Breast Cancer and Hormone Testing - The Breast Cancer Profile

A Conversation with Dr. David Zava, Ph.D. and Dr. John R. Lee, M.D.

During his life, Dr. Lee was the editor of the John R. Lee, M.D. Medical Letter. Besides featuring Dr. Lee's research, the John R. Lee M.D. Medical Letter published numerous interviews with experts in the field of natural hormone balance. This includes the following interview with Dr. David Zava, the founder of ZRT Laboratory and a co-author with Dr. Lee of What Your Doctor May Not Tell You About Breast Cancer. ZRT Laboratory is a leading provider of hormone testing services.

The following interview with Dr. Zava can be found in the August 2002 issue of the John R. Lee M.D. Medical Letter. In the interview, Dr. Zava explains that women who are diagnosed with breast cancer often have a distinct set of hormonal imbalances which he calls "the breast cancer profile". Women can determine whether their hormones fit this profile by taking one of the saliva hormone tests we offer on this web site. Keep reading to learn more!

JLML: Dr. Zava, we understand that you've collected some interesting and important data about breast cancer since we wrote the book about breast cancer together.

DTZ: Yes, I call it the breast cancer profile. It relates to the hormone profiles that we look at in saliva. We've been doing some work with Dr. Rebecca Glaser from Ohio. She's a breast surgeon and has been sending us saliva samples from women who have just been diagnosed with breast cancer. In most cases where the diagnosis is infiltrating ductal carcinomas, the hormone profile is quite distinct.

What I see–even in postmenopausal women–is that their estradiol levels are quite high, even if they've had a hysterectomy, and that's very unusual. Their progesterone levels are extremely low–less than 15–which is almost equivalent to zero. Their testosterone levels are high. This has already been well described in the literature on breast cancer patients.

DHEA sulfate [DHEA-S] is very low, which is a hallmark of most cancers. I think that's related to adrenal dysfunction, but is probably also related to the fact that breast tumors produce high levels of the enzyme sulfatase that cleaves the sulfate off of the DHEA-S, making more DHEA, which is converted into estradiol and testosterone. This, I believe, is one of the reasons why the testosterone and the estradiol are high. You've got everything moving in the direction of making estrogen.

The cortisol profile is odd because it tends to be flat. This has recently been described in the literature (Sephton). You don't have the normal diurnal [twice daily] variation, which is that when you wake up in the morning your adrenals are producing a lot of cortisol, and then it drops down to about one-fifth by nightfall. In breast cancer patients, their cortisol is often the same morning and night (which would mean that it's higher than normal at night).

JLML: So to sum up, the breast cancer patient hormone profile you're seeing is high estradiol and testosterone, low progesterone and DHEA-S, and flat cortisol levels, usually created by high night cortisol. Do you see this profile often in saliva tests?

DTZ: Rarely in the normal population but frequently in women newly diagnosed with breast cancer. Women with less aggressive intraductal cancers rarely have this profile. And women who have had breast cancer and are in remission tend to have a normal profile, so the profile seems to be something that's happening before or during the time that they are diagnosed with cancer.

I think the hormone profile should, and will, be used in the future as an adjunct to tumor imaging procedures (mammography, sonography, etc.).

JLML: In addition to telling women how their hormones need to be balanced, a saliva test could also potentially tell them that their hormonal milieu is predisposing them to breast cancer. What are your thoughts on how this hormonal profile is created?

DTZ: We're getting a pretty good-sized database now, and most of the breast cancer cases that we've done saliva testing for are associated with 10 to 20 years use of conventional HRT.

JLML: Wow, that's a real indictment.

DTZ: But not surprising, it's what the WHI study found in healthy women using HRT for only five years. Compound this with "not so healthy" women using this form of hormone replacement for a lifetime and it's not so difficult to see the problem.

JLML: What other factors come into play in creating the breast cancer hormone profile that you have noticed?

DTZ: A major stressor that occurs several years prior to discovery of the cancer seems to be common. This is what I believe causes adrenal dysfunction, which in turn suppresses the immune system, sets up an estrogen factory, and allows the expression of a preexisting cancer.

JLML: What role do you see progesterone playing here?

DTZ: Progesterone will counter nearly all biochemical pathways that give the tumor cells a growth advantage, by directly inhibiting cancer cell proliferation, suppressing estrogen receptors, preventing blood vessels from forming around the tumor, and enhancing natural immunity by boosting natural killer cell activity, the first line of defense against all cancers.

JLML: Perhaps this is why Cowan found that women producing higher levels of progesterone had fewer types of all cancers. This underscores the importance of having balanced hormones before breast cancer surgery.

DTZ: Exactly. When you cut through a tumor when the patient is estrogen dominant you're going to have some problems. Natural killer cell function will be suppressed locally because of the excessive estrogen forming around the tumor. That's a setup for poor immune response.

Excess estrogens also encourage blood vessel growth (vascularization) and cause the expansion of the capillaries, allowing small clumps of tumor cells to escape to distant sites (metastasis). To make matters worse, high estrogen enhances blood clotting, and small clots form around clusters of tumor cells, making recognition by the already compromised natural killer cells even more difficult. In other words, the chance of metastasis is much greater under conditions of estrogen dominance.

We should be doing a clinical study to look at the effects of progesterone prior to breast surgery, in order to lower the estrogen burden, to lower the rate of cell proliferation, to increase natural killer cell function, to do all the things that are going to increase the probability that a woman is going to survive the breast cancer. If she's operated on without being protected like that, and she's making loads of estrogen and all these profiles are off, then the probability that the cancer cells are going to escape and set up a metastatic site is much higher.

The Mohr study looked at different phases of the menstrual cycle, and found that women who had high levels of progesterone in their bloodstream at the time of surgery were twice as likely to be alive at 10 to 15 years compared to women who had a low progesterone level. It's surprising to me that we haven't done the obvious–give a woman progesterone for a couple of weeks prior to her surgery, look at what's happening to the cancer cells short term, and follow disease-free and overall survival patterns long term.

From the Chang study we know that 20 to 30 mg of progesterone applied directly to the breasts 10 to 13 days prior to surgery reduces the rate of breast cell proliferation, and we know it helps fibrocystic breasts, which is excessive stimulation by estrogen.

We should be studying this in great detail. There's no question at all that progesterone is protective, but because physicians don't have large-scale clinical studies, they won't use it at a critical time when a woman is having breast surgery. Strange, they have no problems using highly toxic chemotherapy or tamoxifen, but are hesitant to try natural progesterone, which is the body's natural anti-estrogen.

JLML: Do you have any insights to share about the Women's Health Initiative study [WHI], which found higher rates of heart disease, breast cancer and stroke in women using conventional HRT?

DTZ: I think you covered it well in the last issue of the newsletter, but there are several things I'd like to point out. The truth of the WHI is that it created a major selection bias by choosing only healthy women to be in the study. If you had heart disease risk factors such as high blood pressure, diabetes, or obesity, for example, you weren't selected.

You can't extrapolate study results from a population of healthy women to the entire population. If you look at the entire population of women, it only includes a relatively small proportion of very healthy women. An incredible forty-two percent of those healthy women chosen to participate in the WHI fell out of the study in the first couple of years because they didn't like the side effects of the drugs. If all of those women had continued, or if they hadn't limited the study to healthy women, there would have been a much higher rate of all the adverse events (breast cancer, heart attacks, thromboembolism) that they found. The results are actually much worse than they appear to be because of the selection bias.

References

Writing Group for the Women's Health Initiative Investigators, "Risks and benefits of estrogen plus progestin in healthy postmenopausal women," JAMA, July 17, 2002, Vol 288, No. 3.

Chang K-J, Lee TTY, Linares-Cruz G, Fournier S, and de Lignieres, B. "Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo." Fertility and Sterility 1995; 63: 785-791. (Premenopausal women)

Mohr PE, Wang DY, Gregory WM, Richards MA, and Fentiman IS. "Serum progesterone and prognosis in operable breast cancer." British J of Cancer 1996; 73: 1552-1555.