Prostate cancer news update: Tuesday, August 19


Recent publications reported on today include:

  • Demonstration of the validity of the Epstein criteria in defining pathologically insignificant prostate cancer
  • A review of the value of sildenafil (Viagra) and similar products in treatment of erectile dysfunction among prostate cancer patients
  • A review of the significance of “gene fusion” and its relevance in prostate cancer

Another recent study by Capitanio et al. appears to have confirmed the validity of the Epstein criteria for definition of pathologically insignificant prostate cancer (PIPCa). The authors set out to identify the rate of biochemical recurrence (BCR) in patients with PIPCa that had been confirmed post-prostatectomy. They drew on a database of 1,358 patients who had been treated by open retropubic radical prostatectomy. and whose surgical specimens had all been whole-mounted, step-sectioned, and subjected to computer-based three-dimensional reconstruction. They identified patients in this database who fulfilled the Epstein criteria for definition of PIPCa (tumor volume ≤ 0.5 mL, Gleason score ≤ 6, organ-confined disease) and compared the BCR-free rates between the PIPCa and non-PIPCa groups. They were able to confirm PIPCa in 69 patients (5 percent). At 1, 2, 5, and 10 years, the BCR-free rates for PIPCa patients were 100 percent, as compared to 97, 91, 74, and 38 percent respectively for the non-PIPCa patients (log-rank P <.0001). They conclude that in patients with PIPCa defined according to the Epstein criteria, radical prostatectomy results in perfect biochemical recurrence-free rates.

Candy et al. have summarized a recent Cochrane report on the efficacy and safety of PDE5 inhibitors (Viagra, Cialis, Levitra, etc.) in the treatment of erectile dysfunction (ED) subsequent to radical postatectomy or radiotherapy in treatment of prostate cancer. This is a readable, thorough, and impeccably “neutral” review of the value of this class of agents in the treatment of ED in prostate cancer patients. The entire article is available on line (but you do have to register with UroToday).

Another BJUI MiniReview, by Morris et al., addresses the potential roles of “gene fusions” in development, diagnosis, and treatment of prostate cancer. This is a much more technically “dense” article that may be difficult for those with little training in biochemistry and molecular biology. Basically, alterations in the ways genes are expressed and function are critical contributors to the development of many malignancies. These alterations often result from  so-called “chromosomal translocations” (in which a piece of genetic material from one chromosome gets moved to another chromosome during cell division) or from the deletion of particular segments of the genome that can lead to changes in the way a particlar gene is expressed, or the fusion of two distinct gene transcripts. Morris and his colleagues provide a sound summary of what we know at present about “gene fusion” and its impact on prostate cancer.

4 Responses

  1. The Capitanio study supports the notion that insignificant PCa is not commonly diagnosed. Only 5 percent were identified and confirmed by surgery? Where does the 80 percent figure comes from? High imagination and dedicated misinformation seems likely …

  2. Ralph: I think if we are to be strictly accurate we need to discriminate carefully between clinically insignificant (which Capitanio et al. do not address) and pathologically insignificant according to the Epstein criteria (which is what they are dealing with).

    There is little doubt that the number of cancers that are clinically insignificant (i.e., indolent) is higher than 5 percent of all cancers diagnosed, but I would agree with you that it seems unlikely to be anything like 80 percent of all the 186,320 cases of prostate cancer that will be diagnosed in the USA in 2008.

    Indeed, if you look at the Capitanio data from another point of view, it is possoble to make the statement that: 97 percent of non-PIPCa patients appeared to have clinically indolent disease at 1 year, 91 percent at 2 years, 74 percent at 5 years, and 38 percent at 10 years, leading to the conclusion that > 30 percent of patients diagnosed with localized prostate cancer have clinically indolent disease for > 10 years.

  3. I took particular note of the gene fusion study and discussion of the gene TMPRSS2. In a presentation at the February 2007 Symposium of the American Society of Clinical Oncology (ASCO) (the organization for physicians treating cancer), it was reported that dutasteride/Avodart upregulates gene IGEBP3 and down regulates genes TMPRSS2 and TFF3, thus causing PC cell apoptosis and inhibiting cell proliferation (not to mention that this 5Alpha Reductase inhibitor also inhibits the conversion of testosterone (T) to the ten times more powerful stimulant to PC cell growth, dihydrotestosterone (DHT), as well as, for those still having a prostate gland, reducing the size of the gland to provide more efficient surgery or radiation effectiveness). (MY NOTE: The report mentioned “IGEBP3,” but I believe it was a miss-print for “IGFBP3:” Insulin-like Growth Factor Binding Protein-3, a tumor suppressing gene that showed increased activity with high dose dutasteride).

    “Twenty-six men were randomized to 0.5 mg of dutasteride and 24 to 3.5 mg of dutasteride daily for four months before surgery. Twenty-five men had surgery alone. Gene expression profiling was performed, finding 32 unique genes that were upregulated by treatment with dutasteride and 98 genes that were down regulated.

    From that group of genes, the researchers said they found at least three specific genes that may play a major role in cancer development: IGEBP3, TMPRSS2, and TFF3.
    They said that IGEBP3, which appears to be upregulated by dutasteride, PROMOTES APOPTOSIS AND INHIBITS CELL PROLIFERATION (my emphasis). Previous studies have reported that the expression of this gene is decreased in patients with prostate cancer.

    The other two genes-TMPRSS2 and TFF3-both appeared to be downregulated. (by dutasteride/Avodart)
    Dr. Mostaghel said TMPRSS2, which is regulated by androgen, PROMOTES THE GROWTH OF PROSTATE CANCER, (my emphasis) while TFF3 BLOCKS APOPTOSIS AND PROMOTES INVASIVE ACTIVITY (again, my emphasis). In addition to its role in prostate cancer, TFF3 is overexpressed in breast cancer and gastrointestinal cancers.”

    See: http://www.medpagetoday.com/MeetingCoverage/ASCOProstate/tb/5119
    Or http://tinyurl.com/3u3jpk

    Here is other information by different researchers making note that TMPRSS2 is a primary factor in promoting the growth of prostate cancer, and in this case estrogen-receptor-beta can also play an important role in suppressing TMPRSS2 and cancer cell growth: “An estrogen-receptor-beta agonist, diarylpropionitrile, limited growth and suppressed expression of TMPRSS2-ERG (0.57-fold increase compared with one-fold increase with ethanol; difference 0.43, 95% CI 0.29 to 0.57).
    The estrogen-receptor antagonist fulvestrant (Faslodex) also reduced TMPRSS2-ERG expression (0.58-fold increase compared with one-fold increase with control; difference 0.42, 95% CI 0.16 to 0.68).
    “Taken together,” the researchers said, “these results indicate that TMPRSS2-ERG fusion can be regulated by [estrogen-receptor] action and that [estrogen-receptor-beta] agonism leads to reduced TMPRSS2-ERG transcript expression, resulting in growth suspension.”

    Full article at:

    http://www.medpagetoday.com/Urology/ProstateCancer/tb/9636

    Here is other information regarding preventing TFF-3 expression:
    Treating and preventing cancer characterized by differential expression of trefoil factor 3 (TFF3) include administering to a patient an agent that modulates TFF3 activity or expression and to reducing the physiological effects of TFF3 expression in cells, including inhibiting cell motility and resistance to apoptosis.
    Full article at:
    http://www.medpagetoday.com:80/MeetingCoverage/ASCOProstate/tb/5119

    AND HERE IS SOME MORE recent news from a London study regarding the importance to stem the aggressiveness of TMPRSS2:

    “Researchers knew that prostate cancers commonly contain a fusion of the TMPRSS2 and ERG genes, but the new study found that in 6.6 percent of cases this fusion was doubled up, creating a deadly alteration known as 2+Edel.
    Patients with 2+Edel have only a 25 percent survival rate after eight years, compared with 90 percent for those with no alterations in this region of DNA.
    “If you get two copies it’s really bad news,” Cooper said.
    Exactly how the duplication makes tumours more aggressive is not clear, though Cooper speculates it could result in higher expression of proteins needed to drive tumour growth or be a more general indicator of genome instability.
    Whatever the mechanism, 2+Edel is a clear-cut marker for risk that Cooper hopes will soon be used alongside existing techniques at the time of diagnosis to decide whether men require treatment.”

    MY POINT IS THAT WITH IT OBVIOUS THAT TMPRSS2 HAS BEEN PROVEN IN RESEARCH TO PLAY A ROLE IN PROSTATE CANCER DEVELOPMENT, ANY MEDICATION FOUND TO SUPPRESS THIS GENE SHOULD BE A REASONABLE ASSET FOR PRESCRIBING – IN THIS CASE, DUTASTERIDE/AVODART!

    AND HERE IS ANOTHER:

    Read this article from Medical News Today:

    They made these comments:
    Important reasoning why dustasteride/Avodart should be a component of
    androgen deprivation therapy

    Dutasteride Induces Apoptosis In Androgen Sensitive Prostate Cancer Cell
    Lines

    UroToday…

    To read the full article, please go to:
    http://www.medicalnewstoday.com/medicalnews.php?newsid=45741

  4. The Morris study about gene fusions was particularly interesting to me. Gene fusions are very common in prostate cancer (CaP) and if I understand the information they are often associated with aggressive tumors.

    I am wondering if the presence of gene fusions in CaP might not be a reliable biomarker for aggressive disease, Additionally, are these fusions a potential target for future treatments?

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