can a Mediterranean diet synergize with/replace herceptin in her2+ bc treatment?

[Lani]

Being looked at in Spain!

1: Clin Transl Oncol. 2006 Nov;8(11):812-20.
HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated. Fatty acid alpha-linolenic acid (ALA; 18:3n-3) in breast cancer cells: the <<fat features>> of the <<Mediterranean diet>> as an <<anti-HER2 cocktail>>.

Menendez JA,
Catalonia. Spain.
Background. Data derived from epidemiological and experimental studies suggest that alphalinolenic acid (ALA; 18:3n-3), the main omega-3 polyunsaturated fatty acid (PUFA) present in the Western diet, may have protective effects in breast cancer risk and metastatic progression. A recent pilot clinical trial assessing the effects of ALA-rich dietary flaxseed on tumor biological markers in postmenopausal patients with primary breast cancer demonstrated significant reductions in tumor growth and in HER2 (erbB-2) oncogene expression. Hypothesis. The molecular mechanism by which ALA inhibits breast cancer cell growth and metastasis formation may involve a direct regulation of HER2, a well-characterized oncogene playing a key role in the etiology, progression and response to some chemo- and endocrine therapies in approximately 20% of breast carcinomas. Methods. Using HER2-specific ELISA, flow cytometry, immunofluorescence microscopy, Western blotting, RT-PCR and HER2 promoter-reporter analyses, we characterized the effects of exogenous supplementation with ALA on the expression of HER2 oncogene, a master key player in the onset and metastasis formation of breast cancer disease. Metabolic status (MTT) assays were performed to evaluate the nature of the cytotoxic interaction between ALA and the humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin(R)). To study these issues we used BT-474 and SKBr-3 breast cancer cells, which naturally exhibit amplification of the HER2 oncogene. Results. ALA treatment dramatically suppressed the expression of HER2-coded p185(Her-2/neu) oncoprotein as determined by ELISA, flow cytometry, immunofluorescence microscopy and immunoblotting techniques. Interestingly, ALA-induced down-regulation of p185(Her-2/neu) correlated with a transcriptional response as no HER2 mRNA signal could be detected by RT-PCR upon treatment with optimal concentrations of ALA (up to 20 muM). Consistent with these findings, ALA exposure was found to dramatically repress the activity of a Luciferase reporter gene driven by the HER2 promoter.

[Lani]

Moreover, the nature of the cytotoxic interaction between ALA and trastuzumab (Herceptin(R)) revealed a significant synergism as assessed by MTT-based cell viability assays. Conclusions. i) These findings reveal that the omega-3 PUFA ALA suppresses overexpression of HER2 oncogene at the transcriptional level, which, in turn, interacts synergistically with anti-HER2 trastuzumab- based immunotherapy. ii) Our results molecularly support a recent randomized double-blind placebo-controlled clinical trial suggesting that ALA may be a potential dietary alternative or adjunct to currently used drugs in the management of HER2-positive breast carcinomas. iii) Considering our previous findings demonstrating the <<HER2 upregulatory actions>> of the omega-6 PUFA linolenic acid (LA; 18:2n-6) and the <<HER2 down-regulatory actions >> of the omega-3 PUFA docosahexaenoic acid (DHA; 22:6n-3) and of the omega-9 monounsaturated fatty acid oleic acid (OA; 18:1n-9), it is reasonable to suggest that a low omega-6/omega-3 PUFA ratio and elevated MUFA levels, the two prominent <<fat features>> of the <<Mediterranean diet>>, should be extremely efficient at blocking HER2 expression in breast cancer cells.

[RhondaH]

"Our results molecularly support a recent randomized double-blind placebo-controlled clinical trial suggesting that ALA may be a potential dietary alternative or adjunct to currently used drugs in the management of HER2-positive breast carcinomas".

I can't WAIT for the WHEL study findings that come out in 2008 and considering the new guideline I posted yesterday from the American Cancer Society regarding diet, exercise etc., I think this is being looked at MORE closely for not only prevention of original dx, but prevention of recurrence (THEY even said diet and exercise could help prevent recurrence). Take care and God bless.

Rhonda

[Tom]

Lani, This news is HUGE ! Can you imagine if HER2 overexpression could be controlled with diet and supplements alone? I really can't get over this. Maybe this explains Mom's positive disease course? I don't know. But I sure hope that's the answer, as it will impact all of us/you.

Thanks,
Tom

[R.B.]

Thank you for this Lani.

It is interesting. I have only briefly skimmed. When I have more time I will look up the trial.

I think it is important to maintain moderate view points, but for a proportion diet must be a factor in risk reduction if nothing else.

Almost since Herceptin appeared I have wondered why they have no trialed omega threes more seriously and in conjunction with herceptin etc.

I have been away from constant following of the subject but herceptin does at least at one level work through the fat pathways as does Tamoxifen, and I suspect others.

Omega three and six are intimately linked with the key hormones.

Omega three and six have been shown in trials to radically alter gene expression. In skeltal muscle HER 2 and BRAC expression were significantly altered in high omega six v a balance of omega three and six.

The number of copies of genes we have has recently been posulated to have a much bigger impact than previously thought....

The Greek Diet post contains lots of related trials.

My constant wish is that they would spend the money on omega three and six trials to get the answers, what ever they are.

As many constantly mutter something that we have changed in the last 60 years that we eat or in our environment must be a key contributor. For me falling omega three and rising omega six is a very good candidate.

RB

[heblaj01]

Very interesting post.
I could not get to the full text or at least to the References section.
The abstract mentions two clinical trials:

1).A recent pilot clinical trial assessing the effects of ALA-rich dietary flaxseed on tumor biological markers in postmenopausal patients with primary breast cancer demonstrated significant reductions in tumor growth and in HER2 (erbB-2) oncogene expression.

2).Our results molecularly support a recent randomized double-blind placebo-controlled clinical trial suggesting that ALA may be a potential dietary alternative or adjunct to currently used drugs in the management of HER2-positive breast carcinomas

I assume the first reference is to the 2005 study of the daily intake of a muffin with 25g of ground flaxseeds for a short period before primary tumor surgery.

Can someone recall the details of the second one?

[jhandley]

Hi
ALA is the omega 3 PUFA found as 60% of flaxseed oil. The flaxseed meal that was used in the muffins had as its effective ingredients lignans..not the ALA..most of which is removed when the meal is made. Remember that the oil can not be heated as it loses its unsaturated properties which are important for its beneficial effects therefore it is not used for cooking. The lignan in the meal (muffins) is in its own right a powerful anticancer/anti her2+ agent.
I think they may be refering to the Javier Menedez(?) study that looked at the effect of DHA, EPD, ALA (flaxseed oil) and olive oil on her2+ cell lines.
Hope this helps.
Jackie

[heblaj01]

Jackie,

Because of the wording In the Menendez abstract (randomized double-blind placebo-controlled clinical trial suggesting that ALA ) I doubt he refers to an experiment on cells but more likely on humans.
In the full text of the results of his previous study comparing the effects of EPA,DHA,ALA he does not use this wording.
One missing piece of research data which may be important for patients is what effect on ER+ cancer cells has supplementation with anyone of the fatty acids targetting HER2+ cells. This can be a concern for two reasons: first, both types of cells may be present in a patient (as opposed to single type cells in lab experiments) & second, some supplements may comprise phytoestrogens whose effect may be either beneficial or detremental depending on circumstances such as disease status (precancerous, primary, metastatic).
An other missing piece of data, more for rigorous scientific purposes than for actual expectations of finding unexpected side effects, would be to submit healthy cells to high doses of the fatty acids.

This said, I still would like to have to have access to the exact referenced clinical trial in the Menendez abstract.
Anyone knows?