Prostate Stem Cell Antigen
Prostate stem cell antigen is a membrane glycoprotein predominantly expressed in the prostate. Although the expression of PSCA has been revealed to be upregulated in the majority of prostate cancers, its biological role in prostate cancer is uncertain . Studies have implicated PSCA in certain stem cell functions like androgen-independent progression, metastasis, or signal transduction in many prostate cancer cells . PSCA expression is associated with Gleason score, seminal vesicle invasion, and capsular invasion in prostate cancer hence, it has potential as a therapeutic target. A correlation was detected between the increase levels of PSCA expression in most prostate cancers and higher Gleason grade and more advanced tumor stage . A function for PSCA in prostate cancer progression is proposed from the observation that it is jointly amplified with c-myc in locally advanced prostate cancers . When the mRNA of other circulating prostate markers like PSA and PSMA were compared with that of PSCA, researchers observed that, although PSCA displayed inferior sensitivity and considerable inability to distinguish between malignant and benign disease, its disease specificity and independent predictive value were the highest .
Use Of Psa In Monitoring Treatment In Advanced Disease
As in the non-metastatic situation mentioned, resistance usually occurs following initial ADT in the metastatic situation. Potential treatments for CRPC include second line ADT , ADT plus chemotherapy , radium-223 and immunotherapy , . Although PSA is used in assessing response to these therapies in patients with metastatic CRPC, changes in its levels are poor predictors of survival , . Indeed, a recent report involving five randomised phase III clinical trials using different treatments showed that a decrease in the number of circulating tumour cells from 1 to zero was superior to PSA for predicting survival . It should be stated however, that unlike PSA, CTC are not believed to be directly under the control of androgens and thus should not be affected by ADT. Measurement of CTC, however, is more expensive than that of PSA and furthermore is not widely available.
Finally, although immunotherapy with sipuleucel-T or administration of the radiopharmaceutical, radium-223 have been shown to increase overall survival, this improvement was not found to correlate with alterations in PSA levels. , . Changes in PSA levels are thus also of limited value for predicting outcome in patients with castrate-resistant metastatic prostate cancer undergoing treatment with sipuleucel-T or radium-223.
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An enlarged prostate can also be the cause of other problems. If the enlarged prostate is causing symptoms, the best treatment would be a natural remedy. In the meantime, there are treatments for a wide range of conditions that cause a man to experience pain. A common surgical procedure involves an electric loop, laser, or electro-stimulation. The procedure is a safe and effective option for treating enlarged or symptomatic BPH.
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Biomarkers For Improving The Diagnostic Accuracy Of Psa
One of the main problems in using PSA to screen for prostate cancer is the lack of specificity, especially when values are < 10 g/L. The consequence of this poor specificity is that large numbers of men may undergo unnecessary biopsy to confirm or exclude malignancy. Thus, 65%75% of men with a PSA level in the 3/410 g/L range do not have biopsy-detectable prostate cancer . To improve specificity and thus reduce the number of unnecessary biopsies/repeat biopsies, several additional or adjunct tests have been proposed . These include percent free PSA, PHI, 4K score and PCA3.
Serum and urinary biomarkers that may be combined with PSA for enhancing the diagnostic accuracy of prostate cancer detection including high grade disease.
| Test | |
|---|---|
| PSA, fPSA, iPSA, HK2, -microseminoprotein, macrophage inhibitory cytokine, 232 SNPb | Serum |
| Methylated GSTP1, SFRP2, IGFBP3, IGFBP7, APC, PTGS2 | Urine |
aMeasured at mRNA level. bThese variables are combined with clinical and histological criteria. PSA, total PSA fPSA, free PSA iPSA, intact PSA HK2, human kallikrein 2 PCA3, prostate cancer antigen 3 MiPS, Mi-Prostate Score TMPRRS2, transmembrane protease, serine 2.
The Biomarker Panels Improved The Specificity Of Ag Pca Detection
For clinical applications, a very high sensitivity is required for the detection of AG PCa. In Table 2, to detect AG PCa from low risk PCa at a fixed sensitivity of 95.0%, the specificity of the four-marker panel of phi, Fuc-PSA, SDC1, and GDF-15, and the combination of phi and Fuc-PSA both had a specificity of 76.0% in comparison to that of 56.0% for phi and 44.0% for PSA alone. Similarly, to detect AG PCa from low risk PCa and non-PCa at the same 95.0% sensitivity, the specificity for the four-marker panel of phi, Fuc-PSA, SDC1, and Tie-2, and the same phi, Fuc-PSA combinations had a specificity of 78.2% and 69.1%, respectively vs 65.5% for phi and 36.4% for PSA alone.
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Biology Of Prostate Cancer
Located under the bladder and in front of the rectum, the prostate is a small, soft gland with the urethra running directly through it . Androgens regulate the prostate gland as the major stimulus for cell division in prostatic epithelium . Although androgens are regarded as major contributors to prostatic carcinogenesis, there is little direct evidence to demonstrate that androgens cause prostate cancer. In part because of the lack of easily measurable hormonal events in men, there is insufficient evidence to establish an indirect role for androgens relative to the cause of the disease .
There is an architectural and cytological similarity between prostate cancers identified clinically and those detected incidentally at autopsy, although differences do exist in numerous pathologic features. Compared to the clinically identified cancers, incidentally found cancers are usually small, sufficiently or moderately differentiated, and confined to the prostate . In addition, unsuspected prostate cancers found at the time of cystoprostatectomy for the treatment of bladder cancer are similar to autopsy cancers . Seventy-eight percent of unexpected prostate cancers found in cystoprostatectomy specimens are small, confined to the prostate, and moderately to well differentiated, compared with only 9% of the clinically detected cancers with such features . Twenty-nine percent of clinically found cancers are advanced as compared with none of the cystoprostatectomy cancers .
The Initial Causes Fda Approved Prostate Cancer Biomarkers 2018
One of the first symptoms of prostate issues is pain or tenderness in the groin or lower back. This can be the result of a noncancerous condition called enlarged prostatic tissue, or it could be an infection of the bladder. In either case, its important to see a doctor as soon as possible. If youre suffering from prostate pain, you may want to consider reducing your caffeine intake.
Another symptom of a potentially enlarged prostate is difficulty starting a stream of urine, leaking, or dribbling. These symptoms are not serious, but theyre still alarming. Most men put up with an enlarged prostate for years before seeking medical attention, but they typically seek treatment as soon as they notice symptoms. Even if you dont have symptoms, its worth getting checked to determine if you have any prostate issues.
If you experience nightly bathroom runs, you may be experiencing an enlarged prostate. You may be having difficulty starting a stream of urine, or you may even be dribbling or leaking during the day. These problems arent life-threatening, but can become a nuisance. You should not ignore these signs and seek treatment as soon as you notice them. If you feel any of these symptoms, you should consult a doctor.
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Potential Prostate Cancer Biomarkers In Development
3.5.1 Prostarix
Prostarix is another PCa biomarker that has potential value in screening/diagnosis. It is a post-DRE urine test that is used to predict the likelihood of having a negative prostate biopsy versus one with occult PCa. This is done using a risk score. The risk score is generated using an algorithm which ranges from 0% to 100%. One hundred percent equates to a 100% chance of having PCa on a prostate biopsy. Therefore, it is used to determine which men will undergo prostate biopsy. Prostarix is used when there is an elevated tPSA and normal DRE, and in some cases, for men who are candidates for a repeat prostate biopsy .
Prostarix measures four metabolites using liquid chromatography mass spectrometry. These metabolites are sarcosine, alanine, glycine and glutamate. Sarcosine especially, has been linked with PCa progression . A study conducted by McDunn et al. 2013, showed that these metabolites improved prediction of organ confinement and 5-year recurrence . However, a study done by Sroka et al. in 2017 that evaluated various amino acids as PCa biomarkers found that sarcosine was not a definitive indicator of PCa when analyzed in pre and post-prostate massage urine samples. Also, the amino acids arginine, homoserine, and proline were mostly seen in the urine samples of PCa patients as opposed to patients with a benign prostatic disease . It is evident that more studies need to be done on Prostarix, and of note, it is not FDA approved.
Table Of Targeted And Immunotherapies For Prostate
| Men with mCRPC whose cancer has progressed following treatment with Xtandi or Zytiga | Inherited mutation in or tumor mutation one ofthe following genes: |
| Men with mCRPC who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy | Inherited or acquired mutation in BRCA1 |
| For the treatment of asymptomatic or minimally symptomatic metastatic | |
| that have progressed after treatment and for which there are no other treatment options | MSI-H ( |
|
For the treatment of solid tumors that have progressed following prior treatment and for which there are no satisfactory alternative treatment options |
Tumor Mutational Burden |
| solid tumors where surgical resection is likely to result in severe morbidity, and for which there are no satisfactory alternative treatments or the cancer progressed following treatment | NTRK fusion |
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Identification Of Biomarkers For Multiplex Immunoassay
In addition to evaluating two previously identified serum biomarkers , additional serum biomarkers with potential relevance to AG PCa were curated through a comprehensive literature search in PubMed. The inclusion of these biomarkers in our multiplex imunoassay panels took into consideration the reported clinically relevant performance characteristics and strength of evidence, biological feasibility supported by existing knowledge/databases such as results from large-scale genomic and proteomics analysis, ability to complement other biomarkers in the selection, their relative abundance in human serum samples, and the likelihood of available resources and constraints . Through in silico analysis, a total of 22 candidate biomarkers were selected to be assessed using a Bio-Plex 200 suspension array system as described previously in 40 sera from patients diagnosed with AG or low risk PCa and benign prostate diseases, which were collected from JHH with institutional approval . Ten candidate biomarkers and one previously reported biomarker were further evaluated using multiplex immunoassays in the 90 patient sera collected from Beth Israel Deaconess Hospital. The multiplex immunoassays had acceptable analytical performance with recoveries of 98% to 104%, intra-assay precision of 0.8% to 4.8%, inter-assay precision of 0.8% to 4.2%, wide dynamic concentration ranges defined by LLOQ and ULOQ, and low LOBs for target protein quantification .
Table 1
Propsa And Prostate Health Index
proPSA, which contains a seven amino acid pro leader peptide, is a molecular form of free PSA , and is more likely to be associated with PCa. Truncated forms of proPSA also exist in serum, which contain five, four, or two more amino acids than PSA. The proPSA form has been identified as the most prevalent form in tumor extracts, which suggests a role for these molecular forms of PSA for the early detection of PCa, and for possibly identifying aggressive PCa .
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Epidemiology Of Prostate Cancer
With an estimated 192,280 new cases in 2009, prostate cancer is one of the most commonly diagnosed malignancies in American men . It is also the second leading cause of cancer death in American males, exceeded only by lung cancer. An estimated 27,360 men will die from prostate cancer in 2009 .
Prostate cancer is a disease of mainly older men. An early observation reports that more than 65% of all prostate cancers are diagnosed in men over the age of 65 . Compared with the occurrences in the White population, the incidence of prostate cancer is approximately 60% higher in Black men, while native Japanese and Chinese populations have a low risk of incidence and mortality . Furthermore, African-American men generally are diagnosed with more advanced stages of prostate cancer and at an earlier age . Consequently, much effort is being placed on detecting prostate cancer in an early, curable stage to decrease the rate of mortality from this disease. Along with genetics, social and environmental factors may act as the determining factors, which may explain why some individuals are at higher risk for developing prostate cancer than are others. Nevertheless, in most cases, this disease can be treated effectively and even eradicated when the disease is detected at a very early stage .
Tissue Type And Disease State Prediction
One limitation of molecular datasets in general is related to the limited number of samples and the high dimensional feature space, leading to the curse of dimensionality,. The issue of dimensionality is usually managed by feature selection or transformation techniques, leading inevitably to a loss of valuable predictive information. Extracting a meaningful low-dimensional latent representation from a molecular profile is the key to success in overcoming the problem of high-dimensional data with small sample size. For this purpose, our approach utilizes an autoencoder composed of a supervised deep learning architecture. The lower dimensional latent representation of the mRNA gene expression profiles is then used in a multi-label classification task by exploiting commonalities and differences across tasks to differentiate the ovarian, prostate, breast tissues and disease states .
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A New Era Of Prostate Cancer Precision Medicine
- 1School of Biomedical Sciences, Queensland University of Technology, Institute of Health and Biomedical Innovation, Brisbane, QLD, Australia
- 2Australian Prostate Cancer Research CentreQueensland, Translational Research Institute, Woolloongabba, QLD, Australia
Prostate cancer is the second most common male cancer affecting Western society. Despite substantial advances in the exploration of prostate cancer biomarkers and treatment strategies, men are over diagnosed with inert prostate cancer, while there is also a substantial mortality from the invasive disease. Precision medicine is the management of treatment profiles across different cancers predicting therapies for individual cancer patients. With strategies including individual genomic profiling and targeting specific cancer pathways, precision medicine for prostate cancer has the potential to impose changes in clinical practices. Some of the recent advances in prostate cancer precision medicine comprise targeting gene fusions, genome editing tools, non-coding RNA biomarkers, and the promise of liquid tumor profiling. In this review, we will discuss these recent scientific advances to scale up these approaches and endeavors to overcome clinical barriers for prostate cancer precision medicine.
Protein Biomarkers And New Proteomic Technologies
Proteomic technologies and proteomics have always been a fascinating area of research for the discovery of cancer-specific biomarkers, improvement in prognosis, and treatment response biomarker identification, contributing to in-depth understanding of cancer pathology and developing new effective therapies . Mass spectrometry has been the forefront for proteomic and peptidomic analysis, identifying thousands of proteins and translating relevant data to clinics. In the past decade, different MS-based platforms like liquid chromatography-tandem MS , two-dimensional fluorescence difference gel electrophoresis , matrix-assisted laser desorption ionization time of flight MS, capillary electrophoresisMS, selected reaction monitoring /multiple reaction monitoring , and parallel reaction monitoring have been developed for biomarker discovery, paving the way for translating it to clinically relevant biomarkers in prognosis and diagnosis.
Table 1. Different studies highlighting the role of proteomic techniques in precision medicine.
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Biomarkers For Treatment Selection
Biomarker tests may be used to select treatments, and help patients avoid side effects from treatments that will not work for them. Biomarker tests used to select a specific treatment are sometimes called “companion diagnostic tests.” These tests may be done on tumor tissue or on blood. See our Testing section for more information.
Experts recommend cancer based on risk groups.
- Men with low and favorable-intermediate-risk prostate cancer and a life expectancy of > 10 years should consider multi-gene tumor testing. Multi-gene tumor testing can help predict how aggressive the prostate cancer is and guide treatment.
- Prostate multi-gene tumor tests include Decipher, Oncotype DX Prostate
Biomarkers Used To Assess The Therapeutic Response
PSA does not always accurately reflect response to therapy for castration-resistant PCa . Newer therapies, such as sipuleucel-T and radium-223, may improve survival without decreasing PSA levels. For cytotoxic or hormonal therapies, PSA responses are not always indicative of clinical response. Radiographic progression and symptomatology are still key parameters for consideration of changing antineoplastic therapy. Discordance between PSA kinetics and clinical response and progression of disease has been regularly observed. The need for biomarkers beyond PSA to predict response to treatment is well recognized. Other helpful serologic tests include hemoglobin, alkaline phosphatase, lactate dehydrogenase , and others. However, there is an unmet need for novel biomarkers to better assist clinical evaluation of therapeutic response in metastatic CRPC.
Circulating tumor cells
The CTC assay is intended for enumeration of CTCs in whole blood, which can be a biomarker for a therapeutic response to antineoplastic regimens. Increased levels of CTCs in the blood of CRPC patients can predict worse outcomes. Evaluation of individual CTCs has allowed further prognostication of PCa. CTCs may be useful for predicting treatment response and survival outcomes associated with cytotoxic and hormonal therapies, but approximately 50% of patients have undetectable CTC levels based on current detection methods. CTC detection techniques with improved sensitivity are under investigation.
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