The following is a transcription of Carole Baggerly's interview with Dr. David Feldman on Vitamin D and Breast Cancer as presented at the 2013 Linus Pauling Conference on Diet and Optimum Health. The webinar aired on May 21, 2013. To view the video, click here. The two windows can be minimized and placed side by side for concurrent viewing.
Vitamin D & Breast Cancer with Dr. David Feldman
Carole Baggerly: Welcome to GrassrootsHealth’s webinar series “Scientists Answer Your Questions.” This week we are interviewing Dr. David Feldman from Stanford University! He is going to be speaking to us about questions I asked during the recent Linus Pauling Institute seminar. Dr Feldman will be speaking on breast cancer and vitamin D.
If you have any additional questions after you have listened to the video that you would like to ask Dr. Feldman please submit them on the survey form and we will get the answers and post the replies up with the video. Here is Dr. Feldman:
CB: We are here today with Dr. David Feldman who just gave a brilliant talk on Vitamin D and breast cancer and I am very happy speak with him. And one of the key things that I would like to ask Dr. Feldman is, what were some of the key items in your presentation today where you see an effect of vitamin D on cancer?
Dr. Feldman: So to be brief, our studies are in mice, that I spoke about, not in people. So we can do very good things for mice who have tumors, whether it is a mouse tumor or even a human tumor, but how much of this will apply to women who have breast cancer remains to be proven. But the data, I think, is highly suggestive of a benefit and they certainly encourage me to try and go forward and study them.
Now what we studied was mostly estrogen receptor positive breast cancers. Vitamin D has many actions that are good for cancer, inhibiting all cancers in terms of inhibiting proliferation and potentiating differentiation, inhibiting invasion and metastasis. We think those would be good for any cancer but we described a few new actions that are particularly good for estrogen receptor positive breast cancer. To summarize, we think that the action of vitamin D is inhibitory of the estrogen receptor, down-regulating it, that it inhibits the synthesis of estrogens in the breast by down-regulating the aromatase, the enzyme that is critical for post-menopausal women to synthesize estrogens in their breast by down-regulating the prostaglandins' synthesis and signaling pathways. This is very important. Prostaglandins are very bad guys in the breast. They stimulate growth and proliferation and invasion but they are also the main stimulator of aromatase.
So why am I focusing on aromatase? Let me just be sure I make this point. Breast cancer is very common in post-menopausal women. Estrogen is a driver and yet it happens in a post-menopausal woman whose ovaries are dormant. So how is that conundrum answered? And the answer is that the breast – especially the adipose tissue and but also the breast cancer cells - have the enzyme aromatase and they can then convert adrenal precursors that are circulating in the blood into local estrogens that are formed in the breast and these are then the driver of proliferation of estrogen receptor positive breast cancer. So inhibiting that local estrogen synthesis is one of the critical ways that oncologists are treating estrogen receptor positive breast cancers. They are using aromotase inhibitors or Tamoxifen, two drugs which will interfere with the estrogenic stimulus of growth and we think that vitamin D can do both of those things – all of those things! So we're very keen on the idea that vitamin D can be a beneficial adjunct, an add-on, to the treatment of estrogen receptor positive breast cancer.
Now in our mouse models we have a couple of otherinteresting findings. One was that dietary estrogen, I'm sorry, dietary vitamin D (lets get off the estrogen for a minute). Dietary vitamin D was as good as doses of calcitriol that were barely or slightly hypercalcemic. In other words, dietary vitamin D was as good as calcitriol in inhibiting the growth of the tumors.
CB: I think for the population listening, could you please explain what you mean by calcitriol and how it's administered?
Dr. Feldman: Sure, so calcitriol is the di-hydroxylated vitamin D – the active molecule. So when you take vitamin D that you buy in the drug store or, nowadays the supermarket, that vitamin D has to be hydroxylated first, usually in the liver, to the 25-hydroxy D. That's what the doctors measure your vitamin D levels with. Then a second hydroxylation step makes the 1,25-dihydroxal vitamin D which is the same as calcitriol. Calcitriol is another name for the 1,25-dihydroxy vitamin D. So that's the active principle and so what's interesting to us is that a cheap, very available molecule was as good as this potentially toxic and expensive prescription drug. So Vitamin D – dietary, was as good as calcitriol, the active hormone, in inhibiting the tumor in the mice. Whether it was a human tumor in the mice or a mouse tumor, both responded similarly because the dietary vitamin D was just as good.
CB: One of the things you showed on one of your slides was the transformation of the rate of growth of the tumor. Can you speak to that a little bit?
Dr. Feldman: OK, so 2 different aspects. One was the tumor growing in the control mice and comparing that to the vitamin D treated or the calcitriol treated mice. We could see a slowing of the growth, even a shrinkage, within one week of being on the diet and by 4 weeks the tumors were about half the size of the control diet. So that was quite dramatic and surprised us that it was that fast and that potent.
Now I'm not sure if you're asking about the other aspect where we looked at after the injection of the tumors into the mice – these are xenographts so we put a certain number of cells into the breast fat pad and we watched to see when the tumor appears, when we can detect it by examining the mice, and it looked as though the vitamin D deficiency in that diet accelerated the appearance of the tumor and the vitamin D supplemented diet delayed the appearance of the tumor.
CB: I think that's absolutely fantastic! I'm sure that you're aware of two recent studies that were published by Bruce Hollis and crew where they had a group of men who were taking 4,000 IU a day in kind of a watchful waiting mode with prostate cancer and another one where Reinhold Veith did some much heavier dosing for some of the men anyway, where they had 50,000 IU a day prior to a prostatectomy and both Dr. Hollis’ group showed a decrease in the positive cores of the biopsies and the results from Dr. Veiths’ also showed positive prior to the prostatectomy. So it's possible that it certainly could be an adjunct to treatment.
Dr. Feldman: Well I know that the study that you're referring to from Dr. Hollis. So it’s a group in the South Carolina Medical Center – The Medical University of South Carolina. I know that – in fact I just gave a lecture there. So the data are somewhat premature to get as excited as you are sounding. It is a nice publication. And they are funded now by the VA to go into renal trial. So what they showed was that in the random biopsies it seemed that there was a little less cancer in the treated compared to the control but there was a great overlap. So they just didn't have enough patients for the data to be compelling. One can hope that this would be an excellent thing to do because the “watchful waiting” or active surveillance category, these are the people who have prostate cancer that looks like it might be the non-invasive kind and instead of operating on them, to avoid over-treating these people are just watched by following their PSA and then repeating their biopsy. And if the cancer looks like it’s becoming invasive then they go ahead and they operate. Now most of the time these people are just watched and nothing is done for them so adding something like vitamin D which has the potential to be helpful with very minimal risk and almost no cost is a tremendous idea. In fact I tried to do that study and we couldn't get it funded so I'm very glad that they're doing it and I think they need more numbers and most of their biopsies don't have cancer in it so the amount of cancer that's been reduced is really overlapping and it's a kind of a random thing. Most of these people have small tumors and most of the biopsies don't have tumor in them. In fact we are hoping to collaborate with them and look at the ability of vitamin D to regulate the genes in those biopsies.
CB: That's fantastic! I think the world has changed so much with vitamin D and cancer since my experience with it many years ago. That's great. I'm glad...
Dr. Feldman: Well, we certainly think that is the ideal population. These are people who actually have the cancer already and they're just being watched – nothing is being done for them!
CB: I have another observation. I had not realized until you commented today and reiterated just now, that breast cancer cells have aromatase which then enable the growth of local estrogens. Did I state that fairly enough?
Dr. Feldman: Synthesis of the local estrogens.
CB: Synthesis of the local estrogens. And one of the things we keep talking about with vitamin D is that the hormone form of vitamin D actually gets created in all of these other tissues not just in the kidney or the liver. So could you speak to that a little bit? Just about all of the tissues and what they do and why this concept of kind of “all over the body” is so important.
Dr. Feldman: Well, there's so many questions there!
CB: Yes, I know!
Dr. Feldman: Let me just be sure we're making the point that the kidney with its 1-hydroxylase produces the calcitriol that circulates. It does that from 25-hydroxy D which is the circulating form of the hormone. Now what has been found that many tissues have the same (bells) – I guess it’s time for lunch, many tissues have that 1-hydroxylase enzyme including breast cancer, prostate cancer, colon cancer to name just a few. So that the tumor may make its own locally synthesized active hormone from the circulating 25-hydroxy D. So that means that there's in a sense two systems. There's an endocrine system where the D is made, the 1,25-D is made by the kidney and then the local system where it’s made and acts in an autocrine or paracrine way within the target tissues. And it’s very analogous to what we just described about aromatase and making estrogens locally. So I think it’s very close when the ovaries stop making estrogens in an endocrine fashion the breast is still able to make it in a paracrine/autocrine fashion and that's the driver of post-menopausal women’s estrogen receptor positive breast cancer. And since that's about 70-80% of all the cancers are estrogen receptor positive and the great, great majority develop in post-menopausal women, that phenomenon of local synthesis is tremendously important.
CB: Could you also speak to ER negative? You made some comments about that too.
Dr. Feldman: Well I didn't really study ER Negative and sometimes we're criticized that we're focusing on ER Positive when there are already good treatments and there are not such good ones for ER Negative. But we didn't start this with the idea that we would focus on ER Negati- ER Positive. What we found made most sense to be looking at ER Positive because of these actions to inhibit aromatase and prostaglandins which are most critical for ER Positive. Now we have hopes to move and study ER Negative and I want to emphasis that the general actions of calcitriol or vitamin D to inhibit proliferation and to inhibit inflammation and so on would be good for ER Negative tumors as well but the special actions, these newer actions that I've described, they're selectively beneficial in ER Positive cancers.
CB: Thank you very much. What would you see at this point of the scientific community - what should they be focusing on right now?
Dr. Feldman: Well, as the IOM has said, they want to see randomized control trials in human subjects. Women with breast cancer or women who are at risk of getting breast cancer. We are actually trying to do a trial in Palo Alto. We were not going ... could not get the funding to do a real trial with outcomes. We were just going to do a short trial just look to see whether we could change the gene pattern from one that looked like it was aggressive to one that looked like it was more slower-growing and having a better prognosis. But our trial has a lot of problems in recruiting subjects because, at least in Palo Alto, most of the women are already taking pretty substantial doses of vitamin D so we cannot enter them and randomize them since they are already on the drug and this is before they knew they had breast cancer and once they know that there's no way that they are going to stop it and we wouldn't ask them to stop it. So we're having some shortage of recruitment.
CB: What about, and on the one hand I have to say I am so happy to hear that because as it means that the work that Grassroots Health does is being somewhat effective in getting the word out. On the other hand, why not create the trial with much higher doses of vitamin D where you're giving maybe 50,000 IU a day instead of the very low doses?
Dr. Feldman: We wanted to do high doses and this trial...
CB: What's a high dose?
Dr. Feldman: Our dose was 10,000 a day.
CB: But that's even considered a “no adverse effect” level.
Dr. Feldman: By some. We're only treating for approximately 3-5 weeks. This is in the neo-agoven period between the biopsy and the surgery so we compare the biopsy sample which is supposed to be pre-treatment - it’s not the case if they're already taking it, but we're compare non-treated biopsy then to what happens after treatment comparing placebo which is now the IOM registered dose against our high dose of 10,000 IU. So we feel safe about giving 10,000 because it’s a short interval. But if we're talking about the population at large, I think we're not there yet to be able to say that 10,000 is not going to be without toxicity. Most of the studies that say that don't really examine these women and look for toxicity so I think people have to be careful about the hype and not accept everything until we really have data and we prove there's a benefit and that the risk is worth taking it.
Now once somebody has breast cancer, the risk of some hypercalcemia is a pretty trivial risk compared to chemotherapy risks of hemorrhage and infection and death so that the oncologists are not that worried about a little hypercalcemia.
CB: That's fantastic. Dr. Feldman, is there anything else you would like to add to this interview? I very much appreciate your time.
Dr. Feldman: Well, it’s a pleasure to talk to you! We are excited about the vitamin D data but again I want to caution the public that there is a lot of hype and one has to be careful about what’s proven and what’s not. I showed a slide about trying to distinguish between an association and causality and so I'll just describe that slide. It's a picture with a little boy next to his mom on an airplane and the little boy says to his mom “I hope they don't put up the sign that says Fasten Your Seat Belts because then the plane gets very bumpy and jumpy!” So that's the problem with association. You really don't know what the cause is and so some of the studies that have made us excited to move forward and do more causality type research, they're very interesting that they got us into this project but we can't, I don't think, make reasonable advice to the public based on those kinds of studies. We need to get the studies done that really prove an intervention gives benefit to women, in this case with breast cancer. So I'm hoping that our trial and other trials will eventually get to that stage.
CB: Thank you. We have for our listening public, maybe even for Dr. Feldman, we have a breast cancer prevention study going as a population study – it is not a randomized trial, where women are participating in the project and they are achieving or getting their serum level to the 40-60 ng/ml range and we're tracking them for a period of 5 years to see what the outcomes are. And we certainly do get various medical reports from them so we always thank our participants for helping provide a lot of this data to further substantiate or see what’s going on with the whole vitamin D effort. But thank you, that was terrific!
Dr. Feldman: Thank you!
CB: You bet! Thanks for coming today to listen to Dr. David Feldman talk about breast cancer and vitamin D. Next week we will be having another introduction to cardiovascular disease and vitamin D by Dr. Stefan Pilz of Austria. He also was an attendee at the vitamin D, excuse me, at the Linus Pauling Institutes' seminar and I interviewed him and asked him questions. Don't forget to sign up then and we're looking forward to see you then.