Precision medicine and primary Gleason pattern 5 prostate cancer

Patients who are initially diagnosed with primary Gleason pattern 5 localized prostate cancer (i.e., having Gleason scores of 5 + 5 = 10 and 5 + 4 = 9) are well understood to have very high-risk disease.

A group of researchers at Johns Hopkins (see Velho et al.) have recently published data on the molecular characterization of a consecutive set of 60 such patients, all of whom underwent a radical prostatectomy as first-line therapy for their cancer between 2005 and 2015.

Now this was a retrospective analysis of the available data, and so we need to be cautious about how much to “read into” these data, but here are some of their key findings:

  • 49/60 patients had somatic sequencing data (i.e., genetic sequencing data on their actual tumor cells) and clinical follow-up.
  • Of these 49 patients,
    • 17/49 (34 percent) had DNA repair gene mutations, including
      • 11/49 (22 percent) with homologous recombination mutations (of which 9 turned out to also be germline mutations)
      • 6/49 (12 percent) with mismatch repair gene alterations
  • 16/49 (33 percent) of patients had TP53 mutations.
  • 29/57 patients (51 percent) had PTEN loss.
  • 29/60 patients (43 percent) went on to develop metastasis, with a time to castration resistance of 12 months.
  • On multivariable analysis of clinicopathologic variables, only two such variables were associated with risk for metastasis
    • Ductal/intraductal histology (hazard ratio [HR] = 4.43; P = 0.002)
    • Seminal vesicle invasion (HR = 5.14; P = 0.002)
  • Among genomic alterations, only TP53 mutation and PTEN loss were associated with metastasis on univariable analysis, and neither remained significant in multivariable analyses.

The authors are very clear that, at best, “These data are retrospective and hypothesis generating.” They go on to conlude that

Potentially actionable homologous recombination and mismatch repair alterations are observed in a significant proportion of patients with very high-risk [prostate cancer] at the time of radical prostatectomy. These findings could inform the design of prospective trials in this patient population.

The important thing that this study shows us is that it is becoming a great deal easier to describe and identify very specific subsets of prostate cancer patients based on genetic/genomic data along with older, “classical” data such as PSA levels, Gleason scores, clinical and pathological stages of disease, etc. As we become better at identifying these very specific subsets of patient and applying the evolving forms of treatment that are now available, it is reasonable to believe that we will also become better at managing and treating many of the patients whose disease, historically, was aggressive and difficult to treat well.

3 Responses

  1. The phrase “potentially actionable “ covers a lot of ground.

    I fall into this category and genomic analysis found some anomalies, but none like the BRCA 1/2 genotypes that had any treatment implications.

    I think looking in the barn after the horse has left for signs of its presence is not the best way to invest our time and money.

    I would prefer that we investigate treatments currently available, like medical marijuana for example, to translate the impressive findings from sterile Petri dish studies to the messy world of patient care.

  2. Dear Al:

    So as I keep having to repeat over and over again for patients … the ability to gain “impressive findings” in Petri dishes (and in animal models) has very little relationship to whether one can translate such findings into clinical effects in humans. It doesn’t matter whether one is taking about marijuana derivatives or other forms of biopharmaceutical.

    We are only at the beginning of actual application of precision medicine. And I still know of absolutely no therapeutic impact of marijuana derivatives in any forms of cancer in humans — other than to mask pain in some cancers in some patients and to offer a form of stress relief and relaxation to others. Much as we would all like to find some magic bullet that would “solve” the cancer problem once and for all, the chances on that happening are — bluntly — non-existent. Prostate cancer can now be subcategorized into something like 27 or more different sets of disorder, and if one looks at all of cancer we hare probably now talking about something like 750+ different disorders (although I don’t think anyone has a really clear idea yet).

  3. Try reading Roberto D, et al. Cannabinoids as an anticancer agent for prostate cancer. J Urol Res. 2017; 4:1090-1097 for starters.

    As for translational research, start with an article by Woolf SB. The meaning of translational research and why it matters. JAMA, 2008; 299:211-213.

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