Advanced Prostate Cancer
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Circulating Folate and Vitamin B12 and PCa Risk

New study below.

It's a big study, involving 6,875 cases from 6 cohorts, & researchers from England, Spain, Norway, Sweden, Greece, Italy, Malaysia & the U.S.A.

"Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels."

No mention of the back story in the Abstract.  But first, I'll mention my own.  This goes back ~8 years.

I had been doing something new, & perhaps risky, so started to have PSA tested monthly.  I had 6 identical readings in the first 6 months, but I began seeing an integrative medicine doctor, who asked why my regular doctor had not addressed a high homocysteine test result.  He had already suggested a hair analysis, which is inexpensive & gives some insight on one's status regarding an array of minerals, good & bad.  This showed zero cobalt.

There are a number of reasons why homocysteine might be high, & they mostly relate to the SAM cycle.  B12 deficiency is one possibility, since B12 is a cofactor in folate processing, which is key to the SAM cycle.  I was taking a B-complex supplement daily, but he told me that it was not uncommon for older men to produce less intrinsic factor [IF] in the stomach.  IF is required for the uptake of B12 in the intestines.  Since B12 is a cobalt-containg vitamin, the absence of cobalt in my hair was suggestive of a B12 deficiency, & this would likely explain my elevated homocysteine.

For $24 I received a 6 month supply of B12, syringes, & instructions on how to inject into belly fat.

There were PSA increases over the next 3 months - a 20% increase in the third.  I was puzzled but did not suspect the B12.  But after the third reading I figured it was prudent to look for a PCa connection.  I found a handful of papers on PubMed from Scandinavia & threw out the B12.

The SAM cycle, which is part of "one carbon metabolism" can be simplied here to:

Methionine ---> SAM ---> Homocysteine ---> Methionine

1]  Methionine is the natural source of methyl in the body, but dietary sources are low.

2]  Methionine converts to SAM, which is the universal methyl donor in the body.

3]  When SAM has dropped off its methy to a cell, homocysteine remains in circulation.

4]  Methionine levels are restored by recycling homocysteine back to methionine.  This requires a dietary methyl donor, & folate (from leafy greens, i.e from foliage) is the normal source for many people.

If a cell does not have enough methyl, its DNA can become unstable.  This is why hypomethylation is associated with cancer.

However, once PCa occurs, the cells become greedy for methyl.  They become hypermethylated.  In particular, DNA CpG islands that are the promoter regions for tumor suppressor genes, become methylated.  This never happens in normal cells.  Methylation effectively silences those genes.

Note that this is not a gene mutation effect.  The silencing occurs above the gene level (i.e. is an epigenetic change) & is therefore reversible.  Several demethylation agents have been developed as potentially useful in cancer.

The Scandinavian studies, in effect, indicated that folate insufficiency was protective.  What I think was going on was that, in a population not heavily invested in PCa screening, folate insufficiency was slowing down progression (because tumor suppression genes were still functional) & lowering the detection rate.  But more importantly, preventing progression to an aggressive form.

In the U.S. where grain products are 'enriched' with synthetic folic acid as a source of folate, & where PSA screening reveals cancer at an earlier stage, the effect on statistics should be far less pronounced.

And folate is not the only souce of methyl.  e.g. betaine, from beets, is a good source.

In other words, one should not expect population studies to be consistent.  Pointless to look at folate status as a surrogate for methyl status, if the population is generally not deficient, or not dependent on folate for methyl.

Earlier researchers who looked at folate status also considered homocysteine.  As expected, elevated homocysteine was 'protective'.

Not really.  Those & other studies - includin B12 studies - were attempting to link a dysfunctional SAM system to PCa incidence / severity.  What those studies couldn't do was report on the methylation status of actual PCa cells.  Implicit, though, is that aggressive PCa has turned off tumor suppressor genes via hypermethylation.

For an American these days, the fortification of grains with folic acid has almost ruled out folate-insufficiency as a PCa-protective strategy. I feel fortunate in being able to flirt with B12 deficiency.  My risk for dementia is perhaps 1% higher, but I have more immediate concerns.

From the new study:

"The association with folate varied by tumour grade ... higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 ..), with no association for low-grade disease. "


Eur Urol. 2016 Apr 6. pii: S0302-2838(16)00379-1. doi: 10.1016/j.eururo.2016.03.029. [Epub ahead of print]

Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls.

Price AJ1, Travis RC2, Appleby PN2, Albanes D3, Barricarte Gurrea A4, Bjørge T5, Bueno-de-Mesquita HB6, Chen C7, Donovan J8, Gislefoss R9, Goodman G7, Gunter M10, Hamdy FC11, Johansson M12, King IB13, Kühn T14, Männistö S15, Martin RM16, Meyer K17, Neal DE18, Neuhouser ML7, Nygård O19, Stattin P20, Tell GS21, Trichopoulou A22, Tumino R23, Ueland PM24, Ulvik A17, de Vogel S21, Vollset SE25, Weinstein SJ3, Key TJ2, Allen NE26; Endogenous Hormones, Nutritional Biomarkers, and Prostate Cancer Collaborative Group.

Author information

1Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK; London School of Hygiene and Tropical Medicine, London, UK. Electronic address:

2Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.

3Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda MD, USA.

4Navarra Public Health Institute, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain.

5Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Cancer Registry of Norway, Oslo, Norway.

6Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands; Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK; Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

7Public Health Sciences Division, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

8School of Social and Community Medicine, University of Bristol, Bristol, UK.

9Cancer Registry of Norway, Oslo, Norway; Institute of Population-based research, Montebello, Oslo, Norway.

10Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.

11Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK.

12International Agency for Research on Cancer, Lyon, France; Department of Biobank Research, Umeå University, Umeå, Sweden.

13Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.

14Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

15Department of Health, National Institute for Health and Welfare, Helsinki, Finland.

16School of Social and Community Medicine, University of Bristol, Bristol, UK; Medical Research Council/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, UK; National Institute for Health Research, Bristol Biomedical Research Unit in Nutrition, Bristol, UK.

17Bevital AS, Bergen, Norway.

18Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

19Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.

20Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.

21Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.

22WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens, Greece; Hellenic Health Foundation, Athens, Greece.

23Cancer Registry and Histopathology Unit, "Civic - M.P. Arezzo" Hospital, ASP Ragusa, Ragusa, Italy.

24Department of Clinical Science, University of Bergen, Bergen, Norway.

25Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Norwegian Institute of Public Health, Bergen, Norway.

26Clinical trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, University of Oxford, UK.



Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear.


To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade.


A study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression.


Incident PCa and subtype by stage and grade.


Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02-1.26], ptrend=0.018, for folate and 1.12 [95% CI, 1.01-1.25], ptrend=0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity<0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28-4.12]; ptrend=0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity>0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation.


The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation.


Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.

Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.


Folate; High grade; Pooled data meta-analysis; Prospective cohort; Prostate cancer; Vitamin B(12)

PMID: 27061263 [PubMed - as supplied by publisher] 

7 Replies

I've been taking 15mg of methyl Folate daily for several months. I'm taking it to increase the effectiveness of escitalopram. Your post would seem to say that I'm increasing my odds of a return of prostate cancer by doing that.  Is that right?


Hi Adlerman,

As I mentioned in my post, the study Abstract omits the back story.  It reads as though folate increases the risk of aggressive PCa.  A better perspective, IMO, is that:

a) aggressive PCa needs the methyl in folate for the suppression of anti-cancer genes, and:

b) methyl deficiency will slow down aggressive disease.

Methyl deficiency has a downside - DNA instability.  But it prevents PCa cells from becoming hypermethylated.

In America & Canada & all of the other countries that followed the U.S.A. lead in the folic acid fortification of grain products, folate deficiency will be rare. Breads, baked goods containing wheat flour, rice dishes, etc, all contain folic acid.

In Europe, Scandinavia & other countries wary of fortification, a significant number of men with PCa have insufficient folate in their diets (in effect, not enough methyl) &, whatever other problems they might have, those men do have less aggressive disease.

Supplementation is supposed to reduce neural tube defects in babies.  The target population is quite narrow: women who might become pregnant in the next month or two.  Folate status at conception is important.  Pregnant women tend to be given vitamins.  The trick is to get folic acid into their bodies fefore they know they are pregnant.

The FDA mandate was, I feel, heavy handed.  It forced all males to participate, as well as females who had not yet reached puberty and females who had entered the menopause.  It forced those with cancer to participate.  There was no discussion about the effect on people with cancer.

In the U.S.A. neural tube defects were reduced by 30%.  This is either a disappointment or a resounding success, depending on one's perspective.

Why has Europe resisted?  The FDA mandate was quite brave.  Whoever had the final word was clearly ignorant of the law of unintended consequences.  From a Chilean paper, 2009, [1]:

"Folate depletion is associated with an increased risk of colorectal carcinogenesis. A temporal association between folic acid fortification of enriched cereal grains and an increase in the incidence of colorectal cancer in the USA and Canada has, however, been recently reported."

The unintended effect of the FDA mandate was to trade healthy babies for old people.

In Chile, which seems to have had widespread folate deficiency:

" ... hospital discharge rates were compared using rate ratios between two study periods, 1992-1996, before folic acid fortification and 2001-2004, after the flour fortification with folic acid was established in the country."

"The ... rate ratio between the two periods ... for colon cancer in the group aged 45-64 years (rate ratio: 2.6 ...) and in the 65-79 years (rate ratio: 2.9 ...)"

Almost triple the incidence for older people!

But here is the good news.  Eventually, fewer people get colon cancer.  Excess deaths are hidden by the drop in the incident rate.  Overall, the population benefits.  But those who do get colon cancer can no longer realistically opt for the protection that folate deficiency offers.

For PCa, Sweden is one of the countries that stands to suffer most from enforced folic acid fortification.  

For someone in North America taking methyl folate, the incremental risk of aggressive PCa is probably quite small - maybe even zero.  For a Swede, that'a a different matter.





I remembered being concerned about homocysteine years ago.  I found one paper for 2001 where homocysteine is considered an indicator of arterioslerosis, but as I recall it really related to inflammation of various sources.   Here's a paragraph (if I can insert it) from that paper.  If you think it would be helpful I can send the whole item.

"McCully: The best evidence in the literature indicates that 350-400

            micrograms a day of folic acid is required to keep the homocysteine

            level in the normal range. As far as vitamin B-12 is concerned, most

            members of the population consume adequate vitamin B-12, about 5 -

            15 micrograms per day. In the elderly, absorptive problems may cause

            a marginal vitamin B-12 deficiency. In the case of vitamin B-6,

            there is perhaps a little less certainty about the exact figure. The

            current RDA for vitamin B-6 is 2 milligrams per day but in the

            elderly cohort of the Framingham survivors, approximately 30-40

            percent of them had an intake that was significantly lower than the

            RDA, in the range of 1.6 to 1.7 milligrams per day. Now, in

            extrapolating from the data of Dr. James Rinehart on vitamin B-6

            deficiency in monkeys, he found that in order to prevent

            arteriosclerotic plaques in these experimental animals (monkeys), he

            had to give the equivalent of about 3.5 milligrams per day of

            vitamin B-6 to prevent arteriosclerosis"

Herb S.


Hi Herb,

It's interesting to see the numbers McCully quotes.

Elevated homocysteine is associated with an increase in risk for cardiovascular disease.  It is therefore considered to be a useful target.  The logic is as follows: (i) elevated homocysteine means that the SAM cycle isn't working properly; (ii) which is probably due to an insufficiency of one or more B vitamins: folate [B9], B12 & B6 being the main suspects; (iii) supplementation will repair the SAM cycle, lower homocysteine & reduce CVD events.

There have been a number of significant intervention trials based on this logic.  Intervention does indeed lower homocysteine, but does not appear to influence CVD risk.

In 2010, there was a meta-analysis of 8 clinical trials involving 37,485 people at increased risk of cardiovascular disease [1]:

"Folic acid allocation yielded an average 25% reduction in homocysteine levels."

"During a median follow-up of 5 years, folic acid allocation had no significant effects on vascular outcomes ..."

For those concerned about homocysteine & CVD, lowering homocysteine does not appear to address the problem.  For men with PCa, there may be survival benefit in not correcting any SAM cycle dysfunction.  For anyone contemplating starting supplementation with B vitamins, I would suggest they monitor their PSA doubling time.

Link [2] is to the  McCully interview.






I just read the McCully paper and my first reaction is"what's happened, homocysteine appears to have disappeared into the woodwork--again!?"  Back in that era,  2000-2003, I was following homocysteine, and trying to do something to improve my outlook (cardiologist very concerned abut heart; prostate cancer recurred, deep depression, and lots of other good stuff!)

I've just gone back to my old records; I was on Folgard, niacin and maybe folic acid itself at different times.  Don't recall taking any Vit B, except as multi-vitamin.

But, at some point my docs and I agreed that they were doing nuthin, and I went back to "conventional" treatment, statin, hi bp meds, ARB, and IAD3.   That was ~13 yrs ago, I left that cardiologist after he urged me to "refrain from any exercise" (I still play racquetball 2x/wk with younger guys at 80), and my psa continues (knock wood) to respond to ADT3, albeit more slowly.

Maybe McCully was/is missing the point?




I recently posted the results of an important clinical trial where a drug lowered LDL cholesterol without reducing CVD deaths.  How long has the simplistic theory been around that LDL is somehow, by itself, responsible for CVD deaths?

The statins seemed to prove the theory - those on statins have reduced mortality risk.  Never mind that in non-statin users, a disturbing number of CVD deaths occur in those with low LDL!

In fact, statins reduce inflammation & studies should have controled for reductions in markers of inflammation.  Those markers are strong predictors of mortality/survival.

The homocysteine monotheory of CVD hasn't exactly fallen yet.  LEF wrote about it in their mag. last May [1]:

"When studies were conducted on high-risk patients using standard B vitamins to modestly lower homocysteine and anticipated benefits did not occur, doctors declared that homocysteine was not a risk factor for vascular disease."

"The problem with these studies is that they were seriously flawed."

I have problems with the LEF article.  e.g.:

"Homocysteine forms in the body from the amino acid methionine. Foods such as cereals, legumes, seafood, meat, and dairy products are rich in methionine so it is difficult for most people to consistently consume a methionine-deficient diet."

Methionine is an essential amino acid.  The body cannot synthesize it.  It would be foolish for anyone to aim for "a methionine-deficient diet."  In addition, methionine does not automatically form homocysteine.  Methionine is a building block for protein.  Methionine that has been converted to SAM will ultimately create homocysteine, but SAN creation is controlled based on the body's need for methyl.

The author fails to understand the role of homocysteine in the SAM cycle.  Homocysteine is produced when the methyl part of SAM is dropped off to a cell.  Elimination of homocysteine creation implies elimination of SAM.  This would result in hypomethylation & DNA instability.

"Fortunately, your body has detoxification enzymes that keep homocysteine levels in safe ranges. These homocysteine detoxification enzymes are dependent on the B vitamins, primarily folate, B12, and B6."

I admire the author's mastery of spin.  My term was "recycle", Faloon says "detoxification".

Detox implies removal from the body, whereas recycling involves conversion back to methionine, so that more SAM can be produced, as needed.  In essence, the need for SAM drives the SAM cycle.

Why does the body recycle homocysteine?  In spite of foods "rich in methionine" mentioned above, it is difficult to meet daily requirements from diet.  My daily requirement, based on weight, could be met by 6 lbs beef, I suppose (if I have done the math correctly).

Because of the SAM cycle, methionine 'used up' in the generation of SAM, is replenished when folate offers up its methyl.  The existence of the cycle implies an evolutionary need for one.

Faloon points to an intervention study that did find benefit - but only in people older than 67.  Which means that the younger group at risk for CVD events were not helped.

"A more striking risk reduction occurred in a clinical trial of elderly individuals published in 2014 who received a statin drug (pravastatin) to lower their cholesterol levels versus placebo. Patients in the placebo group with high homocysteine showed a 1.8-fold higher overall risk of developing fatal and nonfatal coronary heart disease"

From that study [2]:

"The absolute risk reduction in fatal and nonfatal CHD with pravastatin treatment was 1.6% ... in the low homocysteine group and 6.7% ... in the high homocysteine group ..."

Pravastatin has no effect on the SAM cycle, but does reduce inflammation.

In a 2010 study [3]:

"An elevated level of homocysteine (Hcy) has been shown to be a cardiovascular risk factor in the majority of research studies. Recently, it was found to be associated with new risk factors such as inflammatory markers."

"Elevated levels of tHcy, IL-6, TNFα and HsCRP appear to be associated with a greater number of diseased arteries and, consequently, the severity of coronary artery disease."

Ultimately, treatment of chronic diseases & those at risk for them, will involve [IMO] control of inflammation.






Patrick, thanks for your many great contributions to this board. My son has been pestering me to start with B12 shots to boost my energy levels. Reading this thread I think I'll give it a pass.


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