October 2010 Issue | Jeanne Wallace, PhD, CNC




Welcome to Functional Medicine Update for October 2010. This month we are going to deal with a topic that I know has been discussed at length over the last several years in Functional Medicine Update. This month we are going to take a slightly different spin (a different look, a different perspective, a different part of the matrix or the lens upon which we focus information to ultimately arrive at clinical decision-making). The focus this time will be taking the concept of metastatic disorders-proliferative cellular disorders-and sieving it through a different way of looking at the origin, the management, and the progression of cancer.

The Institute for Functional Medicine Symposium titled “Cancer as a Chronic Disease” held in May 2010 dealt with this new context of cancer as a chronic disease. Why would we say it is a chronic disease? As a consequence of a number of the major breakthroughs in therapeutic tools that are available for the treatment of cancer, many people who would have previously not survived from the initial diagnosis are now either in remission or in states of chronic management. What this means is the disease that had a reputation of being a lethal disease, one that leads always to a terminal event, now is a condition that in many cases may be managed more as a chronic disease.

What is the origin of cancer? Why would cancer undergo this transition from a disease with a certain reputation of pathophysiology leading to mortality to that which can be managed? What does that mean about the future as it relates to the management of this condition and maybe its prevention? Those kinds of questions were the focus of the 17th Annual Symposium of the Institute for Functional Medicine, and it’s those types of things that I would like to focus on more in this issue of Functional Medicine Update.

Our clinician of the month this month, Dr. Jeanne Wallace, was one of the most highly rated presenters at the 17thInternational Symposium. Dr. Wallace will be talking about her experience in consultation and patient management in the area of cancer, but I thought I might set the context for her discussion and raise some difference perspectives about how we’re thinking of this disorder.

Let’s first talk a little bit about the nature of what signals a cell-a fully differentiated human cell, a eukaryotic human cell somewhere in the body in a state of developmental biology that is static–to undergo this transformation into a dedifferentiated state that is cell proliferative in nature, invasive, and ultimately has a metastatic potential. The cell is also angiogenic (sending out new blood vessels to nourish the mass as it grows). What would be the process that would trigger that?

The Role of Carcinogens, Both Environmental and Endogenous
Historically, we’ve talked about the role that carcinogens or mutagens play in mutating or altering genomic messages causing nicks (or damage) and chromosomal instability that ultimately produces mistakes. These mistakes cause a regulation of expression factors of this dedifferentiated primordial state of the cell that we call a cancer cell. For much of the past 30 years, this concept of carcinogen-induced cancer has dominated the thinking in the field.

Of course, there are also in situ carcinogens, for instance, estrogens and estrogen byproducts. These may be in situ carcinogens as a consequence of their influence on DNA. We have twice interviewed, on Functional Medicine Update, Dr. Eleanor Rogan from the University of Nebraska. She received a Linus Pauling Award from the Institute for Functional Medicine for pioneering work she has done on the oxidative metabolism of estrogens into the hydroxy estrogens and finally into the quinones. These quinone-like estrogens, the 3,4-quinones, can react very rapidly with electrophilic regions of the genome (DNA) to produce these mutational adducts, which then interpolate in such a way as to cause potential misreading of the genomic message and start neoplasm.

Dr. Rogan has been at the forefront of understanding how an endogenous hormone, estrogen, undergoing specific types of metabolic transformations (in this case to 4-hydroxy estrogens), then can become oxidized into these 3,4-quinones and initiate a cancer. It begs the question: How do you prevent the formation of these endogenous carcinogens? That leads us into the discussion of things like detoxification. How does estrogen get detoxified and ultimately eliminated as a glucuronide or as a sulfate in a non-toxic form that can be excreted either in the feces or in the urine?

Dr. Rogan has pointed out that these particular metabolic transformations of estrogens are facilitated by a group of cytochrome P450s, one of which is cytochrome P4501B1, one of the isoforms in the more than a hundred different members of this family of cytochrome P450 enzymes. And that cytochrome P4501B1 not only resides in the liver in its activity, but also it resides in the breast and it can be activated in breast tissue to increase the production of these 3,4-quinones (estrogen quinones).1

What do you do to prevent the activity of cytochrome P4501B1? One thing is to increase the conversion of estrone and estradiol into agents that would not be allowed to become 3,4 estrogen quinones, and that’s by the 2-hydroxylation pathway, to form the 2-hydroxy estradiol and estrone. The hydroxylation by cytochrome P4501E2 and 1A2 produce these other estrogen metabolites, which then prevent the conversion by 1B1 into the carcinogenic 3,4 estrogen quinones. And we know that cruciferous vegetables that contain the class of phytochemicals called glucosinolates (things like indole-3-carbinol, and 3-hydroxy-2-butanone, and phenylisocyanate, and even including sulforaphane) activate gene expression in the liver and other tissues of the enzymes that are responsible for the formation of the 2-hydroxy estrogens. That’s the explanation for the epidemiology that shows association between women who consume more crucifers and a lower incidence of female hormone-related cancers.2,3

One even sees intervention trialsin which women were given placebos or given supplemental doses of these phytochemicals, particularly I3C or diindolylmethane (DIM), a polymeric conjugant of I3C, and have demonstrated an increase in the excretion of 2-hydroxy estrogens. In the case of I3C one clinical trial showed that approximately 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of women with biopsy diagnosed CIN II-III who were supplemented with either 200 mg/day or 400 mg/d I3C for 12 weeks had remission, as compared to placebo, in which none of the women showed remission. This suggests there is a reversion of the cellular architecture back to normal, at least in this study of women diagnosed with CIN II-III. This study also showed a favorable effect in the 2/16 estrogen ratio, further suggesting the impact these estrogen metabolites on DNA injury.4

We are starting to witness a possible connection between epidemiology and cellular mechanisms of action in how this all relates to environmental factors such as diet, aimed at understanding what may induce or prevent specific cancers. We also recognize that cytochrome P4501B1 is activated by certain types of the conjugated equine estrogen B ring unsaturated estrogens.5 For example, these types of compounds are found in pregnant mare’s urine, but the same compounds are not found in human women. These B ring unsaturated estrogens that are found in equine estrogen hormones can activate cytochrome P4501B1, and therefore may have a preferential metabolism into the 3,4 estrogen quinones, which we’ve said are more carcinogenic.

There are probably a variety of different routes of contribution to changing the balance of metabolism of estrogen. Dioxin is another one that is known to enhance the activity of cytochrome P4501B1 and may increase, then, the burden of these carcinogenic estrogens. As we learn more about the story, we learn more about both what things to avoid and what things to women should be exposed to improve the hormonal balance. This is very similar to what Dr. Sidney Baker has said so many times when asked, “What is the difference between a functional medicine approach towards the patient and a traditional diagnostic, pathophysioloical approach?” His answer is brilliant: “The functional medicine approach is to ask two questions. (1) What is the patient getting too much of? and (2) What is the patient not getting enough of?And to remove those substances that the patient is getting exposed to in excess, and to add back those things that the patient is not getting enough of. ”

This is personalized medicine based on a very simple conceptual framework that has patients being asked different kinds of questions about their histories. This is the concept of antecedents leading ultimately to triggers, producing mediation of various signaling substances that ultimately work on target tissues to produce signs and symptoms. This is a different model than the drive for the name of the pathophysiology and putting a diagnosis on a condition. It is more about asking how you got there rather than what it is that you finally got to.

Cancer may derive in part out of this endogenous and exogenous exposure to carcinogens (as I have just described with the estrogen story), but it goes beyond that. I think this next step is where the world gets both more interesting and probably more confusing. I owe Dr. Barry Boyd, a medical oncologist and integrative oncologist from Connecticut who is associated with the Yale University Medical School program, for starting me down this path of thinking in terms of oncology and oncogenic burden from this perspective.

A number of years ago, Dr. Boyd was asked to speak at the Institute for Functional Medicine Symposium. During his talk he alluded to the fact that insulin signaling plays a very important role in the potential oncogenic risk that a patient might have, and also to the progression of tumors.6

At that point in time I really hadn’t thought much about insulin as being a hormone that had anything to do, principally, with tumorigenesis or oncogenesis. Since that time, however, thanks to Dr. Boyd, I have come to recognize that this is a very, very active area of research, one that has enormous potential, clinical implications, and one that is, fortunately, something that you can intervene against. You can measure insulin signaling and you can manage insulin signaling, so it is not just an esoteric concept that we say, “Oh there’s a risk factor, but there is nothing we can do about it.” In this case, we would say, “Hey, there is a risk factor. Once we understand it, we can do something about it and we can intervene with the appropriate diet and lifestyle, and, if necessary, pharmacology program.”

Kinases Play a Complex Role in the Relationship between Insulin and Cancer
So what’s this all about? What this is about is the recognition that insulin is much more than just a glucose-modulating hormone. I think we have all started to recognize, in this field, the pleiotropic effects that insulin has–the multiple personalities that it has as it regulates a complex set of genes and their expression. It does so by binding to the insulin-binding site (the insulin receptor), and then triggering, through a very complex signaling mechanism, through insulin receptor substrate 1 and down through a variety of interrelated kinase signaling molecules, including Burton tyrosine kinase (BTK) and spleen tyrosine kinase (SYK), and ultimately down through phosphatidylinositol 3 kinase and through MTOR, down through glycogen synthase kinase 3.

This is, I know, sounding very esoteric and biochemical-ish, so let me just summarize what I’ve just by providing an analogy. There is this complex pachinko game, if you know the Japanese pinball game, where you hit a little ball up to the top and then you are able to create, from that, a multiple series of hits of these balls as they move down from the top to the bottom and ultimately you rack up a score. One ball can create multiple actions if you are lucky and you play the game right. That’s very similar to the way kinases work.

We learn in school about biochemistry as linear paths, and we call them metabolic pathways. But really these metabolic pathways are just like tendrils in a web of a network of physiology. We kind of freeze-frame one tendril, which looks linear. A substrate goes to product, and we memorize that, like glucose goes to glucose-6-phosphate, but yet that is embedded within this very complex web of interacting pathways that forms this network.

The network of signaling substances within a cell that translates the outside world to the inside function that ultimately regulates things like mitochondrial function, endoplasmic reticular stress, oxidative phosphorylation, and genomic expression is a series of more than 300 different enzymes that have names (kinases), and I have spoken about these at length in previous issues of Functional Medicine Update. These kinases are phosphorylating enzymes that modulate and modify the function of enzymes in the cell by sticking a phosphate group on something like a serine or a tyrosine residue on the protein chain to slightly modify its structure, which then modifies its function. So they are regulatory. It is like the fine-tuning knob of the body.

As we think about the fine-tuning knob analogy, these are things that can be modulated, by the local environment. The kinase regulation of gene expression is, in part, controlled by the local environment of the cell, which is controlled by the environment of the host. So times of ischemia, or times of dehydration, or times of hyperthermia, or times of toxic exposure, or times of malnutrition, it modifies the expression of this relay race that we call the kinases, That then influences differential expression of the genes.

Let me discussan example of this so it sounds a little bit more reasonable. We’ve all heard recently about the important role that the phytochemical, resveratrol, found in peanut skins and grape skins, has on modulating what are called the sirtuin (silent transduction) genes that are associated with longevity (Sirt1). Sirt1 is an NAD-dependent deacetylase family of enzymes that are modulated in their activity by resveratrol. What has been found recently is if you look at various kinds of compounds that are found in nature, it is not just resveratrol that modulates sirtuin1 in eukaryotic mammalian cells, but also other polyphenols and other phenolic phytochemicals are found to play roles in modulating sirtuin. So it is a symphonic modulation of sirtuin function.

If you start looking at the roles that these sirtuins have on cell function, what you’ll find is that the roles, through NAD-dependent deacetylase activity, are to alter gene expression of some of these kinases. And the kinases ultimately go on to alter the phosphorylation patterns of various proteins and enzymes in the cell, which then modifies its function to make it a cell that is more insulin sensitive; a cell that is more energy economical relative to mitochondrial oxidative phosphorylation; a cell that has lower proliferative potential; a cell that has more apoptotic potential if it has become a transformed cell; a cell that is less prone to inflammatory signaling. These multiple effects-I call them pleiotropic effects-that come out of modulating the sirtuin gene expression, are related to the role that certain environmental substances (in this case dietary polyphenols) have on kinase signaling.

How does such a long-winded explanation connect back to the insulin story? Because insulin is a very powerful modulator of principal intercellular signaling kinase processes that are associated with a whole array of cellular phenotypes/cellular outcomes, not just glucose transport alone. That’s certainly an important part of this (getting the energy molecule-glucose-into cells efficiently). Beyond that, there are many other roles that this alteration by insulin of these signaling pathways has on cellular phenotype. This include things like inflammatory status, cell proliferative status, apoptotic status, cellular architecture (the cytoskeletal structure), and even the effects on mitochondrial oxidative phosphorylation and bioenergetics. If you have a dysfunctional insulin signaling regulatory pathway and you overdrive some of these kinase mediators, what can happen is that you actually change the phenotype of the cell into a personality that can be more prone to transformation into a proliferative cell, (a cell that becomes more relatively angiogenic, a cell that ultimately may become metastatic). The hyperinsulin state associated with insulin resistance has now been found to overdrive specific kinase-modulated pathways that can, in part, increase the relative risk of a metastatic disorder.

There are a whole series of new kinase-inhibiting drugs that are used in cancer treatment. These are profitable blockbuster drugs that are very hard-hitting inhibitors of specific kinases associated with growth of cells and proliferative phenotypes. The challenge with some of these drugs, however, is that because they are so hard-hitting and they are so efficient in locking down specific kinases, you get collateral damage because there are other places where the activity of those kinases may be considered important for housekeeping function of cells. So you can potentially get off-target effects and some fairly severe adverse side effects from these kinase-inhibiting drugs.

Most Well-Known Cancer Diets Have Recommendations in Common
This is to be contrasted with the modulation of kinases more mildly or moderately through insulin signaling and ultimately through the dietary regulation of things like polyphenols or other phytochemicals. When we talk about a diet that may be good for cancer, it is very interesting that many of these diets (be it the Kushi diet program, or the Ornish diet program, or the minimally processed high fruit and vegetable-type diet program) all of these share the characteristics of having a low glycemic load (meaning low insulin stimulating) and having a high phytochemical concentration in terms of modulating, with these phytochemicals, specific kinase-signaling processes. There is undoubtedly something very important buried in this emerging science that is starting to come to light that correlates to the influence that a low glycemic load diet in combination with a phytochemically dense diet may have in regulating the intercellular signal communication process that leads to the outcome of either a quiescent cell or cell division causing proliferation.

Can Insulin Therapy Lead to Greater Risk to Cancer?
This subject ties back to our previous discussion of various endogenous hormones that are converted, like the estrogens, into potential mutagenic or carcinogenic substances. We wouldn’t necessarily call insulin a carcinogen, but we would call it a modifier of gene expression function that can correlate with proliferative disorders. Those of you who have been following the literature know that this story has taken a little bit of an interesting twist in 2010. In 2010, what was found and reported in a number of journals was that individuals who are insulin-requiring diabetics receiving specific forms of insulin therapy appear to have a higher statistical prevalence of cancer.7,8,9 Do certain forms of insulin or certain types of insulin administration actually increase the relative risk to cancer by an overdrive of these signaling pathways? There is quite a debate going on now within the field as to whether this relative risk is highly significant, moderately significant, or insignificant, but I do think that the data are quite clear that certain types of insulin administration in diabetes do appear to be statistically associated with increased incidence of cancers.

Some people seem to want to put labels on molecules and say, “It’s a bad molecule or a good molecule.” Many times I’ve heard the term “arachidonic acid” associated with being considered a bad molecule as a fatty acid metabolite. Yet if you didn’t have any arachidonic acid in your cells, you would have very dysfunctional immune system protection that would put you into an immune-compromised state. So you need adequate levels of arachidonic acid. It is not a good molecule or a bad molecule; it’s a molecule that has important roles to play when in proper balance.

We could have the same conversation about insulin, this polypeptide protein molecule (this peptide hormone). It is not a good or bad molecule; it is a functional molecule in the range of concentrations and activities that leads to healthy homeostatic function. If insulin is too low you get pathology, and if it is too high you get pathology. This is the classic example of Tolman’s Law of pharmacology for all substances: parabolic dose response curve. Everything, including air and water, has a dose too low that leads to death (dehydration for water or hypoxia and oxia for oxygen). But on the other side, there is a dose that can be considered toxic. For water, hyperhydration can be lethal, and for air,hyperoxygenation can be lethal.

It is really the challenge of the functional medicine practitioner to help the patient be in his or her zone of optimal function, at the top of the parabola. Whatever concentration that of substances that induces or supports proper function would be the ideal state. So you are getting optimal function versus concentration. This network is so complex, with literally thousands of things going on in each cell in real time and with each cell type being different from every other cell type. The complexity of this seems overwhelming. That’s why we choose certain kinds of biomarkers to assess the smoke rather than the fire. We look at the shadows on the wall of the cave. We often can’t look at the direct processes going on, so we have to look at the artifacts or the secondary byproducts and we call these biomarkers.

In terms of insulin, because we can’t analyze all the insulin signaling pathways in all the cells and know how it’s turned on and turned off, the biomarkers we use are related to overall insulin signaling processes. These may be things like hemoglobin A1c. Hemoglobin A1c, or glycosylated hemoglobin, is a surrogate biomarker for the relative effectiveness of insulin. There are many other variables and many other factors that are involved in this, so we are oversimplifying to say it is just a measurement of insulin activity, but it is a surrogate marker for insulin.

You might ask, “What is a good level for hemoglobin A1c if we are trying to balance the patient and monitor and manage their insulin signaling?” It used to be we would say that hemoglobin A1c, or glycosylated hemoglobin, was principally useful for following the success of compliance in a diabetic patient in trying to keep their hemoglobin A1c levels below a certain percent of total hemoglobin. Patients with glycosylated hemoglobins of a high percentage were people undergoing this non-enzymatic reaction of glucose with their globin portion of their hemoglobin molecule to glycosylate. The more glycosylation, the more injury to the hemoglobin, but also the presumption of the more injury to many other proteins by this non-enzymatic glycosylation. The suggestion is that this measurement is like time-lapse photography of glucose physiology in the whole body over the life of the red cell (about 120 days).

In medicine, glycosylated hemoglobin was principally being used as a way to monitor compliance and control in a diabetic patient. Over the last decade, however, many more detailed studies have been ongoing looking at glycosylated hemoglobin levels in individuals who have marginal insulin resistance, or what might be considered metabolic syndrome patients (people with refractory insulin resistance with elevated triglycerides and low HDLs and increased abdominal circumference).10 In these cases these patients may not yet be diabetic, but what has been found recently is that their hemoglobin A1c start drifting up. It is not the case that there is a threshold, above which you are suddenly in trouble and below which you are completely safe. It is more of a gradation, as we have seen often in almost all variables that we measure. This is consistent with the parabolic dose response, because a parabola is a continuous curve; it is not a discontinuous curve. You go up one side of the parabola and go to the top, and then down the other side. It is a continuous line.

What does that really mean in terms of following the patient? It means that the serial analyses of biomarkers like glycosylated hemoglobin become very important. It’s not just taking one data point and then trying to make a decision. It is rather trying to follow the patient over time and see what the relative delta (the rate of change) is. Is it going up? Is it going down? Is it staying the same? Going up is not good. Staying the same or going down is considered desirable. We’re using this surrogate biomarker to track the success of therapy and to try to define the environment-let’s call it a “molecular milieu” in the cell-that would reflect proper cellular signaling and proper gene expression patterns. In the patient who is not a diabetic, necessarily, but who has an elevated glycosylated hemoglobin, who may have other family histories of cancer, who may have other risk factors, you might, as part of therapy, direct intentionality towards modulating glycosylated hemogloblin (lowering it) as a biomarker for the influence you are having on insulin signaling and its ultimate influence on cell proliferation.

This is an example of a different strategic approach towards both susceptibility to and the management of cancer. These are the kinds of things that we use as a snapshot to track the patient and to engage in personalized intervention. Another-I would call it adjunctive-biomarker that can be used is high sensitivity CRP as a surrogate marker for inflammatory potential. We know from past experience and discussions we have had in Functional Medicine Update that CRP is a relatively problematic biomarker for inflammatory assessment because it is a pretty downstream marker (C-reactive protein).

What happens in the cascade of inflammation is that upstream there is the production of inflammatory cytokines, triggered by tumor necrosis factor alpha, which then produces interleukin-6 (IL-6). IL-6 then travels systemically and ultimately triggers the liver to induce gene expression of a protein called C-reactive protein. C-reactive protein is kind of a second-signal messenger of inflammation. It is the second guard. It’s not looking at the primary modulator; it’s looking at a secondary effect. But even with that limitation, we see that drifting upward with hs-CRP levels in serology is reflective of chronic inflammation.

I want to put a caveat on that by saying that hs-CRP is very susceptible to outside “noise” in that test. If a person has a cold or the flu, hs-CRP will be elevated for that time period. If a person has an injury, like a musculoskeletal injury, it will be reflected in an hs-CRP test. If a person has a chronic state of some type of a trauma, that can elevate hs-CRP. I think we have to be aware of the fact there can be spikes in hs-CRP that are temporal, and the levels will come back down once the patient has have gotten over that immediate insult. But it is a good marker for inflammatory burden if a patient that has, on a regular basis, with no underlying infection or trauma, an increased level of hs-CRP.

In combination, using the glycosylated hemoglobin test with the hs-CRP test can help us start to develop an understanding of the landscape related to potential risk to various kinds of chronic conditions, one of which-and we are speaking of it here specifically-is that of cancer, a proliferative disorder. What I’m really trying to get you to understand is that as we look at the cancer as a chronic disease question, we’re lead into a using a different lens for assessing information; we’re throwing the net a little broader for collecting information. We’re not just looking at tumor markers, which are the traditional way that you follow a diagnosis of a cancer, but we’re really looking at the molecular milieau and at the intercellular environment, to try to appreciate what is going on at the gene expression level that might, in fact, encourage these metastatic problems.

The last marker that probably should be put on the list-and this list could be fairly long, but one last big pillar that I’d like to add-is genomic instability. We know that oxidative stress induces genomic instability by inducing genomic damage, both at the mitochondrial DNA level and at the nuclear DNA level. Measurements of oxidative stress, like TBA-active materials (TBARS), or looking at 8-isoprostane levels, or looking at 8-hydroxydeoxyguanosine levels in the blood, are surrogate markers for oxidative injury to various biomolecules, including fatty acids or DNA, that reflect the potential for oxidative stress. This is another correlation with genomic instability/genomic damage and ultimately to the oncogenic potential of that cell.

If you were to group together these tests–hemoglobin A1c, hs-CRP and other inflammatory biomarkers, and oxidative stress markers–you would start to observe a landscape that is associated with the potential that we call oncogenic potential. I think it is that type of model that you are going to hear much more about from Dr. Wallace, as it relates to how she counsels physicians and patients who have malignancy in trying to develop the proper physiological environment so that it is less selective for cells that are transformed having a friendly opportunity for proliferation, angiogenesis, and metastases.

This is a very, very different model, I think, than the traditional diagnosis and treatment model in oncology. It is not in place of. That model can still be consistent to a traditional treatment model, but I think what we are looking at is a functional approach towards oncological burden that is hopefully going to be adjunctive and amplify the success of positive outcome in a patient who has early stage malignancy, or is being treated for cancer, or is managing malignancy as a chronic disease. It gives some new tools-some new rules of the road-upon which one can navigate.

You might say, “What’s new about this?” I think what is new about all of this is that this is assembling some of the more recent (and when I say recent I mean within the last decade) understanding of the cellular and molecular physiology of cancer (the whole cancer biology). And then trying to take that cancer biology understanding and apply it clinically, knowing that we are still in a house that is under construction, that we don’t have all of the architecture worked out. It is a very complex network, as I have described, for which much of it is still a mystery, but that doesn’t mean we can’t act. That doesn’t mean the information that we have at hand won’t provide valuable approaches that will augment and improve successful outcome.

With that in mind, I hope I have laid a context for what we are going to be hearing from the expert, the highly ranked presenter at the 17th International Symposium on Functional Medicine, Dr. Jeanne Wallace.


Clinician/Researcher of the Month
Jeanne Wallace, PhD, CNC
1697 East, 3450 North
North Logan, UT 84341

I know you’ve heard this said by me many times: this is the part of Functional Medicine Update you and I both look forward to. Each month, I wrap around our clinician or researcher of the month a little narrative that hopefully explicates and supports and enriches what they have to say. The voice they bring is really the premier reason for being (the raison d’etre) for Functional Medicine Update. Once again we are very privileged to have an extraordinary presenter/clinician who is going to talk to us about a very complicated but important area. This was the focus of the 17th International Symposium on Functional Medicine in May of 2010, which was on titled Cancer as a Chronic Disease.

As we start to learn more about the etiology of cancers, and we learn more about how to put together a comprehensive care program, and as patients now start to survive through the primary therapy into years of life after, the question really becomes, what the best management? How do we manage cancer on the front end, during, and after? Questions of compassionate care become very, very important. This discussion goes beyond buzzwords such as “integrated cancer therapy” or “integrated oncology,” to really look at the whole milieu-the ecos-of this unique condition of cell replicative disorders that we call cancers. We’re very privileged to have Dr. Jeanne Wallace for today’s interview, who, at the 17thInternational Symposium, was the top-ranked speaker out of a very remarkable portfolio of experts in the field that presented over the four days of the Symposium.

Dr. Wallace has pioneered what she terms is a “multi-modal” approach that targets multiple aspects of cancer pathophysiology. We’re going to learn from her directly more about what that means. It all relates to this dysregulated cell signaling and gene expression, how that turns into things like angiogenesis and metastatic processes, and how one then goes about selective apoptosis of transformed cells. How do you redifferentiate cells to their normal architecture? And how do you support, properly, whole organism immune function? These are all parts of different strategic thinking about cancer as a chronic disease and how one might design a program to manage it.

Dr. Wallace is a certified clinical nutritionist. She is a PhD. In 2001, she submitted a Best Case Series of 101 glioblastoma multiformae stage IV brain tumor patients to the National Cancer Institute’s Center for Complementary and Alternative Medicine, and the data was updated in April of 2004 to include 325 cases that were favorably reviewed. She is a member of the Society of Integrative Gynecology and the National Association of Nutritional Professionals, and is just a remarkable and dedicated professional counselor, guide, and presenter.

With that introduction, Dr. Wallace, welcome to Functional Medicine Update and thanks for being with us. Maybe I should start with this first question: What was your path that led you to this extraordinary…I would say both demanding but also fulfilling occupation?

JW: Thanks, Jeff. Thanks for the introduction. It’s nice to be here. I often describe my path here as having been drafted because I didn’t volunteer to work in the field of cancer. I grew up with a large family history of cancer, and watched grandparents and my uncles pass away, and my mother and my sister are both survivors, so I knew as a fairly young person that I wanted to work with cancer patients. I started out doing that in psychology in my training and didn’t feel right there and looked at some other ways of going. It was when a friend of mine developed a stage IV brain tumor that I decided. I was working in the field of nutrition and we couldn’t find anyone to help her, and I decided, “This is it. I have been drafted. This is my calling.” And I really turned the focus of my practice at that time toward a look at primary brain tumors and nutrition. I had been working with some other types of cancer for a couple of years. That really became my full focus at that time. And I’m happy to say she is still alive. It is 13 years later and she is a survivor both of primary brain tumor (a glioblastoma) as well as advanced breast cancer.

Should “Survivors” Actually Be Called “Champions”?
JB: You used a word there that I know we’ll come back to discuss in some aspects over the course of our conversation and that’s the word “survivor.” It has always struck me that that word is kind of passive. It is used quite a bit in this field for people who go through the process and come out the other side successfully. In my experience, “survivor” sounds a little bit…almost weak, because it sounds as if the person was lucky to have survived versus what often happens, which is a very aggressive victory. I have almost wanted to change the common language to say rather than “survivor,” these are “champions” or “victors” or something of that nature. What has your experience been with how patients go to the other side relative to their whole outlook and emotion and approach towards their disease?

JW: I have to agree with you. Certainly it reflects the way the field is sort of set up. We have the oncologists with their single-minded focus (not all of them, but a great number of them) on the cancer cell, and they really view this as a war that they are having difficulty winning with the tools that we have–the weapons of radiation and chemotherapy and surgery–and the idea of the patient just coming in and submitting passively to the treatment. This is not at all the experience I have in working with my clients. These are individuals who see their role very much as being on a team, and that the work that they do-with nutrition, with mind/body medicine, with their attitude, with guided visualization and other complementary therapies-they are very aggressively pursuing this. I agree that “champion” or a “victor” is a much better name for how they would see themselves.

JB: Tell us a little bit-maybe you can use an example of how a patient would, as a client, come to you, and how you might see them and walk through the relationship with them with their disease.

What to Ask. What to Test. Advice from Dr. Wallace
JW: I’m lucky in that the great majority of my clients come because they are referred by oncologists. This certainly wasn’t true 10 years ago. When I work with a client, I put together for them a very lengthy report and some materials that sort of guide them through an understanding of what I call the “oncometabolic milieu.” It is sort of an understanding of the underlying processes in their body, and I focus on the terrain of the environment in their body that is promoting or fostering the progression of the cancer. So I really want to empower those clients so that they understand that there is much they can do to address the cancer in addition to going through the conventional medical treatments. We’re lucky. We get referrals from cancer centers all over the country and outside the US as well.

The clients come and they often don’t have a sense of what we are going to do, so we do some orientation time and give them a sense. One thing that we like to do is we like to look at the environment of their body with a series of tests. We have them fill out extensive intake materials about their medical history, their medications, their diet, and their social life. We collect as much data as we can. Sometimes we don’t use it until later when we get the “aha,” but we do like to collect a lot data. And then we run some tests, because I want to get a sense of what’s going on inside this person’s body.

I want to come back to that term that I coined-that “oncometabolic milieu”-I really have taken that from the idea in cardiovascular disease over the last 10 years that we have come to understand that metabolic syndrome is this antecedent or precursor of events going on in the body that foster and favor that cardiovascular disease process. I think the same thing can be said in cancer. We have had such a narrow focus on the cancer cell, as if it were an island existing in isolation. And what we really see now is that many events going on in the body, such as systemic inflammation, and hypercoagulability, and incompetence of the immune system and dysregulation in hormones, and also metabolic syndrome-these are factors that favor aggressive cancer growth, metastasis, invasion, angiogenesis, and cancer progression. So there is much we can do with nutrition, and also with many of the other complementary therapies, that address this oncometabolic milieu and give the client a way to really be a team member in the care of their cancer.

So we run testing. We, for example, will look at metabolic syndrome. We like to look at the A1c (glycated hemoglobin A1c). We’ll run a high-sensitivity C-reactive protein, fibrinogen, vitamin D levels, sometime different hormone levels, and we’ll look at these to get a sense of where should we put our focus in our counseling with this client. Each cancer patient has a different fingerprint of this syndrome. We might have some clients who have elevated inflammation and elevated fibrinogen, but the immune system actually looks fairly okay, and maybe their blood sugar regulation looks really okay. And for another client, perhaps with the same disease and diagnosis and other similar characteristics, the underlying terrain looks very different for them. They are maybe not in a state of hypercoagulability and inflammation, instead they have metabolic syndrome and deficiencies in vitamin D and other nutrients, elevated copper, for example. We do that testing and then we sort of individually tailor our consulting for the client based on that testing.

JB: You have-in that very extraordinarily condensed, articulate, rapid delivery-covered a huge landscape of important information, so I’d like to go back and pick up a few of the details because that was brilliantly stated. The term that you’ve coined, which I really like, is “oncometabolic milieu.” I wrote a couple of articles that appeared this year on…I’m using a slightly different term but I’m amazed as to how convergent our thoughts were…

JW: I hadn’t seen your articles until I was at functional medicine. I was interesting to see our brains were going along the same pathway and trajectory.

“Oncometabolic Milieu”
JB: They really were. I talked about “oncogenic potential,” but I really like your term better. I think it is a more robust term. Let’s go through some of the subtypes that you just described: the hypercoagulability, the hormones, the metabolic syndrome, hyperinsulinemic condition, the inflammation, oxidative stress, and relationships to nutritional imbalance. You probably use as a surrogate marker–obviously, fibrinogen–to look at coagulability. Tell us a little bit. How does the coagulability component connect to your oncometabolic milieu?

JW: This is really like 10 years of my research sort of coalesced into one theory. What I have done is surveyed the literature for different markers where modulating them, or reaching a certain threshold, can alter the progression of the cancer or alter response to treatment. I have maybe four dozen of these different markers, and I’ve really narrowed it down to five or six markers because they seem the most robust.

If fibrinogen is elevated, a couple of things happen. It increases the metastatic potential of the cancer. This probably happens through several different mechanisms. It may be that the fibrin is sticking to the cancer cells and helping them evade the immune response. It might be that the fiber in fibrinogen is enhancing metastasis directly. It might be that it decreases the circulation and the delivery of oxygen to the tumor site, and those hypoxic areas are then resistant to treatment. Or it may be that chemotherapy doesn’t perfuse out to the tissue because the blood is sort of thick and sludgy because of the high fibrin.

There are multiple mechanisms of action, here. If you look at the literature, there are some different cut-off points. Some studies have suggested that, for example, in lung cancer patients, fibrinogen above 350 is associated with poor survival/poor response to treatment. Some studies have used 310. We use 310 as our cut-off, and so when we measure the fibrinogen, if a client is elevated quite a bit above that, we will advise them on diet and nutritional supplements/botanicals that lower their fibrinogen, do an intervention, say, for 3 months or 6 months, come back and repeat the test to ensure what we are doing in terms of dietary nutritional support is actually effective at altering that particular parameter.

Inflammation-and we use the C-reactive protein, here-and hypercoagulability go sort of hand in hand. Often times when the fibrinogen is elevated, you also see high C-reactive protein. There is such a large body of data and research studies linking systemic inflammation to all types of events in the oncostatic process or oncogenic process. You have increased growth rates, and you have increased rates of infection, and increased weight loss during treatment, and increased metastases, and increased angiogenesis when there is systemic inflammation. The prostaglandins and leukotrienes that are inflammatory-those coming out of COX2 and 5-drive the active growth messengers and they drive the invasion, metastasis, and angiogenesis. When we have an elevated inflammation, we can get a direct benefit from decreasing the inflammatory state, so there is definitely nutritional things and botanical things (dietary things) that we do to try lower the C-reactive protein, and we look at those hand in hand (those two).

JB: It strikes me, as I’m listening to your very wonderful explanation, that it was 1979 in my life. My colleague, Jay Johnson, and I were both associated with the Bellevue-Redmond medical facility. Dr. Leo Bolles was the principal medical doctor there. We had visits from people all over the world that were in the field of nutritional medicine. We had this visit from an oncologist from Australia. He described a very simple in-office procedure that was looking at, basically, how fast blood coagulated, and he had a certain range. And he actually had studied vitamin E and showed that vitamin E could have a positive effect on these cancer patients and it had an impact on this test, a surrogate marker. It is interesting how old things get learned better and better over time and we get more precision. I give him a lot of credit because he was under a lot of criticism from his oncologic colleagues in Australia at the time. They said that this didn’t seem reasonable because there was no mechanism of purported action. You know, 30 years can make a difference in our understanding.

JW: Yes, when your focus is just on the cancer cell, these types of markers of the environment or the terrain in the body don’t make any sense to you. It is one of those things. Ten or 15 years ago, when I talked to oncologists, they really thought that I was out there in left field, or out there in right field, or not even on the map. Not now, especially since I’ve been very careful to document, scientifically, where my approach is coming from. When the client gets a report and they take that to their oncologist, they have 140 pages. It is very well-referenced-some 300 to 500 scientific references-all from the mainstream literature. It can be very eye opening.

On the information side of this, there is a study that just stands out so much for me, and it really-if you haven’t thought about how the environment in the body might be influencing the course of disease for a cancer patient-this study is just such an eye-opening one. It is Donald McMillan, and it was published in Nutrition Cancer in 2001.11

It is a study of 772 cancer patients-predominantly breast, gastrointestinal, and lung cancers. In the beginning of this study he measured the C-reactive protein. There is no intervention, and he waits about 3 years (1000 days), and looks at survival based on the C-reactive protein. And what he found is that using a cut off of 1.0, those patients who had low C-reactive protein, 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of them were still alive at the 1000-day mark. Those patients whose C-reactive protein was elevated above that level, none of them had survived that long.

This C-reactive protein correlation was stronger than stage of disease, extent of disease, and many of the other factors. So it is sort of saying, “Here we are thinking about our cancer patients in terms of stage II disease or stage IV, it was actually a better indicator of survival-overall survival-whether or not they had inflammation.” I really spent quite a bit of time thinking about that. I thought, “This might explain in part why sometimes you have a person with stage II disease whose disease is very, very aggressive and doesn’t survive as long as one of those outliers with stage IV who becomes a long-term survivor. Maybe it has more to do the environment than the characteristics that we are currently using to assess whether or not the cancer will behave aggressively.”

JB: That’s beautifully said. Let’s move next on this list to hormones, because that is a big topic, obviously, with a lot of different molecules under the title “hormones.” Are there some that you find are more problematic or of more importance when looking at those that stand up for clinical evaluation?

Evaluating Cortisol and Estrogen in Cancer Patients
JW: Yes. I’ll test on just two here, those being cortisol and estrogen. We’re very interested in normal pattern of cortisol regulation throughout the day, looking at that Spiegel and Sephton work out of Stanford.12 They showed (and this sort of follow-up to their breast cancer support group study that is so well known)…they are looking at that pattern of normal cortisol secretion throughout the day and finding that dysregulation in that cortisol rhythm was associated with poor survival in breast cancer. We certainly see that in our clients. I think that is probably mediated by many different events in the body. Cortisol, of course, increasing blood sugar and blood sugar dysregulation, we find-in our clinic-a very important factor. So there is the cortisol blood sugar issue. There is probably also elevated cortisol immune suppression going on.

Although I haven’t touched on it with you, there is also a relationship when adrenal function is low; it can drive copper up. The adrenals are needed to stimulate the synthesis of ceruloplasmin, a copper-binding protein. Copper is a cofactor for many of the angiogenic enzymes, like VEGF, and basic fibroblastic growth factor, and HIF1.
So when copper is low, it can slow the process of angiogenesis. When you have elevated cortisol or cortisol dysregulation, hyporadrenia, then what you see is copper is elevated and it favors angiogenesis. High glycemic response (metabolic syndrome) also favors angiogenic response. We’re very interested in cortisol and because of that we do a lot of adaptogens and counseling about reducing stress to normalize that. That is one area where hormones are of great interest to us. Another is estrogens. You know, there is the straightforward “Are-you-looking-at-estrogens-to-say-You-are-positive-for-breast-cancer?” (Or another type of cancer where estrogen drives it, such as with some types of brain tumors, many types of head and neck cancers, and many of the other gynecologic or reproductive cancers?) So that’s an issue, but for us, what we are really focused on about the estrogens is, again, back to angiogenesis. Estrogen drives copper up, so often when we have elevated copper we work very hard to decrease the copper as an antiangiogenic strategy. When you are looking at your free copper (so you have measured a serum copper and a ceruloplasmin), you need both of those numbers to get a sense of the free copper (what will diffuse into the tissues and act on angiogenesis). You are using a simple formula where you take your ceruloplasmin and multiply that by 3 and subtract it from your serum copper to get a free or unbound copper. When you are looking at that, if your serum copper is elevated above 130, you are probably looking at somebody with the estrogen-dominant situation, and you’re not going to be able to address the copper without addressing the hormone balance. On the other hand, if the ceruloplasmin is suppressed, especially below 22, you are probably looking at hypoadrenia and you’re going to need to nourish the adrenals and use some adaptogens in order to successfully get the copper down in your antiangiogenic strategy. In terms of hormones, those are two that are standouts. Sometimes we look at others, but those are probably the two most predominant places we are looking at.

JB: That’s very, very helpful. Again, as I am listening to you I am kind of reflecting back. Years ago-this was probably the early 80s-I did a series of grand rounds at the University of Arkansas School of Medicine, and I met a professor there by the name of John Sorenson. If you do a search PubMed on his name, he published a lot on copper, and particularly as it related to both vascular disease risk and to cancer.13,14 He was one of the first people that I had ever heard to talk about molybdenums and antagonism of copper, and he was actually studying molybdenum salts in animal tumor models, showing that you could prevent angiogenesis. I know there is some work on molybdenum that has occurred since then.

JW: Yes. That’s George Brewer’s work out of the University of Michigan, and he has now three or four preclinical trials (pilot trials) on cancer patients where they have used the off-label drug-it is a drug developed for Wilson’s disease, tetrathyomolybdate. They’ve used that quite successfully in cancer patients to drive the copper levels down.15

JB: Amazing how these things all interconnect when you start looking at a broader picture. Let’s move-this is a good segue, obviously, talking about insulin and its influence on cortisol-to hyperinsulinemic syndrome, which we call metabolic syndrome. Tell us a little bit about how you look at that, how you assess that, and then maybe what your thoughts are about the appropriate kind of food plan or diet plan for patients in that situation.

Cancer and Metabolic Syndrome
JW: Going all the way back to Warburg perhaps, where there was the first acknowledgement that cancer cells are sugar feeders, and there has been such a controversy about that in the literature, and certainly the oncologists have a lot of resistance to that. Moving forward, is it really the sugar itself that is the problem? I don’t think that it is. I think what we are looking at, here, is that we get this metabolic syndrome where we have increase in the insulin and insulin resistance at the same time, and that sort of drives a huge cascade of events. For example, insulin resistance is then going to increase the secretion and production of insulin-like growth factors and decrease their binding proteins, so you have more active insulin-like growth factor that acts as a cascade. And then you have the adipose sites and the different hormones that they make and that is increasing angiogenesis. And then you have the insulin increasing the activity and signaling of aromatase, so you get more free estrogen. It’s like this huge cascade of events that can impact the cancer in many different ways.

You look at the literature and you see for breast cancer patients, colon cancer, and many other cancers, those who have signs/symptoms of metabolic syndrome have greater risk of recurrence, have greater rates of metastases, have significantly shorter survival.16,17 There is also some research showing post-op complications in colon cancer patients are much higher in those with metabolic syndrome. Patients undergoing bone marrow transplant have greater risk of infection. There are several different ways that this can impact the cancer process.

We screen for metabolic syndrome. We don’t use a fasting glucose. We really look at the glycated hemoglobin A1c (so you’re not getting a single snapshot of where the sugar is with the glucose; you’re looking more over a two- to three-month process). And then we are also looking at waist circumference, for example, and HDL cholesterol levels, and just, you know, the whole kit-and-kaboodle.

I want to remember to say: I think it’s really important we (most of us who work, I think, in the integrative medicine field) have this knowledge of metabolic syndrome. You are looking for waist adiposity, and you want to remember that cancer patients in chemotherapy and radiation undergo sarcopenia; they lose muscle mass. So the number on the scale when they step on may be the same, and they may still fit into their clothes, and they may still look “fit” or have a lean body weight, but they may be metabolically obese as a result of having lost that muscle mass. So you want to remember to screen not only those with extra waist circumference, but you want to look at these markers if a person has been in treatment, because certainly they have metabolic syndrome even though they don’t necessarily look apple-shaped, so to speak. So that’s a good point.

And then in terms of the diet, this is just huge. I think a lot of people have approached the diet about “What diet should we give a cancer patient?” based on politics, and dogma, and all different kinds of ideas. I grew up a vegetarian. I was a vegetarian for a very long time. I was wedded to that idea, but when I started having the idea that my clients with cancer needed to have a diet that lowered inflammation, was not high in copper, and did not raise the blood sugar, I really began to look very differently at what I should be suggesting for diet. And instead of coming from the “this is the diet that everybody says is the right diet for cancer patients,” I end up individually tailoring diet for each person based on “How can we get their blood sugar down and the C-reactive protein down?”

So I often find, when I have clients who come in who have been on a vegan diet (and often but not always a vegetarian diet), that they’re having a lot of difficulty regulating their blood sugar on that diet. In particular, the vegan approach, we find, elevates the copper, predominantly because the best food sources of zinc are meat foods. We end up doing a very low refined carbohydrate, very low carbohydrate (almost no starchy carbohydrates-we limit that very strongly), so that the client is getting their carbohydrates predominantly from vegetables and legumes that are low glycemic, and letting them eat, yes, meat, as long as it is organic and pastured or grass-fed. Poultry and eggs, which are often not included in those diets, we find that that is often the best way to regulate the blood sugar.

We look at other things. Do they have digestive incompetence? If you have trouble with your digestion you are not digesting your fats and proteins, and then regardless of including them in the meals you may only be getting your carbohydrates and that causes a spike in your glycemic response after your meals. We look at muscle mass. If they are sedentary then they need to be put on an exercise program with some weight training to build some muscle mass back. We look at stress levels, and cortisol, and nutrient deficiencies like chromium and zinc, magnesium, vitamin D. All of those are involved in the insulin resistance or in blood sugar regulation.

Cancer and Antioxidants
JB: Beautiful response. Let’s move to this concept of free radical oxidation, which often accompanies inflammatory conditions. And we have this whole big thing out there about antioxidants. I know at the Symposium virtually every presenter spoke, or at least touched partly in their discussion, on this antioxidants conundrum. Do you have an opinion or thought about this antioxidant connection with oncogenesis?
JW: I could probably talk your ear off about for several hours. Yes, I definitely have some thoughts about that. And certainly looking at the literature, one thing that really stands out for me is the genetic stability. You know, when the oxidation is increasing you get a lot of genetic instability. In terms of maximizing the treatment, and preventing more aggressive behavior of cancers after tumors, you don’t want that genetic instability. I think a big part of the “controversy” has sort of been a focus on antioxidant supplements. I grin when I say that because I think the antioxidant power of vitamin C, or vitamin E, or some supplement, pales in comparison to a whole food. If you are looking at those charts on the ORAC values, for example, and you see vitamin E comes in at 125 ORAC, says research out of Tufts, and then you look at any respectable fruit-take blueberries-and the ORAC value is 3,250, it’s like you’re not really talking about antioxidants when you are talking about a single nutrient that you are taking as a supplement.

Many of the oncologists who perhaps have not studied antioxidants use that term as if it was an umbrella of one or two things and don’t understand the different types of free radicals. And they are telling their patients not to have any antioxidants, not realizing that if a person goes out and eats a chocolate bar, they are getting antioxidants. As something that we look at, we know with the diet we are recommending, and we are trying to get our clients to eat 8 to 10 (bare minimum), half-cup servings of fruits and vegetables every day, we can see a big change in oxidation when they are doing that.

Cancer and Vitamin D
JB: That’s a beautiful recommendation. Let’s talk briefly about this vitamin D controversy. There is this concept that 1,25-dihydroxyvitamin D as a seco hormone that has great effects on multiple gene expression patterns, and overdrive can increase oncogenic potential, but then underdrive can also increase oxidative potential, suggesting a parabola of optimal levels in tissues of 1,25. But we are measuring the 25, so people, I think, assume that if 25 is low then 1,25 must be low, but we have actually seen, and I’m sure you have as well, there are some cases where people’s 25 are low but their 1,25 are high and the more 25 you give them the more they convert it to 1,25. Do you have a thought about this whole conundrum of vitamin D?

JW: Yes, and that was sort of new for me, something that I got as a gem out of the conference, because we were not measuring 1,25 often. When 25-hydroxy was not going up, then we would come and look at the 1,25 and then we were limiting vitamin D supplements, since we said, “Okay, that’s where it is going and we don’t know how to stop it from going there.” We set our range of optimum vitamin D for the 25-hydroxy between 60 and 80, and I ended up setting that range based on several different studies and my work with autoimmunity, which runs in my family. We were aware, having worked with some autoimmune clients, that when we get the vitamin D to 80, that works sort of as an immune suppressant. That works sort of to induce immune tolerance. When that worked so well, my thinking was, “Well, I probably don’t want to drive the blood level of 25-hydroxy over 80 or I may be suppressing immune response instead of benefitting it.”

I think there is still quite a bit of basic research that needs to be done on vitamin D to answer some of these questions. In our brain tumor group, certainly there is a lovely study out of France by Paul Trouillas in which they used high-dose vitamin D supplements in patients who had completed and failed all other therapies (or more likely those therapies had failed them).18 The chemotherapies, radiation surgery–they had had the maximum of those treatments and their tumors were still growing. They had a fair response rate. I think it was 27{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the patients in that trial had a response, including several complete regressions, and there is a four-year, a five-year, and now a seven-year survivor in that study, which is still ongoing. This is for glioblastoma muliforme, where six months is sort of a median survival and if you make it to a year, in the literature that is considered quite good. Vitamin D having such a strong response as a differentiating agent in that study, we’re still very enamored of using vitamin D for our clients.

I think there is an interplay between vitamin D, vitamin K, vitamin A, and perhaps vitamin C that has not yet been looked at. Having been wedded to the scientific approach of “study this one thing individually,” we really miss a lot in nutrition where there is such an important synergistic effect and interplay of many different nutrients together. I’ll be holding out until we get a clear picture of what those interactions are and what to do.

JB: Very well said. My last question has to do with this digestive incompetence that you referred to. I know there is a big body of literature that is emerging right now about the gut microbiome and how the physiology of this highly diverse community of bugs we have in our gut influences our immune system and cellular function. There is some work suggesting that certain supplements, pre- and probiotics, might be useful in either pre- or post-treatment cases in cancer. What is your experience with pre- and probiotics, if any, at this point?

Cancer and Pro- and Prebiotics
JW: We definitely use them for many reasons. Our clients are on all types of treatments that kill off the great majority of flora in the intestines, and obviously those are so important in helping with immune competence. There are several other things that are important for that healthy eubiosis in the gut. Maybe key among those is when you have those healthy bacteria and you are eating a diet high in soluble fibers, your intestines become a butyrate-manufacturing facility. And butyrate is a histone deacetylase inhibitor. It is a differentiating agent. It is really important for cancer patients. We really want to ensure that our clients have those healthy bacteria at least for that reason, if not also to crowd out unfavorable bacteria, which would, for example, in a breast cancer patient, those bacteria would be using beta-glucuronidase enzyme to reassemble estrogens that had been broken down from the liver. There are several different pathways from which that is really important to do. It is definitely part of our protocols to do that.

JB: Obviously we have just touched the tip of the iceberg. You are a dense treasure-trove of extraordinarily useful information. I guess I’d like to close by asking to look out at the horizon for a moment, and with your experience that you are having both at the evolving frontier of the interface between science and patients, and also with the changing way that patients respond to their own disease, what is your view of the future? How do you see things unfolding?

JW: I’m really excited about where we are right now. Speaking at the Symposium was really exciting to me. I met many oncologists who were there. I’m just thinking ten years ago that kind of discussion-friendly discussion-between where we are with nutrition and complementary medicine, and the integrative field and oncologists, that may not have been possible. I feel like I’ve climbed a mountain, I’m standing at the peak, and I can see out over the field, and I’m actually very excited about where we are. I also think that this approach, I’m happy to be able to share this with people Many practitioners keep all of their secrets very carefully guarded. I don’t feel that way. It is such a big field and I’m happy to share my information. I think one of the pearls of this particular approach is it really allows you to individualize the support for those cancer patients. Whereas often new clients come to me and they’ve seen four or five practitioners and they have the same little bag of 30 supplements that this practitioner gives to every cancer patient and how do I know which ones are actually useful for me and which ones might be doing me harm? This kind of exploration-using some testing to explore the terrain and then individualize the protocol-I’m hoping that the entire field of oncology will move more in that direction, not only the integrative/nutrition/holistic approach being individualized, but also I’m seeing with a lot of the mainstream and conventional treatments that we are moving in the direction of individualizing cancer treatments. I think we are just at the beginning of that, and that’s what we will begin to see over the next five years. I’m excited about it.

JB: Well, I think you are both a very articulate spokesperson for this evolution and also, obviously, a dedicated clinician/professional really assisting people at times that are very challenging in their individual and their family lives. I applaud you. It’s very courageous of you. For our listeners, if you want to be reached, I presume it is through your group, Nutritional Solutions Consulting.

JW: Nutritional Solutions, that’s right.

JB: Which is at nutritional-solutions@comcast.net?

JW: That’s correct.

JB: We’ll put that on the summary. Again, it is nutritional-solutions@comcast.net. People who want to contact you by email. Dr. Wallace, thank you so much for spending the time with us. Again, I am so in admiration for what you are doing. It is a big job, and as they say, you need big people to do big jobs and obviously you are one of them. Thank you so much.

JW: Thank you very much.

What has been the ultimate objective of this month’s Functional Medicine Update? I hope it became very clear to you hearing the eloquent and very, I think, well-framed conversation with Dr. Wallace of how she approaches cancer in her consultations that there is something here, in the functional medicine area, that really deserves much more attention, that deserves much more focus to try to improve outcome and to reduce unnecessary burden of disease and prolong life, if not prevent the disease to begin with. I think that this is a very, very exciting part of the functional medicine story. When we started down this road some 20+ years ago, little did we know where the journey might take us. It was my belief, probably at the onset of our functional medicine model, that we wouldn’t have much to say about oncology. But because we are all connected by the same web-this same web of physiology that connects cancer together with heart disease, with arthritis, with dementia, the functional medicine matrix and that method of thinking provides an insight that can be applied to virtually every state of pathophysiology. So I hope there are some tools and news to use out of this extraordinary discussion with Dr. Wallace.


1 Zhang Y, Gaikwad NW, Olson K, Zahid M, Cavalieri EL, Rogan EG. Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Metabolism. 2007;56(7):887-894.

2 Mulvey L, Chandrasekaran A, Liu K, Lombardi S, Wang XP, Auborn KJ, Goodwin L. Interplay of genes regulated by estrogen and diindolylmethane in breast cancer cell lines. Mol Med. 2007;13(1-2):69-78.

3 Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007;55(3):224-236.

4 Bell MC, Crowley-Nowick P, Bradlow HL, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol. 2000;78(2):123-129.

5 Spink DC, Zhang F, Hussain MM, Katz BH, Liu X, Hilker DR, Bolton JL. Metabolism of equilenin in MCF-7 and MDA-MB-231 human breast cancer cells. Chem Res Toxicol. 2001;14(5):572-581.

6 Boyd DB. Insulin and cancer. Integr Cancer Ther. 2003;2(4):315-329.

7 Hernandez-Diaz S, Adami HO. Diabetes therapy and cancer risk: causal effects and other plausible explanations. Diabetologia. 2010;53(5):802-808.

8 Hassan MM, Curley SA, Li D, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer. 2010;116(8):1938-1946.

9 Gerstein HC. Does insulin therapy promote, reduce, or have a neutral effect on cancers? JAMA. 2010;303(5):446-447.

10 Lipska KJ, De Rekeneire N, Van Ness PH, et al. Identifying dysglycemic states in older adults: implications of the emerging use of hemoglobin A1c. J Clin Endocrinol Metab. 2010 Sep 22. [Epub ahead of print]

11 McMillan DC, Elahi MM, Sattar N, Angerson WJ, Johnstone J, McArdle CS. Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer. 2001;41(1-2):64-69.

12 Sephton SE, Dhabhar FS, Keuroghlian AS, Giese-Davis J, McEwen BS, Ionan AC, Spiegel D. Depression, cortisol, and suppressed cell-mediated immunity in metastatic breast cancer. Brain Behav Immun. 2009;23(8):1148-1155.

13 Crispens CG Jr, Sorenson JR. Evaluation of the anticancer activity of CuDIPS in SJL/J mice. Anticancer Res. 1988;8(1):77-79.

14 Sorenson JR, Wanglia GW. Co-treatment with copper compounds dramatically decreases toxicities observed with cisplatin cancer therapy and the anticancer efficacy of some copper chelates supports the conclusion that copper chelate therapy may be markedly more effective and less toxic than cisplatin therapy. Curr Med Chem. 2007;14(14):1499-1503.

15 Gartner EM, Griffith KA, Pan Q, Brewer GJ, Henja GF, Merajver SD, Zalupski MM. A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer. Invest New Drugs. 2009;27(2):159-165.

16 Shen Z, Ye Y, Bin L, Yin M, Yang X, Jiang K, Wang S. Metabolic syndrome is an important factor for the evolution of prognosis of colorectal cancer: survival, recurrence, and liver metastasis. Am J Surg. 2010;200(1):59-63.

17 Rose DP, Haffner SM, Baillargeon J. Adiposity, the metabolic syndrome, and breast cancer in African-American and white American women. Endocr Rev. 2007;28(7):763-777.

18 Trouillas P, Honnorat J, Bret P, Jouvet A, Gerard JP. Redifferentiation therapy in brain tumors: long-lasting complete regression of gliablastomas and an anaplastic astrocytoma under long term 1-alpha-hydroxycholecalciferol. J Neurooncol.

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