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From the Winter 2019 Quest
Research continues to broaden the horizons of prostate cancer screening and detection. ©David Taylor
In addition to routine PSA screening, recent research has identified and is currently assessing numerous other strategies and tools available for the early detection of prostate cancer.

Baseline PSA testing

A midlife baseline PSA test can be used to guide future screening decisions. A midlife baseline PSA that is higher than the median is a stronger risk factor for prostate cancer than age, race, or family history. The median PSA for a man in his 40s is 0.7 ng/mL.

A baseline PSA can be used to stratify a man’s risk for future diagnosis of prostate cancer, aggressive disease, metastasis, or prostate cancer death. This means that for men with a PSA that is higher than the median PSA for their age group, routine annual screening may be warranted. For men with a low baseline PSA, less vigorous screening may suffice, since data demonstrates that men in this group have a low risk of developing advanced prostate cancer.

PHI Testing

The PHI (Prostate Health Index) blood test is nearly three times more accurate in detecting prostate cancer than the free/total PSA test. PHI measures three forms of PSA, then uses a formula to calculate a combined PSA index to determine a patient’s probability of developing prostate cancer.

Dr. Catalona has been a leader in the studies that led to the FDA’s approval of the PHI blood test.

Continued screening for older men

Guidelines that recommend that PSA testing can be safely discontinued for men older than 75 years are not taking some important points into consideration. Men in this age group account for 26% of prostate cancer cases, 48% of metastatic cases, and 53% of prostate cancer deaths. Older men with a life expectancy of 10 years or more may benefit from early detection and treatment of aggressive prostate cancer.

In addition, some guidelines suggest increasing the biopsy cutoff to more than 10ng/mL for men older than 70 years. However, high-grade prostate cancers produce less PSA on a per-cell basis. Higher PSA cutoff may prevent the timely detection of aggressive prostate cancers.

PSA Velocity and Density

PSA velocity is the rate of change in PSA levels. Some research suggests that the speed of increase in a man’s PSA could be a useful tool for assessing prostate cancer risk. One study found that a PSA velocity of 0.35 ng/mL per year was a better predictor than looking at a man’s last PSA value.

Research also continues to explore PSA density as a predictor of clinically significant prostate cancer. To calculate a patient’s PSA density, the physician measures the volume of the prostate with a transrectal ultrasound and divides the PSA value by the prostate volume.

One recent study assessing PSA density in men with a PSA of 4-10 ng/mL found that using PSA density improved the performance of PSA to detect clinically significant prostate cancer (Gleason grade group 2 or greater). Patients with a PSA density less than 0.08 ng/mL/cm3 were unlikely to harbor prostate cancer with a Gleason grade group of 2 or greater. This was the case regardless of the patient’s race or body mass index. If validated in future studies, PSA density could be used to identify men who could likely forgo prostate biopsies. The authors analyzed data on more than 2,000 men, of whom just over half were African American.

Family history and race

Research has demonstrated that men with a family history of prostate cancer have a prostate cancer-specific mortality benefit if they undergo PSA screening. This suggests that a positive family history of the disease should be taken into account when making screening decisions.

A 2016 nationwide study in Sweden found that the probability of having prostate cancer was higher for men with a strong family history of the disease. Men with more than one close relative with the disease, such as two affected brothers, had the highest chances of also developing the disease.

In the PLCO study, 7.4% of participants had a family history of prostate cancer. These men had a 56% higher risk of being diagnosed with prostate cancer, and a 51% higher risk of dying from the disease.

Multiple research studies have also found that men with African ancestry benefit from earlier and more frequent PSA testing, due to a higher risk of being diagnosed with aggressive disease that progresses quickly.

Research finds new ways to look at things, and the future is promising for the detection of prostate cancer. ©Dan Oldfield

Germline genetic mutations

A major focus of Dr. Catalona’s research program is the identification and validation of germline (inherited) genetic mutations that increase a man’s risk for prostate cancer. This work is important for the future of prostate cancer screening and detection. Certain tests for germline genetic mutations are already available in the clinic.

Some guidelines already recommend assessing for certain genetic mutations known to be associated with prostate cancer susceptibility. Perhaps the most well-known of these are the BRCA1/2 genes.

Research has already found ample evidence linking BRCA2 mutations with increased risks of developing prostate cancer. The IMPACT study found that nearly half of men with a BRCA2 mutation developed prostate cancer, and 71% of these men had intermediate- or high-risk disease. Men in the study without the mutation had lower rates of the disease. Only 33% were diagnosed with prostate cancer, and 43% of these men had intermediate- or high-risk disease.

Mutations in DNA repair genes are also associated with aggressive prostate cancer. To validate this claim, a recent study looked at germline mutation in DNA repair genes in approximately 1,200 men on active surveillance. The overall rates of these mutations were relatively low, with less than 1% of the patients having mutations in BRCA1, BRCA2, or ATM genes. However, over 40% of the men with mutations had their prostate cancer grade reclassified, compared to less than one quarter of men without the mutations. The authors concluded that men on active surveillance with inherited mutations in BRCA1/2 and ATM genes are more likely to harbor aggressive prostate cancer.

Eur Urol. 2019 May;75(5):743-749. doi: 10.1016/j.eururo.2018.09.021. Epub 2018 Oct 8.

The future

In the future, combining all these approaches intelligently will significantly reduce suffering and death from prostate cancer. Current efforts in personalizing medicine support these efforts.

Research data also demonstrates the potential impact of this approach. A recent retrospective analysis found that combining genetic information and PSA scores could lead to more accurate predictions of prostate cancer risk in individual patients. In the study population, using PSA alone predicted 70% of prostate cancers, compared to nearly 89% when looking at patient risk scores based on just seven genetic variants known to be associated with prostate cancer. When the analysis included all known prostate cancer variants provided in the genetic test results and PSA scores, the rate of prediction for prostate cancer was nearly 97%.

The study also suggested that the combined information could provide the basis for risk stratification which could be used to optimize and personalize prostate cancer screening.

J Urol. 2019 Mar;201(3):486-495. doi: 10.1016/j.juro.2018.10.015.

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