New strategies to help doctors and patients make more-informed treatment decisions

If you have just had a prostate specific antigen (PSA) screening test, the words, "Your PSA level is 4," are not particularly welcome. In general, the higher the PSA, the greater the likelihood cancer is present. So, a score of 4 ng/mL is likely to sound warning bells for your doctor to order a biopsy, the results of which are used to help confirm or rule out the presence of cancer. And, if cancer is identified, the biopsy results are also used to help decide whether immediate or delayed treatment is the best course of action.

However, a number of prostate cancer experts argue that a PSA level of 4 is not the best cut-off point for triggering a biopsy. Given recent evidence showing that most cancers identified by PSA screening are not life threatening, it might surprise you to learn that the new threshold is even lower.

What's more, a growing number of doctors are questioning the value of using any single PSA value for all men. Instead, they consider the PSA result as just one of many pieces of information that can be used to help determine a man's risk of having prostate cancer that needs treatment.

PSA Problems

Experts worry that a PSA screening cutoff of 4 ng/mL is not sufficiently sensitive. The term "sensitivity" describes how good a test is at not missing people who have a condition—in this case, prostate cancer. This is referred to as a false negative. In the Prostate Cancer Prevention Trial, for example, 7 percent of men who had a PSA level of below 0.5 ng/mL had cancer, and about 12 percent of those cancers were high-grade, aggressive tumors with the potential to become life threatening; among men with a PSA of 3.1 to 4 ng/mL, 27 percent had cancer, and 25 percent of those were high grade.

As a result of findings from this and other studies, many doctors now recommend lowering the threshold for a standard biopsy from 4 ng/mL to 2.6 ng/mL to pick up some of the men who were missed by using the higher threshold. Of course, while lowering the threshold allows for the identification of more men with prostate cancer, it also means that even more men who don't have cancer or who have non-life-threatening disease will be flagged. Those with cancer may be subjected to medical procedures they may not need, especially if they are older and have other medical problems—a concern that has prompted doctors to rethink their advice about who needs regular screening.

There also is the test's specificity to consider. This term refers to how good a test is at not accidentally labeling people who don't have a condition, such as prostate cancer, as having it. This is referred to as a false-positive result. Many factors, such as benign prostatic hyperplasia (BPH), prostatic inflammation, or even an ejaculation within 72 hours of a PSA test, can cause a false-positive result.

One answer to these dilemmas may be to combine the PSA test results with additional information from other sources to more accurately diagnose prostate cancer and predict the risk of disease progression.

Risk Prediction Tools

One method of predicting risk that is gaining popularity is the use of nomograms. A nomogram considers multiple weighted factors to calculate risk. For example, a nomogram that was developed using information from the Prostate Cancer Prevention Trial attempts to determine your risk of having biopsy-detectable prostate cancer based on information about your race, age, PSA level, family history of prostate cancer, digital rectal examination (DRE) results, whether you've had a biopsy in the past, and whether you take finasteride (Proscar).

Other nomograms that have been developed can calculate outcomes such as the chances that your disease will not progress if you choose a particular treatment or the probability of survival if you have a radical prostatectomy.

It's important to realize that the information obtained from a nomogram is simply a prediction based on population data, much like the insurance industry predicts longevity based on age, medical history, and other factors. While such information can help patients in making decisions, it's not a guarantee of a particular outcome nor is it a substitute for your doctor's clinical judgment.

New Biomarkers

Biomarkers are substances like PSA that can be measured in blood, urine, or other body fluids and used to detect or monitor a disease. Researchers are investigating a number of potential biomarkers that, in the future, may improve upon the PSA test's ability to detect prostate cancer and identify potentially life-threatening tumors. Two promising biomarkers are PCA3 and gene fusions.

PCA3. PCA3 is a test that measures a gene that is overexpressed (60 to 100 times greater) in prostate cancer cells versus noncancerous cells. Cells shed by the prostate containing the PCA3 gene are detectable in the urine.

Researchers report that the lower the level of PCA3 in the urine, the less likely prostate cancer is present. Because PCA3 is not produced or is produced only minimally by noncancerous cells, the presence of conditions like BPH or infection is less likely to produce falsely elevated PCA3 levels.

PCA3 testing is most reliable when done in conjunction with a DRE. Researchers report that when performed after a DRE, the results from PCA3 testing are valid in 98 percent of the cases. If the test is performed without a DRE, validity drops to 80 percent.

Rather than replacing PSA screening, researchers believe that the PCA3 test may help identify or rule out cancer in men with elevated PSA levels but no cancer on the initial biopsy. In addition, some evidence suggests that the test may be useful in helping to identify men who are appropriate candidates for active surveillance. Currently, PCA3 testing is only available through clinical trials in the United States.

Gene fusions. A gene fusion is a hybrid gene formed from two previously separated genes. Scientists have discovered that many prostate cancer patients have gene fusions involving the ERG and TMPRSS2 genes that create a new gene that is thought to promote the development of prostate cancer—and, possibly, a more aggressive form of the disease.

Gene fusions are now being detected in urine and have promise as new biomarkers for prostate cancer. More research is needed, however, before this method of testing moves into the mainstream.

In the Meantime

Regular PSA screening still plays a valuable role for many men. If your doctor recommends regular screening, keep track of your PSA levels and monitor the trends over time. This can help you and your doctor identify trouble signs in the earliest stages. A sign that prostate cancer may be present is a continuously rising PSA even if your absolute PSA score is in the "normal" range.

Publication Review By: H. Ballentine Carter, M.D.

Published: 17 Jun 2011

Last Modified: 19 Feb 2015