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Your PSA is going up.  What’s going on with your prostate?  Do you need a biopsy?  Or, maybe you’ve already had a biopsy that didn’t find cancer, but your urologist is wondering whether you need another one.  What’s the next step?

Good news:  You don’t have to move directly to having needles stuck in your prostate!  It’s not the Monopoly bad-case-scenario of “Do not pass Go, do not collect $200!”  There is a next step!  It’s a “second-line” test:  a blood or urine test that can provide other layers of information beyond the basic PSA test.  There are several good ones out there.  Which one do you need?  Well, as Marlon Brando said in the classic 1953 movie, The Wild One:  “Whadya got?”

There’s no shortage of options!  There are blood tests that provide more nuanced information than the basic PSA test, plus urine tests and even, if you’ve already had a biopsy, molecular biomarker tests, which aren’t done on body fluids but on tissue samples.  These tests can be helpful, not only in diagnosing cancer, but in risk stratification – predicting which cancer is more likely to be aggressive, and which cancer is less likely to need immediate treatment.

Helping us navigate these options is PCF-funded investigator and urologist Stacy Loeb, M.D., of New York University and the Manhattan VA Medical Center.  “First and foremost,” Loeb says, “if a patient has an elevated PSA, the thing to do is to repeat the PSA test at the same lab.  It may feel like backtracking, but step one is to confirm that it even is elevated.”  This is why using the same lab as you’ve used in previous PSA tests is important; what might seem to be a rising PSA might just be a normal fluctuation between labs using different equipment.

However, Loeb adds, “many urologists will order the repeat test as a Free and Total PSA blood test,” because this test is inexpensive and readily available, and because it provides some additional information.   “Free PSA measures whatever PSA in the blood that is not bound to proteins.  The higher percentage of PSA that is free, the more likely you are to be free from cancer.”  This test provides context:  If the percentage of free PSA is higher than 25, then the elevated PSA is more likely to be caused by BPH, benign enlargement of the prostate.  If it’s lower than 25 percent, this doesn’t automatically mean that there’s cancer, but it does raise the likelihood that cancer may be present.

“It’s also important to rule out other causes of an elevated PSA.”  Having prostatitis can raise your PSA; so can having a urinary tract infection.  So can having sex within three days before getting your blood test, because sexual activity stimulates the prostate, which then can release more PSA into the blood.  Similarly – a big oops here for the doctor! – getting your blood drawn after the rectal exam, which stimulates the prostate and shoots PSA out into the blood stream, can make your PSA level temporarily higher.

And then there’s MRI.   “In our practice,” says Loeb, “we’re getting MRIs as the next step for patients who have an elevated PSA.  If the MRI shows a suspicious lesion, we recommend a targeted biopsy.  If the MRI is not suspicious, but we’re still worried because of the patient’s PSA and clinical picture, in that context, a biomarker test could potentially give the extra data point that could help us proceed with a biopsy anyway.  What’s nice about MRI is that it shows us suspicious areas – so in addition to providing information on the risk that significant cancer is present, it also gives us some information on where to look.  The data are very clear that performing targeted biopsies based on MRI findings is a superior strategy to only performing biopsies that sample various locations all around the prostate,” in which cancer is easy to miss.

Now, about those other blood tests:  In addition to the free PSA test, here are two more that include free and total PSA, but look for other factors, as well:

PHI (Prostate Health Index):  PHI not only helps determine if cancer is present; it also can predict the likelihood of finding high-grade cancer on a prostate biopsy.  “PHI also predicts the likelihood of progression during active surveillance,” says Loeb, who with Northwestern urologist William Catalona, M.D., reviewed the effectiveness of PHI for the journal Urology.   “PHI is a simple and inexpensive blood test that can be used not only for biopsy decisions, but for risk stratification and treatment decision-making.” In a Johns Hopkins-led study, PHI outperformed PSA in predicting prostate cancer in general, but proved especially helpful in finding clinically significant (higher Gleason grade) cancer.  It was even better when combined with MRI; in the study, no men who had a PHI score lower than 27 and a PI-RADS of 3 or lower had clinically significant cancer.  (The PI-RADS score indicates the likelihood of clinically significant cancer based on MRI of the prostate). For men who went on to have prostatectomy, a higher PHI score was associated with a higher Gleason grade of cancer and pathologic stage.   PHI also provided discernment, reducing the number of men who needed biopsies without overlooking clinically significant cancer.

4K score:  This blood test combines four prostate-specific biomarkers (three forms of PSA and also human kallikrein 2, a protein made by cells lining the prostate), plus clinical factors including age, to assess a man’s likelihood of having high-grade prostate cancer found at biopsy.  Studies at UCSF, reported in the Journal of Urology, evaluated 4K score and a prostate MRI scan, both for their ability to detect high-grade prostate cancer and to help patients avoid unnecessary biopsies.   “Both of these tests can predict the risk of finding a clinically significant prostate cancer,” cancer that needs to be treated. They found that MRI was a more able predictor of high-grade prostate cancer than the 4K score – however, MRI was not sensitive enough to detect all high-grade prostate cancer, “and 4K testing alone could be sufficient as the initial tool to select patients who may benefit from a biopsy.”  But even better, they found, was combining 4K and MRI:  “Using higher 4K cut points such as greater than 15, combined with MRI… allows for more avoided unnecessary biopsies with minimal missed high-grade prostate cancer cases.”

Loeb adds:  “About 12 percent of the time, MRI can miss something.  So, if we still suspect that cancer may be hiding, that’s a good case for using a biomarker test” like PHI or 4K.  “With a biomarker test and MRI combined, the chance of missing a significant cancer is exceedingly low.”

Urine tests:  One urine test, EPI, is done using a fresh catch urine specimen.  This test can help predict clinically significant prostate cancer in men who have not yet had a biopsy.  Another, the PCA3 test, is done after “a vigorous rectal exam,” says Loeb.  It looks for mRNA levels of a marker, called prostate cancer gene 3, to help rule out other causes of an elevated PSA test, such as BPH or prostatitis.  “It’s FDA-approved for use in men who have had a negative biopsy.”  Then there’s Select MDx, which measures mRNA levels of two biomarkers commonly expressed in prostate cancer, and MiPS, developed at the University of Michigan, which combines PSA with two biomarkers for prostate cancer.  “More head-to-head data is needed comparing all of the different blood and urine markers to find out which is best in different patient scenarios,” says Loeb.

Janet Farrar Worthington
Janet Farrar Worthington is an award-winning science writer and has written and edited numerous health publications and contributed to several other medical books. In addition to writing on medicine, Janet also writes about her family, her former life on a farm in Virginia, her desire to own more chickens, and whichever dog is eyeing the dinner dish.