Description of Procedure or Service

Prostate-specific antigen (PSA) is a glycoprotein that is produced by both normal and neoplastic prostate tissue. In normal conditions, PSA is produced as a proenzyme in the prostate and secreted into the lumen. The propeptide is removed to activate the proenzyme; from there, it undergoes proteolysis to inactivate it. This inactive form may enter the bloodstream and circulate as “free” PSA. This process differs in prostate cancer; the basal cells that normally regulate this activation process are missing, which allows the secreted PSA direct access into the bloodstream. This increases the PSA concentration in the serum.

Due to these reasons, PSA is often used in assessment of prostate cancer, such as screening, monitoring, diagnosis, and treatment management.

Terms such as male and female are used when necessary to refer to sex assigned at birth.

Related Policies:

AHS-G2007 Prostate Biopsy Specimen Analysis

AHS-M2166 Gene Expression Profiling and Protein Biomarkers for Prostate Cancer

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for prostate specific antigen (PSA) testing when it is determined the medical criteria and guidelines below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore, member benefit language should be reviewed before applying the terms of this medical policy.

When Prostate Specific Antigen (PSA) Testing is covered

1. Reimbursement is allowed for average-risk individuals 45 years of age and older (see Note 1), screening for prostate cancer with the total prostate-specific antigen (PSA) test.
2. Reimbursement is allowed for individuals 40 years of age and older (see Note 1), annual screening for prostate cancer with the total (PSA) test when one of the following conditions is met:
   1. Individual is of African ancestry.
   2. Individual has germline mutations that increase risk for prostate cancer.
   3. Individual has a suspicious family history
3. For individuals with previous total PSA results, repeat screening for prostate cancer with a total PSA test, reimbursement is allowed with the following frequency: 
   1. For individuals less than 76 years of age, when total PSA is <1 ng/ml and digital rectal exam (DRE) is normal (if done): Repeat screening at 2- 4-year intervals
   2. For individuals less than 76 years of age, when total PSA is 1-3 ng/ml and DRE is normal (if done): Repeat screening at 1- 2-year intervals.
   3. For individuals greater than 75 years of age, when total PSA is <4 ng/ml and DRE is normal (if done) and no other indications for biopsy: Repeat screening in select patients (see Note 1) at 1-3-year intervals.
4. A percent free PSA, or a follow-up in 6-12 months with total PSA reimbursement is allowed when any of the following conditions are met:
   1. For individuals less than 76 years of age with a total PSA >3 ng/ml and/or a very suspicious DRE.
   2. For select individuals greater than 75 years of age (see Note 1) with a total PSA >4 ng/ml or a very suspicious DRE.
5. For individuals thought to be at a higher risk despite at least one prior negative prostate biopsy, follow-up testing with percent free PSA, reimbursement is allowed.
6. Total PSA testing, reimbursement is allowed, in any of the following situations:
   1. For initial prostate cancer diagnosis in individuals with signs and symptoms of prostate cancer (see Note 2).
   2. For follow-up of individuals with a current or previous diagnosis of prostate cancer.
   3. For ongoing monitoring of individuals who have undergone tumor resection or prostatectomy.
   4. For monitoring response to prostate cancer therapy.
   5. For detecting disease recurrence.

*NOTE 1: According to the NCCN guidelines, “Testing after 75 years of age should be done only in very healthy men with little or no comorbidity (especially if they have never undergone PSA testing or have a rising PSA) to detect the small number of aggressive cancers that pose a significant risk if left undetected until signs or symptoms develop. Widespread testing in this population would substantially increase rates of over-detection and is not recommended.” Additionally, the term individuals in this policy apply to individuals who have a prostate or were born with a prostate.

*NOTE 2: According to ACS, 2023b: “Most prostate cancers are found early, through screening. Early prostate cancer usually causes no symptoms. More advanced prostate cancers can sometimes cause symptoms, such as:

• Problems urinating, including a slow or weak urinary stream or the need to urinate more often, especially at night. 
• Blood in the urine or semen
• Trouble getting an erection (erectile dysfunction or ED) 
• Pain in the hips, back (spine), chest (ribs), or other areas from cancer that has spread to bones
• Weakness or numbness in the legs or feet, or even loss of bladder or bowel control from cancer pressing on the spinal cord.

When Prostate Specific Antigen (PSA) Testing is not covered

Reimbursement is not allowed for:

1. Percent free PSA as a first-line screening test for prostate cancer. 
2. Percent free PSA, free-to-total PSA ratio, and/or complexed PSA tests for the routine screening of prostate cancer.

Policy Guidelines

Prostate cancer is the most common cancer in American men (other than skin cancer) and the second leading cause of cancer death. According to the CDC (2023), more than 236,000 prostate cancer cases are reported annually in the United States, leading to more than 33,000 prostate cancer deaths each year in 2022. The American Cancer Society estimates over 299,000 new cases and 35,000 deaths of prostate cancer in 2024. Prostate cancer survival is related to many factors, especially the extent of the tumor at the time of diagnosis. The five-year survival rate between for men with localized or regional prostate cancer is nearly 100%, while the five-year survival rate for men with distant prostate cancer where the cancer has spread to other parts of the body such as the lungs, liver or bones is 34%. About one man in eightwill be diagnosed with prostate cancer during his lifetime in the United States.

Many cases of prostate cancer do not become clinically evident, as indicated in autopsy studies, where prostate cancer is detected in approximately 30% of men aged 55 or older and approximately 60% of men by age 80. These data suggest that prostate cancer often grows so slowly that most men die of other causes before the disease becomes clinically advanced.

Most prostate cancers use androgen-dependent signaling for development and progression. As the number of targeted therapy agents increase, it is crucial to determine which patients will benefit from these interventions. Understanding the molecular pathology will allow clinicians to provide better patient management. Recent studies have led to the classification of prostate cancer into different subtypes, yet the utility of this in the clinical setting is to be determined.

Prostate-specific antigen (PSA), a glycoprotein produced by prostate epithelial cells, is the most widely accepted biomarker for prostate cancer screening. Levels of this protein can be identified via a simple blood test; many doctors consider abnormal PSA levels to be above 4.0 ng/mL, although there is no official standardized normal or abnormal PSA level. Further, PSA levels tend to increase with age, suggesting that age-specific PSA reference ranges may be important for clinical use.

In serum, PSA can be identified in three forms. The main form is PSA bound by alpha-1 antichymotrypsin and accounts for approximately 75% of total PSA; PSA bound to alpha-2 macroglobulin has also been identified but cannot be detected by commercial immunoassays and represents less than 0.1% of PSA. Coban et al. (2016) reported that, while total PSA levels are an important prognostic factor for predicting prostate volumes, free PSA levels had a higher predictive value.

Analytical Validity

PSA was originally introduced as a tumor marker to detect cancer recurrence or disease progression following treatment. It has been widely adopted for early detection of prostate cancer screening; however, its clinical utility in screening is controversial, and guidelines for PSA screening are conflicting. Non-optimal screening and treatment practices, including excessive screening among older men with lower life expectancy or comorbidities and overtreatment of men with low-risk tumors, have contributed to treatment-related harm and a lower quality of life. Evidence is currently lacking to show that PSA screening actually saves lives; instead, it may only cause overdiagnosis and lead to complications in the treatment of indolent diseases.

PSA is not a cancer specific marker, thereby causing many false results that conflict with other screening methods, such as the digital rectal examination (DRE). For example, PSA may be elevated due to conditions including benign prostatic hyperplasia (BPH) or prostatitis. This is particularly important as BPH is common among men over 50, the most common age group in which prostate cancer is observed. For example, a study performed by Stimac et al. (2014) found PSA levels to be unusual despite testing negative for cancer. The authors concluded that subclinical inflammation had a major influence on free PSA levels only if the total levels was <10 ng/mL, and further note that clinical and acute inflammation produce a different profile of PSA release compared to a subclinical inflammation. Overall, the authors state that the molecular cause of the inflammation’s changes to PSA forms are still unknown. Furthermore, serum PSA is directly tied to the size of the prostate, which increases with age. Older men may see an increased concentration of PSA despite being completely healthy. Other factors such as medication can affect PSA levels as well. Common medications such as statins, NSAIDs, acetaminophen, 5-alpha-reductase inhibitors, and thiazides were all found to reduce PSA levels by varying degrees. 

Clinical Validity and Utility

The utility of PSA-based screening is also in question. A randomized clinical trial focusing on men undergoing a single PSA-based screening (n = 189386) compared to controls not undergoing a PSA-based screening (n = 219439) found no difference in cancer mortality after a median follow-up of 10 years. The mortality rate in 1000-person years was 0.30 in the intervention group compared to 0.31 in the control group, or one extra death per 100,000 patients. Although prostate cancer was diagnosed more often in the intervention group (4.3% compared to 3.6% in the control group), the mortality rate was almost identical between both groups.

A systematic review and meta-analysis of 341,342 patients evaluated the overall effectiveness of prostate cancer screening. Results from this study showed that while PSA screening did lead to an increase in the identification of prostate cancer cases at all stages, it did not necessarily reduce the amount of overall or disease specific mortality rates. This highlights the uncertainty regarding the effectiveness of prostate cancer screening. The authors also noted that “PSA screening is associated with considerable biopsy-related and cancer treatment-related complications.”

In May of 2012, the USPSTF released a grade D recommendation against PSA prostate cancer screening. In 2018, the recommendation was switched to a grade C recommendation, now suggesting that men ages 55 to 69 could be screened for prostate cancer if first counseled about the benefits and harms of screening. Nonetheless, when the grade D recommendation was first released, many researchers were worried that an increase in late-stage prostate cancer cases would be identified, leading to greater rates of prostate cancer-specific mortality. To assess this risk, data from a total of 19,602 patients from nine high volume referral centers in the United States was collected and analyzed during the time that the USPSTF grade D recommendation was in effect. The researchers found that “All centers experienced consistent decreases of low-grade disease and absolute increases in intermediate and high-risk cancer. For any given age and PSA, propensity matching demonstrates more aggressive disease in the post-recommendation era.”

Osses, et al., (2019) assessed the results of 1,134 men screened for prostate cancer in a 19 year follow up study; at the start of the study, all men were between the ages of 55 and 74. Unfortunately, 63% of the cohort was deceased by the 19-year follow-up period for various reasons. Still, the researchers noted that results suggested “a more substantial reduction in metastatic disease and cancer-specific mortality in favor of prostate cancer screening than previously reported.” However, more research needs to be completed with a larger sample size to confirm this conclusion.

Magnani et al. (2021) performed a cost analysis on “first-line prostate cancer management” using real-world data. A total of 3433 patients were included, and outcomes such as active surveillance (AS), surgery, and radiation were considered. Surgery was found to be the most common option, with 54.6% of the cohort compared to 22.3% for radiation and 23% for AS. Over a period of 2 years following diagnosis, AS was found to be the cheapest option at $2.97/day (d), with surgery costing $5.67/d and radiation costing $9.34/d, for “favorable” disease. For “unfavorable” disease, surgery cost $7.17/d and radiation cost $16.34/d. Over a period of 5 years following diagnosis, AS was found to be cheaper than surgery, by an amount of $2.71/d to $2.87 for surgery and $4.36 for favorable disease. For unfavorable disease, surgery remained cheaper than radiation, by an amount of $4.15/d to $10.32/d. The authors did remark that this information came from a single health care system and were based on benchmark Medicare estimates rather than actual payment exchanges.

Baniak et al. (2020) compared the clinicopathologic and molecular characteristics of prostate cancer in 90 younger men (45 years or younger) to 200 men of typical screening age (60-65 years). The authors found that younger men tended to have lower PSA values, but a higher frequency of family history of prostate cancer. No significant differences were found in staging or pathological characteristics of core biopsy specimens between the two groups. The younger cohort was also found to have a higher frequency of “grade group 1 disease” at radical prostatectomy. Finally, no statistically significant differences were found regarding prostatic adenocarcinoma prostate specific recurrence/progression or death between the two cohorts.

Guidelines and Recommendations

The American Association of Family Physicians (AAFP)

The AAFP recommends against use of PSA-based testing for prostate cancer screening. For men between 55 to 69 years of age who are considering prostate cancer screening, the physician should discuss the risks and benefits and engage in shared decision making before undergoing the screening process. In addition, the AAFP recommends against prostate cancer screening in men older than 70. They clarify that for men aged 55 to 69 “The decision to be screened for prostate cancer should be an individual one (Grade: C)”, not to screen for prostate cancer in men aged 70 years and older (Grade: D). However, they also note that “Older age, African American race, and family history of prostate cancer are the most important risk factors for prostate cancer. The workup they describe involve starting with a test to measure PSA in the blood, and then positive results may be followed up with a transrectal ultrasound-guided core-needle biopsy of the prostate to diagnose prostate cancer.

The United States Preventive Services Task Force (USPSTF)

The USPSTF issued additional draft guidelines which recommend that clinicians inform men aged 55 to 69 years about the potential benefits and harms of PSA–based screening for prostate cancer, noting that the decision to be screened should be up to the patient. The USPSTF also states that screening offers a small potential benefit of reducing the chance of dying of prostate cancer. However, they note many men will be harmed due to false positives and its side effects such as overdiagnosis or other complications such as impotence. The USPSTF recommends discussion with a clinician before deciding to screen, ultimately giving this screening a “C” recommendation. Furthermore, the USPSTF recommends against PSA-based screening for prostate cancer in men over 70. The CDC cites the USPSTF recommendation.

Memorial Sloan Kettering Cancer Center (MSK)

The Memorial Sloan Kettering Cancer Center issued screening guidelines on prostate cancer based on the individual’s age. Their guidelines are for men who are expected to live at least ten years. 

For ages 45 to 49: 

• Consider benefits and risks of a baseline PSA level check: 
  • If the baseline test is given, and the PSA level is 3 ng/mL or higher, consider a repeat PSA. If that PSA is still above 3 ng/mL, a secondary test, imaging, or biomarker test may be considered (to confirm or deny the need for prostate biopsy). 
  • If the baseline test is between 1 and 3 ng/mL, consider another PSA test in two to four years. Two years is appropriate if the PSA is closer to three, and four years is appropriate if PSA is closer to one. 
  • If the baseline test is less than 1 ng/mL, consider another PSA test between the ages of 51 and 55. 

For ages 50 to 59: 

• Consider benefits and risks of a baseline PSA level check: 
  • If the baseline test is given and the PSA level is 3 ng/mL or higher, consider a repeat PSA. If that PSA is still above 3 ng/mL, a secondary test, imaging, or biomarker test may be considered (to confirm or deny the need for prostate biopsy). 
  • If the baseline test is between 1 and 3 ng/mL, consider another PSA test in two to four years. Two years is appropriate if the PSA is closer to three, and four years is appropriate if PSA is closer to one. 
  • If the baseline test is less than 1 ng/mL, consider another PSA test at age 60. 

For ages 60 to 70: 

• Consider benefits and risks of a baseline PSA level check: 
  • If the baseline test is given and the PSA level is 3 ng/mL or higher, consider a repeat PSA. If that PSA is still above 3 ng/mL, a secondary test, imaging, or biomarker test may be considered (to confirm or deny the need for prostate biopsy). 
  • If the baseline test is between 1 and 3 ng/mL, consider another PSA test in two to four years. Two years is appropriate if the PSA is closer to three, and four years is appropriate if PSA is closer to one. 
  • If the baseline test is less than 1 ng/mL, no more screening is recommended. 

For ages 71 to 75:  

• Individuals should discuss with a healthcare provider whether or not to perform a PSA test. The decision should be based on prior PSA levels and individual health background. Only consider repeat testing if PSA is high and health is overall good. 

For ages 76 and older: 

• Individuals should discuss with a healthcare provider whether to perform a PSA test. “In this age group, a PSA test is very rarely helpful.”

The National Comprehensive Cancer Network (NCCN)

The NCCN also recommends that patients make informed decisions regarding enrollment in an early detection program. Factors such as personal history, previous testing, family history, and race should be considered for determination if an early detection protocol is implemented. The guidelines stated that most panel members favored informed testing starting at 45. The panel supports screening in men until 75, and then continuing screening only in very healthy patients with little or no comorbidity to detect the life threatening and aggressive cancers. However, widespread screening in this age group is not recommended as it would increase rates of over-detection. The NCCN also relayed their concern about “the problems of overtreatment related to the increased frequency of diagnosis of prostate cancer from widespread use of PSA for early detection of screening.”

For initial testing, the NCCN recommends that “baseline PSA testing should be offered to healthy, well-informed individuals deemed to be at average risk aged 45 to 75 years based on the results of RCTs.” They also recommend screening starting at 40 years for certain higher risk populations, such as those with “African ancestry,” “suspicious family history,” and germline mutations that increase risk of prostate cancer. Further, baseline testing may be ordered along with a DRE, and any elevated levels should be double checked with repeat testing.

The NCCN considers three categories for “early evaluation detection,” men of average risk (45-75 years), men of increased risk (such as men with “African ancestry”, “suspicious family history” and “germline mutations that increase the risk of prostate cancer” [such as BRCA]), and men above 75 years. 

• For men aged 45 to 75 years with average risk, the panel recommends repeat testing every 2 to 4 years if PSA is <1 ng/mL. If the PSA level is 1 to 3 ng/mL, frequency of testing should be every 1 to 2 years. If PSA > 3 ng/ml (or if the DRE is “very suspicious”), a biopsy should be considered. 
• The above decision tree also applies to high-risk populations (African ancestry, suspicious or concerning family history, germline mutations that increase the rate of prostate cancer), though the NCCN recommends starting these evaluations at 40 years rather than 45 years of age. The NCCN also writes to “consider” screening these high-risk populations “annually” rather than the less frequent intervals discussed.
• For select patients over 75 years, repeat testing in select patients at 1 – 3-year intervals is recommended if the PSA is <4 ng/ml, the DRE is normal, and there are no other indications for biopsy. In this case, they also state that one should “consider discontinuing screening if clinically appropriate.” 
• However, in select patients over 75 years of age, if the patient has PSA >4 ng/ml and/or a very suspicious DRE, a repeat PSA test, DRE (if not performed during initial risk assessment), and workup for benign disease is indicated. A multiparametric MRI (mpMRI) should be considered. However, it is noted that “a negative MRI does not exclude the possibility of cancer,” and so it is recommended to “consider biomarkers and/or PSA density when deciding whether to avoid a biopsy in an individual with a negative mpMRI result.”
  • If there is high suspicion for clinically significant cancer, image-guided biopsy via transrectal or transperineal approach with MRI targeting or without MRI targeting is indicated, though MRI targeting is preferred.
  • If there is low suspicion for clinically significant cancer, there should be a follow-up in 6-12 months with PSA/DRE.

The NCCN also comments on several biomarkers’ ability to assess early detection of prostate cancer.  

They note that “Unbound or free PSA (fPSA), expressed as a ratio of tPSA, is a clinically useful molecular form of PSA, with the potential to improve early detection, staging, and monitoring of prostate cancer”, explaining that “Most immunoreactive PSA is bound to the protease inhibitor alpha-1-antichymotrypsin. Other immunoreactive PSA-protease inhibitor complexes, such as alpha-1-antitrypsin and protease C inhibitor, exist at such low serum concentrations that their clinical significance has not been determined.” Another notable proportion of PSA is complexed with alpha-2-macroglobulin (AMG), though “this PSA-AMG complex cannot be measured by conventional assays because of the shielding (or "caging") of PSA antigenic epitopes by AMG.”

Testing for %fPSA is included in the NCCN guidelines as “an option before initial biopsy and for those with a prior negative biopsy” since “The FDA approved the use of %fPSA for the early detection of prostate cancer in individuals aged ≥50 years with a non-suspicious DRE and PSA levels between 4 ng/mL and 10 ng/mL (PSA levels where most secondary testing is done). The multi-institutional study that characterized the clinical utility of this assay showed that a 25% fPSA cutoff detected 95% of prostate cancers while avoiding 20% of unnecessary prostate biopsies.”

The NCCN also includes recommendations for PSA testing in non-screening situations, such as monitoring. Regarding “patients initially treated with intent to cure”, the NCCN recommends testing serum PSA levels “every 6 to 12 months for the first 5 years and then annually.” The NCCN also notes that for men with “high” risk of recurrence, testing PSA every three months may be preferred. For patients with “castrationnaïve disease on ADT [androgen deprivation therapy], PSA measurement may be done every three to six months based on clinical judgement. Moreover, the NCCN notes that “Local recurrence may result in substantial morbidity and can, in rare cases, occur in the absence of a PSA elevation. Therefore, annual DRE is appropriate to monitor for prostate cancer recurrence and to detect colorectal cancer. Similarly, after RT, the monitoring of serum PSA levels is recommended every six months for the first five years and then annually and a DRE is recommended annually. The clinician may opt to omit the DRE if PSA levels remain undetectable.”

The American Cancer Society (ACS)

The ACS recommends that physicians provide patients with information on benefits, risks, and uncertainties of the PSA test, and state that screening not be done until such information is received. The ACS recommends that discussions (and screening) begin at age 50 for individuals of average risk, at age 45 for those at increased risk (i.e., African-American men and men who have a first-degree relative (father or brother) diagnosed with prostate cancer at an early age (younger than 65)”, and at age 40 for those at highest risk (those with more than one first degree relative with a history of early-onset prostate cancer. 

After having this discussion, individuals who want to be screened should get the PSA screening. A digital rectal exam (DRE) may also be performed. Because prostate cancer is growing slowly, the ACS does not recommend PSA screening in any individual without symptoms of prostate cancer and with a life expectancy of less than 10 years. However, they also note that overall health and not age alone is important to decide when to pursue screening.

If the initial PSA test is in normal range, the ACS recommends different testing intervals based on the initial test. For patients with results less than 2.5 ng/mL, the screening interval should be 2 years. For patients with initial results at or higher than 2.5 ng/mL, the screening interval should be annually. 

The ACS remarks that overall health and not age alone is important to decide when to pursue screening. Moreover, “Even after a decision about testing has been made, the discussion about the pros and cons of testing should be repeated as new information about the benefits and risks of testing becomes available” and further discussions must incorporate patients’ health, values, and preferences.

The National Cancer Institute (NCI)

The NCI has deemed the evidence insufficient to determine whether PSA-based screenings or DREs reduce mortality from prostate cancer. The NCI states that although screening can detect cancer in its earlier stages, it is unclear that earlier detection (and treatment) changes the natural course of the disease. The NCI also states that there is significant harm in screening such as overdiagnosis and complications caused by the screenings. Moreover, NCI states there is “solid evidence,” that current treatments such as radical prostatectomy and radiation therapy, result in “permanent side effects in many men.”

The American College of Physicians (ACP)

The ACP agrees with the informed decision-making requirement for PSA testing, and states that clinicians should not screen using the PSA test in patients who “do not express a clear preference for screening”. It is also worth mentioning that “it has been suggested that those who are at high risk may benefit from earlier screening beginning at age 45, while even higher risk men (those with two or more first-degree relatives with prostate cancer before the age of 65), should be screened at age 40.” The ACP recommends against screening with PSA for individuals under 50 or over 70, as the primary target is between the ages of 50 and 69. The ACP also cautions that “clinicians should not screen for prostate cancer using the PSA test in average-risk men aged 50 to 69 years who have not had an informed discussion and do not express a clear preference for screening.” Asymptomatic men over 75 and those with a life expectancy of less than 10 years should also not be offered screening because screening can introduce substantial harms for questionable benefit.

The Society of Urologic Oncology (SUO)

AUA and the SUO collaborated to produce a series of guideline statements. Regarding the use of PSA screening in the early detection of prostate cancer, they expounded that:

• “1. Clinicians should engage in SDM with people for whom prostate cancer screening would be appropriate and proceed based on a person’s values and preferences. (Clinical Principle)” 
• “2. When screening for prostate cancer, clinicians should use PSA as the first screening test. (Strong Recommendation; Evidence Level: Grade A) 
• 3. For people with a newly elevated PSA, clinicians should repeat the PSA prior to a secondary biomarker, imaging, or biopsy. (Expert Opinion)” 
• “4. Clinicians may begin prostate cancer screening and offer a baseline PSA test to people between ages 45 to 50 years. (Conditional Recommendation; Evidence Level: Grade B) 
• “5. Clinicians should offer prostate cancer screening beginning at age 40 to 45 years for people at increased risk of developing prostate cancer based on the following factors: Black ancestry, germline mutations, strong family history of prostate cancer. (Strong Recommendation; Evidence Level: Grade B)” 
• “6. Clinicians should offer regular prostate cancer screening every 2 to 4 years to people aged 50 to 69 years. (Strong Recommendation; Evidence Level: Grade A)”
• “7. Clinicians may personalize the re-screening interval, or decide to discontinue screening, based on patient preference, age, PSA, prostate cancer risk, life expectancy, and general health following SDM. (Conditional Recommendation; Evidence Level: Grade B)” 
• “8. Clinicians may use digital rectal exam (DRE) alongside PSA to establish risk of clinically significant prostate cancer. (Conditional Recommendation; Evidence Level: Grade C)”
• “9. For people undergoing prostate cancer screening, clinicians should not use PSA velocity as the sole indication for a secondary biomarker, imaging, or biopsy. (Strong Recommendation; Evidence Level: Grade B)” 
• “10. Clinicians and patients may use validated risk calculators to inform the SDM process regarding prostate biopsy. (Conditional Recommendation; Evidence Level: Grade B)”
• “11. 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. (Clinical Principle).” 

The AUA and SUO also partnered to discuss advanced prostate cancer as well, reported below.

Regarding the use of PSA screening for the Biochemical Recurrence without Metastatic Disease after Exhaustion of Local Treatment Options, they proposed that “Clinicians should inform patients with PSA recurrence after exhaustion of local therapy regarding the risk of developing metastatic disease and follow such patients with serial PSA measurements and clinical evaluation. Clinicians may consider radiographic assessments based on overall PSA and PSA kinetics. (Clinical Principle).”

Moreover, PSA screening also plays a role in the prognosis of Metastatic Hormone-Sensitive Prostate Cancer, such that “Clinicians should obtain a baseline PSA and serial PSAs at three- to six-month intervals after initiation of ADT in mHSPC patients and consider periodic conventional imaging. (Clinical Principle).”

In patients with Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC), “clinicians should obtain serial PSA measurements at three- to six-month intervals and calculate a PSADT starting at the time of development of castration-resistance. (Clinical Principle).”

Lastly, in patients with Metastatic Castration-Resistant Prostate Cancer, “clinicians should obtain baseline labs (e.g., PSA, testosterone, LDH, Hgb, alkaline phosphatase level) and review location of metastatic disease (lymph node, bone, visceral), disease-related symptoms, and performance status to inform discussions of prognosis and treatment decision-making. (Clinical Principle).” However, “In mCRPC patients without PSA progression or new symptoms, clinicians should perform imaging at least annually. (Expert Opinion)”

The European Society for Medical Oncology (ESMO)

The ESMO recommends against population-based screening for prostate cancer because the reduction in mortality does not offset the harms done, such as overdiagnosis and overtreatment. Early PSA testing should only be offered to men > 50 years, men > 45 years with a family history of prostate cancer, African Americans > 45 years, and BRCA1/2 carriers who are > 40 years of age. Prostate cancer screening should not be performed in asymptomatic men with a life expectancy of less than ten years. ESMO also recommends against screening in asymptomatic men over 70.

The American Association of Clinical Urologists Inc. (AACU)

The AACU recommends use of tissue-based molecular testing to assess risk stratification in prostate cancer treatment decision making. The AACU states pursing germline testing when appropriate is encouraged and support any further research into these tests AACU.

The European Association of Urology (EAU)

In 2021, the EAU released updated guidelines on their position regarding prostate antigen testing, recommending a risk-adapted strategy for the early detection of prostate cancer and reaffirming the joint guidelines in the table above. They noted that an absence of regular and routine widespread PSA testing had led to “opportunistic” testing in several EU member states. In addition, the impact of COVID-19, particularly the redeployment of medical resources to fight COVID-19, as well as a move during COVID-19 to “deprioritize all oncology screening, including PSA testing,” was of strong concern. Their position concluded with the need to reverse current unfavorable trends in order to accurately diagnose advanced stage prostate cancer and save lives.

The European Association of Urology (EAU), European Association of Nuclear Medicine (EANM), European Society for Radiotherapy and Oncology (ESTRO), European Society of Urogenital Radiology (ESUR), and International Society of Geriatric Oncology (SIOG)

Joint guidelines on prostate cancer screening and early detection from the EAU, EANM, ESTRO, ESUR and SIOG include the table below taken from Cornford et al. (2024).

Additional guidelines for the risk-assessment of asymptomatic men from Cornford, et al. (2004) state:

The guideline also notes the presence of newer biological markers, “the use of biomarkers (included in a nomogram) may help in predicting indolent PCa. Several assays measuring a panel of kallikreins in serum or plasma are now commercially available.” However, regarding urine and blood-based biomarker tests, “further studies are necessary to validate their efficacy.”

State and Federal Regulations, as applicable

The FDA has approved several screening tests for prostate cancer beginning with a PSA immunoassay in 1986.

On June 14, 2012, the FDA approved the Access® Hybritech® p2PSA assay created by Beckman Coulter, Inc. From the FDA website: “The Access® Hybritech® p2PSA assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of [-2] proPSA antigen, an isoform of free PSA, in human serum using the Access Immunoassay Systems. Access@ Hybritech® p2PSA is intended to be used in combination with Access® Hybritech® (total) PSA and Access@ Hybritech@ free PSA to calculate the Beckman Coulter Prostate Health Index (phi), an In Vitro Diagnostic Multivariate Index Assay (IVDMIA).”

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use. 

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 84152, 84153, 84154, G0103

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included. 

Scientific Background and Reference Sources

For Policy Titled: Prostate Cancer Screening

1. Freedland S. Measurement of prostate-specific antigen. Updated December 03, 2024. https://www.uptodate.com/contents/measurement-of-prostate-specific-antigen 
2. NCCN. Prostate Cancer Early Detection Version 2.2024. Updated March 6, 2024. Accessed 12/9/2024, https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf 
3. ACS. Signs and Symptoms of Prostate Cancer. Updated November 22, 2023. https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/signs-symptoms.html
4. CDC. Leading Cancer Cases and Deaths, Male, 2021. https://gis.cdc.gov/Cancer/USCS/#/AtAGlance/ 
5. American Cancer Society. Key Statistics for Prostate Cancer. Updated January 16, 2025. https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html 
6. ACS. Survival Rates for Prostate Cancer. Updated January 17, 2025. https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/survival-rates.html 
7. Preston MA. Screening for prostate cancer. Updated June 3, 2024. https://www.uptodate.com/contents/screening-for-prostate-cancer?source=see_link#H30 
8. Bell KJ, Del Mar C, Wright G, Dickinson J, Glasziou P. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. International journal of cancer. Oct 01 2015;137(7):1749-57. doi:10.1002/ijc.29538 
9. Fisher KW, Montironi R, Lopez Beltran A, et al. Molecular foundations for personalized therapy in prostate cancer. Current drug targets. 2015;16(2):103-14. doi:10.2174/1389450115666141229154500 
10. Rodrigues DN, Butler LM, Estelles DL, de Bono JS. Molecular pathology and prostate cancer therapeutics: from biology to bedside. The Journal of pathology. Jan 2014;232(2):178-84. doi:10.1002/path.4272
11. NCI. Prostate-Specific Antigen (PSA) Test. Updated January 31, 2025. https://www.cancer.gov/types/prostate/psa-fact-sheet 
12. Prcic A, Begic E, Hiros M. Actual Contribution of Free to Total PSA Ratio in Prostate Diseases Differentiation. Med Arch. Jul 27 2016;70(4):288-292. doi:10.5455/medarh.2016.70.288-292 
13. Coban S, Doluoglu OG, Keles I, et al. Age and total and free prostate-specific antigen levels for predicting prostate volume in patients with benign prostatic hyperplasia. Aging Male. Jun 2016;19(2):124-7. doi:10.3109/13685538.2015.1131260 
14. Brawley S, Mohan R, Nein C. Localized Prostate Cancer: Treatment Options. American Family Physician. 2018;97(12):798-805.  
15. Fleshner K, Carlsson SV, Roobol MJ. The effect of the USPSTF PSA screening recommendation on prostate cancer incidence patterns in the USA. Nature reviews Urology. Jan 2017;14(1):26-37. doi:10.1038/nrurol.2016.251 
16. Ilic D, Djulbegovic M, Jung JH, et al. Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis. Bmj. Sep 5 2018;362:k3519. doi:10.1136/bmj.k3519 
17. Saini S. PSA and beyond: alternative prostate cancer biomarkers. Cell Oncol (Dordr). Apr 2016;39(2):97-106. doi:10.1007/s13402-016-0268-6 
18. Stimac G, Spajic B, Reljic A, et al. Effect of histological inflammation on total and free serum prostate-specific antigen values in patients without clinically detectable prostate cancer. Korean journal of urology. Aug 2014;55(8):527-32. doi:10.4111/kju.2014.55.8.527 
19. Wang LG, Liu XM, Kreis W, Budman DR. Down-regulation of prostate-specific antigen expression by finasteride through inhibition of complex formation between androgen receptor and steroid receptor-binding consensus in the promoter of the PSA gene in LNCaP cells. Cancer research. Feb 15 1997;57(4):714-9.  
20. Singer EA, Palapattu GS, van Wijngaarden E. Prostate-specific antigen levels in relation to consumption of nonsteroidal anti-inflammatory drugs and acetaminophen: results from the 2001-2002 National Health and Nutrition Examination Survey. Cancer. Oct 15 2008;113(8):2053-7. doi:10.1002/cncr.23806 
21. Hamilton RJ, Goldberg KC, Platz EA, Freedland SJ. The influence of statin medications on prostate-specific antigen levels. Journal of the National Cancer Institute. Nov 5 2008;100(21):1511-8. doi:10.1093/jnci/djn362 
22. Chang SL, Harshman LC, Presti JC, Jr. Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Sep 1 2010;28(25):3951-7. doi:10.1200/jco.2009.27.9406 
23. Martin RM, Donovan JL, Turner EL, et al. Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial. Jama. Mar 6 2018;319(9):883-895. doi:10.1001/jama.2018.0154 
24. Ahlering T, Huynh LM, Kaler KS, et al. Unintended consequences of decreased PSA-based prostate cancer screening. World J Urol. Mar 2019;37(3):489-496. doi:10.1007/s00345-018-2407-3 
25. USPSTF. Draft Recommendation Statement: Prostate Cancer: Screening - US Preventive Services Task Force. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/prostate-cancer-screening 

Specialty Matched Consultant Advisory Panel 8/2019

Medical Director review 8/2019

Medical Director review 4/2020

Specialty Matched Consultant Advisory Panel 8/2020

For Policy Titled: Prostate Specific Antigen (PSA) Testing

Medical Director review 4/2021

Specialty Matched Consultant Advisory Panel 8/2021

Medical Director review 4/2023

Medical Director review 4/2024

Medical Director 4/2025

Policy Implementation/Update Information

For Policy Titled: Prostate Cancer Screening

1/1/2019 New policy developed. BCBSNC will provide coverage for prostate cancer screening when it is determined to be medically necessary and criteria are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (lpr)

6/11/19 Reviewed by Avalon 1st Quarter 2019 CAB. Under “When Covered” section: changed “men” to “individuals.” Under “When Not Covered” section: re-ordered and re-worded indications. Updated “gene expression analysis” general terminology to include “use of Prolaris, Oncotype DX, Promark or Decipher tumor-based molecular assays to guide management of prostate cancer as well as urine testing.” Added PLA codes 0005U and 0047U to Billing/Coding section. Medical Director review 5/2019. (lpr)

10/1/19 Reviewed by Avalon 2nd Quarter 2019 CAB. Policy statement revised to read: BCBSNC will provide coverage for prostate cancer screening when it is determined the medical criteria and guidelines noted below are met. Revised Description Section. Wording changed in the When Covered section. “Medically Necessary” changed to “Reimbursement is allowed…” Wording revised in the Not Covered section. “Investigational” changed to read “Reimbursement is not allowed…” Deleted coding grid. Policy Guidelines updated. References added. Policy noticed 10/1/2019 for effective date 12/2/2019. (an)

12/31/19 Specialty Matched Consultant Panel review 8/21/19. No change to policy statement. CPT code 81542 added to Billing/Coding section for effective date 1/1/2020. (lpr)

3/24/2020 CPT codes 81541, 81551 and PLA code 0005U removed from Billing/Coding section. (lpr)

5/12/20 Reviewed by Avalon 1st Quarter 2020 CAB. Medical Director review 4/2020. Added CPT codes 0005U and 81551 to Billing/Coding section. Switched the term “testing” to “screening” in the “When Covered” section. Added ExoDx prostate, Intelliscore, Select MDX, PCA3, KLK3, Confirm MDX, PPCA to “When Not Covered” section. Updated Policy Guidelines and References. (lpr)

9/8/20 Specialty Matched Consultant Advisory Panel review 8/19/2020. No changes to policy statement. (lpr)

For Policy Titled: Prostate Specific Antigen (PSA) Testing

5/18/21 Reviewed by Avalon 1st Quarter 2021 CAB. Medical Director review 4/2021. Under “When Covered” section: revised and updated to include total PSA testing for average risk individuals aged 45-75 with African ancestry, germline mutations that increase risk for prostate cancer, suspicious family history. Updated Description and Policy Guidelines sections as well as References. Revised and updated Billing/Coding section. Policy title changed from: Prostate Cancer Screening to: Prostate Specific Antigen (PSA) Testing. (lpr)

9/7/21 Specialty Matched Consultant Advisory Panel review 8/18/2021. No change to policy statement. (lpr)

5/17/22 Reviewed by Avalon 1st Quarter 2022 CAB. Medical Director review 4/2022. Updated guidelines/recommendations and references. (lpr)

7/18/23 Reviewed by Avalon 1st Quarter 2023 CAB. Medical Director review 4/2023. Deleted related policies section. Updated policy guidelines and references. Re-ordered and edited “when covered” section for clarity. No change to policy statement. (lpr)

5/15/24 Reviewed by Avalon Q1 2024 CAB. Medical Director review 4/2024. Added related policies section. Updated policy guidelines and references. Edit for clarity: removed reference to TRUS guided biopsy and digital rectal exam (DRE) from coverage criteria #5 in “when covered” section, as these are outside of Avalon’s scope. (lpr)

7/1/25 Reviewed by Avalon 2nd Quarter 2025 CAB. Medical Director review 4/2025. Updated policy guidelines, guidelines and recommendations and references. Under “When covered” section, Item 1 edited age range for average risk annual screening from 45-75 to 45 years of age and older;  Item 2 edited age range for annual screening from 40-75 to 40 years of age and older. Repeat screening edited from 4 years to 3 year intervals. (lpr)