Active Surveillance

[pjoshea13]

New Canadian study below.

It's all very well for Dr. Myers - speaking of overtreatment - to say :"Don't call it cancer" when the Gleason score is 3+3, but 25-30% of such men will progress while on Active Surveillance [AS]. In some cases, a delay in treatment might worsen the outcome.

It isn't as though there aren't tests that might identify those men. & now there is another potential test:

"We demonstrate that a urine-based Classifier Panel of four methylation biomarkers predicts disease progression of AS patients."

Methyl is important for preventing cancer. Low levels (hypomethylation) cause DNA instability. However, when PCa exists, the cells tend to become hypermethylated, & the DNA promoter regions for tumor suppressor genes become methylated (silenced).

The main dietary methyl donor is folate, & methyl intake could be restricted by cutting back on leafy greens. But in countries where grains have been fortified with folic acid (a synthetic substitute for folate), it can be difficult to restrict methyl intake.

Vitamin B12 is a cofactor in methyl processing & one could restrict that.

If methyl is plentiful, aggressive PCa cells will load up on it. If intake is restricted, the Canadian test will be less useful - but restriction will also make the cancer less aggressive.

-Patrick

ncbi.nlm.nih.gov/pubmed/275...

J Urol. 2016 Aug 18. pii: S0022-5347(16)31067-9. doi: 10.1016/j.juro.2016.08.081. [Epub ahead of print]

Urinary DNA methylation biomarkers for non-invasive prediction of aggressive disease in prostate cancer patients on Active Surveillance.

Zhao F1, Olkhov-Mitsel E1, van der Kwast T2, Sykes J3, Zdravic D4, Venkateswaran V5, Zlotta AR6, Loblaw A7, Fleshner NE8, Klotz L5, Vesprini D7, Bapat B9.

Author information

Abstract

PURPOSE:

Prostate cancer (PCa) patients on active surveillance (AS) are monitored through repeated prostate-specific antigen (PSA) measurements, digital rectal exams (DREs) and prostate biopsies. A subset of AS patients will later "reclassify" with disease progression prompting definitive treatment. To minimize the risk of under-treating such AS patients, minimally-invasive tests incorporating biomarkers to identify patients who will reclassify are urgently needed.

METHODS:

We assessed post-DRE urine samples of AS patients for selected DNA methylation biomarkers that were previously investigated in radical prostatectomy specimens and shown to correlate with increasing risk of PCa. Post-DRE urine samples were prospectively collected from 153 men on AS who were diagnosed with Gleason Score (GS) 6 disease. Urinary sediment DNA was analyzed for eight DNA methylation biomarkers by multiplex MethyLight assay. Correlative analyses were performed on gene methylation and clinicopathological variables to test their predictive ability of patient risk-reclassification.

RESULTS:

Using backward logistic regression, a four gene methylation "Classifier Panel"(APC, CRIP3, GSTP1, HOXD8) was identified. The Classifier Panel was able to predict patient reclassification (OR= 2.559; 95% CI= 1.257-5.212). We observed this panel to be an independent and superior predictor compared to current clinical predictors such as PSA at diagnosis or % of tumor positive cores in initial biopsy.

CONCLUSION:

We demonstrate that a urine-based Classifier Panel of four methylation biomarkers predicts disease progression of AS patients. Once validated in independent AS cohorts, these promising biomarkers may help establish a less-invasive method for monitoring patients on AS programs.

Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

Active surveillance; Biomarkers; DNA methylation; Prostate cancer; Risk-reclassification; Word Count

PMID: 27545574 DOI: 10.1016/j.juro.2016.08.081

[PubMed - as supplied by publisher]

[bdriggers]

Excellent post. Aside from the informative food/supplement posts, it would be extremely interesting to see your research in other areas.

Thank you.

[AlanMeyer Moderator]

That was a very interesting post. Thanks.

On the question of methylation:

First a bit of explanation for non-chemists who are interested in this. A "methyl group" is a carbon atom with 3 hydrogen atoms bonded to it and one open position which can very easily be attracted to and bond with an atom in some other molecule, for example, a DNA molecule. When a methyl group bonds to another molecule, that molecule is said to be "methylated". Methylation is a normal part of life in the cell and is sometimes used to "silence" a gene, i.e., prevent the DNA that makes up that gene from being used as a pattern for creating protein molecules. Some biochemical reactions in a cell can cause some DNA to be methylated and some can cause it to be demethylated - causing the gene to either by "silenced" or not. If the gene in question is one that is involved in cell division or in metastatic behavior, then I would think that silencing is a good thing in a cancer cell. But if the gene in question is one that inhibits cell division or metastasis (i.e., a "tumor suppressor" gene"), then silencing would be very bad.

Methylation of DNA is "catalyzed" by one or more proteins called "enzymes" that assist in the bonding of a methyl group to a particular pattern of DNA. Vitamin B-12 is a molecule that assists the enzyme to do its work.

Now for some caveats that I think need to be considered.

1. It's not clear to me that the process of methylation can be reduced by reducing vegetable or vitamin B-12 intake. The amounts of methyl groups and B-12 molecules required wouldn't be very large, and I suspect that there are other sources of both methyl groups and B-12 besides vegetables and vitamin pills that would be sufficient. Note too that many vegetables also have cancer fighting properties - definitely not sufficient to cure cancer, but helpful. So we'd really need to do some studies to find out if dietary changes of this type would help. Maybe they will, but maybe they won't.

2. While the test sounds very promising, it needs to be validated in additional studies and it needs to be commercialized. I don't know if ordinary hospital pathology labs have the capability of doing this kind of testing. It would be necessary for someone to package it in a standardized way that is practical for technicians to perform the test in the same way in different labs, and with standardized numbers for which standard interpretations can be made.

So I think this is promising but, as with everything in advanced medicine, it's probably going to take some time before it becomes usable for patients.

At least that's my current inexpert thinking.

Alan