Calculators, Algorithms, Drug Interaction CheckersTools
Back To Search Results

Prostate Cancer Tissue-Based Biomarkers

Author: Anu R I Author: Shafeek Shamsudeen Editor: Stephen W. Leslie Updated: 5/30/2023 3:57:46 PM

Introduction

Prostate cancer is the malignancy arising from the prostate gland in men. Cancer of the prostate is the fourth most common malignancy worldwide amongst both sexes and is the fifth leading cause of death in men, according to the 2020 census. It is also a malignancy related to a nation’s development index, like breast, lung, and colorectum cancers.[1]

The cumulative incidence and mortality risk are higher in countries with very high Human Development Index (HDI) scores (7.88%) as opposed to those nations with low HDI (3.29%) scores. 

In general, the incidence and mortality of prostate cancer are lowest in Asia and highest in the Caribbean and Africa. Western Europe, Australia, and North America have relatively high incidence rates but low mortality.[1] 

Even though patients with prostate cancer have improved overall survival, from a global perspective, this is a disease that requires attention in terms of better diagnostic and treatment modalities, especially in the metastatic setting. Properly used prostate cancer tissue-based biomarkers can significantly improve prognostic determinations, risk stratification, and treatment selection.

Until recently, prostate cancer diagnosis and risk stratification has been based solely on clinical stage, grade group/Gleason score, and prostate-specific antigen (PSA) levels. The tumor being highly heterogenous, Gleason scoring adopts a sum of scores from two different histological areas. Clinicians use these variables to construct nomograms and risk calculators. The most commonly used prognostic tools are the Partin tables (to predict tumor and nodal stage after radical prostatectomy), the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram (predicts postoperative progression-free survival in addition to the tumor and nodal stage after radical prostatectomy), and the Cancer of the Prostate Risk Assessment (CAPRA) score (to predict postoperative high-risk features, lymph node involvement and recurrence-free survival at 3 and 5 years).[2][3] Additional tools are the Briganti nomogram and the Kattan nomogram.[2][4]

Taken together, these clinicopathological variables and prognostic tools, though somewhat useful in real-world clinical situations, are inadequate to reliably predict the course of the disease as evidenced by real-world experience. Worse, they are rapidly becoming obsolete as the field of oncology is being catapulted by cutting-edge molecular diagnostics revolving around cancer genomics, transcriptomics, biomarkers, and epigenomics.

This article addresses the utility and clinical application of new and cutting-edge prostate cancer tissue-based biomarker assays that have either been approved by regulatory bodies or are in a developmental pipeline awaiting further research.

Etiology and Epidemiology

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Etiology and Epidemiology

While the exact cause of prostate cancer is unknown, variations in the DNA leading to mutations or aberrant gene fusions could be the initiating event. However, there are strong risk factors that facilitate the development of malignancy. Older age, western African ancestry, family history of prostate cancer, especially with segregation of BRCA1 and BRCA2 gene variations, Lynch syndrome, obesity, unhealthy diet style, inadequate beta-carotene, alcohol consumption, smoking, and specific medications are known risk factors with increasing evidence of their contributions to the underlying etiology.[5][6][7][8]

Epidemiology

Most men with prostate cancer will not die from the disease. In the United States, the 5-year overall survival rate is 99%.[9] The American Cancer Society has estimated that it will still kill 34,500 men out of 268,500 newly reported cases in the US in 2022.[10]

Prostate cancer is more common in developed countries than in the Third World.[11] The National Cancer Institute (NCI) has reported that the lifetime risk of acquiring clinically significant prostate cancer (Gleason 4 disease) in the US is 11.6%.[10]

In 60% of countries worldwide (112/185), prostate cancer is the most commonly diagnosed malignancy.[12] Statistically, 7.3% of the total number of new cancer cases and 3.8% of the total number of deaths in 2020 were attributed to prostate cancer, as per GLOBOCAN 2020 data.[13] Worldwide incidence in 2020 was reported as 1,414,000 new cancer cases and 375,304 deaths.[14]

The worldwide incidence of prostate cancer is 30.7 per 100,000, and the global mortality rate is 7.7 per 100,000.

According to the World Cancer Research Fund International, the nations with the highest per capita incidence and mortality rates of prostate cancer are: 

Countries with the Highest Prostate Cancer Incidence per 100,000:

  1. Guadaloupe (184)
  2. Martinique (168)
  3. Ireland (111)
  4. Barbados (110)
  5. St. Lucia (103)
  6. Estonia (102)
  7. Puerto Rico (101)
  8. France (100)
  9. Sweden (99)
  10. Bahamas (98)

Countries with the Highest Prostate Cancer Mortality Rate per 100,000:

  1. Zimbabwe (42)
  2. Barbados (40.3)
  3. Haiti (40.2)
  4. Zambia (40.1)
  5. Jamaica (39.4)
  6. Trinidad and Tobago  (38.9)
  7. Bahamas (36)
  8. Dominican Republic (35)
  9. St. Lucia (33)
  10. Ivory Coast (30)

Pathophysiology

The prostate gland is located at the base of the penis in the pelvis. From a lateral, anatomic view, it is adjacent and anterior to the rectum as well as inferior to the urinary bladder.

The tissue is predominantly glandular, producing an alkaline secretion that constitutes about 25 to 30% of the seminal fluid.

Malignancy arising from the gland is classified as an adenocarcinoma. The commonest metastatic sites are the draining regional lymph nodes and the bony skeleton.[10] Chronic inflammation is also believed to be a facilitator of prostatic malignant transformation and neoplastic development.[15][16] Malignancy is thought to arise from mutations within basal or luminal cells.[17][18] 

The stages of malignant neoplasia are well-studied. It begins with prostatic intraepithelial neoplasia (PIN) and/or atypical small acinar proliferation (ASAP), progresses to localized malignancy, then to advanced cancer with local invasion, and finally to florid metastatic disease.[19]

The genome and epigenome play a crucial role in the initiation and progression of prostatic malignancy. Genome-wide association studies (GWAS) have shown that about 31.5% of the familial relative risk (FRR) is attributed to 167 common variants or susceptible loci in the genome, and approximately 6% are due to BRCA2 and HOXB13. The first GWAS (2006) found single nucleotide polymorphisms (SNPs) in the 8q24 loci, which are believed to influence the oncogene MYC.

Besides HOXB13 and BRCA2, familial mutations have also been found in ATM, CHEK2, BRCA1, RAD51D, and PALB2 genes.[20]

As for common somatic variants found in prostatic cancer, the following are implicated:[21]

  • Deletions in APC, CHD1, ETS2, NKX3.1, and SETD2.
  • Deletions/mutations in ATM, BRCA1, BRCA2, ERF, KMT2A, KMT2C, KMT2D, KDM1A, KDM3A, KDM6A, NCOR1, NCOR2, PTEN, RB1, SMAD4, SMARCA1, SMARCB1, and TP53.
  • Amplification/mutation/splice variant mutations in AR.
  • Fusion/deletion in ERG and ETVs.
  • Mutations in EZH2, FOXA1, IDH1, and SPOP.
  • Amplification in MYC, MYCN, and SETDB1.

The E26 transformation-specific (ETS) family of transcription factors is particularly important in prostate cancer, as TMPRSS2-ERG fusion is seen in ~50% of localized malignancies.[22] (ERG and ETVs are members of the ETS family of transcription factors.)

The molecular biology of metastatic prostate cancer is typified by novel EMT (Epithelial-Mesenchymal Transition) processes.

  • Bone metastasis is supported by stromal cell-derived factor-1 (SDF-1/ CXCL12) and the CXCR4 receptor for homing and invasion of tumor cells.[23] 
  • Hematopoietic stem cells locate and bind to niche via annexin A2 (ANXA2) that is found to be overexpressed in prostate cancer cells.[24] 
  • Tumor-derived exosomes carrying integrins have been implicated in organotropic metastasis.[25] 
  • Increased RANK-RANKL signaling within prostate tumor cells has significantly promoted skeletal metastasis.[26] 

Specimen Requirements and Procedure

Table 1 Contemporary Assays and Techniques 

Sl No. Tissue-based assay Starting material Omics analyzed Technique
1 Decipher

FFPE tissue

Tumor specimen of at least 0.5 mm		 Transcriptome Microarray
2 Prolaris Molecular Score FFPE tissue Transcriptome Quantitative polymerase chain reaction
3 Oncotype DX Genomic Prostate Score  FFPE tissue Transcriptome Reverse transcriptase PCR
4 Somatic Tumor Testing FFPE tissue Genome Next Generation Sequencing  
5 ConfirmMDx FFPE tissue Epigenome Epigenetic multiplex PCR 

Diagnostic Tests

Prostate Specific Antigen (PSA) Screening

There is considerable controversy regarding PSA screenings for prostate cancer. The issue is not that PSA screening does not find prostate cancer but that it leads to overdiagnosis and overtreatment of indolent cancers without clinical significance for the patient.[27] (This would not include men who are found to have a suspicious nodule on physical examination and would need further evaluation.) 

There is a multitude of guidelines from a variety of professional organizations and societies regarding PSA screening. They all recommend a discussion of the risks and benefits of PSA screenings and starting testing in appropriate individuals who desire screening only after the process of shared decision-making has been completed.[27]

There is a clear distinction between recommendations for men at average risk and those at high risk. High-risk individuals would include those men with a direct blood relative with prostate cancer (especially if it appeared at an early age or resulted in death), all those of African descent, a family history of multiple malignancies, Lynch syndrome, or known BRCA2 or similar high-risk germline carriers.[27] Since about 10% of all prostate cancers occur in men younger than 55 and 1% before the age of 50, it seems reasonable to recommend a baseline PSA test at age 45, at least for men with high-risk factors.[28]

All of the guidelines recommend halting routine screenings in men with less than a 10-year life expectancy or by age 70 to 75. The average life expectancy of a generally healthy 75-year-old (according to the Social Security Actuarial Tables) is about 11 years, so the 75-year-old cutoff for routine screenings is suggested.[27]

For a more detailed and comprehensive discussion of the PSA testing controversy, please review our companion StatPearls reference article on "Prostate Cancer Screening."

Summary of Published PSA Screening Guidelines:

  • The American Cancer Society suggests starting PSA screening discussions at age 50 for men at average risk and earlier for high-risk individuals.[29]
  • The American Medical Association recommends discussing PSA screening at age 45 for high-risk men and age 50 for normal-risk individuals.
  • The American Urological Association recommends initial discussions regarding screening for high-risk individuals aged 40 to 54 years and average-risk men 55 years and older.[30] 
  • The European Association of Urology (EAU) recommends starting a review of screenings at age 40 for men with known BRCA2 germline mutations, age 45 for other high-risk individuals, and age 50 for average-risk males.[27]
  • The United States Preventive Services Task Force (USPSTF) currently recommends discussing the pros and cons of PSA screening for prostate cancer with men aged 55 to 69.[12]

Tissue-Based Biomarkers

All of these biomarker tests are intended to help in the decision-making process for patients with a predicted life expectancy of at least ten years and where the results are likely to make a difference in their final treatment selection.[31] (A description and definition of the various prostate cancer risk groups can be found in our companion StatPearls reference article on "Prostate Cancer.")[10]

Of the multitude of assays that have been developed, the most valuable are ConfirmMDx, Decipher, Oncotype DX, Prolaris, ProMark, and Somatic tumor testing for targeted therapy.[32]

ConfirmMDx, developed by MDxHealth, Inc. in Irvine, California, is a tissue-based assay used to predict the incidence of finding malignancy on a repeat biopsy for patients whose initial histology was negative. It reports the likelihood of finding cancer as a percentage.[33] The assay technically employs the epigenetic multiplex polymerase chain reaction (PCR) method to assess promoter methylation of 3 genes RASSF1, GSTP1, and APC, in the biopsy specimen. The concept is based on epigenomic changes that are presumably found in tumor-adjacent normal tissue. The Methylation Analysis to Locate Occult Cancer (MATLOC) and the Detection of Cancer Using Methylated Events in Negative Tissue (DOCUMENT) studies have validated the assay.[34] 

The latter found a negative predictive value (NPV) of 90%, and another study found an NPV of 96% in patients with lower methylation levels.[35] Stewart GD et al. found a 64% reduction of prostate biopsies with ConfirmMDx use.[36][37] The MDxHealth supported Prostate Assay Specific Clinical Utility at Launch (PASCUAL) (NCT02250313) study's results of 600 participants are yet to be published.

Patients who have had a negative prostate biopsy can consider using the ConfirmMDx test if they are contemplating a second biopsy. It is appropriate for patients with unexplained, persistent high, or rising PSA levels. It can also be useful in patients with high-risk factors or even just heightened anxiety about their biopsy results, such as multiple negative biopsies.

The Decipher Prostate Genomic Classifier is useful in two clinical scenarios: for men with localized prostate cancer deciding between active surveillance vs. intervention and in patients with high-risk pathology or clinical features after radical prostatectomy to decide on treatment or observation. The assay gives a result as a Genomic Classifier (GC) score of 0-1.0 (also known as the Decipher Biopsy score or Decipher Radical Prostatectomy score). The clinical endpoints targeted are the 5-year risk of metastasis, the likelihood of high-grade cancer on radical prostatectomy, and the 10-year prostate cancer-specific mortality risk.[38][39][40] A Genomic Classifier score of 0 to 0.45 is considered low risk, 0.46 to 0.6 is considered average risk, and above 0.61 is high risk.

The National Comprehensive Cancer Network (NCCN) guidelines suggest that the assay could be offered to patients with very low, low, and intermediate risk on biopsy, with a life expectancy of a minimum of 10 years. It can also be offered to patients with pathological T2 disease and positive surgical margins, persistent or recurrent PSA levels after radical prostatectomy, or pathological T3 disease to help decide on adjuvant radiation therapy. 

Technically, the Decipher test is a transcriptomic assay that uses the microarray method to study the expression of 22 genes, namely, LASP1, IQGAP3, NFIB, S1PR4, THBS2, ANO7, PCDH7, MYBPC1, EPPK1, TSBP, PBX1, NUSAP1, ZWILCH, UBE2C, CAMK2N1, RABGAP1, PCAT-32, GLYATL1P4, PCAT-80, and TNFRSF19. These genes play an important role in the cell cycle, cell growth, differentiation, and androgen receptor signaling. The assay was developed by comparing 192 RP samples from men with metastatic prostate cancer and 353 healthy controls. The initial validation produced an area-under-curve (AUC) of 0.90.[41] The Decipher biopsy test's score to predict metastasis has been validated with an AUC of 0.8.[42] 

A systematic review of 42 studies using data from 30,407 patients was conducted by Jairath K et al. to analyze the utility of Decipher in clinical decision-making.[43] The group concluded that Decipher GC scores were significant and useful in intermediate-risk cancer and post-prostatectomy cases where they contributed to a change in management.[43] There are currently at least 19 ongoing clinical trials studying the utility of this assay in prostate cancer.[43]

The Oncotype DX Genomic Prostate Score was developed following similar commercial assays for breast and colorectal cancer. This assay is suitable for men with very low and low-risk prostate cancer. The assay offers results as a Genomic Prostate Score (GPS) of 0-100. The resulting score displays the likelihood of Gleason Grade Group 1 or 2 after radical prostatectomy or the likelihood of organ-confined disease after definitive surgery.[44][45] It is, therefore, most appropriate for very low-risk and low-risk disease.

The assay uses reverse transcriptase PCR to study the expression of 12 genes involved in cell proliferation, organization, stromal response, androgen receptor pathway, and five housekeeping genes. TPX2, FLNC, GSN, TPM2, GSTM2, BGN, COL1A1, SFRP4, AZGP1, KLK2, SRD5A2, and FAM13C are the genes measured for expression. Oncotype DX has been validated in various cohorts.[46][47]

The ProMark test was intended for patients with a Gleason grade group (GGG) score of 1 or 2 on biopsy (Gleason 3+3=6 and 3+4=7), which generally represents very low, low, and favorable intermediate-risk disease. The clinical endpoint predicted is the risk of Gleason grade group ≥3, or non-organ confined cancer after radical prostatectomy. Results are depicted as a score of 0 to 1.[48][49] 

The test uses measurements of eight proteins involved in cell proliferation, signaling, and stress response, namely DERL1, CUL2, SMAD4, PDSS2, HSPA9, FUS, pS6, and YBOX1.[50] The assay predicts disease aggressiveness to help decide for or against active surveillance in favor of definitive therapy. 

Validation of the ProMark test showed:[49]

  • The positive predictive value (PPV) for detecting favorable disease with a risk score ≤0.33 is 83.6% with a specificity of 90%. 
  • The positive predictive value (PPV) for identifying unfavorable disease with a risk score >0.80 is 76.9%.

A clinical trial on the "Effects of a new diagnostic test on the care of prostate cancer patients: The ProMark clinical utility study" (NCT04550416) was completed in 2020, but the results have not yet been reported.

The Prolaris prostate cancer prognostic test is used in two clinical scenarios: newly diagnosed patients with prostate cancer (Prolaris biopsy test) and after radical prostatectomy (Prolaris post-prostatectomy test). Results are given as Cell Cycle Progression (CCP) scores of 0 to 6. The clinical endpoint is the 10-year risk of prostate cancer-specific mortality as well as the 10-year risk of biochemical recurrence (BCR) after radical prostatectomy.[51][52][53] 

The NCCN recommends the Prolaris assay for virtually all biopsy-proven prostate cancer patients (very low, low, favorable, and unfavorable intermediate-risk and high-risk) with a minimum life expectancy of 10 years. It can also be used post-prostatectomy. These indications were recently expanded.

Prolaris is a transcriptomic assay utilizing quantitative polymerase chain reaction (PCR) testing to measure the gene expression of 31 cell cycle progression genes against 15 housekeeping genes. The assay has been validated extensively yet is being clinically used relatively sparingly to help decide on active surveillance or definitive intervention (surgery/radiation) in borderline lower-risk prostate cancers.

Somatic Tumor Testing is generally performed on patients with metastatic castration-resistant prostate cancer who have progressed on androgen receptor-directed therapy, irrespective of any prior treatment with docetaxel.[54] It may also be considered in patients with regional or castration-naÏve sensitive metastatic prostate cancer.

Multigene molecular testing for patients with low, intermediate, and high-risk prostate cancer who enjoy an estimated life expectancy ≥10 years is suggested by the NCCN expert committee. The most recent NCCN guidelines recommend tumor genetic testing for homologous recombination repair mutations, microsatellite instability-high (MSI-H), deficient mismatch repair (dMMR) genes, and tumor mutational burden in patients with metastatic castration-resistant prostate cancer (mCRPC). 

  • Homologous recombination repair (HRR) genes: The HRR pathway is a metabolic process that aids the homology-mediated repair of damaged DNA.[55] The genes included in the testing panel for metastatic prostate cancer, as suggested by the NCCN expert committee, are BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. It may be suitable for a PARP inhibitor. (see below)
  • Microsatellite instability (MSI): Microsatellites are short stretches of repetitive nucleic bases. During replication, slippage errors may occur, leading to microsatellite (MSI) and genomic instability. Microsatellite instability is categorized as low, stable, or high. Clinically, the former two states (Low, Stable) are similar.[56] Polymerase chain reaction testing uses Bethesda pentaplex panel to assess microsatellite instability, while Next-Generation Sequencing (NGS) analyzes MSI status over a larger area of the genome.[57] (Next-generation sequencing, or NGS, uses parallel sequencing of multiple small DNA fragments for genomic analysis.)
  • Mismatch repair (MMR) genes: DNA Mismatch repair is a biological process that identifies and rectifies base mismatch, insertion, or deletion mispairs that may occur during DNA replication or recombination.[58] The key players of the MMR pathway are MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2, in addition to significant proteins including ExoI, Pol δ, PCNA, RPA, HMGB1, RFC, and DNA Ligase I.[58] Qualitative functional analysis of MMR genes is measured by immunohistochemistry or by an indirect estimation of intact function assessed by MSI testing using PCR or NGS techniques. The result could be expressed as a deficient or proficient expression.
  • Tumor mutation burden (TMB): From a biological perspective, the Tumor Mutation Burden (TMB) is the total number of mutations present in the DNA of a cancer cell. This is determined by calculating the number of mutations per megabase of the genomic sequence examined.[59] It is calculated during the post-processing step of the NGS assay.[60] A high tumor mutation burden (TMB-H) indicates cancer that may respond to immunotherapy. 

A finding of high microsatellite instability (MSI-H), deficient mismatch repair genes (dMMR), or high tumor mutation burden (TMB ≥10 mut/Mb) is an indicator for the addition of pembrolizumab, an immune checkpoint inhibitor, in appropriate clinical settings.[61] 

PARP inhibitors block the activity of the enzyme polyadenosine diphosphate-ribose polymerase (PARP), which would normally act to repair damaged intracellular DNA. They can effectively treat castration-resistant prostate cancers with HRR (BRCA) mutations. Olaparib and rucaparib are two examples.

  • Olaparib can be used in metastatic castration-resistant prostate cancer and BRCA or other DNA damage repair gene mutations where the malignancy has progressed. 
  • Rucaparib may also be used in metastatic castration-resistant prostate cancer patients who test positive for BRCA mutations and have previously been treated with androgen receptor blockers and taxane-based chemotherapy.
  • The FoundationOne CDx is a tissue-based molecular assay approved by the FDA for metastatic castrate-resistant prostate as a companion diagnostic for Olaparib, the biomarker being a panel of the homologous recombination repair (HRR) genes.

Androgen Receptor Splice Variant 7 (AR-V7) has been associated with more aggressive disease, shorter progression to metastatic cancer, higher PSA levels, greater disease burden, and shorter overall survival in metastatic prostate cancer patients.[62][63] AV-V7 status may also work as a prognostic marker in metastatic disease, suggesting resistance to abiraterone and enzalutamide but not taxanes.[64][65] 

Niclosamide and TAS3681 have been specifically designed to target and inhibit AR-V7, but their clinical use is still being investigated.[63] The NCCN expert committee recommends AV-V7 testing in circulating tumor cells (CTCs) to help decide on a therapeutic choice post-abiraterone or enzalutamide for metastatic castration-resistant prostate cancer.

Future and Investigational Biomarkers

Newer potential biomarkers are being studied and developed, such as:

  • Androgen receptor splice variant 7 (AR-V7) testing using liquid biopsy techniques [66][67]
  • PD-1/PD-L1 testing [68]
  • CD276 testing [69]
  • CD73 testing [70]
  • Tumor-associated macrophages (TAMs) [71]
  • Cytotoxic CD8 tumor-infiltrating lymphocytes (TILs) [72]
  • Regulatory T cells (Tregs) [73]
  • Mast cell testing [74][75] 

The NCCN guidelines mention Ki-67% and PTEN assessment as possible biomarkers, but they are not currently recommended. 

The PTEN/TMPRSS2-ERG test developed by Metamark was designed for patients with a Gleason grade group score of 1 or 2 on biopsy. The assay checks for deletion of PTEN and fusion of TMPRSS2-ERG.[76] Loss of PTEN function is associated with poorer outcomes, and the presence of TMPRSS2-ERG fusion predicts an increased risk of metastasis. The role of these assays in aiding clinical decisions is limited today, and the NCCN expert committee does not currently recommend them. 

A study by Thomas Dillinger et al. found seven genes (SERPINB1, ACSS3, SCGB3A1, NKX2-6, HOXA7, CRABP2, and DHRS4L2) were hypermethylated in malignant tumor samples compared to normal adjacent tissue.[77]

Recent research shows that circular RNAs and linear transcripts could be useful as biomarkers for prostate cancer.

  • A combination of circATXN10 and linSTIL could be a useful biomarker to distinguish normal from malignant prostate cells.[78] 
  • The biochemical recurrence rate could be predicted by linGUCY1A2, linNEAT1, and linSTIL. The method used is RT-qPCR on flash-frozen fresh tumor samples.[78] 

Concise Clinical Summary of Prostatic Tissue Biomarkers:

Prostate cancer tissue-based biomarkers are only useful and recommended for patients with a predicted 10-year or more life expectancy who are at a critical decision point in management. The test results are likely to make a significant difference in treatment selection.

A detailed description and review of the prostate cancer risk groups can be found in our companion StatPearls reference article on "Prostate Cancer." [10]

  • Negative biopsy: ConfirmMDx
  • Very low-risk disease: Oncotype DX, Prolaris, or ProMark
  • Low-risk disease: Decipher, Oncotype DX, Prolaris, or ProMark
  • Favorable intermediate-Risk Disease: Decipher, ProMark, or Prolaris
  • Unfavorable intermediate-risk and high-risk disease: Decipher or Prolaris
  • Metastatic disease: Somatic tumor testing
  • PSA persistence or recurrence after prostatectomy: Decipher or Prolaris

Testing Procedures

All clinically relevant tissue-based biomarkers use FFPE tissue retrieved from a surgical specimen or biopsy as starting material. Fresh frozen tissue is known to be superior for extracting nucleic acids and downstream molecular analysis, but there are practical hurdles in relying on the latter for routine clinical use.[79] 

Irrespective of the starting material for testing, it is mandatory to adhere to all necessary and recommended quality control protocols regarding specimen preparation, storage, and transport for these molecular assays to provide reliable results.

Clinical Significance

Even though patients with prostate cancer have improved overall survival, from a global perspective, this is a disease that requires attention in terms of better diagnostic and treatment modalities, especially at critical decision points and in the metastatic setting. Properly used prostate cancer tissue-based biomarkers can significantly improve prognostic determinations, risk stratification, and treatment selection.

Enhancing Healthcare Team Outcomes

Oncology practice is entering a new age of improved diagnostic testing based on cancer-specific proteins, germline mutations, and genetics. The field is expanding so rapidly that it is difficult for healthcare professionals to keep up. Using the proper testing for the right patient at the right time for the right reason requires an interprofessional team approach, including primary care clinicians (MDs, DOs, NPs, and PAs), urologists, oncologists, genetic counselors, pathologists, cancer coordinators, nursing personnel, and pharmacists working together and communicating effectively to provide optimal advice, counseling, and treatment for their patients. 

The biomarkers can provide significant insight into potential cancers. All practitioners on the case must document their findings and communicate them to the rest of the team so that all caregivers have the same accurate and updated case information from which to make decisions. Nurses will help coordinate referrals and communication between specialties, and in such cases, an oncology-specialized nurse may prove beneficial. This interprofessional paradigm in using these biomarkers will result in improved diagnosis, which will translate into better care and presumably improved patient outcomes. [Level 5]

References

[1]

Sung H,Ferlay J,Siegel RL,Laversanne M,Soerjomataram I,Jemal A,Bray F, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians. 2021 May;     [PubMed PMID: 33538338]

[2]

de Barros HA,Remmers S,Luiting HB,van Leenders GJLH,Roobol MJ,Bekers EM,Amin A,Haynes AM,Delprado W,Stricker PD,van der Poel HG,van der Kwast TH,van Leeuwen PJ, Predictive Value of Cribriform and Intraductal Carcinoma for the Nomogram-based Selection of Prostate Cancer Patients for Pelvic Lymph Node Dissection. Urology. 2022 Oct;     [PubMed PMID: 35803346]

[3]

Nason GJ,O'Connor EM,MacMahon D,Moss B,Considine SW,Cahill A,O'Rourke C,O'Brien FM, Comparison of nomograms predicting lymph node invasion in patients undergoing radical prostatectomy for prostate cancer. Irish journal of medical science. 2018 Feb;     [PubMed PMID: 28478609]

[4]

Ondracek RP,Kattan MW,Murekeyisoni C,Yu C,Kauffman EC,Marshall JR,Mohler JL, Validation of the Kattan Nomogram for Prostate Cancer Recurrence After Radical Prostatectomy. Journal of the National Comprehensive Cancer Network : JNCCN. 2016 Nov;     [PubMed PMID: 27799510]

Level 1 (high-level) evidence

[5]

Chin HW,Kim J,Rasp G,Hristov B, Prostate Cancer in Seniors: Part 1: Epidemiology, Pathology, and Screening. Federal practitioner : for the health care professionals of the VA, DoD, and PHS. 2015 May;     [PubMed PMID: 30766120]

[6]

Gallagher DJ,Gaudet MM,Pal P,Kirchhoff T,Balistreri L,Vora K,Bhatia J,Stadler Z,Fine SW,Reuter V,Zelefsky M,Morris MJ,Scher HI,Klein RJ,Norton L,Eastham JA,Scardino PT,Robson ME,Offit K, Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010 Apr 1;     [PubMed PMID: 20215531]

Level 2 (mid-level) evidence

[7]

Khan HM,Cheng HH, Germline genetics of prostate cancer. The Prostate. 2022 Aug;     [PubMed PMID: 35657157]

[8]

Baena Ruiz R,Salinas Hernández P, Cancer chemoprevention by dietary phytochemicals: Epidemiological evidence. Maturitas. 2016 Dec;     [PubMed PMID: 27823732]

Level 2 (mid-level) evidence

[9]

Steele CB,Li J,Huang B,Weir HK, Prostate cancer survival in the United States by race and stage (2001-2009): Findings from the CONCORD-2 study. Cancer. 2017 Dec 15;     [PubMed PMID: 29205313]

[10]

Leslie SW,Soon-Sutton TL,Sajjad H,Siref LE, Prostate Cancer StatPearls. 2022 Jan;     [PubMed PMID: 29261872]

[11]

Taitt HE, Global Trends and Prostate Cancer: A Review of Incidence, Detection, and Mortality as Influenced by Race, Ethnicity, and Geographic Location. American journal of men's health. 2018 Nov;     [PubMed PMID: 30203706]

[12]

US Preventive Services Task Force.,Grossman DC,Curry SJ,Owens DK,Bibbins-Domingo K,Caughey AB,Davidson KW,Doubeni CA,Ebell M,Epling JW Jr,Kemper AR,Krist AH,Kubik M,Landefeld CS,Mangione CM,Silverstein M,Simon MA,Siu AL,Tseng CW, Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018 May 8;     [PubMed PMID: 29801017]

[13]

Deo SVS,Sharma J,Kumar S, GLOBOCAN 2020 Report on Global Cancer Burden: Challenges and Opportunities for Surgical Oncologists. Annals of surgical oncology. 2022 Oct;     [PubMed PMID: 35838905]

[14]

Wang L,Lu B,He M,Wang Y,Wang Z,Du L, Prostate Cancer Incidence and Mortality: Global Status and Temporal Trends in 89 Countries From 2000 to 2019. Frontiers in public health. 2022;     [PubMed PMID: 35252092]

[15]

Choi N,Zhang B,Zhang L,Ittmann M,Xin L, Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer cell. 2012 Feb 14;     [PubMed PMID: 22340597]

Level 3 (low-level) evidence

[16]

Wang ZA,Mitrofanova A,Bergren SK,Abate-Shen C,Cardiff RD,Califano A,Shen MM, Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nature cell biology. 2013 Mar;     [PubMed PMID: 23434823]

Level 3 (low-level) evidence

[17]

Lawson DA,Xin L,Lukacs RU,Cheng D,Witte ON, Isolation and functional characterization of murine prostate stem cells. Proceedings of the National Academy of Sciences of the United States of America. 2007 Jan 2;     [PubMed PMID: 17185413]

Level 3 (low-level) evidence

[18]

Goldstein AS,Huang J,Guo C,Garraway IP,Witte ON, Identification of a cell of origin for human prostate cancer. Science (New York, N.Y.). 2010 Jul 30;     [PubMed PMID: 20671189]

Level 3 (low-level) evidence

[19]

Shen MM,Abate-Shen C, Molecular genetics of prostate cancer: new prospects for old challenges. Genes     [PubMed PMID: 20844012]

Level 3 (low-level) evidence

[20]

Pritchard CC,Mateo J,Walsh MF,De Sarkar N,Abida W,Beltran H,Garofalo A,Gulati R,Carreira S,Eeles R,Elemento O,Rubin MA,Robinson D,Lonigro R,Hussain M,Chinnaiyan A,Vinson J,Filipenko J,Garraway L,Taplin ME,AlDubayan S,Han GC,Beightol M,Morrissey C,Nghiem B,Cheng HH,Montgomery B,Walsh T,Casadei S,Berger M,Zhang L,Zehir A,Vijai J,Scher HI,Sawyers C,Schultz N,Kantoff PW,Solit D,Robson M,Van Allen EM,Offit K,de Bono J,Nelson PS, Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. The New England journal of medicine. 2016 Aug 4;     [PubMed PMID: 27433846]

[21]

Wang G,Zhao D,Spring DJ,DePinho RA, Genetics and biology of prostate cancer. Genes     [PubMed PMID: 30181359]

[22]

Tomlins SA,Bjartell A,Chinnaiyan AM,Jenster G,Nam RK,Rubin MA,Schalken JA, ETS gene fusions in prostate cancer: from discovery to daily clinical practice. European urology. 2009 Aug;     [PubMed PMID: 19409690]

[23]

Taichman RS,Cooper C,Keller ET,Pienta KJ,Taichman NS,McCauley LK, Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer research. 2002 Mar 15;     [PubMed PMID: 11912162]

[24]

Shiozawa Y,Havens AM,Jung Y,Ziegler AM,Pedersen EA,Wang J,Wang J,Lu G,Roodman GD,Loberg RD,Pienta KJ,Taichman RS, Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. Journal of cellular biochemistry. 2008 Oct 1;     [PubMed PMID: 18636554]

[25]

Hoshino A,Costa-Silva B,Shen TL,Rodrigues G,Hashimoto A,Tesic Mark M,Molina H,Kohsaka S,Di Giannatale A,Ceder S,Singh S,Williams C,Soplop N,Uryu K,Pharmer L,King T,Bojmar L,Davies AE,Ararso Y,Zhang T,Zhang H,Hernandez J,Weiss JM,Dumont-Cole VD,Kramer K,Wexler LH,Narendran A,Schwartz GK,Healey JH,Sandstrom P,Labori KJ,Kure EH,Grandgenett PM,Hollingsworth MA,de Sousa M,Kaur S,Jain M,Mallya K,Batra SK,Jarnagin WR,Brady MS,Fodstad O,Muller V,Pantel K,Minn AJ,Bissell MJ,Garcia BA,Kang Y,Rajasekhar VK,Ghajar CM,Matei I,Peinado H,Bromberg J,Lyden D, Tumour exosome integrins determine organotropic metastasis. Nature. 2015 Nov 19;     [PubMed PMID: 26524530]

[26]

Jones DH,Nakashima T,Sanchez OH,Kozieradzki I,Komarova SV,Sarosi I,Morony S,Rubin E,Sarao R,Hojilla CV,Komnenovic V,Kong YY,Schreiber M,Dixon SJ,Sims SM,Khokha R,Wada T,Penninger JM, Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006 Mar 30;     [PubMed PMID: 16572175]

Level 3 (low-level) evidence

[27]

Jain MA,Leslie SW,Sapra A, Prostate Cancer Screening StatPearls. 2022 Jan;     [PubMed PMID: 32310541]

[28]

Smith CV,Bauer JJ,Connelly RR,Seay T,Kane C,Foley J,Thrasher JB,Kusuda L,Moul JW, Prostate cancer in men age 50 years or younger: a review of the Department of Defense Center for Prostate Disease Research multicenter prostate cancer database. The Journal of urology. 2000 Dec;     [PubMed PMID: 11061892]

Level 2 (mid-level) evidence

[29]

Wolf AM,Wender RC,Etzioni RB,Thompson IM,D'Amico AV,Volk RJ,Brooks DD,Dash C,Guessous I,Andrews K,DeSantis C,Smith RA,American Cancer Society Prostate Cancer Advisory Committee., American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA: a cancer journal for clinicians. 2010 Mar-Apr;     [PubMed PMID: 20200110]

[30]

Carter HB, American Urological Association (AUA) guideline on prostate cancer detection: process and rationale. BJU international. 2013 Sep;     [PubMed PMID: 23924423]

Level 1 (high-level) evidence

[31]

Eggener SE,Rumble RB,Armstrong AJ,Morgan TM,Crispino T,Cornford P,van der Kwast T,Grignon DJ,Rai AJ,Agarwal N,Klein EA,Den RB,Beltran H, Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020 May 1;     [PubMed PMID: 31829902]

[32]

Lokeshwar SD,Syed JS,Segal D,Rahman SN,Sprenkle PC, Optimal Use of Tumor-Based Molecular Assays for Localized Prostate Cancer. Current oncology reports. 2022 Feb;     [PubMed PMID: 35080739]

[33]

Van Neste L,Bigley J,Toll A,Otto G,Clark J,Delrée P,Van Criekinge W,Epstein JI, A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection. BMC urology. 2012 Jun 6;     [PubMed PMID: 22672250]

Level 2 (mid-level) evidence

[34]

Partin AW,VAN Criekinge W,Trock BJ,Epstein JI,VAN Neste L, CLINICAL EVALUATION OF AN EPIGENETIC ASSAY TO PREDICT MISSED CANCER IN PROSTATE BIOPSY SPECIMENS. Transactions of the American Clinical and Climatological Association. 2016;     [PubMed PMID: 28066067]

[35]

Van Neste L,Partin AW,Stewart GD,Epstein JI,Harrison DJ,Van Criekinge W, Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies. The Prostate. 2016 Sep;     [PubMed PMID: 27121847]

[36]

Stewart GD,Van Neste L,Delvenne P,Delrée P,Delga A,McNeill SA,O'Donnell M,Clark J,Van Criekinge W,Bigley J,Harrison DJ, Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. The Journal of urology. 2013 Mar;     [PubMed PMID: 22999998]

Level 2 (mid-level) evidence

[37]

Partin AW,Van Neste L,Klein EA,Marks LS,Gee JR,Troyer DA,Rieger-Christ K,Jones JS,Magi-Galluzzi C,Mangold LA,Trock BJ,Lance RS,Bigley JW,Van Criekinge W,Epstein JI, Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. The Journal of urology. 2014 Oct;     [PubMed PMID: 24747657]

Level 1 (high-level) evidence

[38]

Cooperberg MR,Simko JP,Cowan JE,Reid JE,Djalilvand A,Bhatnagar S,Gutin A,Lanchbury JS,Swanson GP,Stone S,Carroll PR, Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013 Apr 10;     [PubMed PMID: 23460710]

Level 2 (mid-level) evidence

[39]

Klein EA,Yousefi K,Haddad Z,Choeurng V,Buerki C,Stephenson AJ,Li J,Kattan MW,Magi-Galluzzi C,Davicioni E, A genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed by radical prostatectomy without adjuvant therapy. European urology. 2015 Apr;     [PubMed PMID: 25466945]

Level 2 (mid-level) evidence

[40]

Ross AE,Johnson MH,Yousefi K,Davicioni E,Netto GJ,Marchionni L,Fedor HL,Glavaris S,Choeurng V,Buerki C,Erho N,Lam LL,Humphreys EB,Faraj S,Bezerra SM,Han M,Partin AW,Trock BJ,Schaeffer EM, Tissue-based Genomics Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men. European urology. 2016 Jan;     [PubMed PMID: 26058959]

[41]

Erho N,Crisan A,Vergara IA,Mitra AP,Ghadessi M,Buerki C,Bergstralh EJ,Kollmeyer T,Fink S,Haddad Z,Zimmermann B,Sierocinski T,Ballman KV,Triche TJ,Black PC,Karnes RJ,Klee G,Davicioni E,Jenkins RB, Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PloS one. 2013;     [PubMed PMID: 23826159]

Level 2 (mid-level) evidence

[42]

Klein EA,Haddad Z,Yousefi K,Lam LL,Wang Q,Choeurng V,Palmer-Aronsten B,Buerki C,Davicioni E,Li J,Kattan MW,Stephenson AJ,Magi-Galluzzi C, Decipher Genomic Classifier Measured on Prostate Biopsy Predicts Metastasis Risk. Urology. 2016 Apr;     [PubMed PMID: 26809071]

[43]

Jairath NK,Dal Pra A,Vince R Jr,Dess RT,Jackson WC,Tosoian JJ,McBride SM,Zhao SG,Berlin A,Mahal BA,Kishan AU,Den RB,Freedland SJ,Salami SS,Kaffenberger SD,Pollack A,Tran P,Mehra R,Morgan TM,Weiner AB,Mohamad O,Carroll PR,Cooperberg MR,Karnes RJ,Nguyen PL,Michalski JM,Tward JD,Feng FY,Schaeffer EM,Spratt DE, A Systematic Review of the Evidence for the Decipher Genomic Classifier in Prostate Cancer. European urology. 2021 Mar;     [PubMed PMID: 33293078]

Level 1 (high-level) evidence

[44]

Cullen J,Rosner IL,Brand TC,Zhang N,Tsiatis AC,Moncur J,Ali A,Chen Y,Knezevic D,Maddala T,Lawrence HJ,Febbo PG,Srivastava S,Sesterhenn IA,McLeod DG, A Biopsy-based 17-gene Genomic Prostate Score Predicts Recurrence After Radical Prostatectomy and Adverse Surgical Pathology in a Racially Diverse Population of Men with Clinically Low- and Intermediate-risk Prostate Cancer. European urology. 2015 Jul;     [PubMed PMID: 25465337]

Level 2 (mid-level) evidence

[45]

Klein EA,Cooperberg MR,Magi-Galluzzi C,Simko JP,Falzarano SM,Maddala T,Chan JM,Li J,Cowan JE,Tsiatis AC,Cherbavaz DB,Pelham RJ,Tenggara-Hunter I,Baehner FL,Knezevic D,Febbo PG,Shak S,Kattan MW,Lee M,Carroll PR, A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. European urology. 2014 Sep;     [PubMed PMID: 24836057]

[46]

Brooks MA,Thomas L,Magi-Galluzzi C,Li J,Crager MR,Lu R,Abran J,Aboushwareb T,Klein EA, GPS Assay Association With Long-Term Cancer Outcomes: Twenty-Year Risk of Distant Metastasis and Prostate Cancer-Specific Mortality. JCO precision oncology. 2021;     [PubMed PMID: 34036236]

[47]

Covas Moschovas M,Chew C,Bhat S,Sandri M,Rogers T,Dell'Oglio P,Roof S,Reddy S,Sighinolfi MC,Rocco B,Patel V, Association Between Oncotype DX Genomic Prostate Score and Adverse Tumor Pathology After Radical Prostatectomy. European urology focus. 2022 Mar;     [PubMed PMID: 33757735]

[48]

Shipitsin M,Small C,Choudhury S,Giladi E,Friedlander S,Nardone J,Hussain S,Hurley AD,Ernst C,Huang YE,Chang H,Nifong TP,Rimm DL,Dunyak J,Loda M,Berman DM,Blume-Jensen P, Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error. British journal of cancer. 2014 Sep 9;     [PubMed PMID: 25032733]

[49]

Blume-Jensen P,Berman DM,Rimm DL,Shipitsin M,Putzi M,Nifong TP,Small C,Choudhury S,Capela T,Coupal L,Ernst C,Hurley A,Kaprelyants A,Chang H,Giladi E,Nardone J,Dunyak J,Loda M,Klein EA,Magi-Galluzzi C,Latour M,Epstein JI,Kantoff P,Saad F, Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015 Jun 1;     [PubMed PMID: 25733599]

Level 1 (high-level) evidence

[50]

Alford AV,Brito JM,Yadav KK,Yadav SS,Tewari AK,Renzulli J, The Use of Biomarkers in Prostate Cancer Screening and Treatment. Reviews in urology. 2017;     [PubMed PMID: 29472826]

[51]

Cuzick J,Stone S,Fisher G,Yang ZH,North BV,Berney DM,Beltran L,Greenberg D,Møller H,Reid JE,Gutin A,Lanchbury JS,Brawer M,Scardino P, Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. British journal of cancer. 2015 Jul 28;     [PubMed PMID: 26103570]

Level 1 (high-level) evidence

[52]

Cuzick J,Swanson GP,Fisher G,Brothman AR,Berney DM,Reid JE,Mesher D,Speights VO,Stankiewicz E,Foster CS,Møller H,Scardino P,Warren JD,Park J,Younus A,Flake DD 2nd,Wagner S,Gutin A,Lanchbury JS,Stone S,Transatlantic Prostate Group., Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. The Lancet. Oncology. 2011 Mar;     [PubMed PMID: 21310658]

Level 2 (mid-level) evidence

[53]

Sommariva S,Tarricone R,Lazzeri M,Ricciardi W,Montorsi F, Prognostic Value of the Cell Cycle Progression Score in Patients with Prostate Cancer: A Systematic Review and Meta-analysis. European urology. 2016 Jan;     [PubMed PMID: 25481455]

Level 1 (high-level) evidence

[54]

Pan J,Zhao J,Ni X,Gan H,Wei Y,Wu J,Zhang T,Wang Q,Freedland SJ,Wang B,Song S,Ye D,Liu C,Zhu Y, The prevalence and prognosis of next-generation therapeutic targets in metastatic castration-resistant prostate cancer. Molecular oncology. 2022 Oct 9;     [PubMed PMID: 36209367]

Level 2 (mid-level) evidence

[55]

Li X,Heyer WD, Homologous recombination in DNA repair and DNA damage tolerance. Cell research. 2008 Jan;     [PubMed PMID: 18166982]

Level 3 (low-level) evidence

[56]

Li K,Luo H,Huang L,Luo H,Zhu X, Microsatellite instability: a review of what the oncologist should know. Cancer cell international. 2020;     [PubMed PMID: 31956294]

[57]

Lee Y,Lee JA,Park HE,Han H,Kim Y,Bae JM,Kim JH,Cho NY,Kim HP,Kim TY,Kang GH, Targeted next-generation sequencing-based detection of microsatellite instability in colorectal carcinomas. PloS one. 2021;     [PubMed PMID: 33524032]

[58]

Li GM, Mechanisms and functions of DNA mismatch repair. Cell research. 2008 Jan;     [PubMed PMID: 18157157]

Level 3 (low-level) evidence

[59]

Sha D,Jin Z,Budczies J,Kluck K,Stenzinger A,Sinicrope FA, Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors. Cancer discovery. 2020 Dec;     [PubMed PMID: 33139244]

[60]

Meléndez B,Van Campenhout C,Rorive S,Remmelink M,Salmon I,D'Haene N, Methods of measurement for tumor mutational burden in tumor tissue. Translational lung cancer research. 2018 Dec;     [PubMed PMID: 30505710]

[61]

Abida W,Cheng ML,Armenia J,Middha S,Autio KA,Vargas HA,Rathkopf D,Morris MJ,Danila DC,Slovin SF,Carbone E,Barnett ES,Hullings M,Hechtman JF,Zehir A,Shia J,Jonsson P,Stadler ZK,Srinivasan P,Laudone VP,Reuter V,Wolchok JD,Socci ND,Taylor BS,Berger MF,Kantoff PW,Sawyers CL,Schultz N,Solit DB,Gopalan A,Scher HI, Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA oncology. 2019 Apr 1;     [PubMed PMID: 30589920]

[62]

Li H,Wang Z,Tang K,Zhou H,Liu H,Yan L,Guan W,Chen K,Xu H,Ye Z, Prognostic Value of Androgen Receptor Splice Variant 7 in the Treatment of Castration-resistant Prostate Cancer with Next generation Androgen Receptor Signal Inhibition: A Systematic Review and Meta-analysis. European urology focus. 2018 Jul;     [PubMed PMID: 28753843]

Level 1 (high-level) evidence

[63]

Sobhani N,Neeli PK,D'Angelo A,Pittacolo M,Sirico M,Galli IC,Roviello G,Nesi G, AR-V7 in Metastatic Prostate Cancer: A Strategy beyond Redemption. International journal of molecular sciences. 2021 May 24;     [PubMed PMID: 34073713]

[64]

Hörnberg E,Ylitalo EB,Crnalic S,Antti H,Stattin P,Widmark A,Bergh A,Wikström P, Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PloS one. 2011 Apr 28;     [PubMed PMID: 21552559]

[65]

Scher HI,Lu D,Schreiber NA,Louw J,Graf RP,Vargas HA,Johnson A,Jendrisak A,Bambury R,Danila D,McLaughlin B,Wahl J,Greene SB,Heller G,Marrinucci D,Fleisher M,Dittamore R, Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer. JAMA oncology. 2016 Nov 1;     [PubMed PMID: 27262168]

[66]

Lieb V,Abdulrahman A,Weigelt K,Hauch S,Gombert M,Guzman J,Bellut L,Goebell PJ,Stöhr R,Hartmann A,Wullich B,Taubert H,Wach S, Cell-Free DNA Variant Sequencing Using Plasma and AR-V7 Testing of Circulating Tumor Cells in Prostate Cancer Patients. Cells. 2021 Nov 18;     [PubMed PMID: 34831445]

[67]

Pacheco-Orozco RA,Montealegre-Páez L,Cayol F,Martínez-Gregorio H,Oliver J,Frecha C,Vaca-Paniagua F,Perdomo S, AR-V7 as a Biomarker for Resistance to Treatment with Abiraterone/Enzalutamide in Three Latin American Countries: A Hypothetical Cost-Saving Analysis. The oncologist. 2020 Dec;     [PubMed PMID: 32721059]

[68]

Fay AP,Antonarakis ES, Blocking the PD-1/PD-L1 axis in advanced prostate cancer: are we moving in the right direction? Annals of translational medicine. 2019 Mar;     [PubMed PMID: 31032288]

[69]

Liu S,Liang J,Liu Z,Zhang C,Wang Y,Watson AH,Zhou C,Zhang F,Wu K,Zhang F,Lu Y,Wang X, The Role of CD276 in Cancers. Frontiers in oncology. 2021;     [PubMed PMID: 33842369]

[70]

Turiello R,Pinto A,Morello S, CD73: A Promising Biomarker in Cancer Patients. Frontiers in pharmacology. 2020;     [PubMed PMID: 33364969]

[71]

Yuri P,Shigemura K,Kitagawa K,Hadibrata E,Risan M,Zulfiqqar A,Soeroharjo I,Hendri AZ,Danarto R,Ishii A,Yamasaki S,Yan Y,Heriyanto DS,Fujisawa M, Increased tumor-associated macrophages in the prostate cancer microenvironment predicted patients' survival and responses to androgen deprivation therapies in Indonesian patients cohort. Prostate international. 2020 Jun;     [PubMed PMID: 32647642]

[72]

Miyake M,Hori S,Owari T,Oda Y,Tatsumi Y,Nakai Y,Fujii T,Fujimoto K, Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma. Cancers. 2020 Oct 27;     [PubMed PMID: 33121123]

[73]

Meng F,Han X,Min Z,He X,Zhu S, Prognostic signatures associated with high infiltration of Tregs in bone metastatic prostate cancer. Aging. 2021 Jul 6;     [PubMed PMID: 34229299]

[74]

Hempel Sullivan H,Heaphy CM,Kulac I,Cuka N,Lu J,Barber JR,De Marzo AM,Lotan TL,Joshu CE,Sfanos KS, High Extratumoral Mast Cell Counts Are Associated with a Higher Risk of Adverse Prostate Cancer Outcomes. Cancer epidemiology, biomarkers     [PubMed PMID: 31932412]

[75]

Pittoni P,Colombo MP, The dark side of mast cell-targeted therapy in prostate cancer. Cancer research. 2012 Feb 15;     [PubMed PMID: 22307838]

Level 3 (low-level) evidence

[76]

Jamaspishvili T,Berman DM,Ross AE,Scher HI,De Marzo AM,Squire JA,Lotan TL, Clinical implications of PTEN loss in prostate cancer. Nature reviews. Urology. 2018 Apr;     [PubMed PMID: 29460925]

[77]

Dillinger T,Sheibani-Tezerji R,Pulverer W,Stelzer I,Hassler MR,Scheibelreiter J,Pérez Malla CU,Kuroll M,Domazet S,Redl E,Ely S,Brezina S,Tiefenbacher A,Rebhan K,Hübner N,Grubmüller B,Mitterhauser M,Hacker M,Weinhaeusel A,Simon J,Zeitlinger M,Gsur A,Kramer G,Shariat SF,Kenner L,Egger G, Identification of tumor tissue-derived DNA methylation biomarkers for the detection and therapy response evaluation of metastatic castration resistant prostate cancer in liquid biopsies. Molecular cancer. 2022 Jan 3;     [PubMed PMID: 34980142]

[78]

Rochow H,Jung M,Weickmann S,Ralla B,Stephan C,Elezkurtaj S,Kilic E,Zhao Z,Jung K,Fendler A,Franz A, Circular RNAs and Their Linear Transcripts as Diagnostic and Prognostic Tissue Biomarkers in Prostate Cancer after Prostatectomy in Combination with Clinicopathological Factors. International journal of molecular sciences. 2020 Oct 22;     [PubMed PMID: 33105568]

[79]

Gao XH,Li J,Gong HF,Yu GY,Liu P,Hao LQ,Liu LJ,Bai CG,Zhang W, Comparison of Fresh Frozen Tissue With Formalin-Fixed Paraffin-Embedded Tissue for Mutation Analysis Using a Multi-Gene Panel in Patients With Colorectal Cancer. Frontiers in oncology. 2020;     [PubMed PMID: 32232001]