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.

 

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 perhaps high-level overview of the history and the presence of breast cancer treatment with hormonal therapies?

 

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. Can you believe it showed a difference in the incidence of breast cancer amongst nuns compared to women who weren't in nunneries? And the person making this observation correctly attributed this to some sort of use of the breasts. The first classical way people think of people 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. And that turned out to be exactly the case, a small series of women who had their ovaries removed. These were obviously premenopausal women. Some of them showed enormous objective responses to this. It was very, very gratifying. But the real science of this took many, many, 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 60s 1960s, a radioimmunoassay and radioreceptor essay, and 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, very easy to understand that porn breast cancer was a hormone-dependent illness. It became appreciated, of course, that at puberty, a woman's extra girl's estrogen levels rise, and she developed stress. And it was appreciated shortly after that that if you gave a man estrogens, he would grow breasts. And of course, the outstanding, though perhaps subtle observation about this is that if, for example, I gave you, Dr. Titov, if I gave you estrogens, you would grow breasts. But you wouldn't turn into a breast. You would have limits on growth. And that's exactly what happens to women. At puberty, they develop breasts in their breasts, even though their bathe in estrogens for the next seven or eight decades of their lives 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. And therefore, it became clear in the 1940s, I think originally, that you could scientifically develop endocrine therapies for women involving the removal of organs 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. And for many years, it was popular and very successful. To remove the pituitary do hypothesis ectomy, which also by removing gonadotrophins and ACTH would result in false and 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 several of those, interfering with estrogen action. And when given to the right women, they result in breast cancer regression.

 

It's also this clear story 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. And 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. And those trials, which are still being analyzed now 30 and 40 years later, resulted in profound improvements in survival. And in fact, jurors have many women who would have otherwise died. And the single greatest advance, 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 that the rest of the body. And 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, 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.

 

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?

 

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 1/3, 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. And 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. And 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. And those studies have been done involving multiple countries and involving 10s of 1000s of women. And for example, using a drug called tamoxifen, women who are on an intent to treat basis will prescribe 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 55 0% reduction in breast cancer. That's extraordinary. It'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. And in studies using those drugs, easily 70%, seven 0% 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. And therefore even, there's no reason not to try them, because they're the side effects if you have them. People don't like they feel hot flashes. They don't feel right or something. 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?

 

Absolutely. So it's a question of just inertia in clinical practice.

 

Well, it's also because the other problem, of course here, is it's one thing to treat someone with cancer patients with cancer, it's a horrible diagnosis, people are willing to suffer tremendous side effects. But if you're, 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, the lung toxicities. There's no leukemia. They're not toxic drugs. They cannot have subjective side effects, and some women, but I repeat, the most common side effect is nothing.

 

Comparing Tamoxifen, which is much widely known with the aromatase inhibitors such as anastrozole, does anastrozole, you know, is it the more modern chemoprevention of breast cancer medication? How should the consideration be given?

 

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, don't increase your estrogen concentrations. So aromatase inhibitors are primarily used in postmenopausal women. Now, Tamoxifen does rarely has some toxicities that are worrisome. One to 2% of women will have deep venous thrombosis and occasionally pulmonary embolus. Now that's a serious side effect—no question about it. But if you screen patients, for patients 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 know, you might say I'll have nothing to do with it. But of course, that has. It's 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, what you would do here, but most people don't play odds like that correctly. They just get afraid and don't do things.

 

So for postmenopausal women, Tamoxifen versus anastrozole at this point,

 

so for premenopausal women, Tamoxifen does work as a chemoprevention agent that was proven in two huge studies involving, as I said, 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 in most patients are postmenopausal. But the benefits of 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, Well, why don't we wait till women are postmenopausal and then give them an aromatase inhibitor which A is more effective and be you know, you're going to be preventing most breast cancer, and that makes sense to me too. I would take half a loaf here. These Trump's 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 then the morbidities associated even with non-invasive breast cancer are substantial.

 

There are two main sources of estrogen, you know, the ovaries and body fat, and you know, 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. Well, these

 

Are 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 surds ser DS, selective estrogen receptor down regulators if you wish for the strength is the main drug of that. Still, they will shortly be orally available surds over the next couple of months, which are even more active than full for strength and are very exciting. But the exact answer to your question is randomized trials, 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 are usually the first line except now because of other well done randomized trials, the addition of another class of drugs CDK, four, six 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 that single agents because it seems that these combinations, at least with the CDK, four, six inhibitors are vastly more effective.

 

And why are these medications, such as you know, tamoxifen or aromatase inhibitors LHRH or GnRH agonists I 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. So there,

 

to best answer your question, you need to separate whether we're talking about metastatic disease or the adjuvant setting. We're giving these drugs to prevent recurrence in the metastatic disease setting unless toxicity intervenes, which is pretty uncommon. Pretty uncommon. The drugs continue till the patient progresses. There's no reason to stop them. Most 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 Oh, very ectomy who are for ectomy? There were certainly patients who responded more than a decade. Their patient, I mean, so obviously, you would continue in 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 that when Tamoxifen was first used to prevent a recurrence, people gave it for a year. And it worked. So then people did studies that have compared two years to one year and two years was better than 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 CDK, four, six inhibitors have been for shorter periods. And the reason for that is partly because the CDK, four-six 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 anan 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 Gianna 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 that for poor or 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 studies. 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. 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 gonna five years is a great number. But there's nothing set in stone about five years. And 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, and you're cured.

For acute leukemia, probably two or three years is more than enough, and firm 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, two marks 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, is that 25 years later, and 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. So 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, quote, 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. And 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? So 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, 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 they're 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 to relapse will be at a reasonably low rate, thank goodness, for decades to follow.

 

This is very important, but there are also estrogen mimetics and environmental horses in the environment that people are talking about. Even the I read 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 sharpened has a thermal paper. What about the environmental hazards that mimic estrogen horror hormones?

 

Yeah, this is a very important question. But I, I tend to be relatively skeptical. I agree that their environmental estrogens are true. They're the things that get into plastic bottles. They're all kinds of stuff. They've some very, 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 that that could remain to be proven. And I would say that 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. And 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, 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 screw hole skin cancers. And why do they get because they're climbing up and down chimneys, they're getting these cold TARS, which contain nasty things? And they didn't shower as well as they might; they accumulated in certain parts of their body surfaces, their body, and they all got cancers. That makes perfect sense, okay. And so people started to study that this is data from the 50s and 60s, but it's wonderful literature. It's fascinating. And one of the models they used was what was called the mouse, your skin. Mice have little ears, and they would paint these ears with all these cultivars. And sure enough, the mice would all get skin cancers on their ears. And 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 in the animals, hardly surprisingly, didn't give your cancer. So you had a dose-response, right? Then they did interesting things if they came along, and they painted a dose of this carcinogen on the ear at a low dose that would not cause cancer. And then they came along, and they started doing this, you're rotating the ear or scratching it, the animals all got your cancer. But if they didn't give the low dose of the carcinogen, and they just scratched and irritated the year, they didn't get cancer. So the scratching and irritating was a promoter of a carcinogen that 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 or 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. Okay. 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.

Some environmental estrogens are not just promoters that make the mammary gland grow. But some of them conform. ADEQ ducts are to DNA. And they form adducts onto DNA and are steered to the wrong places. Because these estrogens bind to the estrogen receptor, they translocate to the nucleus they go to transcriptionally active sites. And because some of them are catacomb, estrogens can cause mutations. They bind to DNA, which explains why a different estrogen that was notorious dioctyl, still Bestival DS caused cancers in women, not because it promoted tumors, Puppy crested cause DNA adducts. It was a true carcinogen.

 

Very interesting. What about the purchase? It is interesting. Yeah, it's a fascinating story. And it certainly, you know, tells you about the complexity on the one hand, but the simplicity on the other.

 

Right, and it certainly explains exactly why it explains why estrogens are promoters, in the same sense that a low dose carcinogen will cause skin cancer in the mouse ear. If you have exposure to certain carcinogens, you take away the estrogen promotion with an aromatase inhibitor or Tamoxifen-like drug. You don't get cancer because you're not promoting them. You're raising an extremely important point. An interesting point. A long time ago. People were trying to relieve menopausal symptoms in women, and they would give them estrogens when their estrogens went away naturally. And they found that when they gave women estrogens, like Premarin, wonderful news, women felt great. It felt great. You know, they didn't have menopausal symptoms. Their hot flashes went away. They were happy and always well with the world, except they all got endometrial cancer. They were indeed low-grade and easily treatable. But the risk of getting into mutual cancer went through the roof when you started giving women estrogens because they promoted the growth of the endometrium in the uterus. So, some wise person said, why don't we give them estrogens plus progestins because we all know that in the normal menstrual cycle, the prolific proliferative endometrium that you have during the first half of the menstrual cycle is converted to a non-proliferative, secretory phase. When you get progestins during the luteal phase of your menstrual cycle, and then when it stops, you shed your endometrium, and a woman has her menstrual You're in and all as well with the world. So everybody said, no problem here. Let's just give women estrogen, so they feel good. And let's give them progestins on top of that, so they won't get endometrial cancer. Makes perfect sense. Except it's not true. They don't get into material cancer, but they get even more breast cancer. Because, unlike the uterus, progestins stimulate the growth of the normal breast. So if you do little needle biopsies of the breast and measure division mitotic rates in the breast in a pre-menopause woman, it's highest during the luteal phase of her menstrual cycle, it goes up so that it was already known decades ago that progestins would likely stimulate the breast.

Additionally, in randomized trials that were done many years ago, it was shown that breast density, a sign of proliferation on mammography, went up when you put women on estrogens plus progestins, compared to estrogens alone. So it was entirely predictable. That was when someone finally got around to the Women's Health Initiative trial, which randomized 8000 postmenopausal women to placebo or 8000 postmenopausal women to estrogens plus progestins. The sad result of that study was that after five years of estrogen plus progestin, so-called hormone replacement therapy, breast cancer incidence was double-doubled. So estrogens plus progestins are horrible drugs for breast cancer risk. Amusingly women who had already had a hysterectomy are for whom there was no reason to give progestins because there was no uterus to stimulate. A second Women's Health Initiative trial was done in which women who had had a hysterectomy were randomized to Premarin and estrogen versus nothing. And amusingly and wonderfully, in that study, there was no increase in breast cancer risk with Premarin alone. So that the real risk factor is progestins. Progestins are horrible drugs for breast cancer promotion. Plus, they're terrible for vasculature and heart disease. They just shouldn't be given to anybody, mostly, is what I think.

 

What about opposing progestins? I mean, in the same as anti-estrogen medications, antiprogestin medications, and breast cancer. So let's

 

Say there are some anti progestins and this has been a very politicized environment because if you think about it, just for a moment, you'll realize that a drug that box progestin action would be a perfect drug to induce an abortion in premenopausal, and this is so these drugs are you 486 and others were developed by people like the population cancel as a cheap contraceptive, you know, or as a morning-after pill if you wish. And so they've enjoyed a very unpleasant reputation. And it's been hard to get some studies done in some cultures because of this. Anti progestins as a treatment for breast cancer have had some mild success. They do have activities as steroid agents. They haven't been very successful, but it makes sense what you're saying many breast cancers are progesterone receptor-positive as well as being estrogen receptor-positive. The same could be said about drugs that target the androgen receptor we first showed. I hate to say nearly 50 years ago that it was easy to detect androgen receptors in breast cancer. We published that in the 70s. And more recently, there have been some trials of anti-androgens are antigens that are non-virilizing. In women with breast cancer and particularly triple-negative breast cancer, they've been some successes there, and that's a story that's unfolding.

 

Aromatase inhibitors can be of two types. So exemestane is type one or steroidal or reversible aromatase inhibitor anastrozole. letrozole I example of type two non-steroidal reversible aromatase inhibitors, how to choose correct AI's for specific breast cancer patient and makes no

 

Difference whatsoever. Alright, for the aromatase inhibitors, it makes no difference. This is a case of drug companies going up Martino trying to lobby one against the other just because they're meat two drugs. Randomized trials of one AI versus another suggest no difference in my view. They are almost completely cross-resistant. Rarely a patient who says gee, this drug makes me feel terrible. I'll try a different one, and sometimes, either because it's lucky or psychological, or there's some minor difference in the pharmacology I'm switching to another one, works. Still, they're almost equally efficacious, equally efficacious.

People are very. So there's only one surd around now that's full of a strand, which is a pain in the ass because you have to take it by injection, and you're behind once a month, and it's a little bit uncomfortable. But the main problem with full strength is that its pharmacology is such that you really, really at the very edge of effective concentrations. It's very hard to get enough drugs into people. And so it's very interesting that in the newest trials of oral surgery, which are more potent, it turns out that many of these drugs seem to work in patients who have progressed on fulvestrant or full the strand failures, and that everybody's excited about these drugs. I'm very excited about them. And it remains to be seen how they will replace fulvestrant. Maybe they'll become frontline. The trials being discussed are underway with CDK, four, six inhibitors. So this may be a very important step forward in more effective treatment for women with breast cancer. I'd rather not use brand names because they're still in development. But the most recent ones have been had already been in randomized trials. I suspect they're either about to be in front of the FDA. I think approvals this spring or summer are likely for at least one of them. Yeah, that's great. And I mean, these are often used in excuse me, this is a Robin used in metastatic disease. And as I've said several times in our discussion today, the natural history of these things is to immediately try to advance them to the adjuvant setting. And I suppose even consider them in prevention trials, but no one wants to do prevention trusted, too expensive. They're too costly. There's too much of a downside. I'm truck companies desperately afraid of them. And that's unfortunate, but it's the truth. And the problem with adjuvant studies is good news. The good news is that if you take patients with early-stage breast cancer, even though I've told you that they can continue to relapse for decades, the fact is if you take women who discovered by mammography, mammography who have !!! Toned and zero breast cancer, and you put them on standard endocrine therapy, you're not going to see 10% of them recur in five years. So if you're going to try to improve on that, think of the 10s of 1000s of women you have to treat and how long you have to follow them. So the data here will be very slow and coming and very expensive to obtain.

 

When breast cancer happens in premenopausal women, production of estrogen by the ovaries can be suppressed by medications and also by surgical removal of ovaries, so medications LHRH inhibitors generation LHRH agonists, or GnRH agonists, such as Goserelin Leuprolide surgeries called BSO bilateral cell pingo for ectomy, how LHRH agonists used in those settings and how to choose between medical and surgical suppression of ovarian cancer. Ovarian?

 

Yeah, I got the question. It's probably not rationally, though, particularly some women, particularly younger women, may already be at risk, genetic risk of breast cancer, they're happy to have their ovaries out. So that very ectomy makes sense because they feel like they're at risk of ovarian cancer. The second issue, of course, is that some much younger women eventually would like to potentially go back and have children, and if your ovaries are out, that's a little bit tricky to do. So, you know, those people would be better served by suppression in terms of the various the two main drugs that are useful, to be honest with you, it's mostly determined extremely, unfortunately, by insurance companies that say we'll pay for one and not for the other. I mean, that's nonsense. That's one of the critically horrible aspects of care in this country. I'm just gonna get on a soapbox here. You can't stop me. You can just edit this out of the conversation. And that is that. That is if you look at reasons why physicians quit medicine or burnout. One of the most common reasons given is endlessly dealing with third-party payers and trying to justify with so-called peer-to-peer discussions with people who are your peers and don't know what they're talking about, about how to treat patients. Eventually, it gets people going crazy. I've had any number of set settings where I put a patient on Lupron this, and No, no, you can use the other one. And you say why? And they say well because that's what we're going to pay for, and it endlessly makes you crazy, endlessly makes you crazy.

 

Hormonal treatment for breast cancer is called New adjuvant chemotherapy when chemotherapy is given before surgical operation, and home immunotherapy after surgical operation for breast cancer is called adjuvant therapy. How to select new adjuvant and adjuvant chemotherapy hormonal therapy protocols for treating breast cancer, are they the same.

 

So you can use Neoadjuvant therapy and cranial neoadjuvant therapy, chemotherapy or adjuvant chemo or adjuvant endocrine so you can do both. There's no difference in survival in randomized trials that you can't get away from having suggested neoadjuvant therapy and adjuvant therapy. So it doesn't matter enormously what you do. But in terms of survival, but in the neoadjuvant setting, you have many, many, many advantages. First of all, it's easy for patients with larger tumors to downstage them. So a patient who might not be suitable for lumpectomy and breast conservation. Almost all patients will respond to neoadjuvant chemotherapy, and most patients will respond to neoadjuvant endocrine therapy so that tumors will shrink. One, it shows you what therapy will work. So can guide therapy once the tumors are removed. From a research point of view, were extremely enthusiastic about neoadjuvant therapy because you have an initial biopsy. And then, when the patient goes to surgery after the neoadjuvant therapy is completed, you can get more tissue. And you can see the effect of your treatment's perturbation was. And it's a tremendously valid way to develop new therapies. There is something called excuse me. I'm talking a lot. There's something called pathologic complete response. And miraculously, depending on the disease subtype 3040 5060, occasionally 70% in some subsets of patients will have every last cancer cell disappear from the breast when you give them neoadjuvant therapy. That's fabulous. And PCR is a tremendous predictor of survival. So we know that patients who have a PCR don't commonly need additional systemic therapy after the surgery, which is wonderful. So it's very useful for guiding therapy, but there's not a big survival advantage, giving it before or after, at this time. Neoadjuvant endocrine therapy doesn't induce complete responses as often, mostly because the therapy probably isn't given for long enough. And now, some wonderful new adjuvant trials are going to go for six or eight months to see the effect of longer-term neoadjuvant endocrine therapies, and I await those trials with tremendous interest. Finally, in the United States, we amazingly over-treat patients. It's just amazing. You see people in their 80s, they're informed and not well, and people are talking about mastectomy and radiation therapy and all this other stuff. But there's a lovely study done in England for women over 80 who were diagnosed with breast cancer that was ER-positive, over 80 ER-positive, they put them on Tamoxifen, no surgery, no radiation, just a pill. And the majority of those women died of something else.

In other words, Tamoxifen for these elderly women with indolent ER-positive breast cancer was enough to control their disease till something else got them. And I think that that's a, so that speaks to that. I mean, that's the mother of all neoadjuvant studies because you're giving it before any therapy, and you're just not quitting. That so it's obvious that that can be very effective. Plus, it's Childsplay. To follow a woman to see if you're controlling the disease or breast, if she's got a lump, you can feel it takes thumb and index finger to tell whether she's doing well or not, right, just or your simple imaging test. So there's no emergency here. So neoadjuvant therapy in infirm patients could be very attractive in my mind, but it's not done so much in this country. England has led the way there.

 

No one's tried it there, man. Well, some years ago, I hate to say how many when we first developed neoadjuvant therapy at the NCI when I ran the breast cancer program there. We didn't know how to do it. Who knew no one had ever done it before. So we took women, and we said, we don't know how long to give it. So we'll just give it until we reach the best response and just keep giving them cycle after cycle. We don't care. And as long as we can measure what's going on, why would we stop right as long as the tumor is shrinking?

And interestingly, even though neoadjuvant regimens these days are usually four or six cycles of therapy, the median number of cycles, the best response in our hands was five Five, which means that half the women took 789 10 cycles to get to their best response. So that was very, very instructive. So I don't think even the best ways to do this had been fully, and maybe the best way is to base it on how the patient herself is doing, rather than on some preconceived cookbook regimen boil for half an hour.

 

Immunotherapy is, you know, making huge advances in several cancers certainly applied in breast cancer. You did some important work on the estrogen receptor and immunotherapy of breast cancer in terms of the estrogen receptor signaling in suppressing the immune response to cancer. Could you discuss that briefly, perhaps?

 

Immune therapy is very attractive. People love it. Then most women advocates feel that their immune system has failed them. They're very excited about immunotherapy trials. And suppose you look at the class of drugs, the only ones out there right now, the checkpoint inhibitors, in my opinion. In that case, the data are qualitatively not quantitatively qualitatively different for breast cancer versus other tumors. Suppose you look at checkpoint inhibitors given to patients with small cell lung cancer, patients with melanoma, stuff like that. Not all patients benefit. But many of the patients who benefit have prolonged, complete responses that can persist after you stop the therapy. Something has been set in motion in those tumors that has unblocked the immune system and has led to complete control of those tumors. And it's miraculous. It's wonderful. Unfortunately, it doesn't apply to all patients with melanoma. But there is a tremendous subset of these patients who now are five years or more out with metastatic melanoma, which used to be an absolute death sentence. Absolute death isn't wonderful. Breast Cancer doesn't do that. Take the checkpoint inhibitors, even for triple-negative breast cancer, which is the more responsive to immune therapies, in the metastatic setting. You can see some mild increases in response rate or duration, but they're not. In my opinion, they're not tremendous, and they're not maintained for long periods. Now, just published this week, Keynote, the keynote trial in the New England Journal, looked at a checkpoint inhibitor and triple-negative breast cancer in the adjuvant setting. And the data are positive. And it is practice-changing. I've discussed this with my colleagues, and most of them say, Okay, we're going to do this, we're going to add the immunotherapy, but there's no survival data yet. And if you look at the overall outcome, it's not miraculous. It's an improvement. It's a stepwise improvement. I'm not trying to denigrate it. And I'm not trying to say not to do it. But it does appear that there are other aspects of the immune system in breast cancer, which appear qualitatively different from many other kinds of cancer, which have yet to be completely worked out. And so, I think it's going to require other kinds of interventions, other forms of immunotherapy potentially, to get breast cancer to respond right now. I just don't think it's the same success story that we see in other tumor types.