Emerging biomarkers for prostate cancer diagnosis, staging, and prognosis

The introduction and widespread adoption of PSA has revolutionized the way prostate cancer is diagnosed and treated. However, the use of PSA has also led to over-diagnosis and overtreatment of prostate cancer resulting in controversy about its use for screening. PSA also has limited predictive accuracy for predicting outcomes after treatment and for making clinical decisions about adjuvant and salvage therapies. Hence, there is an urgent need for novel biomarkers to supplement PSA for detection and management of prostate cancer. Despite the progress in developing new biomarkers, several obstacles remain before such biomarkers can be clinically used. These challenges include analytical and regulatory barriers, issues with study design and data analysis that lead to lack of reproducibility of promising results, and the lack of large scale trials to adequately assess the utility of promising biomarkers. In this article we discuss the challenges in biomarker research and the statistical considerations for biomarker evaluation. There is a plethora of promising blood and urine based biomarkers. For the purpose of this review, we focus on PSA derived forms, human kallikrein 2, Early Prostate Cancer Antigen, Transforming Growth Factor-Beta 1 and Interleukin-6, Endoglin, PCA3, AMACR and ETS Gene Fusions. These biomarkers have shown promise in early studies and are at various stages of development. However, in the future it is very likely that a panel of biomarkers will be used to achieve sufficient degree of certainty in order to guide clinical decisions. To be able to be used commercially such a panel will have to answer clinically relevant questions in a simple and cost-effective way.     

Emerging promising biomarkers for treatment decision in metastatic castration-resistant prostate cancer

Prostate cancer is one of the most common causes of death in males. Even if treatment is often of curative intent in early stages of the disease, up to 50% of patients relapse after primary therapy. Moreover, 10% to 15% of patients present in a primary metastatic stage of disease. In the past years the treatment landscape of metastatic castration-resistant prostate cancer expanded due to the development of second-generation antiandrogens (abiraterone acetate, enzalutamide), chemotherapeutic agents and radium-223. With the availability of several therapeutic lines, we are now confronted with the problem of choosing the most suitable therapy in each state of disease. As often observed in clinical routine, prostate specific antigen is not sufficient for early prediction of a therapy response. Furthermore, biomarkers for prediction of the optimal first-line therapy are badly needed in order to avoid primary resistance.Therefore, the present short review article gives an overview of currently available clinical and preclinical biomarkers for treatment response to metastatic castration-resistant prostate cancer therapeutic agents with the aim of providing support for a personalized decision-making process in everyday use.     

Circulating biomarkers for prostate cancer

Due to its significant applicability for early detection, risk prediction and follow-up evaluation, prostate specific antigen (PSA) has revolutionized our ability to treat prostate cancer patients. With the prevalent use of PSA for early detection during the last two decades, disease characteristics have been altered towards early detected, localized tumors with a high chance of cure following local therapy. This advantage faces the risk of overdetection and overtreatment. In addition, PSA lacks both, sensitivity and specificity to accurately detect patients at risk of prostate cancer. Therefore, novel biomarkers are urgently needed to improve identification of men at risk of having the disease and to predict the natural behaviour of the tumor. Recent advances in the evaluation of high-throughput technologies have led to the discovery of novel candidate markers for prostate cancer. This article will briefly discuss current PSA-based strategies and review several novel biomarkers for prostate cancer, detectable in blood.     

Immunohistochemical biomarkers for bladder cancer prognosis

Urothelial carcinoma of the bladder (UCB) is an especially complex and heterogeneous disease with a broad spectrum of histologic findings and potentially lethal behavior. Despite advances in surgical techniques, as well as intravesical and systemic therapies, up to 30% of patients with non‐muscle‐invasive UCB and 50% of patients with muscle‐invasive UCB experience disease progression, recurrence, and eventual death. Standard prognostic features, such as pathologic stage and grade, have limited ability to predict the outcomes of this heterogeneous population. Current risk‐stratification algorithms using clinical and pathologic parameters are limited in their prognostic ability. Molecular medicine holds the promise that clinical outcomes will be improved by more accurate prognostication and directing therapy towards the mechanisms and targets associated with the growth of an individual patient's tumor. Immunohistochemical analysis of biomarker expression has provided insight into the molecular pathogenesis of UCB and offers the potential for improving clinical decision making. Numerous candidate immunohistochemical biomarkers for patients with UCB have been identified, with those relating to the cell cycle and apoptosis/cell proliferation being the most extensively studied. The present review discusses the most promising immunohistochemical biomarkers. Special attention is paid to recent data from a multi‐institutional collaboration that has implemented a regulated, phased biomarker discovery and validation pathway. Because UCB tumorigenesis and progression is a process involving multiple genetic and epigenetic alterations, multiple biomarkers need to be integrated into a prognostic signature to accurately predict outcomes. There is no doubt that biomarkers will eventually guide our clinical decision making regarding follow‐up scheduling and treatment choice.     

New circulating biomarkers for prostate cancer

The introduction of prostate-specific antigen (PSA) revolutionized prostate cancer (PCa) screening and ushered the PSA era. However, its use as a screening tool remains controversial and changes in the epidemiology of PCa have strongly limited its prognostic role. Therefore, we need novel approaches to improve our ability to detect PCa and foretell the course of the disease. To improve the specificity of total PSA, several approaches based on PSA derivatives have been investigated such as age-specific values, PSA density (PSAD), PSAD of the transition zone, PSA velocity and assessment of various isoforms of PSA. With recent advances in biotechnology such as high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation. Given the plethora of candidate PCa biomarkers, we have chosen to discuss a select group of candidate blood-based biomarkers including human glandular kallikrein, early prostate cancer antigens, insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBP-2 and IGFBP-3), urokinase plasminogen activation system, transforming growth factor-beta1, interleukin-6, chromogranin A, prostate secretory protein, prostate-specific membrane antigen, PCa-specific autoantibodies and alpha-methylacyl-CoA racemase. While these and other markers have shown promise in early phase studies, no single biomarker is likely to have the appropriate degree of certainty to dictate treatment decisions. Consequently, the future of cancer prognosis may rely on small panels of markers that can accurately predict PCa presence, stage, metastasis, and serve as prognosticators, targets and/or surrogate end points of disease progression and response to therapy.     

Other biomarkers for detecting prostate cancer

Prostate‐specific antigen (PSA) has been used for detecting prostate cancer since 1994. Although it is the best cancer biomarker available, PSA is not perfect. It lacks both the sensitivity and specificity to accurately detect the presence of prostate cancer. None of the PSA thresholds currently in use consistently identify patients with prostate cancer and exclude patients without cancer. Novel approaches to improve our ability to detect prostate cancer and predict the course of the disease are needed. Additional methods for detecting prostate cancer have been evaluated. Despite the discovery of many new biomarkers, only a few have shown some clinical value. These markers include human kallikrein 2, urokinase‐type plasminogen activator receptor, prostate‐specific membrane antigen, early prostate cancer antigen, PCA3, α‐methylacyl‐CoA racemase and glutathione S‐transferase π hypermethylation. We review the reports on biomarkers for prostate cancer detection, and their possible role in the clinical practice.     

Social disparities,health risk behaviors,and cancer

Background

Overall cancer incidence rates decreased in the most recent time period in both men and women, largely due to improvements in surgical therapeutic approaches (tertiary prevention) and screening programs (secondary prevention), but differences in cancer incidence and survival according to socioeconomic status are documented worldwide. Health risk behaviors, defined as habits or practices that increase an individual’s likelihood of harmful health outcomes, are thought to mediate such inequalities.

Discussion

Obesity has been related with increased cancer incidence and mortality due to imbalance of leptin and adiponectin which are connected to activation of PI3K, MAPK, and STAT3 pathways and decreasing insulin/insulin-like growth factor (IGF)-1 and mTOR signaling via activation of 5 AMP-activated protein kinase (AMPK), respectively. Physical activity has been associated to prevent cancer by the aforementioned obesity-related mechanisms, but also increasing level of circulating vitamin D, which has been related to lower risk of several cancers, and increasing prostaglandin F2a and reducing prostaglandin E2, which are both related with cancer prevention and promotion, respectively. A large number of different substances may induce themselves a direct cytotoxicity and mutagenic action on cells by smoking, whereas alcohol promote immune suppression, the delay of DNA repair, inhibition of the detoxification of carcinogens, the production of acetaldehyde, and the contribution to abnormal DNA methylation. The combined smoking and alcohol drinking habits have been shown to increase cancer risk by smoke action of increasing the acetaldehyde burden following alcohol consumption and alcohol action of enhancing the activation of various procarcinogens contained in tobacco smoke.

Conclusions

Interventions at the social level may be done to increase awareness about cancer risks and promote changing in unhealthy behaviors.

     

Identification of docetaxel-related biomarkers for prostate cancer

Prostate cancer (PCa) which was the second commonly diagnosed malignancy, contributed to the top fifth carcinoma death in men. Nevertheless, the main chemotherapeutic agent docetaxel came to failure due to chemoresistance. Recently, increasing evidence suggested the importance of tumour microenvironment (TME) in PCa. The present study aimed to explore the specific TME in PCa and find biomarkers related to both immune infiltration and docetaxel. The docetaxel-specific genes and differential expression genes comparing PCa with normal control samples were derived using DESeq2 and zinbwave with GSE140440 , TCGA and GTEx datasets. Immune-infiltration-related genes were identified using CIBERSORT and co-expression network analysis. Key genes related to both docetaxel and immune infiltrating in PCa, including nine genes, namely ZNF486, IFI6, TMOD2, HSPA4L, ITPR1, LRRC37A7P, APOC1, APOBEC3G, and ITGA2, were determined by overlapping above three gene sets. ITGA2 was then defined as the hub gene for its significant prognostic implications. Further validations conducted on Oncomine, GEO, TISIDB, MSigDB, and The Human Protein Atlas confirmed the docetaxel-specific and immune infiltrating characteristics of ITGA2. To sum up, our findings could provide a better understanding of immune infiltrating and docetaxel-resistance in PCa, mostly, ITGA2 could serve as potential prognosis biomarkers and targets for the combination of docetaxel.     

Mental health outcomes in elderly men with prostate cancer

ObjectiveTo examine the burden of mental health issues (MHI), namely anxiety, depressive disorders, and suicide, in a population-based cohort of older men with localized prostate cancer and to evaluate associations with primary treatment modality.Patients and methodsA total of 50,856 men, who were 65 years of age or older with clinically localized prostate cancer diagnosed between 1992 and 2005 and without a diagnosis of mental illness at baseline, were abstracted from the Surveillance, Epidemiology, and End Results–Medicare database. The primary outcome of interest was the development of MHI (anxiety, major depressive disorder, depressive disorder not elsewhere classified, neurotic depression, adjustment disorder with depressed mood, and suicide) after the diagnosis of prostate cancer.ResultsA total of 10,389 men (20.4%) developed MHI during the study period. Independent risk factors for MHI included age≥75 years (hazard ratio [HR] = 1.29); higher comorbidity (Charlson comorbidity index≥3, HR = 1.63); rural hospital location (HR = 1.14); being single, divorced, or widowed (HR = 1.12); later year of diagnosis (HR = 1.05); and urinary incontinence (HR = 1.47). Black race (HR = 0.79), very high-income status (HR = 0.87), and definitive treatment (radical prostatectomy [RP], HR = 0.79; radiotherapy [RT], HR= 0.85, all P<0.001) predicted a lower risk of MHI. The rates of MHI at 10 years were 29.7%, 29.0%, and 22.6% in men undergoing watchful waiting (WW), RT, and RP, respectively.ConclusionOlder men with localized prostate cancer had a significant burden of MHI. Men treated with RP or RT were at a lower risk of developing MHI, compared with those undergoing WW, with median time to development of MHI being significantly greater in those undergoing RP compared with those undergoing RT or WW.     

Income-based disparities in outcomes for patients with chronic kidney disease.

The impact of income on outcomes for patients with end-stage renal disease (ESRD), who are largely relieved of structural and financial barriers to care, is poorly understood. We conducted a prospective cohort study of 3,165 patients who developed ESRD in the early 1990s to examine whether low-income patients with ESRD have poorer health outcomes than their socioeconomically advantaged counterparts, and, if so, to determine whether greater health insurance can reduce this disparity. We found that increasing neighborhood income was associated with decreased mortality and an increased likelihood of placement on the renal transplant waiting list. The presence of private insurance coverage in addition to Medicare improved rates of listing for transplantation in a graded manner, with the greatest effect among those living in neighborhoods below the 10th percentile of income, but had no effect on socioeconomic disparities in mortality. Our results suggest that low-income patients with ESRD experience persistent financial barriers to transplantation that can be addressed with greater health benefits. However, they also experience higher mortality that is caused by personal and/or environmental factors that differ by social class. Clinicians, researchers, and policymakers must address these social, cultural, psychologic, and environmental determinants of health to improve the survival of patients with ESRD.     

Predictive biomarkers for drug response in bladder cancer

Bladder cancer is a heterogeneous disease. Interpatient heterogeneity in response to a drug limits treatment options and impairs improvement of patient survival. For example, approximately half of patients do not respond to cisplatin‐based combination chemotherapy, although it is the standard of care for muscle‐invasive and metastatic bladder cancer. The development of robust predictive biomarkers is expected to improve outcomes by enabling clinicians to use chemotherapy only in the patients who will benefit from it. Recent advances in the molecular characterization of bladder cancer showed that the basal subtype of bladder cancer and tumors with inactivating mutations in DNA damage repair genes were associated with greater benefit from cisplatin‐based chemotherapy. The present review summarizes current efforts to develop predictive biomarkers for drug response in bladder cancer, focusing on those that predict the response to cisplatin‐based chemotherapy for advanced bladder cancer. We also review the current situation with regard to the identification of predictive biomarkers for response to intravesical therapy, immune checkpoint inhibitors and molecularly‐targeted drugs. We also discuss the future applications of new technologies, including liquid biopsies and patient‐derived organoids that will also serve as resources for the identification of biomarkers in bladder cancer.     

Furan and p-xylene as candidate biomarkers for prostate cancer

Background

Prostate cancer (PCa) is the most frequently diagnosed noncutaneous malignant tumor among males in the Western world. Prostate-specific antigen has been considered the most important biomarker for PCa detection; however, it lacks specificity, leading to the search for alternative biomarkers. Volatile organic compounds (VOCs) are released during cell metabolism and can be found in exhaled breath, urine, and other fluids. VOCs have been used in the diagnosis of lung, breast, ovarian, and colorectal cancers, among others. The objective of this study was to identify urinary VOCs that may be sensitive and specific biomarkers for PCa.

Cell type-specific analyses for identifying prostate cancer biomarkers

Cancers of the prostate contribute substantial morbidity and mortality to the male population. The correlation of prostate cancer incidence with aging suggests that the disease burden associated with prostate carcinoma will increase dramatically over the next several decades. Despite the large number of fatalities directly linked to prostate cancer, most men harboring the disease will die of other causes. This fact poses substantial dilemmas for screening programs designed to diagnose cancers at an early stage, as the optimal approach also would provide guidance as to which cancers could or should be observed, versus those malignancies that require curative therapy, and whether localized treatments are sufficient or if additional systemic interventions are indicated. To address these issues, substantial resources have been focused on the identification of biomarkers capable of specifically and sensitively diagnosing prostate cancers and providing prognostic information. However, the discovery and use of biomarkers must contend with the complexity and heterogeneity of body fluids and tissues. This review describes approaches that use cell type-specific analysis methods to identify cancer-associated features with the potential of distinguishing individuals with cancer of the prostate.