Editing Prostate Cancer: Diagnosis and evaluation (section)

=== Other ===

==== Transrectal Ultrasound (TRUS) Biopsy ====
* Patients with clinical indications to confirm diagnosis of prostate cancer undergo TRUS biopsy
* '''Biopsy threshold'''
** [https://pubmed.ncbi.nlm.nih.gov/23659877/ '''2023 AUA Guidelines on Early Detection of Prostate Cancer''']
***'''<span style="color:#ff0000">May be tailored for select patients, similar to risk-stratified re-screening intervals</span>'''
****'''For patients with BRCA mutations, biopsy referral threshold should be 3 ng/mL''' 
***'''<span style="color:#ff0000">Clinicians and patients may use validated risk calculators to inform the SDM process regarding prostate biopsy</span>'''
****Pre-biopsy Risk Calculators
***** Concept: improve prediction models by combining variables
***** [https://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-calculators '''ERSPC''']
*****[https://riskcalc.org/PCPTRC/ '''PCPT V2''']
*****[https://riskcalc.org/PBCG/ '''PBCG''']
******'''In one study, investigators compared PBCG with PCPT and concluded that PCPT performed better in minority groups.'''
***PSA velocity should not be used as sole indication for secondary biomarker, imaging, or a biopsy.
***'''Adjunctive urine or serum markers may be used when further risk stratification would influence the decision regarding whether to proceed with biopsy.'''
****Several blood and urine markers are available, alone or in combination, to further risk stratify patients with a mildly elevated PSA, typically between 2.5 and 10 ng/mL.
*****'''Serum based'''
******'''Percent free PSA'''
*******Most widely available adjunctive test
*******Lower percent free PSA is associated with greater likelihood of identifying prostate cancer on biopsy.
******'''PSA density'''
*******Higher PSA density (serum PSA [ng/mL] divided by imaging measures of prostate volume [cc]) is associated with the risk of identifying clinically significant prostate cancer on biopsy
*******The Panel recognizes the continuous nature of risk associated with the spectrum of PSA density values and cautions against use of threshold values in isolation
******4Kscore
******IsoPSA
******Proclarix
******PHI
******STHLM-3
*****'''Urine based'''
******Post-DRE Urine
*******PCA3
*******MPS
*******SelectMDx
*******TMPRSS:ERG
******Urine
*******ExoDx Prostate Intelliscore
*******MiR Sentinel
******Tissue
*******Confirm MDx
*****Such tests may be of value among patients with modestly elevated PSA tests, especially in patients with a prior negative biopsy in whom PSA alone is not recommended as the sole trigger for rebiopsy.
*** '''When the risk of clinically significant prostate cancer is sufficiently low based on available clinical, laboratory, and imaging data, clinicians and patients may forgo near-term prostate biopsy.'''
***<span style="color:#ff0000">'''Role of prostate biopsy in very elevated PSA'''</span>
****'''<span style="color:#ff0000">If PSA > 50 ng/mL </span>'''(and no clinical concerns for infection or other cause for increased PSA (e.g., recent prostate instrumentation)), '''<span style="color:#ff0000">may omit a prostate biopsy in cases if (2):</span>'''
*****'''<span style="color:#ff0000">Biopsy poses significant risk (e.g., anticoagulation, significant comorbidity, frailty)</span>'''
*****'''<span style="color:#ff0000">Need for prostate cancer treatment is urgent (e.g., impending spinal cord compression from metastases)</span>'''
****Imaging to establish extent of disease or confirm metastasis may be helpful if an immediate biopsy is not performed.
***'''If MRI performed prior to biopsy'''
****'''<span style="color:#ff0000">If no abnormal lesions on prostate MRI but concern for elevated risk for GG2+ prostate cancer, proceed with a systematic biopsy.</span>'''
*****≈1 in 10 patients who have a negative prostate MRI may have GG2+ cancer on biopsy,
******Negative predictive value (NPV) of a “negative” MRI (defined as PIRADS 1 to 2) to detect GG2+ prostate cancer among biopsy-naïve patients was 91%.
*****A systematic biopsy should include a minimum of 12 cores
*****Various templates employing these principles exist for transrectal and transperineal approaches.
****'''<span style="color:#ff0000">For biopsy-naïve patients with abnormal lesions on prostate MRI, perform targeted biopsies and may also perform a systematic template biopsy.</span>'''
*****Adding a systematic biopsy to the target only approach
******Advantage:
*******Optimizes cancer yield, potentially finding more GG2+ cancer
********Incremental yield of off-target biopsy samples may be influenced by the sampling error associated with software image registration at targeted biopsy
******Disadvantages:
*******Potentially finding more GG1 cancer
*******May increase patient discomfort and other biopsy-associated complications due to larger number of cores
***'''Repeat biopsy[https://pubmed.ncbi.nlm.nih.gov/23659877/]'''
****'''<span style="color:#ff0000">If prostate biopsy demonstrates</span>'''
*****'''<span style="color:#ff0000">Malignancy: discuss [[Management of Localized Prostate Cancer]]</span>''' (+/- staging studies, if applicable)
*****'''<span style="color:#ff0000">High-grade Prostatic Intraepithelial Neoplasia</span>'''
******'''<span style="color:#ff0000">If focal (one core): should not perform immediate repeat biopsy.</span>'''
*******Risk of any cancer detected (not just high-grade) in subsequent biopsies is 20-30%, which is the same risk following an initial benign biopsy.
******'''<span style="color:#ff0000">Multifocal: may proceed with additional risk evaluation.</span>'''
*******Risk of GG2+ detection in repeat biopsies of patients with multifocal HGPIN is ≈30%, which is not higher than in those without this finding.
*******Repeat biopsy after multifocal HGPIN should be based on PSA and DRE evolution, and mpMRI findings.
*****'''<span style="color:#ff0000">Atypia</span>'''
******'''<span style="color:#ff0000">Atypical small acinar proliferation (ASAP): should perform additional testing.</span>'''
*******ASAP alone on needle biopsy is associated with a 30-50% risk of prostate cancer detection on repeat biopsy, with ≈10-20% of these being GG2+.
*******Additional testing may include repeat systematic needle biopsy with consideration of mpMRI +/- targeted biopsy, PSA, and biomarkers (serum- or urine-based)
******'''<span style="color:#ff0000">Atypical intraductal proliferation (AIP): should perform additional testing.</span>'''
*******AIP describes lesions with greater architectural complexity and/or cytologic atypia than would be expected in HGPIN but lacking definitive criteria for the diagnosis of intraductal carcinoma (IDC-P). AIP encompasses many of the lesions formerly designated cribriform HGPIN, exhibiting loose cribriform architecture with moderate cytologic atypia, but lacking marked pleomorphism or necrosis.
*******AIP, as either the sole finding or together with GG1 cancer only, warrants additional testing, which may include early repeat systematic needle biopsy or MRI +/- targeted biopsy. The timing of additional testing should be based on reassessment of risk
*****'''<span style="color:#ff0000">Negative: reassess risk of undetected or future development of GG2+ disease</span>'''
******'''<span style="color:#ff0000">At the time of re-evaluation after negative biopsy, clinicians should use a risk assessment tool that incorporates the protective effect of prior negative biopsy.</span>'''
*******The guideline recommends utilizing validated risk calculators, particularly calculators that incorporate previous negative biopsy and mpMRI use in the repeat biopsy setting.
********[https://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-calculators ERSPC]
********[https://riskcalc.org/PCPTRC/ PCPT V2]
********[https://riskcalc.org/PBCG/ PBCG]
*******PSA level alone should not be used to decide whether to repeat the prostate biopsy in patients with a previous negative biopsy.
******'''<span style="color:#ff0000">Based on risk assessment, SDM whether to</span>'''
*******'''<span style="color:#ff0000">Discontinue screening</span>'''
********'''Screening should not be discontinued based solely on a negative prostate biopsy.'''
*******'''<span style="color:#ff0000">Continue screening</span>'''
********If continuing screening after a negative biopsy, patient should be re-evaluated within the normal screening interval (2-4 years) or sooner, depending on risk of clinically significant prostate cancer and life expectancy.
*******'''<span style="color:#ff0000">Perform adjunctive testing for early reassessment of risk.</span>'''
********If concern remains elevated for GG2+ based on PSA density, previous MRI findings, or other factors,  consider adjunctive testing (blood, urine, or tissue tests), or MRI (if not previously performed) to further risk stratify the patient if results are likely to influence the decision regarding repeat biopsy or otherwise substantively change the patient’s management.
*********'''Biomarker testing'''
**********After a negative initial biopsy in patients with low probability for harboring GG2+ prostate cancer, clinicians should not reflexively perform biomarker testing.
***********In patients with a negative biopsy, with low probability for GG2+ disease, it is unlikely that additional biomarker tests will be informative.
**********ConfirmMDx
***********The only tissue-based biomarker assessing epigenetic changes in GSTP1, APC, RASSF1 in negative biopsy tissue
***********Developed in the MATLOC study and validated in the DOCUMENT study to detect any prostate cancer and not specifically for GG2+ disease.
**********Unclear how to integrate the use of these tests with mpMRI in prostate cancer early detection.
**********It is imperative clinicians are familiar with biomarkers, understand what information or data each test provides, and consider whether additional information will impact  management decisions before ordering a test.
*********'''<span style="color:#ff0000">MRI prior to repeat biopsy</span>'''
**********'''<span style="color:#ff0000">In patients undergoing repeat biopsy with no prior prostate MRI, a prostate MRI should be obtained prior to biopsy.</span>'''
**********'''<span style="color:#ff0000">In patients with indications for a repeat biopsy who</span>'''
***********'''<span style="color:#ff0000">Do not have a suspicious lesion on MRI, may proceed with a systematic biopsy.</span>'''
************Factors that may identify patients likely to have clinically significant prostate cancer after a negative biopsy and a negative MRI include
*************PSA density > 0.15 ng/mL
*************PHI density value > 0.44
*************PSA velocity of ≥0.27 ng/mL/year
***********'''<span style="color:#ff0000">Have a suspicious lesion on MRI, should perform targeted biopsies of the suspicious lesion and may also perform a systematic template biopsy.</span>'''
************Ultimately, the decision to perform systematic sampling in addition to target sampling should be based on an integrated evaluation of MRI factors such as quality and confidence in target presence and clinical factors such as PSA, technique of initial biopsy, and time since prior systematic biopsy.

*'''The choice of a PSA threshold for recommending a prostate biopsy is controversial'''.
** Historically, many would recommend prostate biopsy once a patient’s serum PSA level is >4.0 ng/mL. However, '''data from the Prostate Cancer Prevention Trial demonstrated an overall prostate cancer detection rate of 15% for all men with a PSA level < 4.0 ng/mL and nearly 15% having a Gleason score of 7 or greater, suggesting no absolute safe threshold.'''

==== Genetic testing ====
* Germline mutations are inherited from parents; all cells have the mutation except red blood cells
*Somatic mutations are acquired

===== Indications =====

====== AUA ======
* '''[https://pubmed.ncbi.nlm.nih.gov/35536144/ 2022 AUA Guidelines on Clinically Localized Prostate Cancer]'''
** '''<span style="color:#ff0000">Recommended (5):'''
**# '''<span style="color:#ff0000">Ashkenazi Jewish ancestry'''
**#* '''Particularly in patients with Grade Group 2 or higher disease'''
**# '''<span style="color:#ff0000">Known family history of familial cancer risk mutation'''
**#* '''Examples: BRCA1, BRCA2, ATM, Lynch-syndrome associated genes'''
**# '''<span style="color:#ff0000">Strong personal or family history of related cancers'''
**#* '''Examples: breast, colorectal, ovarian, pancreatic, upper tract urothelial carcinoma'''
**# '''<span style="color:#ff0000">Strong family history of prostate cancer'''
**#* '''Examples: first-degree relative or multiple second-degree relatives diagnosed with Grade Group 2 or higher prostate cancer, particularly at early age (< 60 years), particularly if metastatic or lethal'''
**# '''<span style="color:#ff0000">Adverse tumor characteristics'''
**#* '''Examples: High-risk disease; intermediate-risk disease with intraductal or cribriform morphology'''

====== NCCN ======
*'''NCCN (version 2.2021)'''
** '''<span style="color:#ff0000">Recommended (5):'''
**# '''<span style="color:#ff0000">Ashkenazi Jewish ancestry'''
**#'''<span style="color:#ff0000">Positive family history of high-risk germline mutations (e.g. BRCA 1/2, Lynch syndrome)'''
**#* '''BRCA-cancers (5): breast, ovarian, pancreatic, prostate, melanoma'''
**#* '''Lynch syndrome cancers: (8) colonic (most common), endometrial (second most common), prostate, urothelial, adrenal, gastric, pancreatic, uterine, ovarian, and sebaceous carcinomas'''
**#'''<span style="color:#ff0000">Personal history of breast cancer'''
**#'''<span style="color:#ff0000">Metastatic (distant or regional (node-positive) prostate cancer'''
**# '''<span style="color:#ff0000">High- or very-high risk localized prostate cancer'''
** '''Optional (2)'''
**# '''Intermediate-risk with intraductal or cribiform histology'''
**# '''Personal history of colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract, or small intestine'''

==== Stockholm-3 (STHLM-3) ====
*Multiplex test combining
**Clinical variables (age, first-degree family history of prostate cancer, and previous biopsy)
**Blood biomarkers (total PSA, free PSA, ratio of free to total PSA, hK2, MIC-1, and MSMB)
**Polygenic risk score (PRS)
*Has been evaluated as a first-line screening test for predicting the risk of GG2+ prostate cancers.[https://pubmed.ncbi.nlm.nih.gov/26563502/]
**STHLM-3 found to have a higher predictive accuracy compared to PSA alone (area under the curve [AUC] 0.74 versus 0.56) and reduced unnecessary biopsies by 32%
** Further validation in diverse populations to confirm these findings will be necessary to move forward into practice.

==== Polygenic risk score (PRS) ====

* Genetic tests used to predict a person’s risk of developing prostate cancer.
*Typically constructed as the weighted sum of a collection of genetic variants, usually single nucleotide polymorphisms (SNPs) defined as single base-pair variations from the reference genome[https://pubmed.ncbi.nlm.nih.gov/35251129/]
*Little evidence to mandate which SNP panel or PRS to use and where to threshold risk to create strata with different screening intensities.
*At the time of evidence review, no PRS tool has been shown to discriminate between aggressive and indolent prostate cancer risk