The accurate assessment of risk profiles among high-risk prostate cancer patients

A key question in management of prostate cancer is the risk that a particular patient has disease — at the time of diagnosis — that will progress over time to become metastatic. The ability to answer this question with accuracy is fundamental to the need for aggressive, early treatment.

At present, we know that men initially diagnosed with high-risk forms of prostate cancer are all at some significant degree of risk for metastatic prostate cancer and potentially prostate cancer-specific mortality. However, we also know that — even among high-risk patients — there are men who will have very aggressive forms of prostate cancer that progress quickly and men whose disease may progress much more slowly even if it can’t be arrested.

A new paper just published by Evans et al. in JAMA Oncology has described a whole new way to try to identify different types of patient with high-risk disease, based on what is known as their DNA damage and repair (DDR) system — i.e., the effectiveness and efficiency with which each patient is able, without external help, to avoid and/or repair deleterious (“bad”) mutations and errors in gene copying that can lead to cancers and other clinical problems.

Evans et al. were able to use data from > 1,000 high-risk patients, all of whom had undergone radical prostatectomies at one of three well-known academic institutions, to do two things:

  • Define a series of nine DDR “pathway profiles” (based on genetic data from 545 of the patients — the “training” cohort)
  • Validate the idea that patients with specific DDR pathway profiles were more or less likely to go on to have metastatic disease (by using three, pooled sets of data from 232, 130, and 183 other patients)

This is clearly a complex paper that is based on identification of 17 different sets of genes and a technique known as gene set enrichment analysis or GSEA that we aren’t even going to try to explain (because we’d probably get it wrong anyway).

The bottom line to this paper is that Evans et al. have been able to show that

  • DDR pathway genes seem to be rarely mutated.
  • There are some distinctly different clusters of DDR pathways in men with high-risk prostate cancer (nine as defined by GSEA analysis in thsi study).
  • DDR pathway “enrichment” (i.e., having a “better” DDR capability) is
    • Only weakly related to things like age, Gleason score, and PSA level
    • Strongly related with androgen receptor pathway enrichment for 13/17 DDR gene sets.
  • The DDR pathway profile prognostic signature created using the training cohort was significantly associated with biochemical recurrence-free survival, metastasis-free survival , and overall survival in the pooled validation cohorts.
  • The DDR pathway profile prognostic signature performed better in prediction of metastasis-free survival in younger patients (hazard ratio [HR] = 1.67) than in older patients (HR = 0.77).

Now clearly this new type of biomarker system is not yet “ready for prime time” (even if we can afford it), but it does indicate the progress we are continuing to make toward the personalization of treatment for those men who are at highest risk for prostate cancer-specific metastasis and death. If we are truly able to project risk for prostate cancer metastasis accurately among high-risk patients at the time of diagnosis and initial treatment, then this will help us to determine just how aggressively to treat such men early on in order to maximize their chances for long-term remission.

To quote the paper’s authors:

A DDR pathway signature showed strong prognostic performance with the long-term outcomes of metastasis-free and overall survival that may be useful for risk stratification of high-risk prostate cancer patients.

4 Responses

  1. Very interesting, especially for me, as I am at high risk according to clinical PSA and Gleason sum. I forget what T2c contributes to.
    I might have missed something, but don’t these claims imply that a man can be low risk according to D’Amico staging but high risk according to a DDR signature?

  2. Dear George:

    No. All the patients studied in this set of patients were high-risk according to the D’Amico/NCCN criteria. They had to be in order to be enrolled in the study. What this study shows is that even within the high-risk patients, some are at far higher risk than others, and we may be able to predict who is which.

  3. Thanks again for reporting this interesting and thought-provoking paper.

    I have a number of comments and questions, but I’m holding off until I get further into the complete paper and commentary, which I found are available via JAMA (selecting JAMA Oncology, the January 7, 2016 issue, as part of a free trial for a month’s worth of issues (plus apparently recent issues).

  4. And then what to do?

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