Do new, prospective data mean the 4KScore test is “proven” for use in prime time?

According to data from a large, prospective, multi-institutional trial carried out here in the USA, the 4KScore test has shown a high degree of ability to accurately identify men with a Gleason score of 3 + 4 = 7 or higher which was subsequently confirmed on prostate biopsy.

The paper by Punnen et al. was another of those presented at the ongoing Genitourinary Cancers Symposium in Orlando, Florida, and offers strong evidence that, for many men, an initial 4KScore test (after a prior PSA test suggests possible risk for prostate cancer) may be wiser than an immediate biopsy — assuming that there are no other clear signals of prostate cancer risk. Additional information about the study is also available in a report on the UroToday web site.

As some readers will be aware, the 4KScore test uses data from a standard blood sample that combines information from four different kallikrein assays (total PSA, free PSA, intact PSA, and hK2), along with the patient’s age, his rectal exam result, and the results of any prior biopsy, to create an actual risk “score”. In the trial discussed here, Punnen et al. used the 4KScore results for 1,012 men who were undergoing risk assessment at 26 different institutions in the US between October 2013 and April 2014. The goal was to determine whether each individual patient was likely to have a positive prostate biopsy with a Gleason score of 3 + 4 = 7 or higher. All patients subsequently underwent a systematic TRUS-guided biopsy, regardless of their PSA level or any other clinical findings.

What Punnen and his colleagues report is, basically, the following:

  • 781/1,012 men (77.2 percent) had either a negative biopsy result or a positive biopsy result with a Gleason score of 6.
  • 231/1,012 men (22.8 percent) had a positive biopsy result with a Gleason score of 3 + 4 = 7 or higher, among whom
    • 23.0 percent (i.e., 10.7 percent of all men biopsied) were Gleason 3 + 4 = 7.
    • 12.8 percent (i.e., 5.8 percent of all men biopsied) were Gleason 4 + 3 = 7.
    • 7.4 percent (i.e., 3.5 percent of all men biopsied) were Gleason 8.
    • 5.5 percent (i.e., 2.6 percent of all men biopsied) were Gleason 9.
    • 0.6 percent (i.e., 0.3 percent of all men biopsied) were Gleason 10.
  • The 4KScore was able, prospectively, to predict the probability of a Gleason score of 3 + 4 = 7 with an extremely high degree of accuracy.
  • The 4KScore was significantly more accurate than the PCPT risk calculator in predicting risk for a Gleason score of 3 + 4 = 7 or higher (p < 0.0001).
  • If it is assumed that a 9 percent probability of cancer with a Gleason score of 3 + 4 = 7 is a reasonable threshold for biopsy of the prostate, then use of the 4KScore in this cohort of patients would have
    • Avoided unnecessary biopsies in 434/1,012 men (43 percent)
    • Led to a delay in diagnosis of 24/231 cancers (10.4 percent) with a Gleason score of 3 + 4 = 7 or higher

Punnen et al. conclude that:

The 4Kscore demonstrated excellent accuracy in detecting high-grade prostate cancer. It is a useful tool in selecting men who are likely to have high-grade disease and most likely to benefit from a prostate biopsy versus those men with no cancer or indolent cancer.

It will be interesting to see whether the National Comprehensive Cancer Network’s guidelines committee — and/or the American Urological Association’s comparable committees — are willing to accept these prospective data as sufficient evidence to recommend a role for the 4KScore test in the work-up of a patient with an elevated PSA level prior to implementation of prostate biopsy.

What is not reported in this study are: the number of men who had a Gleason 6 biopsy result; the number of men who had a negative biopsy result; and the accuracy of the 4KScore in differentiating between these two categories of patients. The degree to which the absence of this information may affect the value of the 4KScore test is likely to be debatable depending on one’s point of view about the necessity for early diagnosis of indolent and low-risk forms of prostate cancer.

4 Responses

  1. This confirms the findings of an earlier prospective trial by Lin et al. It’s always good to have confirmation from independent trials. I think the 4KScore is a potentially valuable tool for detecting the kind of prostate cancer we most want to detect, and eliminating unnecessary biopsies. The only problem is the cost — $395 is steep! By comparison, the Prostate Health Index (PHI), was found to be similarly effective in a comparative study published by Nordstöm et al. last year. PHI only costs $80 and is guaranteed to be covered by insurance. Between the two, I’d go for PHI.

  2. Yes, for now the cost is steep. They are currently working to obtain reimbursement for the 4KScore Test by payers in the U.S. and abroad. It looks like the 4KScore has already obtained a approved CPT code and publication date. Code 0010M effective 7/1/2015, to be published 11/1/2015.

    The CPT® Editorial Panel has approved the early release of the most recently approved administrative Multianalyte Assays with Algorithmic Analyses (MAAA) codes (4Kscore™ Test, OPKO Diagnostics, LLC 0010M), so it looks like insurance re-imbursement is just down the road.

    I see they also were assigned a Protocol ID from the National Cancer Institute Early Detection Research Network.

    As far as the PHI in comparison, here is a comment from one urology group:

    “PHI and 4Kscore tests provide somewhat different information. As a result, one is not better than another. Rather they provide complementary information. While either test is useful by itself, together they provide a fuller picture of prostate cancer risk for individual man. Prostate Health Index (PHI) test predicts the risk of having prostate cancer. 4KScore test predicts the risk of having high-risk prostate cancer. Because prostate cancer is an evolving disease these tests together may provide a more-rounded picture about longer-term risk of aggressive prostate a cancer in men.”

  3. John,

    We want to be careful about quoting opinions of some urology group and taking it as fact. While it’s true that the 4KScore is better at predicting higher grade cancers, as shown in the Lin et al. study I linked in my reply above, it is also true that PHI seems to be better at predicting higher grade, higher stage, and higher volume cancers at least in one small scale study published by Ferro et al.

  4. Allen,

    From the Nordstrom et al. paper presented at the European Association of Urology in 2014:

    “The four-kallikrein panel showed AUCs of 69.0 when predicting any-grade PCa and 71.8 when predicting high-grade cancer (Gleason score ≥ 7). Similar values were found for PHI: 70.4 and 71.1, respectively. Both models had higher AUCs than a base model with PSA value and age (p < 0.0001 for both); differences between models were not significant. Sensitivity analyses including men with any PSA level or a previous biopsy did not materially affect our findings. Using 10% predicted risk of high-grade PCa by the four-kallikrein panel or PHI of 39 as cut-off for biopsy saved 29% of performed biopsies at a cost of delayed diagnosis for 10% of the men with high-grade cancers. Both models showed limited net benefit in decision analysis. The main study limitation was lack of digital rectal examination data and biopsy decision being based on PSA information.”

    Also, a note to the sitemaster. You cite absence of the information regarding Gleason 6 biopsy as it relates to the value of the 4KScore. Note the following from David Okrongly — President, Diagnostics Division:

    “We’re getting ready to begin a very large study in active surveillance using a cohort that has been followed for five years now under active surveillance. Active surveillance is when a man is diagnosed with Gleason 6 or indolent cancer, they go onto a program of repeated PSA testing and biopsying and we think that the 4Kscore test should provide exceptional clinical value in awarding biopsies during active surveillance.”

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