Prostate Cancer Screening Part 2 - 016
Innovative approaches
This newsletter is about innovative ways some doctors are trying to improve prostate cancer screening. This, like the previous newsletter, is a more technical article as part of my goal is to educate not only men with prostate cancer but also doctors. I’ll return to my personal story about having advanced prostate cancer in the next newsletter.
Prostate cancer screening only using a prostate-specific antigen (PSA) blood test and digital rectal exam (DRE) needs to be improved because it results in:
False positives tests - high PSA levels but no evidence of prostate cancer
Overdiagnosis - finds too many slow-growing prostate cancers that would not result in complications or death
Biopsy complications such as pain, bleeding, urinary tract infections, and serious bloodstream infections
And once prostate cancer is detected, some men are overtreated, resulting in cardiovascular complications, osteoporosis, depression, dementia, impotence, and urinary incontinence.
I recommend viewing a presentation I found online by Gerald L. Andriole, Jr., MD, Director of Urology in the National Capital Region at the Brady Urological Institute at Johns Hopkins University. I summarize part of his presentation in this article.
Dr. Andriole discusses a study that showed the median PSA value for men ages 40-49 ranges from 0.5-0.7 ng/ml. Based on knowing the median normal PSA levels for men starting at age 40, he feels this study supports the National Comprehensive Cancer Network’s (NCCN) recommendations for beginning to discuss the risks versus benefits of PSA screening with men at age 40 who have the following risk factors:
African ancestry
Family genetic (germline) mutations that increase the risk for prostate cancer
For example, BRCA1 and especially BRCA2 mutation
Suspicious family history
1st or 2nd-degree relative with metastatic prostate cancer, ovarian cancer, male breast cancer, female breast cancer ≤45 y, colorectal or endometrial cancer ≤50 y, or pancreatic cancer
two or more 1st or 2nd-degree relatives with breast, prostate, colorectal or endometrial cancer at any age
Screening men ages 40-49 with these risk factors and finding a PSA greater than 0.5-0.7 ng/ml should result in a referral to a urologist, as these men have a higher risk for the development of prostate cancer.
Guidelines that recommend considering PSA testing at an earlier age create recommendations for when to repeat PSA testing or recommend additional testing, including prostate biopsy, based on risk factors, age, and PSA level. This is an intelligent approach since it doesn’t try to fit all men into a “one size fits all” category regarding prostate cancer screening because, as I have repeatedly stressed, prostate cancer is a highly heterogeneous (diverse) disease.
A more nuanced approach to screening men for prostate cancer is that in addition to PSA and digital rectal exam (DRE) of the prostate, practitioners should consider additional prostate cancer biomarker tests.
These other biomarker tests look for genetic evidence of prostate cancer in either the blood or urine and can be combined with multiparametric magnetic resonance imaging (mpMRI) to help doctors decide if there is enough evidence to justify a prostate biopsy.
Dr. Andriole’s recommendations to improve prostate cancer screening include:
Better identify men at an above-average risk
Simplify the message to patients and Primary Care Providers (PCPs) on PSA screening
Identify patients with clinically significant prostate cancer earlier
Reduce unnecessary prostate biopsies
Enhance risk stratification to better select patients who need interventional treatment
Better identify men at an above-average risk
To better identify men at above-average risk, you should consider:
Family history
African ancestry
Obtaining a baseline PSA at an earlier age
Other blood tests such as 4KScore and PHI
Urine tests such as SELECT, PCA3, and ExoDx
Combing the above tests
Using prostate cancer risk calculators
Germline testing to check for such things as BRCA
The use of novel imaging:
Dr. Andriole also recommended a direct-to-consumer test called the Prompt Genetic Risk Score to help men understand their prostate cancer risk. It measures multiple single nucleotide polymorphisms (SNPs) obtained by swabbing the inside of your cheek. The lab provides a risk score based on the number of SNPS present that are associated with prostate cancer.
SNPs are genetic abnormalities, but the effect of a single SNP is small. However, when numerous SNPs for prostate cancer risk are combined, a genetic score can be generated, resulting in improved risk prediction.
When I updated this Substack post on March 22, 2025, I discovered that another company, Invitae, had bought the company that developed the Prompt test. Invitae gained acquisition rights to the Prompt test and redirected its internet URL to a LabCorp webpage promoting the purchase of a different Invitae prostate cancer genetic test.
I’m sure this cannibalization is common among companies with competing products.
Simplify the message to patients and Primary Care Providers (PCPs)
Dr. Andriole makes this recommendation because numerous PSA screening guidelines are presented to physicians, ranging from no PSA cut-off levels to various PSA cut-off levels that vary by age. The average primary care physician, and even many urologists, haven’t read the clinical trial papers on which those guidelines are based. And many physicians are unaware of the various PSA screening guidelines that exist.
He suggests that primary care physicians be given a PSA level of between 1 and 1.5 ng/ml as the threshold for referring their patients to a urologist. He goes on to cite a clinical trial that showed a baseline PSA level < 1 is associated with a very low 10-12.5 year risk of clinically significant prostate cancer. He also cites another study recommending that if the PSA is ≥ 1.5ng/ml or the PCP identifies an abnormality on DRE, the patient should be referred to a urologist.
I will play the devil’s advocate based on my experience as a general internist and seeing what primary care physicians do in the non-academic medical community. I think this recommendation would result in a dramatic increase in referrals to urologists.
This could be good or bad, depending on whether the urologist has kept up with the medical literature as Dr. Andriole has. I would say that most urologists in the non-academic medical community have not studied clinical trials like Dr. Andriole and would feel compelled to screen these referred patients more aggressively with unnecessary prostate biopsies.
Suppose the primary care physician is referring to a urologist in an academic teaching center, especially a urologist in a prostate cancer center of excellence. In that case, I don’t have a problem with the referral if the baseline PSA is between 1 and 1.5 ng/ml. That’s because I think these urologists are more likely to keep up with the medical literature and, thus, are more likely to manage these men appropriately.
The need for better screening measures
Dr. Andriole opines that men are not getting screened early enough with lower PSA cut-off levels, and many are getting inadequate biopsies, which missed cancers that were present.
He clarifies that office-based random transrectal twelve-core prostate biopsies miss a whopping half of all cancers. By random, he means the urologist did not use mpMRI or micro-ultrasound to help identify cancer in the prostate gland and guide the biopsy.
All prostate biopsies are guided by ultrasound, but Dr. Andriole recommends that for better detection of prostate cancer during a biopsy, urologists should use micro-ultrasound, which is better at visualizing suspicious areas in the prostate.
Microultrasounds operate at 29 Mhz versus conventional ultrasounds at 6-9 Mhz. This higher frequency offers a 300% improvement in the resolution of prostate tissue, resulting in exquisite imaging detail.
This lets the urologist better visualize known tissue patterns, which can indicate aggressive prostate cancers. These micro-ultrasound-guided biopsies can be done transrectally or transperineally and combined with mpMRI for even better imaging.
One study showed that micro-ultrasound-guided biopsies increased the detection rate of clinically significant prostate cancer by 12% compared to conventional ultrasound. Another large study showed that the micro-ultrasound sensitivity for detecting clinically significant prostate cancer was significantly higher than the mpMRI sensitivity.
Dr. Andriole says that a “high-quality prostate biopsy” consists of combining mpMRI with micro-ultrasound. Theoretically, by getting this kind of high-quality biopsy, you could avoid a saturation biopsy, and thus fewer cores, but still maintain accuracy for detecting clinically significant prostate cancer.
Reduce unnecessary prostate biopsies
Consider using biomarker tests, as recommended in the NCCN guidelines, to reduce unnecessary prostate biopsies for men with an elevated PSA. Many biomarker tests have been developed to help refine patient selection for biopsies, decrease unnecessary biopsies, and increase the specificity of cancer detection without missing a substantial number of higher-grade cancers.
NCCN guidelines recommend only using biomarker tests validated in clinical trials. These include:
percent free PSA (%f PSA) - blood
Prostate Health Index (PHI) - blood
4Kscore - blood
Select mdx - urine
ExoDx Prostate Test (EPI) - urine
PCA3 - urine
One study examined the cost-effectiveness of using the PHI, 4KScore, Select MDx, and EPI in men with an elevated PSA. It concluded that applying biomarkers in men with an elevated prostate-specific antigen decreased the number of unnecessary biopsies by 24%—34%. It determined that the two most cost-effective tests were the SelectMDx and the EPI tests.
Another study looked at various algorithms combining certain biomarkers with mpMRI and found that some algorithms would avoid up to 45% of unnecessary biopsies and only miss < 5% of high-grade cancers.
Enhance risk stratification
Once prostate tissue is taken, by either biopsy or prostatectomy, tests can be performed on the tissue to help determine the cancer’s aggressiveness and help predict outcomes, especially in low- or intermediate-risk men.
These tests include:
Dr. Andriole restricts these tissue-based multigene tests to high-volume Gleason 6 disease and low-volume Gleason 3 + 4 disease. He feels these tests do not provide much more information for very low-risk (low volume G 6) or very high-risk (high volume G 3 + 4 or G 4 + 3 or higher) prostate cancer.
The NCCN guidelines specifically reference the Confirm mdx, which may be considered as an option for men contemplating a repeat biopsy because it may identify individuals at higher risk of a prostate cancer diagnosis on repeat biopsy.
In summary:
Aggressively screen men with a positive family history, early in life elevated PSA, and African American men.
Refer men to a Urologist with a PSA of ~1.5.
Don’t automatically biopsy for an elevated PSA. Get mpMRI, micro-ultrasound, and biomarkers.
Do high-quality prostate biopsies and avoid random transrectal biopsies.
When cancer is detected, consider all patient and tumor factors before treatment.
A simplified approach
Dr. Andriole has some great ideas, but many of the biomarker tests he suggests are expensive and may be unnecessary. For the average urologist, probably the simplest approach is:
Obtain a detailed family history to help stratify risk for prostate cancer.
Always repeat the PSA after considering any factors that may have caused or contributed to the high reading.
Wait an appropriate amount of time before repeat testing.
Always add a percent-free PSA with repeat PSA testing. Lower is better, with a 25% or less cutoff of free PSA recommended for patients with PSA values between 4.0 and 10.0 ng/mL.
If the PSA remains high, obtain a mpMRI of the prostate and ensure the radiologist calculates the PSA density by dividing the PSA level by prostate volume. A PSA density >0.15 ng/mL/g suggests a higher cancer risk.
By this point, most urologists will have enough information to help patients make informed decisions about whether a prostate biopsy is indicated. If there is still a question of whether to proceed with a biopsy, some NCCN-recommended liquid (blood or urine) biomarkers could be ordered.
Post biopsy:
If a high-volume Gleason 6 or a low-volume Gleason 7 (3 + 4) is present on biopsy, order the Decipher Prostate test on the biopsied tissue to further stratify risk.
If the biopsy tissue shows no cancer but the patient is considered high-risk, per NCCN guidelines, order the Confirm mdx test on the biopsied tissue to further stratify risk.
Until the next one, stay healthy.
Much love,
Keith