A newly proposed way to classify types of prostate cancer progression


An article by a respected group of researchers at the University of Texas M. D. Anderson Cancer Center in Houston, published in the August issue of Cancer Discovery, proposes a new classification system for progression of prostate cancer over time. This has implications for the appropriate development and use of markers for use in treatment and drug development.

The publisher (the American Association for Cancer Research) has kindly provided us with a full text copy of the article entitled “Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer” by Logothetis et al. We should point out immediately that the commentary below will not able able to do full justice to a a 12-page, dense, and highly illustrated article. At best we will attempt to summarize some of the key points made by Dr. Logothetis and his colleagues.

As the authors note up front, the historic classification of prostate cancers has been based on the disease stage, the Gleason score, and the patient’s treatment status (e.g., progressive disease after first- or second-line therapy; responsive to androgen deprivation therapy [ADT]; with or without evident metastasis; castration-resistant; and so on). What such a classification does not do, however, is describe a link between the molecular biology of prostate cancer in a specific individual and the reasons to treat him in a specific manner (i.e., a “mechanistic foundation” for decisions about treatment). With the arrival of multiple new drugs for the treatment of progressive prostate cancer over the past 3 to 4 years, and with many more new drugs in the development pipeline, the need for such a mechanistic foundation on which to base the treatment of progressive prostate cancer is an imperative today.

In explaining why they believe that a new classification system for the progression of prostate cancer is necessary, Logothetis et al. write that:

Our recent understanding of the molecular mechanisms of prostate cancer progression has determined that the androgen receptor (AR), oncogenes/tumor suppression, and microenvironment are the major mechanisms that lead to prostate cancer progression and will provide such markers to guide therapy approaches. Therefore these mechanisms need to be incorporated into a classification system designed to guide therapy.

They further state that:

The salient feature of advanced prostate cancer progression is the bone-forming and bone-homing nature of metastases. These findings led investigators to hypothesize that the prostate cancer tumor microenvironment in bone plays a role in prostate cancer progression.

They go on to describe a new molecular classification of prostate cancer progression based on three phases, as follows:

  • An endocrine-driven phase which is dependent on the presence (and biologic levels) of dihydrotestosterone (DHT) and driven by the conversion of testosterone to DHT by 5α-reductase enzymes
  • A micro-environment-dependent phase which encompasses the transition from endocrine-driven to paracrine-driven prostate cancer, and which indicates the onset of potentially lethal disease
  • A tumor cell autonomous phase which can be characterized clinically by the presence of a large tumor mass in the prostate itself, or in the lymph nodes, and visceral metastases without a commensurate rise in the patient’s PSA level (with predominantly lytic bone metastases if bone metastases are present)

For each of these phases in the progression of the disease, Logothetis et al. carefully go on to describe (a) the molecular mechanisms underlying the phase of the disease and (b) the potential for development of markers to identify the earliest stages of this phase of the disease and the possibility to apply such markers in the application of current therapies and the development of new treatments. It is impossible to cover the details of their proposed model in this article.

What is really important to patients here is that Logothetis et al. are laying out a model and a classification system that starts to address a fact that we are all very aware of and that has come up regularly in discussions about the treatment of progressive disease:

  • Most new drugs developed today for the treatment of advanced prostate cancer have “average” (median) survival benefits of 2 to 4 months compared to a placebo or older therapies, but
  • A subset of patients regularly and clearly do a lot better on specific drugs.

This has to have something to do with how those drugs are working in those specific individuals who respond well. Clearly, if we can select the right patients and treat them with the right drugs at the right time, based on a much more accurate mechanistic model for the progression of prostate cancer, we may well be able to demonstrate that certain subsets of patients with progressive prostate cancer respond a lot better than others to specific types of treatment. True targeting of specific drug types to specific patient types necessitates a disease classification of the type proposed by Logothetis et al. — a classification that takes account not just of things like Gleason score and whether or not the patient has metastatic disease, but one that takes account of a range of molecular factors like AR signaling, genotypes, phenotypes, oncogenes/tumor suppression, and the tumor microenvironment.

Prostate cancer support group leaders and other educators should be able to obtain a copy of the full text of this paper through their local medical library or other sources. We would encourage them to do so.

6 Responses

  1. Thank you. I look forward to reading the article some day. It is fascinating to watch a major paradigm shift in progress that offers so much hope.

  2. Well, how about that? Finally recognizing the presence (and biologic levels) of dihydrotestosterone (DHT) is driven by the conversion of testosterone to DHT by 5α-reductase enzymes! I would be interested if the full paper then recognizes the importance of a 5a-reductase “inhibitor” (5ARI) (dutasteride/Avodart or finasteride/Proscar) to prevent testosterone conversion to DHT.

  3. Chuck:

    I quote from the original article:

    “The 5-α-reductase inhibitors finasteride and dutasteride are used to prevent the conversion of testosterone to DHT to interrupt DHT’s growth-promoting signaling. However, the Prostate Cancer Prevention Trial … and Reduction by Dutasteride of Prostate Cancer Events … trial showed that finasteride and dutasteride reduced the rate of low-grade cancers but did not have any effect on high-grade cancers. In addition, the Reduction by Dutasteride of Clinical Progression Events in Expectant Management trial … showed that a significant number of patients with low-grade cancers at initial diagnosis did not have detectable cancer on subsequent repeat biopsies after dutasteride treatment compared with placebo. These findings support the hypothesis that some low-grade cancers are dependent on DHT …. The grade-dependent effects of finasteride or dutasteride point to therapeutically relevant heterogeneity of androgen signaling networks that are different between low-grade and higher-grade cancers.”

  4. Mike

    Thanks for posting. I purchased the article and it is really interesting (and was worth the money).

    Bill

  5. I anticipated your response, Mike, but I have accumulated way too much evidence of the importance of a 5AR inhibitor in androgen deprivation therapy, along with my own longevity of nearing 17 years and counting with dutasteride/Avodart as part of my continuing ADT. I know I’ll be proven correct in my continuing support of dutasteride/Avodart accompanying the LHRH agonist or antagonist and antiandrogen when ADT is considered necessary in reining in/managing the continued presence of prostate cancer.

  6. Dear Chuck:

    Please note … not “my” response. You aked what the paper said and I just let you know!

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