We have long cautioned about whether the presence of apparent biologic “markers” in men with prostate cancer (“association”) is necessarily an implication that a specific marker really indicates anything clinically important. A paper published by a European team now helps to put this in perspective.
The most common genetic alteration in patients with prostate cancer is fusion of the so-called TMPRSS2 gene to the ERG gene. (If you want to know what these abbreviations stand for, please see the abstract of this paper by Boormans et al.) The presence of this fusion gene, TMPRSS2-ERG, has been thought, for quite a while, to have high potential as either a diagnostic marker for prostate cancer or a prognostic marker for prostate cancer progression — or perhaps both.
Expression of TMPRSS2-ERG is regulated (controlled) by the presence of androgens, so Boormans and colleagues set out to investigate whether the expression of TMPRSS2-ERG predicts response to endocrine treatment in patients with hormone-naïve, node-positive prostate cancer. Based on what we think the TMPRSS2-EPR fusion gene does, this would seem to be a strong and reasonable possibility.
The investigators analyzed data from 85 patients diagnosed with regionally advanced (node-positive) prostate cancer who had had no treatment at the time of lymph node dissection and then followed the patients over time as they were treated with hormone therapy. The analysis allowed them to associate the presence or absence of expression of the TMPRSS2-ERG fusion gene with clinical response to hormone therapy byexamining a primary end point (the time from start of hormone treatment to the occurrence of three consecutive rises in PSA that were at least 2 weeks apart and resulted in two major increases over the lowest PSA achieved) and three secondary end points (time to PSA nadir, cancer-specific survival, and overall survival).
Here are the results of their study:
- TMPRSS2-ERG was expressed in 42/71 patients (59 percent) for whom relevant data could be analysed. The remaining 29 patients did not express the gene.
- The median duration of response to endocrine therapy was 20.9 months for gene fusion-positive patients as compared to 24.1 months for gene fusion-negative patients, and this 3.2-month difference was not statistically significant in a group of patients this small.
- There were no significant differences between the two groups of patients with respect to any of the secondary end points.
The authors conclude that, although expression of the TMPRSS2-ERG fusion gene is common in untreated prostate cancer patients with lymph node metastases, expression of this androgen-regulated gene did not correspond with duration of response to hormone therapy.
Now this negative result should not be taken to mean that there is no potential value to the presence of the TMPRSS2-ERG gene in assessing risk for prostate cancer and prostate cancer progression. This was only a small trial, after all. But the trial does seem to show that expression of TMPRSS2-ERG is not a good candidate as a marker we will be able to use to identify patients with early metastatic disease who will respond better or worse to hormone therapy.
In other words, we have now shown that despite a clear “association” between the presence of the fusion gene and the presence of clinically evident, node-positive prostate cancer, that association did not “translate” into a clinically useful marker that we could use to predict a good (or a poor) response to hormone therapy. We will have to hope that presence of the TMPRSS2-ERG fusion gene can be used to predict something else about prostate cancer — otherwise what we will have is a very common “marker” that has no apparent clinical value.
Filed under: Diagnosis, Living with Prostate Cancer, Risk | Tagged: association, fusion, gene, marker, TMPRSS2-ERG |
THE "NEW" PROSTATE CANCER INFOLINK 
Certainly conflicts with my information:
In a presentation at the February 2007 Genitourinary Cancers Symposium of the American Society of Clinical Oncology (ASCO), 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 5-alpha-reductase inhibitor also inhibits the conversion of testosterone (T) to the 10 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). [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.
“She 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.”
Here is a link to 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.’ ”
Also of interest is that it appears the presence of TMPRSS2-ERG is less common in prostatic intraepithelial neoplasia (PIN), considered a possible precursor to prostate cancer development, and may not be involved in the initiation of prostate cancer cell development. However, once prostate cancer cell development has occurred, the presence of TMPRSS2-ERG becomes more prevalent.
Here is other information regarding preventing TFF-3 expression:
“Treating and preventing cancer characterized by differential expression of trefoil factor 3 (TFF3) includes 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.”
And here is some more recent news from a London study regarding the importance of stemming 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 being 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.
Dear Chuck:
Actually the original report above does not necessarily conflict at all with the additional information you refer to.
The difference is context. You are referring to laboratory studies that definitively show certain types of association. The study by Boormans and his colleagues is a clinical study that was unable to demonstrate a correlation in clinical practice.
To prove your point we need at least a small study that clearly shows that a well-defined group of patients carrying the TMPRSS2 gene gain clinical benefits from treatment with dutasteride as compared to a placebo. Without that study, everything is speculation.
We have seen over and over and over again that what one can demonstrate in a laboratory doesn’t necessarily turn out to be true in clinical practice. Life would be so much easier if what one could demonstrate in the lab was always true in clinical practice!
Ah, but friend Sitemaster, I also referred to human studies with the presentation at the February 2007 Genitourinary Cancers Symposium of the American Society of Clinical Oncology (ASCO). Though a small study, it recognized the role of dutasteride in down-regulating that gene, as well as TFF3, and the upregulating of IGEPB3 (which I believe was meant to be IGFPB3 but may be wrong) with an effect of promoting PC cell apoptosis as well as inhibiting cell proliferation. TMPRSS2 is being studied in much research. Several poster presentations regarding TMPRSS2 were made at the 2007 IMPACT (Innovative Minds in Prostate Cancer Today) gathering of 600 Research Scientists and 100 PC survivor/advocate “Consumer Reviewers.”
Ah, but friend Chuck, the study you refer to looks like a clinical study, but actually it isn’t one. It is a laboratory study of levels of expression of certain genes in men before and after treatment with dutasteride, but it is only a laboratory analysis of an association. Certainly the expression levels of the genes were reduced, but (to coin a phrase) so what?
To quote the report you refer to, “The investigators identified the changes in tissue excised in prostatectomy. Dr. Mostaghel said, however, that dutasteride did not change the clinical course of treatment.”
We need data from a prospective, clinical study — one in which the patients’ TMPRSS2-ERP levels are measured before treatment, after treatment (at specifically defined times), and correlated to the clinical outcomes at those predefined times. It doesn’t matter what we can show in the lab. We have to be able to show that the gene expression levels correlate prospectively to clinical outcomes in patients. The only valid measure of success or failure is whether disease did or did not progress in a well-defined patient population.
Ah, but Sitemaster, what I have researched and read satisfies me of the importance of dutasteride/Avodart both as a medication to hopefully prevent or prolong the diagnosis of prostate cancer as well as an important medication in androgen deprivation therapy. (I’m enjoying the “ah”s.)