NICM and Integria Healthcare: Researchers spotlight phytonutrients’ effect on breast cancer
02 Feb 2024 | NICM and Integria Healthcare
We met with two natural therapists, Dr. Diana van Die from NICM Health Research Institute at Western Sydney University in Australia, and professor Kerry Bone, at Integria Healthcare, to discuss their review of phytonutrients’ effects following breast cancer. The researchers dive into the study’s findings on the impact of soy isoflavones, enterolactone, lignans, green tea and cruciferous vegetables on breast cancer recurrence and mortality, and what the research says on effective doses of these phytonutrients.
My name is Yolanda van Gal, and I'm a senior journalist at Nutrition Insights, and today I am joined by two natural therapists.
We have Doctor Diana from D from NICO at Western Sydney University in Australia, and we're joined by Professor Carrie Bone, who is consulting for Integraa Healthcare.
Diana and Carrie both, worked on a review among a group of, researchers examining the effects of different phytonutrients, on breast cancer, and they reviewed several observational studies.
So let me first ask you both what prompted this research?
It was really driven by the need for authoritative evidence to help inform breast cancer patients and clinicians, who are, or to find ways to reduce the risk of breast cancer recurrence and mortality, and, , obviously to avoid increased risks.
You've looked at different exposures, different nutrients, what exposures did you choose and why these in particular, and could you enlighten us a bit on the study design that you chose?
Basically, we chose those exposures that, Could be provided in supplemental form.
And also for which there was a sufficient body of evidence for a systematic review and meta meta-analysis.
And so we narrowed in on four key phytonutrient groups, the, the isoflavones in soy, the lignans in flaxseed or linseed, the, Glucosinolates in the cruciferous vegetables, and finally, green tea and the catechins in, in green tea because they're all, things that are actually used by natural therapists as supplements and indeed, we're, we are looking for reliable.
Viable evidence in the context of breast cancer survival.
Kerry and one of our oncologists, collaborators from Johns Hopkins, Channing Paella, and I spent quite a bit of time searching the literature before we, we settled on the design, and it was really when , Professor Carla Bisfani, the, the breast oncologist from Johns Hopkins joined the team.
That we decided on the systematic review and meta-analysis of observational studies, of, of obviously of these exposures, on breast cancer recurrence, breast cancer mortality and all cause mortality.
And the reason we looked at those two separately is because women with breast cancer don't necessarily die from breast cancer.
We included studies that measured both, you know, pre-diagnostic intake, As as studies that looked at post diagnostic intake, and the women in the studies were either post-treatment or currently undergoing treatment for breast cancer.
Now, and I understand that you were not the first to conduct a meta-analysis of these specific exposures.
What would you say was different about this study?
Yeah, there had been quite a few systematic reviews and meta-analysis of these exposures already, some of which had produced conflicting findings.
So we really scrutinize those at the beginning and we discovered, the, the differences were partly due to the studies that they included, but also there was sort of differences in classification and interpretation of, study outcomes, particularly the term, disease-free survival was interpreted differently, and also, exposure assessment time frame, so, Sometimes it wasn't that obvious from the study whether it was measured pre-diagnostically or post-diagnostically, so, we addressed those issues.
We also provide an update of the research.
But in addition to that, when Cecilia Cura from the, the Danish Cancer Institute joined the team, she, provided extra data for a, a lignant study that they had conducted and an interolactactin study, and that meant that we had longer follow-up data than had been published in the, any of the previous meta-analysis.
Yes, and, and as as that, we were also interested in what actual amounts and indeed corresponding doses of supplements that were proven to be the, the most effective in these studies.
Previous meta-analyses, and it's typical for most meta-analysis, they look at high versus low intakes, but this might miss important information, for example, if there's a U-shaped curve or you might even find a lower dose, might be optimal.
And another critical factor was to understand the timing of introducing these phytonutrient exposures.
You know, was it early intake or lifelong established dietary intake prior to diagnosis that had the impact, or was there any strong evidence, and again reflecting on a supplemental position if these phytonutrients were introduced after diagnosis.
And another feature of our study was grading of the certainty of the evidence and not just the statistical significance.
So we used the grade scale that had been adapt adapted by the World Cancer Research Fund in conjunction with the American Institute of Cancer.
So confidence then is the result, is, it's, it's a product of statistical significance and the grade.
So we can be most confident of a result if the grade is probable or convincing, and there's a significant reduction in risk.
Very interesting, and then let's dive into those findings.
What did you find?
There were two main findings that we can be most certain of, which we graded as probable, and, and that means there's strong research indicating that they contributed to the results we're seeing, but not strong enough to say there was a convincing causal link.
And that was for the soy isofla bones, there was a 26% reduced risk of breast cancer recurrence overall, and that was particularly in the postmenopausal women, where it was a 28% reduction.
And the other, the other main finding was that enterolactone, which is measured in serum or plasma, was associated with reduced risk of breast cancer specific mortality and all-cause mortality, both by around 30%.
Again, when we stratified by menopausal status, the results were only significant in post-menopause, where we saw around 35% reductions in both kinds of mortality.
The enterolactone situation is quite complex.
It's a phytoestrogen that is metabolized from lignan precursors that occur in the diet or in supplements.
SDG is the main one, and that's quite high in flaxseed, but also, other, other foods contain it and, Certain other lignans also get metabolized to enterolactone, and they're found in seeds, particularly sesame seeds, nuts, legumes, whole grain, and even fruit and vegetables.
Now the greatest risk reduction we saw was for the highest serum plasma enterolactone levels at 80 nanograms per liter.
How that relates to an equivalent amount in a supplement or or as a dietary intake is quite complex because of the role of the gut microbiome in producing the enterolactone from the lignan precursors, and that's highly variable between different people and would depend on their diets, among other things.
Interestingly, the results for the lignans themselves were not significant, although they were in the same direction as the enterolactone findings.
There was also one paradoxical result that baffled us, and that was that in premenopausal women, there is a significant increased risk of breast cancer-specific and all-cause mortality from dietary lignant intake.
And this doesn't fit with our understanding of phytoestrogens, for example, if, if it was due to an estrogenic effect, you would expect that to occur post-menopausally when estrogen receptors, many of them are vacant, not pre-menopausally, because, enterolactone, for example, would have almost an anti-estrogenic effect due to competitive inhibition at estrogen receptors, so.
It lacks a kind of biological plausibility.
Yeah.
And this could be due to chance or confounders that weren't controlled for, and the largest study of the three that was in this meta-analysis didn't control for cancer treatment.
And as the authors themselves and Cecilia Cura was, was the lead author commented in that publication, it's problematic because treatment as would be expected to have a much larger effect on survival than diet and lifestyle would.
Other possible confounders of the gut microbiome, the long time between measurement and diagnosis of breast cancer in the pre-diagnostic studies, and changes in diet, during that time.
Yes, so these premenopausal lignan findings, we graded them as suggestive, which means that there's, it's not yet strong enough to justify any recommendations, but nonetheless, we believe this does require , further investigation and as we've already said, the, the, the sources of appreciable quantity of lignins, is the flaxseed or linseeds, sesame seeds, broccoli, Brussels sprouts, and cashews.
So, you know, we, we fall short of recommending that, that premed.
Menopausal women with a breast cancer diagnosis, avoid these, these foods.
And the highest mean lignan intake, included in the studies was more than 9 mg a day.
So that's around, for example, a third of a tablespoon of flaxseed or linseed per day.
So, while it is premature to make any recommendations regarding lignans premenopausally, in postmenopausal women with breast cancer, including lignans in the diet may be beneficial, but because we need a healthy gut flora to generate those enterolactones, that would be a requirement for any benefit.
So, green tea, was associated with a 44% reduced risk of recurrence in women with stages one and two breast cancer, so in the earliest stages.
However, these results we also graded as suggestive, and that was because of the small number of studies in the meta-analysis and again the lack of plausible biological mechanisms.
That analysis just included two studies from Japan.
And in Japan that's green tea is part of the traditional diet, of course, and they measured their intake before diagnosis.
So while the existing evidence means we can't make any recommendation for introducing green tea post breast cancer diagnosis, it, it, they, they at least suggest that it's, it's safe to consume after such a diagnosis.
Yeah.
And then for cruciferous vegetables, that result surprised us a bit, to, to be honest, the, the results were inconclusive.
However, only dietary levels were examined and the average intake was quite low.
In all but one Asian study, the median was 25 g or less per day, which is about 1/6 of a cup of, you know, cabbage or broccoli, whatever.
And the Asian study, had a medium of 93 g per day which converts to about, Less than 2/3 of a cup.
Yes, so, so in effect from supplemental doses of the glucosinolates or their metabolites like, like DIM, for example, , are typically an order of magnitude higher than, than the amount that was achieved in, in these dietary studies, so.
So we can't rule out a benefit from such supplementation and it certainly is currently popular among some natural therapists to supplement with these glucosinolate metabolites like indulsary carbonny or or or or DIMM.
So then, when we look at what you found in the review, what what does it say about the most effective doses, and how do these compare with like supplemental doses?
With soy isoflavones, it compares very.
The greatest risk reduction was at 60 mg a day of isoflavones, that's typically 2 to 3 servings from a dietary source.
And there wasn't much of an increased benefit from higher doses.
And we've already mentioned the issues with enterolactones.
But obviously 9 9 mg a day, or more of lignans was, was in the study.
The, the green tea, Studies that were typically being from Japan.
In one it was 3 to 5 cups a day, and in the other 5 cups a day.
And only one study looked at the EGCG levels, and that was 30 to 40 mg a cup.
So, but there are supplements that can achieve those, those sort of doses, as most of them contain the equivalent of 1 to 2 cups per, per dose.
And what would you say, does the review say about future research directions?
What should that look like?
As clinicians advising patients who present after diagnosis of breast cancer, the main question that we're interested in, is whether the effects of introducing these foods at that stage are the same as for early intake, and the data didn't answer that question.
It was a, it's a bit confusing, the studies that measure post-diagnostic intake are not just looking at, People who started them after diagnosis, it means that they actually, Applied the, the, the food frequency or the dietary questionnaire after diagnosis, but that will capture people who've been eating it all their lives, as as the ones who, who started it post diagnosis, so, That's why we, we just don't have the data about people.
You know, who only began it after diagnosis.
Yeah, so, so, so we definitely, as Diana was saying, we definitely need more -designed studies in all, all of these endpoints that consider these issues of dose, timing, and, and also the co-founder of cancer treatment.
All of the women in this, these studies were undergoing conventional treatment, so, and that can vary.
Also, as, as flagged, the lignans in pre-menopause finding also warrants further investigation to see if, if it does have any validity and obviously for the cruciferous vegetables, given the, what appears to be the low general low dietary intake in, in these studies, , it would be worthwhile to perhaps look at , A study where it was supplemented in, in some way.
And finally, there is also the issue of fermented soy versus non-fermented soy, and that hasn't been picked out and understood to a high level as yet.
OK, so plenty still to work on in the, in the research community.
Is there anything else that you either of you would like to say about this topic?
Yes, I think it's important to stress that these studies are in women who have had treatment for the cancer, and that these foods and phytonutrients are not being recommended as alternatives to treatment.
But summing up, our analysis does suggest that this is a profitable area for future research because certain phytonutrients may indeed have a positive impact on disease progression in breast cancer survivors and, and supplemental use of these phytonutrients could play a significant role here.
Very interesting to hear.
Thank you both so much for joining me today and for your valuable insights into this review.
