasingly recognized in a subset of mCRPC patients with aggressive disease. Although this may limit the use of PSMA-based imaging as a standalone modality in advanced PC, loss of PSMA uptake may also provide non-invasive and clinically relevant molecular insight on patients' underlying tumor biology.
| S-EPMC8350242 | biostudies-literature
Project description:BackgroundPatient-related factors such as concern about cancer are believed to influence both men's decisions to undergo prostate specific antigen (PSA) testing and to have definitive treatment if diagnosed with low risk prostate cancer (PCa). The potential link between screening frequency and choice of active surveillance (AS) for low risk disease has not been studied previously. Our aim was to investigate whether there is any association between PCa screening frequency or previous negative prostate biopsy and uptake of AS among men with low risk PCa.MethodsThis register-based study included all men ?75?years from Stockholm who were diagnosed with low risk PCa from 2008 to 2014 (n?=?4336). Pre-diagnostic PSA testing and biopsy histories were obtained from the Stockholm PSA and Biopsy Register, a population-based register for the Stockholm country. The association between previous screening/biopsy history and AS uptake (based on primary treatment recorded in the National Prostate Cancer Register) was examined using multivariable logistic regression.ResultsForty seven percent of men with low risk PCa underwent AS. Uptake was associated with older age, very low risk disease, more recent diagnosis and absence of family history. None of the screening/biopsy measures (testing frequency, mean interval, PSA velocity, highest pre-diagnostic PSA or prior negative biopsy) were associated with uptake of AS among men with low risk PCa. Generalisability to settings with different policies and practices may be limited.ConclusionWe found no evidence that screening frequency and negative biopsy influence uptake of AS among Swedish men with low risk PCa. Further research is required to determine factors that still present barriers for men taking up AS.
| S-EPMC6683376 | biostudies-literature
Project description:BackgroundAbnormal metabolism and perturbations in metabolic pathways play significant roles in the development and progression of prostate cancer; however, comprehensive metabolomic analyses of human data are lacking and needed to elucidate the interrelationships.MethodsWe examined the serum metabolome in relation to prostate cancer survival in a cohort of 1812 cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Using an ultrahigh-performance LC-MS/MS platform, we identified 961 known metabolites in prospectively collected serum. Median survival time from diagnosis to prostate cancer-specific death (N=472) was 6.6 years (interquartile range=2.9-11.1 years). Cox proportional hazards regression models estimated hazard ratios and 95% confidence intervals of the associations between the serum metabolites (in quartiles) and prostate cancer death, adjusted for age at baseline and diagnosis, disease stage, and Gleason sum. In order to calculate risk scores, we first randomly divided the metabolomic data into a discovery set (70%) and validated in a replication set (30%).ResultsOverall, 49 metabolites were associated with prostate cancer survival after Bonferroni correction. Notably, higher levels of the phospholipid choline, amino acid glutamate, long-chain polyunsaturated fatty acid (n6) arachidonate (20:4n6), and glutamyl amino acids gamma-glutamylglutamate, gamma-glutamylglycine, and gamma-glutamylleucine were associated with increased risk of prostate cancer-specific mortality (fourth versus first quartile HRs=2.07-2.14; P-values <5.2×10-5). By contrast, the ascorbate/aldarate metabolite oxalate, xenobiotics S-carboxymethyl-L-cysteine, fibrinogen cleavage peptides ADpSGEGDFXAEGGGVR and fibrinopeptide B (1-12) were related to reduced disease-specific mortality (fourth versus first quartile HRs=0.82-0.84; P-value <5.2×10-5). Further adjustment for years from blood collection to cancer diagnosis, body mass index, smoking intensity and duration, and serum total and high-density lipoprotein cholesterol did not alter the results. Participants with a higher metabolic score based on the discovery set had an elevated risk of prostate cancer-specific mortality in the replication set (fourth versus first quartile, HR=3.9, P-value for trend<0.0001).ConclusionsThe metabolic traits identified in this study, including for choline, glutamate, arachidonate, gamma-glutamyl amino acids, fibrinopeptides, and endocannabinoid and redox pathways and their composite risk score, corroborate our previous analysis of fatal prostate cancer and provide novel insights and potential leads regarding the molecular basis of prostate cancer progression and mortality.
| S-EPMC9594924 | biostudies-literature