A new analysis of a large data set compiled by Kaiser Permanente suggests that combining PSA data with genetic risk data may offer a much more effective way to assess risk for clinically significant prostate cancer.
Now it is probably fair to say that many American consumers would have been dubious about the chances that a large managed care organization would actually want to make sure that it was finding men at significant risk for prostate cancer with accuracy by using the PSA test. Surprise!
This new study by Hoffman et al., which is available as a full-text article in Nature Communications, is based on findings from a so-called “genome-wide association study” (GWAS) of PSA levels in a total of > 45,000 men (28,503 in the Kaiser Permanente database and another 17,428 in so-called “replication cohorts” that could be used to check the initial findings). PSA data on these 45,000+ men include nearly 500,000 PSA measurements going back to the early 1990s.
The research team (which comprised staff from both Kaiser Permanente and the University of California, San Francisco) describe the following key findings:
- Detection of 40 genome-wide significant (P < 5 × 10−8) single nucleotide polymorphisms (SNPs):
- 19 novel SNPs
- 15 SNPs that had previously been identified for PSA (14 of which were also prostate cancer-associated)
- 6 SNPs previously identified for prostate cancer only
- At least half of the 40 SNPs are PSA-associated independent of prostate cancer.
- The 40 SNPs explain 9.5 percent of PSA variation in non-Hispanic whites.
- The remaining GWAS SNPs explain an additional 31.7 percent of PSA variation.
- This percentage is higher in younger men, supporting the genetic basis of PSA levels.
So what does any of this mean in terms of evaluation of men’s risk for prostate cancer?
We know that PSA tests on their own are not good indicators of prostate cancer risk. They simply aren’t sensitive enough, and they lead to a lot of men having unnecessary biopsies and then unnecessary treatment too, which comes with more risk (for complications and side effects) than benefit (in terms of extended survival and avoidance of metastatic disease). But it has also been well understood that not testing for risk of prostate cancer increases risk for not diagnosing sufficiently early the forms of aggressive prostate cancer that really do need to be treated.
Because of the unusually detailed data that Kaiser Permanente has collected on its members over the past 30 years and longer, according to one of the co-senior authors, it was possible for the research team
to link every man in the study to our electronic clinical data and determine not just that they had a test, but also the level and frequency of testing over many years.
Now the current study was not sensitive enough to identify the specific genetic loci responsible for the additional variation is risk introduced by the genetic data. And, in fact, the results further suggest that additional genetic predictors of PSA levels are likely to be uncovered in further research. But …
If we can gain increased understanding of how a given patient’s genetic predisposition is related to his elevated PSA, this could help clinicians to better evaluate PSA test results and so better predict the patient’s actual risk of prostate cancer — maybe by “normalizing” the results of PSA testing based on each individual’s natural PSA levels or maybe by adjusting the threshold(s) used to determine if a test result should trigger further testing (inclusive of prostate biopsies or at least multiparametric MRI scans when necessary).
This process isn’t “ready for prime time” as yet, but we continue to make progress on how best to combine data categories from differing types of medical information resource to move toward a more sophisticated paradigm for deciding who is at real and definable risk for clinically significant prostate cancer and who really isn’t. And if we can refine this paradigm significantly, we should be able to become much, much better at treating the men who need to be treated and sparing the men who are at zero risk of clinically significant, progressive prostate cancer.