For years, Alan W. Partin, M.D., Ph.D., Director of the Brady Urological Institute, has been looking for a “better PSA .” This is because, even though PSA blood testing (along with the digital rectal exam — for more, read story) has helped diagnose prostate cancer early in hundreds of thousands of men, it has also been responsible for a lot of unnecessary biopsies; also, confusion over how to interpret PSA has caused some cancers to be missed.
“Presently, using PSA , we biopsy nearly five men to find one prostate cancer,” says Partin. “While biopsy is relatively safe and an effective way to diagnose prostate cancer, if we had a better test that could decrease the false positive biopsies from four out of five to, say, one out of two, that would be a great improvement.”
“ Presently, using PSA , we
biopsy nearly five men to find
one prostate cancer.”
So strongly does Partin believe in the need for better tests for prostate cancer, that he has made this a priority at Hopkins. Several labs at the Brady and the Pathology Clinical Chemistry Department, with research led by Partin, Robert Getzenberg, Ph.D., Robert Veltri, M.D., Daniel Chan, Ph.D., and Lori Sokoll, Ph.D., have focused on testing molecules that have the potential to be more accurate than PSA . Some of this work has led to something called the Prostate Health Index (PHI). “It’s a mathematical equation,” says Partin, “that combines PSA , free-PSA and proPSA , to more accurately predict the need for a biopsy.” In a large trial, the PHI was calculated from blood tests of 1,372 men at eight different medical centers who underwent prostate biopsy; 430 of these men were found to have prostate cancer. “PHI better predicted the presence of cancer than PSA or free-PSA alone,” says Partin. “In addition, PHI predicted the aggressiveness of the cancer with accuracy.”
Exactly what the PHI is sounds like something on a college prep test: “It’s the ratio of a PSA precursor protein to free PSA multiplied by the square root of the PSA score at diagnosis,” says Veltri, director of the Fisher Biorepository & Biomarker Laboratory at the Brady. He presented the results of another recent study at the annual meeting of the American Association for Cancer Research in Washington, D.C. The work is also due to be published in Urology. Veltri, Partin, Jonathan Epstein, M.D., and H. Ballentine Carter, M.D., studied 71 men who were in the Johns Hopkins Hospital Proactive Surveillance Program; 39 of these eventually developed an “unfavorable biopsy,” which means that either the Gleason grade had gotten higher, or the volume of cancer had increased. (In addition to the yearly biopsy, these patients also received a digital rectal exam twice a year.)
Combining PHI with DNA analysis of biopsy tissue, “we were able to identify 70 percent of men who could safely undergo active surveillance,” says Veltri. The PHI was higher in men who ended up having unfavorable biopsies; similarly, the amount of DNA in and near the biopsied areas where the cancer was found was significantly higher in men who were going to develop an unfavorable biopsy. Putting the information from the blood and tissue samples together made a big difference, even though at face value, the men seemed more alike than not, with similar-looking tumors, Gleason scores, and PSA levels.
“Our findings were slightly surprising,” Veltri adds. “The level of pro-PSA by itself was not able to predict who would develop an unfavorable biopsy. However, the PHI and DNA measurements were able to tell us which men were going to need treatment.” Two research fellows, Sumit Isharwal, M.D., and Dan V. Makarov, M.D., made important contributions to this investigation, and were instrumental in generating several other publications on this active surveillance research.