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Biomarkers for determination prostate cancer: Implication for diagnosis and prognosis
Abstract
Prostate cancer (PCa) belongs to most common cancers and it is the second leading cause of cancer death in men. A genetic predisposition or acquired genetic and epigenetic changes with effect of other factors, such as advanced age, race and environmental factors contribute to PCa development. PCa is a very heterogeneous disease that is characterized by different clinical behavior, from indolent, slow-growing tumors to aggressive, fast-growing tumors with lethal progression. Early diagnostics and identification of PCa type are crucial prerequisites for efficient treatment of patients. Recently, the diagnostics of early stages of PCa is based mostly on evaluation of prostate-specific antigen (PSA) in serum of patients. Men with high levels of PSA undergo biopsy in order to determine histopatological grading of PCa - Gleason scoring which classifies tumors from most to least differentiated as well as staging - determination of the status of their primary tumors, with or without lymph node involvement. The results from this screening diagnosis lead into conventional treatment, including radical prostatectomy and brachytherapy. In case of advanced PCa, conventional treatment continues with androgen deprivation therapy. However, in many cases the cancer recurs. Therefore, the clinicians and researchers are forced to find more precise and sensitive biomarker suitable for PCa diagnostics as well as prognostics and therapy. This paper provides review of current most promising molecular and immunohistochemical biomarkers in PCa diagnosis, prognosis and clinical behavior.
... It is helpful in the diagnosis of a patient [5,6]and gives the clinician assistance regarding the treatment that is most suitable in the given circumstance [7]. The existing diagnostic PCa biomarkers need to be re-designed or transformed to be more disease specific and precise in order to avoid overtreatment of PCa and reduce morbidity/mortality [8,9].Presently, there is a plethora of PCa biomarkers accessible for diagnosis; however, these markers have low sensitivity, specificity, and accuracy, making them inadequate screening clinical methods and techniques. Consequently, the optimal biomarker for PCa would be one that is non-invasive, has a high specificity, and is more reliable than PSA. ...
... The clinicopathological and many other properties of PCa and BPH are described in Table 1. The median age of PCa patients was 65.95 (range, , and 29 of the PCa cases had Gleason scores of 6 or 7, indicating a low to intermediate Gleason scores, while only 19 had Gleason scores of 8 or 10, indicating a high Gleason score (8,9,10). The PCa category consisted of 26 vegetarians, 22 non-vegetarian, 14 smokers, and 34 non-smokers, and 17 alcoholics, 31 non-alcoholic. ...
Background
Plasma microRNAs (miRNAs) have recently garnered attention for their potential as stable biomarkers in the context of Prostate Cancer (PCa), demonstrating established associations with tumor grade, biochemical recurrence (BCR), and metastasis. This study seeks to assess the utility of plasma miRNAs as prognostic indicators for distinguishing between high-grade and low-grade PCa, and to explore their involvement in PCa pathogenesis.
Methodology
We conducted miRNA profiling in both plasma and tissue specimens from patients with varying PCa grades. Subsequently, the identified miRNAs were validated in a substantial independent PCa cohort. Furthermore, we identified and confirmed the gene targets of these selected miRNAs through Western blot analysis.
Results
In our plasma profiling investigation, we identified 98, 132, and 154 differentially expressed miRNAs (DEMs) in high-grade PCa vs. benign prostatic hyperplasia (BPH), low-grade PCa vs. BPH, and high-grade PCa vs. low-grade PCa, respectively. Our tissue profiling study revealed 111, 132, and 257 statistically significant DEMs for the same comparisons. Notably, miR-373-3p emerged as the sole consistently dysregulated miRNA in both plasma and tissue samples of PCa. This miRNA displayed significant overexpression in plasma and tissue samples, with fold changes of 3.584 ± 0.5638 and 8.796 ± 1.245, respectively. Furthermore, we observed a significant reduction in KPNA2 protein expression in PCa.
Conclusion
Our findings lend support to the potential of plasma miR-373-3p as a valuable biomarker for predicting and diagnosing PCa. Additionally, this miRNA may contribute to the progression of PCa by inhibiting KPNA2 expression, shedding light on its role in the disease.
... Prostate cancer is a multifactorial disease and the most frequently diagnosed malignancy associated with significant mortality and morbidity in men. The well-established risk factors are age, ethnicity, family history of prostate cancer and genetic predisposition (1). In addition, dietary factors, such as the intake of red meat, and smoking have been considered as potential prostate cancer risk factors (2). ...
... Additionally, the CYP1A2 rs2069514 and rs762551 polymorphisms are reported to be associated with increased enzyme activity in smokers (51,52). Hormones, such as androgens and oestrogens, are known to be contributors to the development and progression of prostate cancer (1,53). Furthermore, the CYP1A2 enzyme is well documented as being the most active in the metabolic conversion of oestradiol to 2-hydroxyoestradiol (54). ...
The role of the cytochrome P450 1A2 (CYP1A2) rs2472299, rs2470890 and rs11072508 polymorphisms in prostate cancer risk, disease progression and tumour development remains unclear. The potential associations of these three CYP1A2 polymorphisms and haplotypes with prostate cancer susceptibility and its clinicopathological characteristics were therefore investigated. The present case-control study consisted of 522 patients with prostate cancer and 554 healthy controls. High-resolution melting analysis was used to determine the CYP1A2 polymorphisms. No significant association in prostate cancer risk was seen for CYP1A2 rs2472299 and rs11072508. However, a significantly decreased risk of prostate cancer was found for CYP1A2 rs2470890 [odds ratio (OR), 0.67; P=0.02] in the recessive model. After analysis of the associations of clinical status and these three CYP1A2 polymorphisms, the CYP1A2 rs2470890 and rs11072508 polymorphisms showed a positive association with a higher Gleason score (rs2470890 OR, 1.36, P=0.04 in the allelic model; rs11072508 OR, 1.37, P=0.04 in the allelic model and OR, 1.60, P=0.03 in the dominant model). All three polymorphisms showed a significant positive association with pathological T stage in the additive, allelic and dominant genetic models (P<0.05). Haplotype analysis revealed that the most common haplotypes 'GTT' and 'ACC' were significantly associated with pathological T stages 3 and 4 (OR, 0.62; P=0.02 and OR, 1.54; P=0.03, respectively). A significant association was found between the 'GTT' haplotype and the Gleason score (OR, 0.71; P=0.03). In conclusion, these CYP1A2 polymorphisms and haplotypes have the potential to predict prostate cancer disease progression.
... LC-MS is increasingly being used to explore pharmaceutical compounds across multiple stages, from drug discovery to identifying impurities and degradation products [76]. It has proven effective in quantifying tissuespecific complexity and highlighting metabolic changes in response to anticancer drugs [77]. Alongside statistical analyses, LC-MS is a powerful and efficient diagnostic tool for human diseases [78]. ...
Citation: Al-Daffaie, F.M.; Al-Mudhafar, S.F.; Alhomsi, A.; Tarazi, H.; Almehdi, A.M.; El-Huneidi, W.; Abu-Gharbieh, E.; Bustanji, Y.; Alqudah, M.A.Y.; Abuhelwa, A.Y.; et al. Metabolomics and Proteomics in Prostate Cancer Research: Overview, Analytical Techniques, Data Analysis, and Recent Clinical Applications. Int. J. Mol. Sci. 2024, 25, 5071.
... The growth of prostate tissue and prostate cancer cells heavily relies on the pathway mediated by the androgen receptor and testosterone [21]. Identifying biomarkers specific to cancer and targeting mutations can facilitate focused treatment approaches for prostate cancer [22]. The understanding of the association between arsenic exposure and prostate cancer is still limited. ...
Arsenic exhibits varying degrees of toxicity depending on its many chemical forms. The carcinogenic properties of arsenic have already been established. However, the precise processes underlying the development of diseases following acute or chronic exposure to arsenic remain poorly known. Most of the existing investigation has focused on studying the occurrence of cancer following significant exposure to elevated levels of arsenic. Nevertheless, multiple investigations have documented diverse health consequences from prolonged exposure to low levels of arsenic. Inorganic arsenic commonly causes lung, bladder, and skin cancer. Some investigations have shown an association between arsenic in drinking water and prostate cancer, but few investigations have focused on exploring this connection. There is currently a lack of relevant animal models demonstrating a clear link between inorganic arsenic exposure and the development of prostate cancer. Nevertheless, studies using cellular model systems have demonstrated that arsenic can potentially promote the malignant transformation of human prostate epithelial cells in vitro. The administration of elevated levels of arsenic has been demonstrated to elicit cell death in instances of acute experimental exposure. Conversely, in cases of chronic exposure, arsenic prompts cellular proliferation and sustains cellular viability, thereby circumventing the constraints imposed by telomere shortening and apoptosis. Furthermore, cells consistently exposed to the stimulus exhibit an augmented ability to invade surrounding tissues and an enhanced potential to form tumors. This review aims to portray mechanistic insights into arsenic-induced prostate cancer.
... It is classified as a heterogeneous disease with a range of clinical behaviors, from deadly tumors to aggressive tumors, and is characterized by diverse clinical behavior. This makes early diagnosis and the detection of PCa aggressiveness essential preconditions for effective patient treatment [117]. Padoan et al. [22] performed peptidome analysis of serum and post-prostatic massage urine specimens to identify PCa biomarkers. ...
Cancer remains the second most common cause of death after cardiovascular diseases, accounting for nearly 10 million deaths in 2020. Although the incidence of cancer increases considerably with age, the cancer burden can also be reduced and have a high chance of cure through early detection, appropriate treatment, and care of patients. The development of high-throughput analytical approaches, like matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), contributes to identifying a pool of proteins/peptides as putative biomarkers for the early detection, diagnosis, and tumor progression. The purpose of the current review is to present an updated outline of recent proteome/peptidome research to establish putative cancer biomarkers using MALDI-TOF MS and highlight the applicability of statistical analysis in the oncology field. The pros and cons of MALDI-TOF MS application on cancer diagnostics and monitoring will be discussed, as well as compared with tandem mass spectrometry (MS/MS)-based proteomics (e.g., liquid chromatography–tandem mass spectrometry). In addition, pre-analytical (e.g., sample quality control) and analytical (e.g., sample pre-treatment, instrumental analytical conditions) properties that influence the robustness of MALDI-TOF MS data will be also discussed.
... Prostat kanseri (PCa), erkeklerde en sık görülen ikinci kanser türü ve kansere bağlı ölümlerin önde gelen nedenleri arasındadır (Rawla et al., 2019, Ziaran et al., 2015. Prevalansı gelişmiş ülkelerde yaygın olmasına ragmen, gelişmekte olan ülkelerde bu kanser türünün oluşum oranları artmaktadır (Center et al., 2012). ...
... It aids in determining a patient's prognosis (Spires et al. 1994, Stamey et al. 1999, Lilleby et al. 2001) and provides guidance to the clinician as to the most appropriate course of treatment (Roach et al. 1994, Lughezzani et al. 2013. To prevent overtreatment of PCa and reduce the mortality rate, we need to re-design or transform the current diagnostic PCa biomarkers which should be more cancer specific and accurate (Velonas et al. 2013, Ziaran et al. 2015. In the current situation, lots of PCa biomarkers are available for diagnostic purposes, but their low sensitivity, specificity, and accuracy make them poor screening clinical tools. ...
Background
Prostate cancer (PCa) is the most prevalent (20%) pathological cancer among males globally. MicroRNAs (miRNAs) are short (19–22 nucleotide), conserved, noncoding molecules that regulate post-transcriptional processes either by repressing or degrading mRNA or by translation inhibition binding to complementary sites on mRNA. The goal of this study was to find out whether differentially expressed microRNA (DEM) could be used as a potential marker in the prognosis and diagnosis of PCa.
Methodology
The miRNAs profiling was done both from plasma and tissue samples of the same PCa patient (n = 3) by real-time quantitative PCR (qRT-PCR) and compared with BPH (benign prostatic hyperplasia) patients (n = 3) as controls and further validation of selected miRNAs.
Results
We found 55 significant overexpressed DEMs, 44 significant underexpressed DEMs in plasma and 6 significant overexpressed DEMs, 27 significant underexpressed DEMs in tissue compared between PCa and BPH. Furthermore, there were eight miRNAs namely miR-190b, miR-215, miR-300, miR-329, miR-504, miR-525-3p, miR-527, miR-548a-3p found to be significantly differentially expressed in plasma and tissue samples via profiling, however only three showed concordant expression. After validation, miR-190b-5p were shown to be significantly downexpressed with fold changes of 0.4177 (p value – 0.0072) and 0.7264 (p value – 0.0143) in plasma and tissue samples, respectively. The expression of miR-215-5p was shown to be significantly overexpressed with fold change of 1.820 (p – 0.0016) and 1.476 (p – 0.0407) in plasma and tissue samples, respectively. Furthermore, miR-527 was shown to be significantly downexpressed with fold changes of 0.6018 (p – 0.0095) and 0.6917 (p – 0.0155) in plasma and tissue samples, respectively.
Conclusion
According to our findings, plasma miR-190b-5p, miR-215-5p, miR-527 levels alteration is consistently linked with PCa tissue. For establishing significant miRNAs as biomarkers, additional research of a larger population is needed.
Prostate cancer is one of the malignancies that affects men and significantly contributes to increased mortality rates in men globally. Patients affected with prostate cancer present with either a localized or advanced disease. In this review, we aim to provide a holistic overview of prostate cancer, including the diagnosis of the disease, mutations leading to the onset and progression of the disease, and treatment options. Prostate cancer diagnoses include a digital rectal examination, prostate-specific antigen analysis, and prostate biopsies. Mutations in certain genes are linked to the onset, progression, and metastasis of the cancer. Treatment for localized prostate cancer encompasses active surveillance, ablative radiotherapy, and radical prostatectomy. Men who relapse or present metastatic prostate cancer receive androgen deprivation therapy (ADT), salvage radiotherapy, and chemotherapy. Currently, available treatment options are more effective when used as combination therapy; however, despite available treatment options, prostate cancer remains to be incurable. There has been ongoing research on finding and identifying other treatment approaches such as the use of traditional medicine, the application of nanotechnologies, and gene therapy to combat prostate cancer, drug resistance, as well as to reduce the adverse effects that come with current treatment options. In this article, we summarize the genes involved in prostate cancer, available treatment options, and current research on alternative treatment options.
The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene expression analysis showed that steroid biosynthesis pathway is activated in enzalutamide resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide resistant prostate xenograft tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly up regulated in enzalutamide resistant prostate cancer cells compared to the parental cells. Knock down of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized enzalutamide resistant prostate cancer cells to enzalutamide treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance, targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients.
Copyright © 2015, American Association for Cancer Research.
This study aimed to investigate the role of AR-V7 in development of castration-resistant prostate cancer (CRPC) and to determine whether the AR-V7 expression in CRPC tissues can predict cancer-specific survival. We enrolled 100 localized prostate cancer (PCa) (cohort 1), 104 newly diagnosed metastatic PCa (cohort 2), and 46 CRPC (cohort 3) patients treated at our institution. The expression of AR-V7 in PCa was assessed by immunohistochemistry. Cox regression models were used to evaluate the predictive role of all covariates for the development of CRPC in cohort 2 and for cancer-specific survival in cohort 3. Time to CRPC and cancer-specific survival curves were estimated using the Kaplan-Meier method. AR-V7 expression rate in cohort 3 was significantly elevated compared with other two cohorts (p < 0.001). Multivariate analysis revealed that AR-V7 was an independent predictive factor for CRPC development (HR = 2.627, p = 0.001) and for cancer specific survival (HR = 2.247, p = 0.033). Furthermore, the AR-V7 expression was associated with shorter survival in CRPC patients. Our results demonstrated protein AR-V7 levels in primary tumors can be used as a predictive marker for the development of CRPC and as a prognostic factor in CRPC patients. Therapy targeting AR-V7 may help prevent PCa progression and improve the prognosis of CRPC patients.
Background:
The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.
Methods:
We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.
Results:
A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.
Conclusions:
Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).
Background:
α-Methylacyl-CoA racemase (AMACR) participates in the oxidation of branched chain fatty acids and is highly expressed in prostate cancer (PCa). The aims of this study were to verify if the AMACR inhibitor trifluoroibuprofen (TFIP) had anticancer effects and to determine the best route for in vivo administration.
Materials and methods:
In vitro effects of TFIP were verified by using three non-tumour prostate epithelial cell lines, a series of eight PCa cell lines and six cell derivatives. In vivo experiments were performed using PC3 and 22rv1 xenografts grown in nude mice with TFIP administered intraperitoneally or by oral gavage.
Results:
AMACR was expressed in PCa cell lines but was absent in normal and BPH cells. Although androgen-independent (AI) cell lines originating from androgen-dependent (AD) LnCaP cells displayed increased AMACR expression, the levels of this enzyme were higher in AI with respect to AD cell lines. TFIP induced: (1) down-modulation of AMACR expression; (2) suppression of the survival Akt/mTOR signalling pathway and (3) down-modulation of cyclin D1 and survivin with G2/M arrest and apoptosis. TFIP exhibited antitumour effects independently of the administration method. Nevertheless, oral administration was associated with acute toxicity at doses >75 mg/Kg/day. A dose of 75 mg/Kg administered biweekly reduced the toxicity whereas limited toxic effects were observed at 50 mg/Kg/day. Intraperitoneal administration of 75-100 mg/Kg/day was not toxic.
Conclusions:
AMACR is a good pharmacological target for treatment of PCa and TFIP is a suitable anticancer compound with parenteral administration being the preferred route.
SPINK1 over-expression has been described in prostate cancer and is linked with poor prognosis in many cancers. The objective of this study was to characterize the association between SPINK1 over-expression and prostate cancer specific survival.
The study included 879 participants in the US Physicians' Health Study and Health Professionals Follow-Up Study, diagnosed with prostate cancer (1983 - 2004) and treated by radical prostatectomy. Protein expression of SPINK1 was evaluated by immunohistochemistry on tumor tissue microarrays.
74/879 (8%) prostate cancer tumors were SPINK1 positive. Immunohistochemical data was available for PTEN, p-Akt, pS6, stathmin, androgen receptor (AR) and ERG (as a measure of the TMPRSS2:ERG translocation). Compared to SPINK1 negative tumors, SPINK1 positive tumors showed higher PTEN and stathmin expression, and lower expression of AR (p<0.01). SPINK1 over-expression was seen in 47 of 427 (11%) ERG negative samples and in 19 of 427 (4%) ERG positive cases (p=0.0003). We found no significant associations between SPINK1 status and Gleason grade or tumor stage. There was no association between SPINK1 expression and biochemical recurrence (p=0.56). Moreover, there was no association between SPINK1 expression and prostate cancer mortality (there were 75 lethal cases of prostate cancer during a mean of 13.5 years follow-up [HR 0.71 (95% confidence interval 0.29-1.76)]).
SPINK1 protein expression may not be a predictor of recurrence or lethal prostate cancer amongst men treated by radical prostatectomy. SPINK1 and ERG protein expression do not appear to be entirely mutually exclusive, as some previous studies have suggested.
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand. Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR downregulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone). Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab). Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent). Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogentic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited. New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit. Novel agents targeting bone metastases are being developed following the success of zoledronic acid and denosumab. Finally, all of these modalities do not appear curative, suggesting that clinical trial enrollment and a better understanding of biology remain of paramount importance.
We review the clinical trials and observational studies literature regarding the clinical and economic burden of bone metastasis and skeletal-related events (SREs) in prostate cancer, and discuss current gaps in understanding the impact of bone metastasis in this disease.
Trial data indicate that SREs occur in half of prostate cancer patients with bone metastasis in the absence of treatment, and 30-45% among those who receive bone-modifying agents. In the United States, the cost of SRE ranged from $7553 per radiation episode to $88 838 per bone surgery episode. Prevalence of SRE, time to SRE occurrence, and cost of SRE varied across studies because of differences in study populations, follow-up period, and the algorithm used to measure SRE. There is limited evidence on the clinical and economic impact by SRE subtype. Information regarding patient-reported outcomes and costs from the patient's perspective is lacking.
Bone metastasis and SREs in prostate cancer patients are associated with considerable morbidity, reduced survival, and substantial economic burden. Consistent study methodology, particularly the measurement of SREs, is necessary to allow comparison of estimates across studies. The inclusion of patient-centered clinical and economic outcomes in future research will provide pertinent information regarding the burden of bone metastasis and SREs.
Objective
To examine and quantify the contemporary association between ADT and three separate endpoints: coronary artery disease (CAD), acute myocardial infarction (AMI), and sudden cardiac death (SCD), in a large United States contemporary cohort of PCa patients. Materials and Methods
Overall, 140,474 patients diagnosed with non-metastatic PCa between 1995 and 2009 within the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database were abstracted. Patients treated with ADT and those not receiving ADT were matched using propensity-score methodology. Ten-year CAD, AMI, and SCD rates were estimated. Competing-risks regression analyses tested the association between the type of ADT (GnRH agonists vs. bilateral orchiectomy) and CAD, AMI, and SCD, after adjusting for the risk of dying during follow-up. ResultsOverall, the 10-year rates of CAD, AMI, and SCD were 25.9, 15.6, and 15.8%, respectively. After stratification according to ADT status (ADT-naïve vs. GnRH agonists vs. bilateral orchiectomy), the CAD rates were 25.1 vs. 26.9 vs. 23.2%, the AMI rates were 14.8 vs. 16.6 vs. 14.8%, and the SCD rates were 14.2 vs. 17.7 vs. 16.4%, respectively. In competing-risks multivariable regression analyses, the administration of GnRH agonists (all P<0.001), but not bilateral orchiectomy (all P≥0.7), was associated with higher risk of CAD, AMI, and SCD. Conclusions
The administration of GnRH agonists, but not orchiectomy, is still associated with a significantly increased risk of CAD, AMI, and, especially, SCD in patients with non-metastatic PCa. Alternative forms of ADT should be considered in patients at higher risk of CV events.