Hormonal Therapy for Breast Cancer: Prevention, Treatment, and Advances

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• History of Hormonal Therapy
• Breast Cancer Prevention Strategies
• Tamoxifen vs Aromatase Inhibitors
• Combination Therapies and Treatment Duration
• Long-Term Recurrence Risks
• Environmental Estrogens and Risk Factors
• Full Transcript

History of Hormonal Therapy

Dr. Marc Lippman, MD, traces the history of hormonal breast cancer treatment back centuries. He notes that observations from 17th century Italy showed differences in breast cancer incidence between nuns and other women. The first scientific approaches emerged in the late 19th century with ovarian removal in premenopausal women. Dr. Marc Lippman, MD, explains that major advances came with the ability to measure hormones through radioimmunoassays in the 1960s.

Dr. Lippman describes how endocrine therapies evolved from surgical organ removal to drug treatments. He states, "Drugs such as what was commonly referred to as anti-estrogens were developed." These medications interfere with estrogen action and cause breast cancer regression in appropriate patients. Dr. Marc Lippman, MD, emphasizes that these treatments moved from metastatic disease to adjuvant settings, profoundly improving survival rates.

Breast Cancer Prevention Strategies

Dr. Marc Lippman, MD, presents compelling data on breast cancer prevention through hormonal interventions. He reveals that anti-hormonal therapies can prevent 60-75% of all breast cancers when used for five years. Dr. Marc Lippman, MD, explains epidemiological evidence showing later puberty onset correlates with significantly lower breast cancer risk. He notes that women whose periods start at age 16 have approximately one-third the risk of those starting at age 12.

The oncology expert discusses prevention trials involving tens of thousands of women. Dr. Marc Lippman, MD, states, "Using a drug called tamoxifen, women prescribed it for five years had about a 50% reduction in breast cancer." He emphasizes that aromatase inhibitors show even better results, preventing approximately 70% of breast cancers in postmenopausal women. Dr. Lippman addresses concerns about side effects, noting that most women cannot distinguish between active medication and placebo in blinded trials.

Tamoxifen vs Aromatase Inhibitors

Dr. Marc Lippman, MD, provides detailed comparison between tamoxifen and aromatase inhibitors for breast cancer treatment and prevention. He explains that aromatase inhibitors work primarily in postmenopausal women because functioning ovaries in premenopausal women can overcome the medication's effect. Dr. Marc Lippman, MD, notes that tamoxifen remains the option for premenopausal women, with protection lasting up to 20 years after five years of treatment.

Dr. Lippman addresses safety concerns about both medication classes. He acknowledges that tamoxifen carries a 1-2% risk of deep venous thrombosis and approximately 1 in 150 risk of endometrial cancer after five years of use. However, he emphasizes that aromatase inhibitors "are not associated with any important organ system toxicities." Dr. Lippman tells Dr. Anton Titov, MD, that risk-benefit analysis strongly favors these medications given their dramatic risk reduction capabilities.

Combination Therapies and Treatment Duration

Dr. Marc Lippman, MD, discusses modern combination approaches to hormonal breast cancer treatment. He explains that CDK4/6 inhibitors combined with aromatase inhibitors dramatically increase both response rates and duration in metastatic disease. Dr. Marc Lippman, MD, states that these combinations are becoming standard because they're "vastly more effective" than single agents alone.

Dr. Lippman addresses treatment duration questions for Dr. Anton Titov, MD. He explains that in metastatic settings, endocrine therapies continue until disease progression due to minimal toxicity. For adjuvant treatment, five years became established through empirical trials showing superior outcomes compared to shorter durations. Dr. Marc Lippman, MD, notes that combining GnRH agents with tamoxifen or aromatase inhibitors proves more effective in premenopausal women with poor prognosis, typically given for about three years.

Long-Term Recurrence Risks

Dr. Marc Lippman, MD, presents crucial information about long-term recurrence risks in estrogen receptor-positive breast cancer. He makes a striking statement: "For estrogen receptor-positive breast cancer, which is the majority of breast cancers, the answer probably is you're never cured." Dr. Lippman references studies following over 100,000 women showing recurrence rates continue as a straight line upward for 25 years after initial treatment.

Dr. Marc Lippman, MD, explains that bone marrow examinations reveal persistent breast cancer cells in essentially all patients with ER-positive disease. Dr. Marc Lippman, MD, discusses environmental factors influencing recurrence years after diagnosis. He tells Dr. Anton Titov, MD, that obesity, metabolic syndrome, diabetes, depression, and stress all conclusively increase recurrence rates. Remarkably, Dr. Lippman cites randomized trials showing stress management through cognitive behavioral therapy reduces recurrence rates a decade later.

Environmental Estrogens and Risk Factors

Dr. Marc Lippman, MD, addresses concerns about environmental estrogens and their role in breast cancer risk. While acknowledging environmental estrogens exist in plastics and other products, he expresses skepticism about their quantitative contribution to breast cancer risk. Dr. Lippman points to Asian populations with high soy consumption showing no increased breast cancer risk as evidence that endogenous estrogens overwhelm these environmental exposures.

Dr. Lippman provides important context about estrogen's role as a cancer promoter rather than carcinogen. He explains the historical distinction between carcinogens that cause DNA damage and promoters that enhance cancer development. Dr. Lippman uses the example of BRCA mutation carriers, noting that castration dramatically reduces their breast cancer risk because estrogens aren't present to promote cancer development from genetic predisposition. This framework helps understand why reducing estrogen exposure through medications provides such powerful protection.

Full Transcript

Dr. Anton Titov, MD: Hello from New York! We are with Dr. Marc Lippman, an eminent expert on the endocrine treatment of breast cancer. We will discuss hormonal treatment of breast cancer.

Dr. Marc Lippman is a Professor of Oncology and Medicine at Georgetown University in Washington, DC. Professor Lippman is a pioneer in the endocrine treatment of breast cancer. He holds board certifications in endocrinology and metabolism and medical oncology.

Dr. Marc Lippman obtained his MD from Yale University and did a residency in medicine at Johns Hopkins University and a fellowship in endocrinology at Yale University and at NIH.

Dr. Lippman's interest in the rigorous science of endocrinology, coupled with his practical interest in improving breast cancer treatment, has set him on a remarkable path of discovery and many distinguished leadership academic positions.

Dr. Lippman was Head of the Medical Breast Cancer Section at the NIH, Professor, and Chair of Internal Medicine at the University of Michigan, Professor of Medicine and Chair of Medicine Department at the University of Miami, and Deputy Director of the Sylvester Comprehensive Cancer Center at the University of Miami. He was also a Professor of Medicine and Pharmacology and Chair, Department of Oncology, at Georgetown University in Washington.

Professor Marc Lippman published over 400 articles in peer-reviewed medical journals in oncology and has received numerous national and international awards for his works on endocrine aspects of breast cancer. I also strongly recommend reading Dr. Lippman's autobiographical note called "Chaos theory and a career in medicine," which you can find online.

Dr. Anton Titov, MD: Professor Lippman, hello and welcome! Professor Lippman, you created the first model of hormone-dependent human breast cancer, and you've been at the forefront of hormonal breast cancer treatment ever since. Could you please give a high-level overview of the history and the presence of breast cancer treatment with hormonal therapies?

Dr. Marc Lippman, MD: Sure. It's been appreciated for about 300 years that hormones played some role in breast cancer. Epidemiology studies in Verona, Italy, in the 17th century showed a difference in the incidence of breast cancer amongst nuns compared to women who weren't in nunneries. The person making this observation correctly attributed this to some sort of use of the breasts.

The first classical way people think of understanding endocrine therapy was done in the late 19th century, when someone first thought that perhaps removing the ovaries might have a beneficial effect on breast cancer. That turned out to be exactly the case. A small series of women who had their ovaries removed—obviously premenopausal women—some of them showed enormous objective responses to this. It was very gratifying.

But the real science of this took many years to uncover because people didn't know how hormones worked. Not only did they not know how hormones worked, but they weren't able to even measure them. The concentrations of hormones required the invention in the early 1960s of radioimmunoassay and radioreceptor essay. Suddenly, endocrinology became a science.

Suddenly, it was possible to measure incredibly low concentrations of all kinds of steroid and peptide hormones. Feedback loops became clear. And it became very easy to understand that breast cancer was a hormone-dependent illness.

It became appreciated that at puberty, a woman's estrogen levels rise, and she develops breasts. It was appreciated shortly after that if you gave a man estrogens, he would grow breasts. The outstanding observation is that if I gave you, Dr. Titov, estrogens, you would grow breasts. But you wouldn't turn into a breast. You would have limits on growth.

That's exactly what happens to women. At puberty, they develop breasts, and even though they bathe in estrogens for the next seven or eight decades of their lives, their breasts don't particularly change. Breast cancer remembers that phenotype some of the time. Breast cancer remembers this responsiveness to estrogens, except when you give a breast cancer estrogens, it has forgotten how to stop growing.

So it continues to grow and spread as long as it's stimulated. Therefore, it became clear in the 1940s that you could scientifically develop endocrine therapies for women involving the removal of organs like ovaries.

Of course, as I mentioned, in the adrenal glands, you have to substitute back glucocorticoids because they're essential for life. But the adrenals are the source indirectly of estrogens which can stimulate the breast. For many years, it was popular and very successful to remove the pituitary—hypophysectomy—which also by removing gonadotrophins and ACTH would result in false hormone levels and regressions of breast cancer.

The major advances in the 70s and 80s were to learn how to do these things without ablative surgery. Drugs such as what was commonly referred to as anti-estrogens were developed. There are several of those, interfering with estrogen action. When given to the right women, they result in breast cancer regression.

It's also clear that for almost all oncology, as things start to work in the more advanced disease settings for women with metastatic disease, the same therapies can be advanced to earlier stages of the disease. This is exactly what happened with endocrine therapy of breast cancer, obviously first used for patients with metastatic disease and then very imaginatively used to prevent recurrences of the disease when women had their primary breast cancer treated by mastectomy or lumpectomy.

Those trials, which are still being analyzed now 30 and 40 years later, resulted in profound improvements in survival. In fact, they have saved many women who would have otherwise died. The single greatest advance unquestionably in the treatment of breast cancer, which has resulted in extraordinary falls in mortality rate, has been the adroit use of either hormone therapy or, in some cases, chemotherapy to treat women at the time of their local therapy when breast cancer has not overtly spread to the rest of the body.

More recently, it's become clear that these endocrine therapies can prevent breast cancer. Though these treatments aren't used as widely as they should be, in my opinion, you can prevent 60 to 75% of all breast cancer in women by treating them for five years with therapies that interfere with their hormone levels. The data are unequivocal and very compelling. But unfortunately, these therapies aren't as widely used as they should be.

Dr. Anton Titov, MD: Professor Lippman, you mentioned that the prevention of up to 70% of all breast cancers could happen with anti-hormonal therapies. Could you please discuss more strategies to prevent breast cancer at the age of precision medicine?

Dr. Marc Lippman, MD: Certainly. It's not so much precision here because 100% of men or women will grow breasts before puberty if you give them estrogens. So it's nothing precise. Estrogens can stimulate about 100% of normal breast tissue. It's obvious.

Now, because that's the case, it's also been clear from all kinds of epidemiology studies that women who have a later onset of puberty have a much lower risk of breast cancer. This has been known for decades. For example, a woman whose period starts at age 16 has about one-third the risk of breast cancer of a woman whose periods started at age 12. Isn't that amazing? Four years difference has that big effect multiple decades later.

As people have gotten bigger from birth onwards, since height and weight control the onset of puberty, the onset of puberty in the United States is age 10. So there's no question that longer exposure to hormones increases the risk of breast cancer. It's just one of the reasons why western world women have much higher risks of breast cancer than people who lived in Asia in the previous century when their breast cancer risk was 10% of that of women living in the West.

As western lifestyle has swept over the world, we've seen gigantic increases in the risk of breast cancer. Because this is so clear, because we understand that these hormonal factors can strongly influence breast cancer, we know that women who have premature menopause have a lower risk of breast cancer. It became obvious when we had drugs that could interfere with estrogen action to try them in breast cancer prevention trials.

Those studies have been done involving multiple countries and involving tens of thousands of women. For example, using a drug called tamoxifen, women who are on an intent to treat basis were prescribed tamoxifen for five years. Not all of them took it. But if you compare the women who were prescribed tamoxifen for five years compared to women who didn't take it, they had about a 50% reduction in breast cancer. That's extraordinary.

And of course, as I've just gotten through saying, easily a third of those women didn't even take the pills for the five years. Similar studies have been done with other drugs which interfere with hormone action, so-called aromatase inhibitors. These drugs block the conversion of androgen precursors produced by the adrenal glands to estrogens.

These are very potent drugs, mostly for postmenopausal women. In studies using those drugs, easily 70% of all breast cancers were prevented with five years of use of those drugs. So they're extremely effective. The problem is that many women are afraid to use them, and many physicians are afraid to prescribe them because many of these drugs have been labeled as having serious side effects.

The fact is that in randomized, double-blind trials in which women cannot tell whether they're getting placebo or tamoxifen, or placebo or an aromatase inhibitor, the overwhelming majority of women cannot successfully identify whether they're on the treated drug or the placebo. So the most common side effect of one of these drugs is nothing. It's nothing.

Therefore, there's no reason not to try them, because if you have side effects and don't like them—if you feel hot flashes or don't feel right—if it occurs, stop the drug. No harm, no foul. But if most women would take these drugs and have no side effects whatsoever, and reduce the risk of breast cancer by 75%, it seems kind of silly not to try them, don't you think?

Dr. Anton Titov, MD: Absolutely. So it's a question of just inertia in clinical practice.

Dr. Marc Lippman, MD: Well, it's also because the other problem is it's one thing to treat someone with cancer. Patients with cancer have a horrible diagnosis; people are willing to suffer tremendous side effects. But if you're well and you're dealing with the statistical risk reduction, you don't want to have any side effects.

So a lot of literature, lots of garbage frankly that's on the internet, have scared people away from doing things that under most circumstances are harmless. Aromatase inhibitors are not associated with any important organ system toxicities. No heart, no liver, no kidney, no lung toxicities. There's no leukemia. They're not toxic drugs.

They can have subjective side effects in some women, but I repeat, the most common side effect is nothing.

Dr. Anton Titov, MD: Comparing tamoxifen, which is much widely known, with the aromatase inhibitors such as anastrozole, is anastrozole the more modern chemoprevention of breast cancer medication? How should the consideration be given?

Dr. Marc Lippman, MD: So, first of all, aromatase inhibitors really can't be used in premenopausal women. But the overwhelming majority of breast cancer are in postmenopausal women. So that's not a huge problem. You can't use aromatase inhibitors in premenopausal women because you have functioning ovaries.

If you reduce estrogen concentrations with an aromatase inhibitor, gonadotrophins go up, and you stimulate a functional ovary, and you make more estrogen, so you overcome the block. You can't do that in a postmenopausal woman because her ovaries don't work anymore. So her rising gonadotrophins don't increase estrogen concentrations. So aromatase inhibitors are primarily used in postmenopausal women.

Now, tamoxifen does rarely have some toxicities that are worrisome. One to 2% of women will have deep venous thrombosis and occasionally pulmonary embolus. That's a serious side effect—no question about it. But if you screen patients for those who've had previous histories of this, who are inactive, who have obesity, you can use tamoxifen reasonably safely.

One woman in 150 who takes tamoxifen for five years will develop low-grade endometrial cancer readily treated by hysterectomies. Now, if you're a normal person and you don't have any risks at all, and someone tells you a drug might cause endometrial cancer, you might say I'll have nothing to do with it. But of course, that has a risk-benefit ratio.

If you can reduce your risk of a lethal disease, breast cancer, by 50%, you run half of the 1% risk of getting an easily treatable endometrial cancer. Obviously, if you're playing the odds, that's what you would do here. But most people don't play odds like that correctly. They just get afraid and don't do things.

Dr. Anton Titov, MD: So for postmenopausal women, tamoxifen versus anastrozole at this point—

Dr. Marc Lippman, MD: So for premenopausal women, tamoxifen does work as a chemoprevention agent. That was proven in two huge studies involving north of 10,000 patients. The risk of breast cancer is much lower in women under the age of 50 than we think tragically with premenopausal breast cancer.

The median age of breast cancer is 56; actually, most patients are postmenopausal. But what's remarkable in these prevention trials, which had been followed up for many years, is that the five years of tamoxifen, the protection persists for 20 years—20 years after that.

So in many cases, you might say, why don't we wait till women are postmenopausal and then give them an aromatase inhibitor, which is more effective, and you're going to be preventing most breast cancer? That makes sense to me too. I would take half a loaf here.

These treatments just aren't widely used to prevent breast cancer. And it's very unfortunate because breast cancer is still the most common malignancy of women overwhelmingly, and the morbidities associated even with non-invasive breast cancer are substantial.

Dr. Anton Titov, MD: There are two main sources of estrogen: the ovaries and body fat. There are three perhaps major classes of hormonal medications to treat breast cancer: LHRH agonists, or GnRH agonists they're also called; selective estrogen receptor modulators, SERMs; and aromatase inhibitors. How to choose between these medications to reduce estrogen effects in breast cancer?

Dr. Marc Lippman, MD: You're correct, and your list is incomplete because now people separate drugs like tamoxifen or SERMs—selective estrogen receptor modulators—from a class of drugs called SERDs, selective estrogen receptor down regulators. Fulvestrant is the main drug of that. Still, they will shortly be orally available SERDs over the next couple of months, which are even more active than fulvestrant and are very exciting.

But the exact answer to your question is randomized trials. These are empiric questions that look at both efficacy and toxicity and try to make statements about the most effective. In metastatic disease for postmenopausal women, aromatase inhibitors are somewhat more effective than tamoxifen and are usually the first line.

Except now, because of other well done randomized trials, the addition of another class of drugs—CDK4/6 inhibitors—drugs that block one pathway of resistance, have been proven overwhelmingly that when combined with an aromatase inhibitor, dramatically increase both response rates and double response duration. So that's extremely exciting.

And those drugs have now been promoted to adjuvant trials, where they are also very encouraging. So the single use of tamoxifen or aromatase inhibitors is probably going out of fashion as single agents because it seems that these combinations, at least with the CDK4/6 inhibitors, are vastly more effective.

Dr. Anton Titov, MD: And why are these medications, such as tamoxifen or aromatase inhibitors, LHRH or GnRH agonists, used in combination? What is the rationale for their use together? And perhaps there are some instances when they should not be used in combination at this point.

Dr. Marc Lippman, MD: To best answer your question, you need to separate whether we're talking about metastatic disease or the adjuvant setting. In the metastatic disease setting, unless toxicity intervenes—which is pretty uncommon—the drugs continue till the patient progresses. There's no reason to stop them.

For the most part, as I've already said, the toxicities of these therapies are very minimal, vastly offset by the risks of progressive metastatic disease. So endocrine therapies can be given endlessly until patients progress. In the old days, when patients were treated by ovariectomy or hypophysectomy, there were certainly patients who responded more than a decade.

So obviously, you would continue the current therapy until patients didn't respond anymore. In the adjuvant setting, most of these studies once again have been done empirically over many decades. So when tamoxifen was first used to prevent a recurrence, people gave it for a year, and it worked.

Then people did studies that compared two years to one year, and two years was better. Then people compared five years to two years, and five years was better than two years. So five years became something of an established empirical standard for breast cancer treatment.

Some of the new studies in the adjuvant setting with CDK4/6 inhibitors have been for shorter periods. The reason for that is partly because the CDK4/6 inhibitors are so fiendishly expensive, and no one wants to pay three, four, or $5,000 a month. So much of this isn't an efficacy issue but an expense issue.

And that's, in my opinion, extremely unfortunate that that kind of decision is made under those circumstances. In terms of combining these therapies, recently, a series of studies have proven that in premenopausal women, if you interfere with ovarian estrogen production with a GnRH agent, as you mentioned, or just by ovariectomy, then if you give an aromatase inhibitor or tamoxifen, it's far more effective than giving the tamoxifen alone.

So for poor prognosis younger women, whom we are treating to prevent breast cancer recurrence, the fact is that usually it's combined when possible with GnRH agents to suppress the ovary. And those treatments are usually for about three years because that's all people want to tolerate.

Now, there's one issue here that you're dancing around, you haven't brought up, but which I want to bring up. It's extremely important. For cultural reasons have nothing to do with biology, people in the United States have come to understand if you're free of disease for five years, all will be well.

They've used five years as some sort of line in the sand for being cured of a disease. And it's a pretty good standard. For example, for colorectal cancer, if you go five years after your surgery and you haven't recurred, you're not going to. Five years is a great number.

But there's nothing set in stone about five years. If you look at the most common cancer in young men, testicular cancer, probably if you go two years and you don't recur, you're cured. Probably three years is more than enough. For head and neck cancers, if you go five years, you're cured.

For acute leukemia, probably two or three years is more than enough. For B-cell lymphomas, three or four years probably enough to have cured most patients. For estrogen receptor-positive breast cancer—ER-positive breast cancer, which is the majority of breast cancers—the answer probably is you're never cured.

Let me repeat that. You're never cured. In studies that have been done involving more than 100,000 women with ER-positive breast cancer, if you look at their recurrence rates following the completion of five years of induction treatment—surgery and an induction treatment, tamoxifen or an aromatase inhibitor—those women for the next quarter of a century (that's how long the studies had been) for the next 25 years, their recurrence rates are a straight line going up.

There is no evidence for a cure of estrogen receptor-positive disease. Now, if you're diagnosed when you're 60, and 25 years later you haven't yet recurred, the fact that you might still be at risk of recurrence is a little irrelevant because we get to be 95. You're going to die of something else.

But the point that I'm making is, if you look in the bone marrow of estrogen receptor-positive breast cancer patients who have been "cured" of their disease—they had early-stage breast cancer—and you look at their bone marrow, essentially all of them have breast cancer cells in their bone marrow.

So the problem of estrogen receptor-positive breast cancer, which is the majority of breast cancer, isn't so much getting every last cell. It doesn't happen. It is that the woman somehow exists with some viable breast cancer cells in her body, which unfortunately in some women reactivate.

Sometimes people use the word dormancy for these cells, but we know they're there. And we also know that many things in the environment that can occur years after a breast cancer diagnosis can influence whether she recurs or not years later. If the woman gets obese, if the woman gets metabolic syndrome, if the woman gets diabetes, if the woman gets depression, if the woman is unduly stressed—all of these things conclusively have been shown to increase recurrence rates.

And the only way you can recur is if there were breast cancer cells present that could recur. And these things can occur years, decades later. One of the great mysteries, actually one of the areas that I work in, has been to understand how these macro-environmental things—distress, depression, obesity, diabetes—how could they talk to breast cancer?

How does the breast cancer cell living in your bone marrow know that you had a bad day? How does the breast cancer cell living in your bone marrow know that you had a pepperoni and cheese pizza instead of the kale salad? It's a very important question and speaks to other means of preventing breast cancer recurrence because we know it's not hocus pocus.

It's randomized trials. We know that women who lose weight have a lower recurrence rate. We know that women whose diabetes is treated have a lower recurrence rate. We know that women who've had stress management in randomized trials, unbelievably, we are certain that women who have stress management following their breast cancer diagnosis have lower recurrence rates than women who don't.

That's astounding. I mean, you need a sense of wonder to say, how could it be that 12 weeks of talking therapy, cognitive behavioral therapy that reduces distress—which is good for everybody—would everybody benefit from that? How could it be that those women who did this have had less breast cancer ten years later? And the data are compelling.

So these are critical issues in understanding hormone treatment of breast cancer. One of the reasons people have sometimes proposed continuing endocrine therapy beyond five years is that there are trials that have suggested giving aromatase inhibitors for ten years. And this makes perfect sense, assuming there's no toxicity, because we know that we don't eradicate every last cell for ER-positive breast cancer.

There's no evidence that patients who continue will relapse at a reasonably low rate, thank goodness, for decades to follow.

Dr. Anton Titov, MD: This is very important, but there are also estrogen mimetics and environmental hormones in the environment that people are talking about. Even in thermal paper, there are estrogen mimetics. So you take your boarding pass, and that's a thermal paper; you take a receipt from the store—it has thermal paper. What about the environmental hazards that mimic estrogen hormones?

Dr. Marc Lippman, MD: Yeah, this is a very important question. But I tend to be relatively skeptical. I agree that there are environmental estrogens. They're the things that get into plastic bottles. They're all kinds of stuff. Some very fine investigators have shown these things. That's not the question.

The question is, how quantitatively do they contribute to breast cancer risk? One way to get at that is to look at environments where people are exposed to these things. So one of the main environmental estrogens was soy-like products from soybeans and stuff like that. But if you look at, for example, Asian women who do or Asian women who don't use soy products, it's no difference in breast cancer risk.

And probably, in my opinion, at least in a western lifestyle, these relatively small environmental estrogens are overwhelmed by endogenous estrogens. It's sort of like a mole on your neck. I just don't think it adds too much. But that could remain to be proven. And I would say that is a potentially still open question.

There's one other thing that we need to discuss to answer your question honestly. And that is, you need to understand that estrogens are fundamentally considered to be promoters of cancer. To understand what I'm talking about, you have to go back to literature that is 60 or 70 years old to understand the difference between a carcinogen and a promoter.

By definition, a carcinogen is something that causes cancer. And usually, it's something that causes DNA damage. A classic example you may recall from epidemiology was from chimney sweeps. For a long time in England in the 17th and 18th centuries, it was known that chimney sweeps all got scrotal skin cancers.

And why do they get it? Because they're climbing up and down chimneys, they're getting these coal tars, which contain nasty things. And they didn't shower as well as they might; they accumulated in certain parts of their body surfaces, and they all got cancers. That makes perfect sense.

And so people started to study that. This is data from the 50s and 60s, but it's wonderful literature. It's fascinating. One of the models they used was the mouse ear. Mice have little ears, and they would paint these ears with all these coal tars. And sure enough, the mice would all get skin cancers on their ears.

They did lots of structure-activity relationships, different amounts, different doses. And eventually, you could find a dose for most of these carcinogens if you painted less and less; eventually, the animals hardly surprisingly didn't get cancer. So you had a dose-response.

Then they did interesting things: if they came along and painted a dose of this carcinogen on the ear at a low dose that would not cause cancer, and then they came along and started scratching or irritating the ear, the animals all got cancer. But if they didn't give the low dose of the carcinogen and they just scratched and irritated the ear, they didn't get cancer.

So the scratching and irritating was a promoter of a carcinogen. And in that same sense, estrogens promote already genetic events that occur in women. For example, formal proof of this is that for women carrying BRCA mutations, women who have the breast cancer gene have a 90% chance of getting breast cancer in their lifetime.

If those women are castrated—I'm not recommending it—but if they happen to be castrated, their risk of breast cancer is minimal because the estrogens aren't there to promote the genetic event. Why did I give you this long story? One, it's interesting, but number two, I told you this story because now it comes back into environmental estrogens.