#278 ‒ Breast cancer: how to catch, treat, and survive breast cancer | Harold Burstein, M.D., Ph.D.

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My guest this week is Dr. Harold Bernstein, who goes by Hal. Hal is currently a Professor of Medicine.

At Harvard Medical School. He earned his MD and PhD in.

Cellular immunology from Harvard Medical School as.

Well as a Master's Degree in History of Science from Harvard University.

Hal trained in Internal Medicine at the.

Massachusetts General Hospital before his Medical Oncology fellowship at Dana Farber Cancer Institute.

He joined the staff of Dana Farber and he is also on staff at.

Brigham and Women's Hospital, where he is a clinician and the Clinical investigator, the Breast Oncology Center.

His research interests include therapy for early stage and advanced stage breast cancer, healthcare for breast cancer survivors, and quality of.

Life and psychological issues among women with histories of breast cancer.

This is an episode I have wanted.

To do for a very long time.

As you know, I've already done an.

Episode or two on prostate cancer, and.

While prostate cancer is the second leading.

Cause of cancer death for men, it's no surprise that breast cancer is the.

Second leading cause of cancer death for.

Women and therefore this episode is long overdue.

In this episode, we talk about all.

Things related to breast cancer, beginning with of course, the anatomy of the breast and the endocrinology of the breast. We speak about the increasing rate of.

Breast cancer over the past decades.

We speak about the changes to a woman's breast throughout her life and how.

That relates to understanding the pathology of breast cancer. We talk about the different kinds of.

Breast cancer, including the precancerous lesions of ductal carcinoma in situ and lobular carcinoma in situ, dcis and lcis, and all the way to invasive breast cancer and the various stages.

Talk about the different ways that you would classify these things And I think Hal does a masterful job of taking.

It into the three categories of breast cancer. This was an obvious thing that I hadn't really considered until the discussion, and.

I find it to be now a.

Much more helpful framework for myself.

We speak about the different types of.

Breast cancer screening available, including the utility of self exams, mammograms, ultrasounds, MRIs and more.

And we talk about the importance of.

Early screening and detection as it relates to breast cancer. This is, interestingly, still a very controversial topic.

We then talk about the available treatments for the different types of breast cancer.

And again, we'll go into much greater.

Detail about how someone listening to this.

With breast cancer can understand which bucket they're in of the three and what the implications are.

We end the discussion by speaking about.

The role of genetics in breast cancer.

Of course, many people have heard of the BRCA mutations. We talk about the role that they.

Play, but they're not the only genes.

Involved in breast cancer. So we have a more thorough discussion about that. We also touch on male breast cancer.

This is something that many people are.

Surprised to learn exists. But I personally have a very close.

Friend who was diagnosed with breast cancer.

Fortunately, it was caught at an early.

Enough stage and he's doing fine. But this is never something that should be too far off your radar. So without further delay, please enjoy my conversation with Dr. Harold Bernstein.

Hey Hal, thank you so much for joining me today. This is a topic I've been really wanting to do a deep dive on for quite some time. We've done a deep dive on prostate cancer a couple of times. I think we're long overdue to talk about the second leading cause of cancer death for women, which is of course breast cancer. But maybe just briefly, give listeners a little bit of a sense of your background, the post you sit in and the work you do.

Well, first, thanks for being here. I want to learn how to live longer, so I'm hoping that we'll have a two way conversation here. It's great to be able to speak with you and your audience. I'm a professor of medicine at Harvard Medical School and a medical oncologist. And here at Dana Farber Cancer Institute where I specialize in breast cancer. I trained in medical school as an MD, PhD student and I got a PhD in immunology. Following that I was a house officer studying internal medicine at Mass General and came over to Dana Farber to do medical oncology where I've been for the rest of my career. In my day to day work, I see A lot of patients who run a very active and busy clinic here at Dana Farber. I'm involved in a lot of teaching at the medical school and for our fellows. I do a lot of both clinical research and clinical education in including guidelines work with asco, the nccn, the St. Gallen Pathways, and other international and national groups interested in breast cancer care.

Let's just give people a little bit of a sense of the magnitude of breast cancer. What is a woman's lifetime incidence of breast cancer?

So the famous statistic is that American women have about a 1 in 8 lifetime risk, or 12% lifetime risk of developing breast cancer.

What fraction of those cases will be fatal?

The good news is that only a small fraction of those will be fatal. The fatality or the mortality associated with breast cancer depends on the stage at which it is caught, and it also depends on the subtype of breast cancer, because we have different treatment programs for each of the different subtypes of breast cancer. So if you look very broadly across the board, There are roughly 275,000 cases of breast cancer in the United States every year, and there are roughly 38,000 deaths. So if you assume a steady state, we are curing 80 to 85% of women with breast cancer, but roughly 15 to 18% are still at jeopardy for recurrence and death from the disease.

Okay, I like to start kind of at the beginning with a little bit of the anatomy. I think one of the challenges, of course, of diagnosing breast cancer is that you don't get to look directly at the place where the tumor arises the way you do, for example, with colon cancer or skin cancer or cervical cancer, for that matter. So it probably behooves us to spend some time explaining everything from the embryology to the prepubescent anatomy to the maturation process of the breast, and then perhaps even what happens during menopause. So how would you describe the development and changes of a breast during a woman's life? With a specific nod to how this will factor into helping us understand the pathology of breast cancer development during some.

Of those stages, the breast is a gland. It is fundamentally a sweat gland, if you look at the pure embryology of it. And it is the defining feature of what it is to be a mammal. And as you alluded to, the breast goes through different stages of maturation and development in the life of a woman. It begins as a quiescent area of tissue, and then during puberty, because of the hormonal changes, develops enlargement and maturation of the glands, such that they become able to eventually secrete milk if the woman becomes pregnant. And the breast is largely composed of two types of tissue. The majority of the volume is actually just fat and nonspecific stromal elements. And the thing that determines the size of the breast in a woman is just really how much non glandular tissue there is. All women, more or less, have the same amount of glandular tissue in the breast, the milk generating component of the breast, if you will. And those ducts radiate from the various breast tissues into the nipple, which has multiple orifices. And the God given purpose here, of course, is to nurse the child. Breast cancers largely arise from the ductal or the glandular tissue. And in this respect, breast cancer shares its origins with almost all common cancers. Prostate cancer, colon cancer, lung cancer, where it is the glandular part of the organ from which arises the malignant cell. One of the interesting things about breast cancer and normal breast development is that there has been, over the past decades, a rise in the incidence of breast cancer. The rate of breast cancer. And one of the likely contributors relates to both the early puberty that we are now seeing in women. Girls are starting to menstruate at a far younger age in the 2000s than they were 100 years ago, or certainly 150 years ago, owing probably to better nutrition and better just general health. And that means that the breast development and the exposure of the breast to estrogens starts earlier. And women are also menstruating for longer, again, largely owing to better health. And women are having, at the population level, in the developed countries, at least, fewer children. And they tend to nurse those children for a shorter duration of time. Again, this rarely describes an individual patient, but at the population level, the rates of breast cancer are highest in the most developed societies. And many people think it relates to these issues of childhood nutrition, pubescent nutrition, number of pregnancies, duration of nursing. And that accounts for a lot of the difference in the incidence rates that we see between, say, the United States and other parts of the world. Interestingly, as people shift societies because they move, or as other societies become more developed, their rates of breast cancer tend to go up to mirror those of the US or western European populations.

I remember one of the discussions we had in first year medical school coming up on 30 years ago was the study of Japanese women who moved to the United States and within a generation went from very, very low rates of breast cancer to assuming the same rate, the same high rate of breast cancer as American women. And of course, I think, at least for me, the takeaway of that was we could never know what the causative driver was, given that there are so many things that are happening. But clearly there's an environmental component to this. Whether it's some combination of food, exercise hormones, stress levels, pollution. I don't know what the answer would be, of course, but you would have a very long list of things that could change, that could amount for such a dramatic shift. As opposed to saying, for example, there's genetic differences that are accounting for this. We're obviously going to talk at length about the genetic drivers of this. But that wouldn't explain the one generation shift, of course.

Well, that's right back to the 19th century. One of the first cancer epidemiological findings was that nuns who never became pregnant were at greater risk for developing breast cancer. And along with the discovery of scrotal cancers in chimney sweeps, it was one of the first real steps forward in the epidemiology of cancer biology to help people begin to get a sense of what was causing cancer. And so I think you make a good point that the environment, by which I don't specifically mean, like the atmosphere or the pollutants or all those kinds of things, but the environment in which a person grows up is gonna have an impact on their breast cancer risk. Now, the dilemma here is that for any given individual, we almost never have a good sense of what their intrinsic risk of breast cancer is, aside from, and I'm sure we'll get to this, the family history in genetic cancers and why they get breast cancer now and why they got it in one breast and not the other breast. And all those things remain very mysterious. And for someone who takes care of breast cancer patients, it's a source of real frustration. There are some tumors where we really think we. Why they're at greater risk. You know, the smoking and lung cancer, at least you can imagine how this arose. Whereas breast cancer is often a disease of very healthy women, Women who have gone to great lengths to care for themselves. And despite that, they are encountering a breast cancer diagnosis, which is often frustrating.

Do you recall I wasn't actually aware of the epidemiologic studies in the early parts of the 20th century that identified nuns as higher risk. I'm very familiar with the work on scrotal cancer and chimney sweeps. The hazard ratios there were alarmin. I mean, they were hazard ratios of 4 and 5,6. It was very easy to make the causal link. Do you know how high the hazard ratios were for nuns versus Non nuns in breast cancer, to be honest, I'm.

Not sure they even articulated as hazard ratios back in the day. And just to be clear for your audience, I wasn't there when these studies were being done, but it was seen that these nuns were at a greater risk of developing breast cancer. And again, we're talking about a time that predates radiology. One of the reasons you could do epidemiology on scrotal tumors or breast tumors is because you could see. And in fact, breast cancer was known to the ancients. It is described in Hippocratic type writings and other documents from antiquity, and it was the one cancer that would commonly be visually seen. People undoubtedly had other kinds of cancers in the era, but in a time before you had imaging, there were rather few that you would actually visually encounter. So breast cancer is a very ancient disease in that respect. And it was one of these things that people appreciated that for whatever reason, nuns were at greater risk. And so nowadays we would say it's because they were not pregnant and were not nursing and all those kinds of things which clearly change the risk. The interaction between pregnancy and breast cancer risk is both very interesting and complicated. So multiple pregnancies lower the risk of breast cancer. One pregnancy transiently increases the risk, and then it comes down as time goes by. And no pregnancies are associated with a slightly higher risk of developing breast cancer. And that's not related to the in vitro fertilization or other hormonal supplements. They've looked at that with a lot of rigor, particularly the Scandinavian databases where they have outstanding public health registries of all the patients in the Scandinavian countries. Infertility, for instance, is a slight risk for breast cancer, but the treatments for infertility per se are not. The other thing, and I don't want to get too far ahead of ourselves, but the other thing to say is when we talk about increased risk, there's a huge difference between a population increased risk and the risk for a given patient. So at the outset, we said 1 in 8 lifetime risk in the United States, that's 12, 13% a woman who has early onset of menarche, menstruation or hormone replacement therapy, such that they have longer estrogen exposure or shorter period of nursing or fewer pregnancies, they might have a 25 or 30% greater risk of breast cancer, but that only moves the needle from around 12% to around 15%. The risk at the population level is big. The risk for an individual is still pretty small for these kinds of factors.

Do we have a sense of the difference between things that drive the increase in risk versus things that drive an increase in mortality. So, for example, in prostate cancer, it's generally well understood that the prevalence of prostate cancer approximates the decade of life of the male. So basically, half of men in their 50s have some prostate cancer. Gleason 33 is not a prostate cancer you would take out, but on autopsy you would find it. By the time a guy is in his 70s, you might expect there's a 70% chance he has prostate cancer. And of course, the challenge then of the urologist is understanding which man is going to die from versus with prostate cancer. A moment ago you gave the example of hormone replacement therapy, and of course that's a topic we've covered in such alarming detail here that it needs no further rehashing. But the punchline is, while the Women's Health Initiative demonstrated that women taking conjugated equine estrogen plus MPA had a 25% increase in the risk of breast cancer, it never translated to an increase in mortality. And similarly, the woman who took conjugated equine estrogen alone saw 24% decrease in breast cancer. So my point there being, do we have a sense of which risk factors are driving mortality versus just incidence?

No. And yes, again, population level. This gets us into the subsets of the different cancers that we speak about. So there are really three major flavors of breast cancer. There is estrogen receptor positive, so called HER2 or HER to negative breast cancers. And those are the most prevalent kinds of breast cancer. They account for 70 to 75%, if not more, of all breast cancers. They are the tumors most likely to be found on screening mammography, as opposed to presenting with a lump in the breast. They tend to have ounce for ounce, size for size, the most favorable prognosis in most but not all instances. And they peak in incidence at around age 65 in the United States. So that is the sort of public health face of a lot of breast cancer. But there are other types of breast cancer as well, presumably, which have some different epidemiologic risk factors. And those include what's called triple negative breast cancer, which is lacking estrogen receptor, progesterone receptor, and HER2, hence triple negative. Those tumors have an earlier onset, are more common in younger women, are more common at the population level in African American women, are less likely to be the kind detected on a screening mammogram as opposed to a clinical finding, and are a riskier flavor of breast cancer. And similarly, HER2 positive breast cancers, which were tumors that have an amplification of the HER2 neu oncogene and account for about 10 to 15% of all breast cancers. Those tumors were classically described in younger women. And again, there's the epidemiology of HER2 positive breast cancer as opposed to ER, positive breast cancer is not really well described. So in general, older women are more likely to have better prognosis breast cancers at diagnosis because of the subset that arises in them. And younger women tend to have more aggressive flavors of breast cancer. Again, in broad strokes, Hal, I want.

To go over that again because I think that's just a fantastic overview of basically the three subtypes. I also want to point out that you did not talk about progesterone receptor except in the negative when you talked about the triple negative case. Let's go back. Case one is, I'm assuming it's er, positive, PR agnostic, HER2 negative, correct?

That's correct. Though the vast, vast majority of those tumors also express progesterone receptor.

You made the case. Again, these are the ones that are showing up more likely on mammography. They're also showing up in older women. Median age, I think you said about.

65 across the whole age spectrum, but the peak is at 65 and that's correct.

Obviously we're going to dive into the therapeutic options, prognoses, et cetera. You then talked about triple negative, though you didn't give a distribution or a number on that. I'm just doing the math in my head. That seems to be about 10 to 15% of the population.

Correct.

Okay, so 10 to 15% are triple negative. Again, that's ER negative, PR negative, HER2NEU negative. These skew younger.

Again, you can see them anywhere. I see 80 year olds who have triple negative breast cancer, but they tend to skew younger. There is an interesting relationship between race and triple negative breast cancer and there's been a lot of really excellent studies to suggest that there may be some real demographic genetic differences that predispose. We tend to see triple negative breast cancers also in BRCA1 mutation carriers. So there's a, a clear link between specific genetic syndromes such as BRCA and triple negative disease. But they also tend to be more virulent. So they're more likely to present as a lump in the breast or a physical exam finding as opposed to readily being identified on a screening mammogram.

You mentioned a higher prevalence in African American. Where do Asian women fit into this? Do they skew to any more than others?

They don't have any enrichment in general over the US Distribution.

The last one you talked about was all the HER two new positives, which includes your triple positives and frankly, agnostic of ERPR. But HER2NEU positive.

Correct. And that's collectively about 15% of all breast cancers split half and half between those that are ER positive, HER2 positive, and ER negative, and HER2 positive.

Okay, so again, that includes all of your triple positives. And there's the distinction there. A biologic one, Hal, or are you making that distinction more because of Hercept? And I guess I should just clarify for the listener, because there's a targeted therapy for the HER2 neu receptor positive cancer.

You're exactly right. So trastuzumab or Herceptin is the target of therapy, and that has been the revolutionary treatment in the management of HER2 positive tumors. So there is a biological difference. There is a specific region of the chromosome 17 that's amplified, giving overexpression of the HER2 neu oncogene. That's presumably a driver for a fraction of these breast cancers. But it's also very important because it allows us to bring a specific targeted therapy to play.

Let's talk a little bit about what happens to a breast during or post menopause. Obviously, we understand some things that are happening during menopause. So estrogen progesterone levels are falling dramatically. Presumably, there are anatomical changes occurring in the breast as the breast no longer needs to maintain the infrastructure for lactation. Anything worth talking about there specifically, as it pertains to increasing risk only indirectly.

So estrogenization of the breast does account for breast density, which is something that is often seen on a mammogram. And there is a relationship between more breast density and a slightly greater risk of developing breast cancer. Presumably that relates somehow to the woman's lifetime exposure to estrogen. And so postmenopausal women who have more dense breast tissue on mammogram are at slightly greater risk of developing breast cancer. And it's not simply that the density makes it harder to see the breast cancer.

Just to interject, Hal, to make sure, I understand, is estrogen controlling ductal density.

It's more about the soft tissue component.

Of the breast, the actual fatty tissue.

In a premenopausal woman, obviously, with the monthly cyclical variation, the breast will have changes in both the ductal tissue and the other tissues. And I want to be clear, if anybody listening to this is an embryologist or a breast surgeon, they're rolling their Eyes here, because I'm not going to get all the details correct. But in broad terms, there is monthly change in the breast architecture and tissue. But for postmenopausal women on the screening mammogram, that density reflects the fibrous tissue, the fatty tissue in the breast, not specifically the glandular tissue.

Okay. And then just kind of bringing it back to a point, full circle. You mentioned at the outset that regardless of the size of a woman's breast, so if you compare a woman with an A cup to a D cup, the glandular tissue is still relatively consistent. I actually took that to mean the risk of breast cancer by breast size was also relatively similar, given that they're dealing with the same amount of glandular tissue. Is that an incorrect assumption?

That's a correct assumption.

It is. Okay.

Breast size at the extremes tends to correlate with obesity. There is a weak but detectable link between obesity and breast cancer risk. So perhaps a slight, slight increased risk that's confounded. To your point, we don't fundamentally think that breast size affects risk.

Okay. But density per se does, and not just from a detection standpoint.

Correct. Density is a marker that is associated with a slightly increased risk.

Again, but all of these, we're talking small risks. Yeah.

One in eight to a one in seven or six lifetime risk. So it's the kind of thing that, from the public health point of view, is very important for any given woman. Rarely is a huge driver. And I just point that out to draw a distinction between a genetic syndrome or specific behaviors like smoking that we know are clearly a dominant risk factor for many different kinds of tumors and things like that.

Let's talk a little bit about some of those other modifiable risk factors then. So we know that, I guess the WHO would say that the top two environmental triggers for cancer are, in order, smoking and obesity. Now, I've always thought that obesity is just a proxy for insulin resistance and that it's really the hyperinsulinemia, the excess growth factors in the inflammation that track with obesity, rather than the adiposity per se, that is driving that risk. How much do those two factors, smoking and call it obesity, and right up to type 2 diabetes, how much are those moving the needle at the individual level for risk?

So smoking really is not a major risk factor for breast cancer. My shorthand. You know, it's simply a matter of the smoke affects the aerodigestive tract and some of the internal organs, like the kidneys, that end up filtering out some of the carcinogens and stuff. But it's really not part of the breast story, if you will. Obesity, as we mentioned, is a relatively weak risk factor relative to many others, and certainly not one that has allowed us to say, for instance, stratify patients for high risk screening versus not or offer reassurance to a woman that she is not at jeopardy for breast cancer because of lean body mass or things like that.

Okay, let's talk a little bit about the types of lumps that can show up in a breast and let's start at the benign end of the spectrum. So how often will a woman either doing a correct self exam and by the way, I'm so far from this myself in my current practice that I don't know if it's still in vogue or not in vogue to teach women how to do a self exam of the breast, but maybe you could clarify that for me. But if a woman is doing a self exam of the breast and then if she's also getting an exam from say someone like yourself, who knows what they're doing, what's the probability that a woman in her lifetime is going to feel a lump and then what fraction of those lumps turn out to be benign?

Most women have variations in the texture of the breast. And so almost all women have breast tissue or other things that one can feel and they can appreciate that vary. And in younger women these may change with the monthly cycle. And in postmenopausal women they may represent, you know, just residual breast tissue. If you lose weight, you might feel some of that, that architectural tissue more readily than other times. And so there's a lot of normal lumpiness, if you will, to the breast. In our advice to patients, I think it's worth that they have an awareness of their body and a general sense of what feels normal to them and what feels different from normal to them. It's been pretty hard to show that a regular monthly breast self exam or a rigid approach to self palpation adds that much. There have been some studies in China where they literally had tens of thousands of patients who were taught how to do a breast exam versus not really didn't change the mortality from breast cancer. But what does change the mortality is a real awareness of the body and of the breast. And our message to women is if you feel something different suspicious concerning seek evaluation. Because nowadays we can usually get people imaging studies, whether it's mammography or ultrasound, combined with an exam by a breast surgeon or a breast expert and usually do a quick evaluation that most of the time reassures the patient that this is a benign finding in the breast itself. Some patients may need further evaluation, either with follow up imaging or even with some kind of a needle biopsy. But the majority of these findings are not going to be breast cancer. Again, having said that, the most important thing is if a patient does appreciate a change in the breast or a lump in the breast. Certainly if a physician or other clinician provider feels something suspicious, it is very important to get appropriate imaging and if necessary, a tissue biopsy to make sure we understand exactly what's going on.

Now, if a woman ends up having a lump and the lump is suspicious enough that it requires more than just reassurance that it's nothing, the next step is going to be what? So if a woman has a mammogram that that shows a lump that is suspicious with or without calcification, what is the algorithm for evaluating that lump and when does it go down the path of more imaging versus a needle biopsy versus an excisional biopsy?

Again, the key takeaway is if people feel a lump, they should seek medical evaluation. For patients who have findings either on physical exam or on imaging, the imaging team, the quality of radiology has become really terrific at most places around the country. And they can often look at findings and say, yeah, you know, this looks like a benign change, or yeah, this same thing was seen a year ago and five years ago when the patient had a mammogram and it hasn't evolved in any way, so it's reassuring. Or they can say, I'd like to get more imaging. So sometimes patients are referred for additional ultrasound or MRI imaging to be sure. And sometimes it's necessary to get a tissue biopsy to really understand what exactly is going on. And nowadays that usually begins with an image guided needle biopsy or core needle biopsy, where using an ultrasound or other imaging device, the radiology team knows exactly sort of where to pinpoint the lesion within the breast. They use a very fine gauge needle to extract a tissue biopsy that's around the width of a pencil lead. And with that, they can look under the microscope and usually make a clean diagnosis about what's going on within the breast itself.

So do you have a sense of the number of. If we go to the point where we're actually getting a biopsy, what fraction of those turn out to be a benign lesion such as a fibroadenoma?

I don't have an immediate answer. I will follow up with you and try and get you the answer. But I would guess that the majority of These do. And for most women it turns out to be very reassuring that either it is a benign lesion like a fibroadenoma, or a pre or even a pre pre cancerous change in the breast that might warrant additional follow up or surveillance. It is not truly breast cancer.

Got it. Which would be the analog of finding a polyp in the colon which gets removed, which puts you on alert for more screening, but of course is not cancer itself.

That's correct. And in fact, we may get to the point of talking about ductal carcinoma in situ or dcis, which is a precancerous lesion where the cells are beginning to accumulate within the duct but have not penetrated into the rest of the breast tissue. And the analogy I give to patients all the time is this is like a colon pop follow. It's a growth. It is a precancerous growth. We treat it so that it doesn't blossom into a full blown cancer, but in and of itself it is not a cancer lesion.

That's a great pivot to that. I do want to talk about dcis and lcis, so maybe first explain it going back to the anatomy, the difference between ducts and lobules and then how does that factor into ductal carcinoma in situ versus lobule carcinoma in situ?

The ductal tissue of the breast includes sort of a highway, if you will, where the milk would come out of the breast and then at the end of it, a parking lot, if you will, where the sort of terminal lobule where the gland terminates and the milk would be generated, if you will. And again, my breast cancer surgeon friends are rolling their eyes, but that gives you a flavor of what we're talking about.

We'll include in the show notes a great figure of the. This figures tend to be easier to follow I think, sometimes than the words here.

The relationship between lobular carcinoma or lobular carcinoma in situ and ductal carcinoma or ductal carcinoma in situ really don't exactly correlate to the architecture of the normal gland itself. It's really how the cells look under the microscope, if you will. You can see changes in these cells that are staged along the way towards cancer. So one of the things that that is associated with an increased risk of breast cancer is if there are prior changes in the breast that suggest abnormal amounts of proliferation or atypical appearing cells which are sort of the pre precancerous stages. So oftentimes a woman might have a biopsy that Shows what's called atypical hyperplasia. There are too many cells present. That's the hyperplasia. And those cells don't look exactly normal. The nucleus begins to look a little more aggressive and things. And if you're familia about Gleason scores, the Gleason score is beginning to drift up there. And ADH atypical ductal hyperplasia or alh atypical lobular hyperplasia are lesions that put a woman at slightly greater risk for developing breast cancer in the decades to follow. The numeric risk is still pretty small, probably only about a half to 1% per year risk of developing breast cancer and follow up. But it's one of those precursor lesions that begins to, to flag a patient as being at greater risk for developing breast cancer. And then the next step along the way would be in situ carcinoma. So these are cells that have taken one more step towards looking like cancer. And if you were to look under the microscope, the cell itself looks like it's almost a cancer cell, but it is respecting some of the normal membranes of the breast gland. It's not penetrating into the breast tissue. It hasn't gone through whatever the final steps of full blown carcinogenesis are, such that that cell can now persist, thrive outside of that gland and begin to develop its own blood supply or even metastasize somewhere else in the body, which is how we think of breast cancer. So you will encounter those lesions along the way. Many women have been diagnosed with these precursor lesions, particularly alh, adh. They can show up as architectural changes in a mammogram. They can show up as calcifications in a mammogram. It's rare to find that you actually even feel these things, though sometimes it's an incidental finding if you're evaluating a lump in the breast. And those are things that warrant regular surveillance. And in some instances we can actually now use antiestrogen medicines like tamoxifen to help slow the development of any malignant cells in a patient with those problems.

Do we have a sense of how often those things exist? For example, we know from autopsy studies, as I said, the prevalence of low grade prostate cancer that is not causing any other issue. Do we have similar autopsy studies in women where we are looking at women who have died from some other cause and examining breast tissue and looking for the prevalence of all of these associated changes up into DCIS and lcis?

I don't have a good answer for you. It's certainly a common enough problem that it wouldn't surprise me if someone's done a study of this and reported on it. The distinction I would draw is those classic autopsy studies of men. I believe they were from automobile accidents back when I used to read these papers finding that they had prostate cancer. We're still talking about something a little different in the breast. So these are pre cancerous changes. They're not uncommon. Many of them will never move further. And that's different from breast cancer where the tumor can be indolent, it can grow slowly, but we're not so sanguine that these are tumors that would sort of never require treatment or never be a clinical problem for a patient. Patient.

Does every breast cancer start as a ductal carcinoma or lobular carcinoma in situ?

Many do. Particularly hormone receptor positive breast cancers, Triple negative breast cancers, which probably have something of a different cell of origin within the duct channel, a little less of the glandular component and a little more of the sort of architectural stromal element of the gland. You will often encounter triple negative tumors that do not have of DCIS associated with it. But probably the vast majority of hormone receptor positive, er, positive breast cancers emerge from these multi stage evolution of these precancerous lesions.

So is the majority of DCIs then captured through screening, mammography and or other forms of screening in higher risk women where you're using more than mammography, such as ultrasound or MRI?

That's right. 70 years ago, DCIS would present as a lump in the breast because the cells would just kind of keep accumulating within the duct disease of the breast, where the cells would literally creep out of the nipple and sort of form what looked like a crust on the surface of the nipple or the breast, which was again the growth of these precancerous cells. But in modern practice those still exist, but they're really rare. The vast majority of the time DCIS is identified following a mammogram because of calcifications or other subtle changes that appear on the mammogram.

How is DCIS staged? Isn't there actually an invasive dcis, which would be the closest thing to an actual cancer? Am I making that up or misremembering that?

Well, DCIS by definition lacks an invasive component. So DCIS is stage 0 breast cancer, or as I like your nomenclature earlier, I call it a colon polyp of breast cancer. It really is a benign growth that we want to treat so that it does not become an invasive cancer. The difference between the colon polyp, if people can sort of picture the little mushroom growing sort of in the lumen of the colon and the DCIS is that that the DCIS cells are not as mushroom forming, if you will, and they can creep and crawl through the ductal space, so you can end up with a more diffuse distribution of the DCIS cells in the breast than you might encounter from an isolated colon polyp.

So once DCIS is identified and assuming it's done through a core biopsy, what are the next steps?

So this is actually a really interesting area of research. So I'm going to start by just saying what we typically do for most cases, and then we can talk about some of the areas of controversy for most women who have DCIS diagnosed on a core biopsy because there were calcifications or other changes in the breast. The first step is to do an excisional biopsy, a surgical biopsy, where the area of tissue is surgically removed. And we do that for two reasons. One is we want to remove the affected portion of the breast, to remove the area of the breast that has dcis. And secondly, because there is some upstaging that happens. So about 15 to 20% of the time when a woman has the certain surgical excision of an area of dcis, there will actually be a small component of invasive breast cancer adjacent to that space or nearby that's removed as well, which upstages the diagnosis from stage zero or DCIS to an early stage breast cancer. And it's important to know that and to remove that affected portion of the breast. So that's almost always the first step.

In treatment in that case there. Do you also do a sentinel node biopsy if you discover that? I know we'll come back to that and talk about, indeed detail. But I just want to ask the question before I forget.

So the sentinel node biopsy we do routinely in invasive breast cancers because we want to find out if the cancer has spread to the axillary, the armpit lymph nodes. And we can, by we here, I mean, again, my surgeon friends who are still rolling their eyes as we're talking here. But they can inject a radioactive tracer and blue dye into the breast tumor. They track that into the armpit. It allows them to identify the so called sentinel lymph node or lymph nodes, which are hot from the radioactivity and blue from the contrast dye. And you can find out by removing a couple of those nodes whether the cancer has spread to the armpit, which is really important staging information that's going.

To be done in those 15 to 20% of women who are getting upstaged. You're going to get a wet read in the operating room.

You might, but usually not.

Okay, got it.

If you're just having that lumpectomy where the portion of the breast is being removed and it's not known to have invasive cancer ahead of time, if there is a finding of invasive cancer, then the patient would need to go back for a second operation to do the sentinel lymph nodes. So the exception to this is sometimes there's a lot of DCIs in the the breast or for whatever reason the patient has chosen to have a mastectomy for dcis. So this is necessitated sometimes by the extent of the affected area relative to the size of the breast. Some women will have diffuse changes in the breast that require a mastectomy. Others might have a personal preference for it. And if the whole breast is being removed for dcis, then they will also do sentinel lymph node mapping of the lymph nodes in the armpit. Because once you remove the breast, you can't go back, back post hoc and do the sentinel node mapping. If there is an occult area of cancer found within that area of dcis.

And I'm guessing, though, after they've had the excisional biopsy of the dcis, you get the pathology back a week later and it says, you know, in fact, there is some invasive component here. You still have a compromised sentinel node biopsy at that time, I assume, because you've actually taken the tumor out. Right.

Presumably, the sentinel node's doing its thing, and it's still very feasible to do sentinel node math after an initial lumpectomy byps.

But you don't have a tumor to inject into.

They know where the tumor bed was. You don't have to inject the tumor itself. You're tracking the lymphatic channels in that portion of the breast. So you can use the bed or the area.

All right, so the other 80 to 85% of women will emerge from surgery. They'll be told, good news, there was no invasive cancer there. So this was neither diffuse DCIS nor invasive cancer cancer. What is the standard of care today for dcis?

So following DCIS removal, if you've had a mastectomy, usually that's all you need. And there is no further treatment for dcis. For women who have had a lumpectomy, then there are a couple of options that they can think about. One is to do radiation therapy. So one of the interesting things about DCIs, as we noted earlier, is the cells tend to creep along the ductal channels and these all arborize out throughout the breast space and the cells can kind of sneak around in there. So radiation therapy has been shown in many, many studies to lower the risk of in breast recurrence, including both more DCIS and including the development of invasive breast cancer. So for younger healthy women, 65, 70 and younger who have DCIS, it's pretty standard to give a course of radiation therapy to the breast breast to lower the risk of recurrence of DCIS within the breast itself. And then there's another option of adding an anti estrogen therapy. So medicines like tamoxifen or aromatase inhibitors, both of which work by depriving the tumor area of estrogen, can also lower the risk of in breast recurrence of DCIS or lower the risk of developing invasive cancer after dcis. The downside to those treatments is we usually recommend many years of therapy, have a lot of side effects that are manageable for most women. But when you're talking about a DCIS lesion which isn't a full blown cancer, a lot of women wouldn't be sufficiently interested in the couple of percentage points reduction in the risk of recurrence or more DCIS for having to take a medicine for many, many years that has side effects related to its anti estrogen effects. So typical would be lumpectomy, strong consideration of radiation therapy, and then above and beyond the that, discussing whether or not to offer anti estrogen treatments. And with that, most women do very, very well.

When you get the pathology back, you're also getting the receptor status back on the dcis.

They will test it for estrogen receptor. And as with invasive cancer, the vast majority of DCIS lesions are estrogen receptor positive because it's the precursor lesion.

For most breast Cancers, there's no HER2NEU status on a DCIS.

Or there is, it can be tested, but we don't usually do so because clinically it's not actionable. We don't offer treatment. Treatment. That's right.

Let's talk about risk reduction. So if you took all women who had DCIs who underwent a lumpectomy and were found to only have dcis, had no invasive cancer and you did nothing, how many of those women will go on to get invasive breast cancer with breast cancer?

So the thing you want to know is what does the DCIS look like under the microscope? Because one of the really important prognostic markers for both DCIS and for invasive breast cancer is what we call a graph grade. So higher grade, grade 3 DCIS lesions, often associated with what's called necrosis, which just means the cells are kind of dying in the ductal space because they're sort of outstripping the oxygen supply. There's no blood vessels that feed dcis. Those lesions have a slightly greater risk of in breast recurrence than would lower grade, typically more estrogen receptor positive, less comedoneonecrosis type lesions. And so the span ranges from from 5 to 10% at the low risk end to 20, 25% at the higher risk end. Without further treatment, with treatment with radiation therapy, you bring way down the risk of recurrence of DCIs or of new breast cancer for both those kinds of lesions, such that it's usually into the low single digits nowadays.

Does that reduce mortality also or just recurrence?

No. The interesting thing about DCIS is treating DCIS has actually never been shown to affect mortality because you're so far ahead head of the diagnosis that there probably isn't a survival benefit. And this is what's led to some really interesting trials looking at if we can do less for dcis. So Shelley Wong, who's a very distinguished breast surgeon down at Duke, has really been a force in the development of these trials where they are doing more or less what you proposed, which is what if you just took it out and followed it and see what happens. In some instances they're not even doing that excisional biopsy, they're doing a core biopsy and saying, oh, it's just dcis. We're just going to follow, follow you.

So that's interesting though, because then they're willing to miss the 10 to 15% of women that have invasive cancer.

Correct. That's an ongoing study in the NCI led cooperative groups. And one of the things can be really interesting is to see is that really adequate. The other thing that comes into play here is one's perception of risk, because for some women, having a 10 to 15% risk over the next decade of having a recurrence or a breast cancer in the breast is a very low risk, 85, 90% chance they would be fine. They're not eager to have more surgery or to have radiation therapy, and so they're comfortable with that. Other women will look at the same number and say, gosh, I don't really want to deal with this. If you're telling me that three to four weeks of radiation can lower my risk down to 1 to 2% chance of having a problem, I'm willing to sign up and do the Radiation treatment. So these become very nuanced discussions that have to reflect both the magnitude of the risk, as we've been discussing the possible benefit and the patient preferences become real important here.

How well are radiation oncologists able to shield the heart? For example, do you find women making a different decision if this is left side versus right side dcis, or is the amount of radiation that's delivered in this for DCIS so low compared to say, invasive breast cancer that it's a non issue?

So the radiation treatments are fundamentally the same for invasive cancer and for dcis. In fact, one, one of the things that's been persistently a confounding part of the discussion about DCIS is that treatments for DCIS look almost identical to the treatments for invasive breast cancer. So if it's a lumpectomy, it's the same kind of surgery. You're looking for negative margins, you're talking about radiation therapy afterwards. It's all very similar to if you were being treated for an early stage invasive breast cancer. So the issue of left and right, what you're alluding to is the historic experience, which is that radiation therapy to left sided breast cancer in the past important point was associated with a greater risk of coronary artery disease. And that is because in the early days of breast radiation, they would radiate the breast straight on, if you will, as though someone was standing in front of you shooting an arrow right at your heart and that's where the beam of radiation was going. Nowadays, and for the past 18 to 20 years or more, 30 years almost, now, we don't do that. And by we, I mean my radiation oncology friends and colleagues. What they do is called tangential field radiation for most things, where they very carefully map out the anatomy of the chest and the breast and they use the radiation coming in from the sides in what are, if you were drawing a circle, sort of tangent lines to the circle to irradiate the breast tissue while sparing the underlying chest wall, lung and particularly heart. So while any patient who gets breast radiation will be counseled as part of the decision making process that there is a risk of accelerated coronary disease, in modern contemporary practice, that risk is incredibly low. And not just do they set up the fields differently, but now there are a lot of other tricks, including specific blocks that radiation doctors can use and what's called a breath holding technique, where they synchronize the radiation treatment to holding the breath. So if you exhale, the heart moves closer to the breast, if you will. If you take a Big breath in the chest expands, the heart falls back, back, and you have more space between the breast and the heart. And so they nowadays synchronize the radiation beam, which is a zap that moves at the speed of light to your breath holding. So they say, take a big breath in. And so the risk to the heart is extraordinarily low.

What about other risks, just briefly, in terms of skin damage or other risks? Sickness, any persistent damage from radiation under the current way of it, depends a.

Little bit on how much radiation is done and where they have to go. So if you have a breast cancer, particularly a large breast cancer with extensive regional lymph nodes, then that's where you start talking about doing more extensive radiation to the chest wall, the regional lymph nodes, sometimes even the internal mammary nodes. And there, while they can still spare the vast majority of the heart, it becomes a little trickier to fully avoid the heart. There is a risk of so called dumonitis, inflammation of the lung from some of the radiation scatter. There is a risk of secondary skin cancers, which you can rarely see after the radiation. And there's a lot of short term side effects. Getting the radiation treatment is like having a bad sunburn, or as we say in Boston, a wicked bad sunburn on the breast tissue itself, where the breast gets red, sore, swollen. It accumulates during the course of the radiation, just as a sunburn accumulates during your day at the beach. That can be very physically uncomfortable over time. That resolves, the skin heals, the tissue sort of fades from a lobster red to a pink and then to a tan color and eventually back to normal skin tone.

What percentage again of DCIs are estrogen receptor positive?

Something like 80 plus percent. The vast majority.

Got it.

So then to the next question, which is what is the Natural history of DCIs? Er, positive DCIs with and without estrogen blockades.

In terms of recurrence, estrogen blockade helps lower the risk further beyond what radiation does. One of the cleanest studies we have of this is a study called NSABP B24, which is an old study. And in that study it built on a previous study called B17. So in B17, they randomized patients to surgery alone for DCIS lumpectomy alone versus lumpectomy plus radiation. And in that study, at 10 years, about 25 or 30% of the women who had surgery alone had had a recurrence or second cancer of DCIS or invasive cancer in the breast. Radiation cut that in half to about 12 to 15%. And then in the follow on study B24, they did okay, lumpectomy plus radiation, with or without tamoxifen. And again it lowered the risk further by about half. Again, the dilemma there is that that study is old enough that we've gotten much more sophisticated in terms of the imaging we offer to the breast, looking at the margins very carefully, making sure there's no extraneous calcifications. So most people think that the baseline risk after surgery alone Nowhere approximates that 25 to 30% kind of number anymore. It's much lower for most patients who have mammographically detected dcis. And so the rules apply. So it drops it by half. Drops it by half. But the absolute benefit is a lot smaller because the Basel risk is no longer way up here, it's kind of down here. And so for that reason, the marginal benefits of the anti estrogen approaches are something on the order of 3 to 5% in terms of preventing a recurrence. And some of that benefit actually relates to the prevention of a second problem in the opposite breast, because the drug therapy obviously affects both breasts. And so you can help prevent a new cancer in the opposite breast, which adds a percentage point or two of the benefit. So it's a relatively small gain to be using antiestrogens after dcis. Some patients, it clearly makes sense because of the extent or other features of the tumor. Some will pursue it because they like the idea of the secondary benefit in the opposite breast. Many women will pass on the anti estrogen therapies even as they receive other treatments for DCIs. One of the academic questions is, can you use the antiestrogens instead of the radiation? And that's part of other studies that are going on where women might get surgery for the dcis, then be put on antiestrogens without the radiation. And we're going to see in the modern era if that's an acceptably beneficial approach.

I think a lot about hormone replacement therapy and what tamoxifen does to women, especially pre menopausal. I'm amazed that that's the more interesting academic question when the radiation, as you point out, is getting safer and safer and more and more efficacious. It seems to me that the real jugular question is how long can we justify giving tamoxifen to women with dcis, given the really devastating consequences. If you think about it's basically putting women into menopause at a young age, depriving them of estrogen. We think about the long term consequences on their bones, the vasomotor symptoms, the sexual side effects. Your calculations are sort of the same as where I'm coming out when I do the math on the NSAB CBP24 study, which is we're talking about a 3 to 5% reduction of recurrence over a decade with no change in mortality. It's interesting to hear that the majority of women do not elect for that. If I'm hearing you correctly, it sounds like the majority of women say, I'll take my lumpectomy, I'll do a little bit of radiation, but I'm not going to take tamoxifen for five years.

It's part of a comprehensive discussion. But I think you've done the analysis the way many women would and say, you know, now I'm not sure that really adds up for me. And one of the other things, in addition to the safer features of the radiation therapy, we're now offering shorter durations of radiation treatment. Historically, the standard was 25 fractions. We're now down to 16 fractions for most women. And in Europe and increasingly in the US there's interest in looking at yet shorter courses of radiation, down to about five days of treatment. So at some point that becomes a very compelling option, I think, and for many women, that would be great news.

Now, Hal, when I was in medical school, and maybe a little bit beyond the traditional thinking, so I know this is can't be right anymore, but was that with lcis, which was much less frequent than dcis, it was more of a systemic concern. And that your risk of contralateral breast cancer was sufficiently high that. My gosh, were they at one point recommending bilateral mastectomies for LCIs? Am I making that up?

I don't think you were making it up, but that's not an approach we would endorse today. So LCIS is probably best thought of as a field risk marker. It's one of those things that you might have talked about in other contexts, like leukoplakia in the throat, which increases the risk of developing head neck cancers or other field defects. Clearly, the diagnosis is saying this patient is at greater risk for developing cancer. And historically, the teaching was that actually the risk was the same in each breast. With very large studies, there's probably slightly greater risk in the affected breast itself. There's probably something specific and a little bit clonal going on there, but it can increase the risk of a second breast cancer as well. So what we usually offer patients like that is, in fact, very close monitoring. And many of those women will consider, consider anti estrogen therapy to lower their risk of developing breast cancer. However, LCIS is not a lesion that is readily thought of as one you treat with surgery alone or surgery plus radiation. So that's an area where LCIS sort of management diverges from DCIS management.

And for all radiographically suspicious lesions that go down this pathway, what's the distribution of LCIs versus DCIs? How much less is the LCIs?

I would say it's about 20% of the diagnoses compared to DCIs, but I'm ballparking that.

But roughly 4 to 1. Any differences there demographically? Are we seeing more LCIs in older women, younger women, different changes in estrogen receptor status, anything like that?

No. LCIS is almost universally a hormone receptor positive, estrogen receptor positive lesion. There's a rare entity called pleomorphic LCIs, which is a pathologic diagnosis that's a more variable, turbulent flavor of perhaps LCIs, and certainly of lobular breast cancer, polyomorphic lobular breast cancer. But otherwise it's the same kinds of demographic trends that we've been alluding to.

Okay, when a woman has lcis, do we know the natural history of that as a progression to invasive cancer and how it differs, in other words? I realize that it's more of a global marker of risk within the breast as opposed to a local marker, but is it also a higher risk that breast cancer will occur?

Yeah. So lcis, along with those things we alluded to earlier, like atypical ductal hyperplasia, atypical lobular hyperplasia, sort of a pre. Pre cancerous lesion, and it does increase the risk of eventually developing breast cancer. We have some very good data, again from the nsabp. And just by way of disclosure, I work with the NSABP as chair of one of their data safety and monitoring boards. So I know their database. I don't have any other commercial conflicts of interest, but I do work with the NSAP. So they did a study called the P1 study, which was a prevention study. The goal of this study, which was published over 20 years ago, was to see if tamoxifen could lower the risk of breast cancer diagnosis in women who were at intermediate to moderate risk of developing breast cancer. And so in that trial, they included a lot of women who had lobular carcinoma in situ, and those women were at greater risk of developing, developing breast cancer. So that risk, just to be quantitative, so I'm looking this up as I speak to you, was there was a rate of 13 per thousand women, 13 per thousand women per year. And tamoxifen cut that in half down to about five or six per thousand women per year. So you know, it makes a few percentage points difference as a preventative agent. Again, the key point here is the absolute risk for developing breast cancer in any given span of time is still pretty low following a diagnosis of LCD lcis. But those patients do warrant monitoring, obviously mammography, and they should consider, or they can consider anti estrogens to help lower that risk.

So this study took women who were at high risk, who had been diagnosed or had not yet been diagnosed with lcis.

Not yet diagnosed with breast cancer. Yeah, they had higher risk because of family history or because of atypical hyperplasia. There was a whole algorithm that went into the risk assessment.

These women took tamoxifen for how long?

Five years versus a placebo.

It reduced by less than 1% in absolute risk the occurrence of breast cancer.

So the overall diagnosis of breast cancer in that study was about 4% through five years of follow up. And tamoxifen cut that in half to about 2%. So the drug quote works, unquote. And so for women who are at higher risk or who are very motivated, activated tamoxifen and subsequently other anti estrogens have been shown to lower that risk of diagnosis. But for most ordinary risk women, that risk is sufficiently low that the relative reduction only amounts to a percentage point or two. And so it's not an approach that has been enthusiastically embraced by most general population patients.

Did that reduction in risk translate to a survival benefit or just an incidence?

It did not, for a couple reasons. One is obviously the risk is really low. Second, we have good treatments for those women who do develop breast cancer. And third, if you're using tamoxifen as a preventative, arguably you're preventing the most treatable types of breast cancer from arising. So you're pulling out the better actors, if you will. And what's left are tumors that remain somewhat resistant to the anti estrogens and therefore more worrisome.

Yeah, I might not have a dog in this fight because I'm not a woman. But boy, the thought that 98 out of 100 women are unnecessarily exposed to tamoxifen for five years to save two cases of breast cancer, that doesn't translate into any survival benefit. My goodness.

One of the frustrations for people who are really interested in cancer prevention has been that for most people, in any given span of time, the risk of developing a cancer is pretty low, even in that Study which sought to enrich for a group of women who were at slightly greater than average risk of breast cancer. Cancer. The absolute benefit turns out to be modest. And it's been a drug that only the most motivated patients would be inclined to pursue.

Yeah. God. I think it really places the onus of really capturing a great consent with the physician. I worry that some of those women might not know what they're signing up for when they do it. I know a number of women who have taken tamoxifen for DCIs, wives of friends, for example. And a year in they're sort of calling me some saying what the hell is going on? Is this really necessary? And then I kind of walk them through the math and I say, look, I think you ought to talk to your oncologist because no doctor can predict how badly you will have side effects. Some women probably take tamoxifen and it goes off without a hitch. But I think it's worth revisiting that discussion with your physician and saying, look, I'm one year into a five year course, I'm premenopausal and this drug has ruined my life. Life. I don't think any doctor would advise that woman to keep taking the drug.

So you make a couple of really great points here. The first is it is a nuanced conversation. We're living at a time when it's often hard for clinicians to find that time to have these kinds of very detailed conversations with patients. And so it's really important that they talk to people who will invest the time to speak about that. Secondly, there will be patients for whom taking this medicine is really important and they feel very reassured by it. And for many it will be a different decision. And third is, I don't want us to demonize the anti estrogen medicines too much. They clearly have side effects. I'm sure we'll get to a discussion of those. But in terms of global health, Tamoxifen and other anti estrogens have cured more people of cancer than anything else we do in oncology, aside from surgery itself. So these are really important medicines from the global battle against breast cancer. And while there are legion side effects, and we spend a lot of time clinic addressing those and talking about them and alerting patients to them and managing them, these remain really important medicines for invasive breast cancer, for pre invasive cancers like dcis, and for pre cancerous lesions, it's been a more complicated area to discuss because the benefits look pretty small to most people.

Anything else you want to say about, by the way? DCIS or lcs. Before we start to talk about invasive.

Breast cancer, the shared element here is mammography, and we're going to get to invasive breast cancer momentarily. But the reason we make diagnoses of DCS and LCIS is often because of mammography. So one of the critiques of mammography, which I think is important to acknowledge, is that when you have a national screening mammography program, you're going to see an upsurge in the cases of DCIS and lcis. And this has led some to question whether we are over diagnosing cancer on mammography. It's part and parcel of the same thing for the cancers where we have successful screening programs, one way they work is because they allow you to diagnose precancerous conditions. So fundamentally, that's what a Pap smear does. So a Pap smear is looking for obviously cervical cancer, but it's also looking for the pre cancerous changes that you can identify on the Pap smear. A colonoscopy is a very effective screening tool for colon cancer because it allows you to both treat the lesion, the polyp, which is the precancerous one, and identify those who are at risk for more of them so they get more frequent screening. You do diagnoses of skin lesions, dermatologist's office, and some of them will be benign and others will be skin cancers. But you're going to have an uptick in these precancerous findings as well. So that is the nature of a successful screening program. You are finding precancerous lesions. The debate as it relates to breast cancer is how much treatment should we offer in these precancerous instances. But that's why there's more dcis and LCD cis and it is a natural consequence of a successful screening tool for the tumor.

Before we leave that, let's add in a word on ultrasound and mri. So again, bringing it back to our prostate analogy, the workhorse of prostate cancer screening is the psa. So not an apples to apples comparison, because it's not an imaging test, but by itself really lacks the specificity to be a high yield tool. And, and so in many cases, actually, as you probably know, the PSA is being abandoned, which is unfortunate because it can be used provided you look at the density and the velocity of the psa. But instead, of course, higher risk patients are being evaluated and being more quickly sent for mri. And it's a multi parametric mri. We can explain what that means, but I assume it's a very similar phase of MRI that's being done in breast cancer where it's looking, looking at a high quality image, T1 and T2 weighted image, along with diffusion weighted imaging and the use of contrast as well. In the case of prostate, this is scored with a RADS score that ranges from 1 to 5. And that's where the radiology can sort of assign a probability of suspicion. So can you talk a little bit about how ultrasound and MRI work for breast cancer and how they sharpen the resolution in the screening stage?

The screening tool that's most important is the mammogram, and that is supplemented by sort of an awareness of one's own body. Interestingly, we may get to this later on when we talk about global impact of breast health interventions. But just teaching women to find a lump and go see a doctor has, in many developing countries actually lowered the fatality rate of breast cancer because it allows early detection. So there is awareness of the body method. When we're talking about screening mammography, what they're looking for are architectural changes, irregularities, calcifications that might be a sign of an invasive cancer. And that's the gold standard for most folks. The mammogram is not a perfect tool. Any woman who's had a mammogram will tell you what an imperfect tool it is. It's hard to exactly position the breast correctly. It depends a lot on a radiology technician to do a good image, the mammography radiologist to interpret it correctly, a correct comparison back and forth from the older images to the newer ones. And sometimes the breast itself can be difficult to view because of breast density or other features in the breast. And that's where other imaging can be helpful. So occasionally people may need an ultrasound to support a mammogram finding. It's not a reflex per se, and it's not universally recommended. In fact, studies have not really shown that ultrasonography dramatically improves the outcomes if you are found to have breast cancer. But in some women who have denser breast tissue or other suspicious findings, it's a pretty routine, routine thing. MRI is a very sensitive tool for finding abnormalities in the breast. It does not replace the need for a mammogram. But for women who are at very high risk of getting breast cancer, classically these are women who have strong family histories or who have a known hereditary predisposition like a BRCA1 or 2 mutation. MRI is very important for early detection of cancers and is routine for those women, but not for the general population.

Population does the mammogram have a similar sort of radiographic scoring where you have a rads score of 1, 2, 3, 4, 5.

Correct. So these are definitions put forward by the academic radiology community and they're widely used in clinical practice. They call it a Birad score. And they range from zero, which is there's nothing of concern, to five, which is, oh my gosh, that looks like a cancer. And in between is a gradation. And. And there are very well done standards of what those gradations mean. The breast imaging has become very sophisticated and at large centers. They focus a lot on the quality of the imaging and the review. And all of them are required to maintain their data. And they know if you had a Birads three, how many of them eventually became a breast cancer within a couple of years versus not. And there are accepted standards for what all this should mean. It's sort of like the aviation industry. They've gotten really good at quality control and safety measures. And it's really a very refined and sophisticated field of clinical care given how.

Much MRI has changed prostate cancer diagnoses. And I keep drawing this analogy, but I think they're very similar. Those data exist, for example, where if you know the PSA and you know the PSA density and you know the PI RADS score, you have a complete distribution of whether or not there's no cancer present. A Gleason 3 3, which you'll watch and wait. A Gleason 34 which needs to come out, or a 44 which should have come out last year. You know that a priori, before you biopsy, does that level of resolution exist with the combination of Birads and any other factor that you can put in, for example, the mammographic insight or other parameters, a family, family history.

The short answer is no. The guiding force of breast cancer management is really what the tissue biopsy defines and the finding on the mammogram screening. The imaging itself doesn't tell you as much as you would like to know. There are a few overarching pearls you can say slowly evolving lesions tend to be hormone receptor positive and those tend to have a better prognosis. Things that pop up quickly tend to be more virulent or proliferative lesions which have a less good prognosis. But those are not standard markers of risk that you would use to judge what therapy a patient needed.

All right, so let's now talk about what fraction of women that show up with something suspicious. Either they present with something suspicious or they're undergoing screening. And on Mammography and or follow up imaging, there's something suspicious enough to warrant that needle biopsy. What fraction of those needle biopsies turn out to be invasive cancer on contact?

Well, it depends a lot on what the abnormality is. So in other words, if you have a birads 4 lesion, the radiology team is signaling that's a very suspicious lesion that should have a high chance of being DCIS or invasive breast cancer. Birads 4, 3, it's probably, I forget the exact number, but I want to say like a less than 5% chance that that's a malignant lesion. There's that gradation within there and different groups have then different thresholds internally about what gets biopsied. Having said that, I think the message to share with patients or people in the general audience would be that a lot of the time, even if there's a so called callback for a mammogram finding and the mammogram team wants to do additional infrastructure imaging or there's even a recommendation for a biopsy, a lot of the time these will still be for precancerous or even benign lesions. And it doesn't automatically mean that the patient has breast cancer.

When you quoted obviously the numbers at the beginning of the episode about the number of cases of breast cancer in the US per year, I don't recall the number. Was it about 250,000?

Yeah, I said 275, I think, but it's about 250,000 to 300,000.

That's just invasive. Obviously that doesn't include any of those DCIS. LCIS cases is correct.

Correct. There's ballpark, another 50 to 60,000 cases of DCIS.

Walk us through the diagnostic and staging procedure for a woman who on that core biopsy comes back a couple of weeks later, pathologist says, I'm sorry, the news is bad, we have invasive cancer. So first of all, what news is coming back with that? In addition to the obvious, which is what I just said, coupled with receptor status, what other information is coming back with respect to graph grade or other cellular machinery? And then walk us through the completion of staging.

Yeah, so the core biopsy is very helpful for both defining what the diagnosis is. Is it precancerous? Is it dcis? Is it invasive breast cancer? And then they would also comment on the grade. So the grade is judged as grade one, grade two or grade three. Grade three. The cells are kind of growing wildly and sort of all over the place. Grade one, the cells tend to still form structures that Are recognizable as glandular structures. Structures. And the analogy here would be to a Gleason score. It's not quite a one to one analogy, but, you know, the higher the number, the more sort of abnormal the cells are. And they would also do biomarker testing for those three markers we alluded to at the beginning. Estrogen receptor, progesterone receptor, and HER2 or HER2.

Is there anything else that they look at there or is it just those?

There are a lot of things they can look at. So they also sometimes comment on the proliferation rate by using a test called the Ki67, which is a proliferation measure. They can also comment on whether or not tumor infiltrating lymphocytes or TILs are present. That is a prognostic marker in triple.

Negative breast cancers in particular, presumably a favorable prognostic sign.

I'm assuming it's a favorable marker in triple negative. That's right. They will comment if they can see any, on whether or not lymphovascular invasion is present. Sometimes they can see the cancer cells sort of burrowing into a blood vessel or a lymphatic channel. And that is a marker of somewhat greater risk of the breast cancer. So those are things you can all see on the core biopsy. And then those same tests are typically redone, Especially if you're at a different institution. They're redone at the time of the definitive surgery.

And the definitive surgery here is always going to be a modified radical mastectomy. Or is there any situation where the lump is small enough that you will just do a lumpectomy with sentinel node.

The good news here is that for women who have early detection of breast cancer, the majority are going to be candidates for so called breast conserving surgery, also known as a large. So in that instance, only the affected portion of the breast is removed. The rest of the volume of the breast is left intact. So the next definitive surgery for most women would be a lumpectomy where the affected portion of the breast is surgically removed. And at the same time, the surgeon would typically do a sentinel lymph node biopsy. So they would look into the armpit, remove a couple of lymph nodes, 1, 2, 3, and see if there's cancer in those lymph nodes. And then you'll have the full stage information. Now, for some women, there is still discussion about a mastectomy. That may be because of family history or genetics. It might be because of personal preference, it might be because of the size of the tumor relative to the size of the breast is such that a lumpectomy isn't adequate for achieving a cosmetic result that people would think is acceptable. Or it may be that there's sort of diffuse changes throughout the breast that require it. So it's very individualized at that point. But with early detection, most women are going to be candidates for a lumpectomy.

Maybe walk through the TNM staging Just so people get a sense of what are the three big things that are driving prognosis. Because now we're going to put people into four stages, 1, 2, 3, 4, with some A's and B's thrown in there.

So as with all cancer staging, stage four is metastatic or cancer that is spread beyond the tissue of origin. So in breast cancer that means there's a breast cancer, but it has spread to the bone, the lung, the liver, those kinds of organizations organs. Metastatic disease. Stage one. At the other end of the spectrum is a tumor that is 2 cm or smaller, so that's about the size of a nickel or smaller. And the lymph nodes are negative. Stage 2 includes slightly bigger tumors, bigger than 2cm and or involvement of some of the axillary, the armpit lymph nodes. Stage three is a progressively larger cancer and similarly affecting more lymph nodes. Lymph node involvement is the biggest single prognostic marker for early stage breast cancer, by which we mean not involving some other organ elsewhere in the body. And there's sort of a relatively sharp cut between sort of node negative tumors and node positive cancers. All of it's really a spectrum. So breast cancer is really interesting if you have big enough study. A one centimeter cancer is less risky than a one and a half centimeter, which is less risky than a two centimeter, which is less risk than a two and a half centimeter centimeter and so forth. There's another axis that goes by nodal status. Node negative is less risky than 1, 2, 3, 4. It's all very linear. And then finally there's a third dimensional axis about the biology of the tumor where triple negative cancers, again ounce for ounce, size for size, will have a more aggressive natural history. Her two positive tumors historically were also a very aggressive tumor. Now we have some of our most successful outcomes with treatment of HER2 positive cancers within this large group of ER positive HER2 negative cancers. The risk depends on some of these biomarkers like grade, so low grade, intermediate grade, higher grade, how robust the expression of the estrogen receptor is. And nowadays we also use so called genomic tests like the oncotype DX recurrence score to understand for that large group of cancers, how risky they are and whether they warrant chemotherapy. So I tend to describe it, as would many others, as sort of a three dimensional axis of the tumor size, the nodal status, and then these biological features as well, all of which are likely to affect risk of recurrence.

And just to be clear for the listener, Hal, it's important that they understand that all of that is in the M0 case, the non metastatic case. So all bets are off. When we have metastatic disease, the prognosis is awful.

No, the prognosis is different, but it's not awful. There are women who are living a long time nowadays with metastatic disease. We even occasionally think we might cure some people with metastatic disease, though that's not usually the goal going into it. It's only in the fullness of time.

What fraction of women today would live 10 years?

Very small percentage and largely in this group of HER2 positive breast cancers, where we think we have very effective therapies these days. Big difference is, is the tumor still confined to the breast and the lymph nodes, so that with a combination of surgery and radiation therapy to the chest and then drug therapy to prevent recurrence either in the chest or anywhere else in the body, we can cure the cancer or at least aim to achieve a cure for the cancer. As opposed to that stage four distinction where it has spread to other important organs. Where usually we don't actually speak of curing the cancer, we speak of managing it, treating it, keeping it at bay for a long time. And there will be women who will live for years and years and years with advanced or metastatic breast cancer cancer. That's the separation between functionally stage three and four.

What is the median survival today for stage four breast cancer?

It's about five years. And it depends again on the subtype of the breast cancer, triple negative breast cancers. It's more modest, her two positive breast cancers. Actually it's moving further and further out beyond that.

Can you tell me again the distinction between the stage two and the stage three? Is it more separated by the number of lymph nodes or the size of the primary?

It's both. If you have a large tumor bigger than 5cm, that becomes a so called T3 cancer. And if you have T3 cancer with any degree of nodal involvement, that becomes a stage three breast cancer. If you have four or more positive nodes, regardless of the extent of the size of the tumor, that's stage three. If you have Involvement of the supraclavicular nodes, that's stage three. And so you got to sort of get the grid out and look up all the correct criteria.

Can you give me full survival? So not five year, not median, but 10 year, like actual cure rate for stage one, two and three?

Well if you look at the American Cancer Society statistics, they update them every year and I can look up the numbers and give them at the fingertips, but in ballpark.

Yeah, ballpark's fine.

Stage one, isolated to the breast, 10 year cancer free survival nowadays often on the order of 90% or more. Stage two, more, more like, and I'm ballparking here, but 75 to 80%. Stage three, more like 65 to 75%. And again, it depends a lot on not just the stage but on the biology of the tumor and the kinds of treatments that people get.

Now the grade, the 1, 2, 3 grade on pathology, that doesn't factor into any of the staging. Is it more of a subtle issue that comes in when you are thinking about different chemoids regimens?

I'm not trying to mince words. There is a staging criteria that factors in things like grade and that can be used in some of the more up to date American Joint Commission on Cancer staging criteria. They do look at some of the things like grade usually though it's less discussed because it mostly relates to the outcomes in ER positive breast cancer. So triple negative breast cancers are almost always grade three. Most HER2 positive breast cancers are grade two or three and they all get treated with the trastuzumab drug. And it's really in that gradation of the vast majority of cancers, the ER positive ones, where low grade clearly does a lot better than higher grade cancers and needs different treatment approaches.

I guess before we go on to treatment, I've had many disagreements with people over the years when it comes to arguments around aggressive screening. To me one of the most compelling arguments for aggressive screening of breast cancer, let's just limit it to breast cancer. Cancer really is explained by what you just said, coupled with another observation which is if you catch a breast cancer that is 2cm or smaller without lymph node involvement, the chances that you will be cured, which we use as 10 year remission, is 90 to 95%. And without exception, the larger the tumor is at presentation and the greater the lymph node involved involvement, the lower your survival. And of course if it spreads beyond the breast. Let's not mince words, there is no long term survival. We also know that when we give women Chemotherapy in the adjuvant setting. I'll let you explain what that is in a moment. And we give virtually the identical chemotherapy for women in the metastatic setting. The survival difference is profound. Profound. It's a huge difference. Suggesting that tumor burden must matter. All of this is a long winded way of saying the better we are able to identify breast cancer early on. Seems to me our best bet at curing cancers, which acknowledges you will catch more cancers. In other words, you will increase the size of the pool of women who have cancers. There will be lead time bias, all of those things will be true. But ultimately, ultimately it seems to me, mathematically, by definition, you are also going to cure more women of cancer because you will shift the risk pool towards stage one tumors. Do you agree with that?

I do. And I think most people who take care of breast cancer patients would very much agree with that. As you may know, there is still debate as to how valuable screening could be. It's a complicated subject in the sense that most of the studies that were done showing screening was valuable were concluded by, by the late 1980s. They showed that screening did contribute to improvements in mortality. Since then, the therapy for breast cancer has gotten a lot better, which arguably cuts both ways. On the one hand, it means that it minimizes some of the benefits of early detection because you're not just cutting it out. And you are able to treat metastatic or systemic disease, which is ultimately the life threatening part of breast cancer, and prevent recurrence, which on some level diminishes the value of early detection. On the other hand, early detection is clearly still associated with better long term prognosis. The drugs are more effective, or you can use the same drugs or fewer drugs when the tumor is smaller to get better results. So I think all of us who are in the cancer community feel strongly that mammography is a very important tool. Not to take us away from thinking about how we treat in the United States, but as you make know, breast cancer is now the most common diagnosis of cancer. Aside from non melanoma skin cancer. It's the most common cancer diagnosis in the world for almost all countries on earth.

I didn't know that, Hal. You're saying it's more common than lung cancer?

More commonly diagnosed in lung cancer because the outcomes are better. There's still more fatalities from lung cancer, but it's the most common diagnosis of cancer in women in almost every country on earth. There are still some places in sub Saharan Africa where their cervical or other gynecologic tumors outpace Breast cancer. But almost everywhere else, it's the number one diagnosis of cancer in women, and in total, it's the largest cancer diagnosis. So the point of this story is to say that from a global health point of view, it's becoming a huge issue for countries that historically we've not thought of cancer as a big driver of mortality in. And this relates to the welfare advances in many countries around the world as they've been becoming more affluent, better and nourished, and becoming more Western in that sense, that they now have cancer problems that are looking more and more like the kinds of cancer issues that we see in the United States and Western Europe and other developed countries. So the importance of mammography globally is growing, not shrinking. And one of the challenges is there is simply insufficient medical manpower, woman power to adopt widespread screening programs in many parts of the world right now. And there's been a lot of really cool artificial intelligence research to suggest that you can look at breast imaging, perhaps even in the future, without a radiologist to begin to identify women who warrant either more detailed evaluation or other diagnostic workup. But this is going to be a huge problem in the coming decades as breast cancer spreads, if you will, to really become a global disease.

So let's talk a little bit about the treatment and we'll go back and do it through the lens of the staging. So a woman comes out of the definitive procedure, which again is going to be a lumpectomy, with a sentinel node biopsy. The sentinel node is negative. They will not undergo a formal lymph node dissection. She will be told she had stage one breast cancer. Is she receiving effectively the same treatment as the DCIS woman, where she's going to get radiation for local control and then depending on the receptor status, she'll either get tamoxifen if it's ER positive, Herceptin if it's HER2NU positive. Is there any treatment beyond that?

So the first thing to say is that's a very common, common problem in the United States. The most common presentation of breast cancer is of a stage one breast cancer found on a mammogram, which has a very good prognosis after surgery. But almost all patients will be candidates for some type of what we call adjuvant therapy. So adjuvant therapy are treatments that are designed to help prevent a recurrence after surgery. It's not unique to breast cancer. We use adjuvant therapy in colon cancer and in some sarcomas and in certain prostate cancers and, and in other kinds of cancers. As well. And sometimes patients ask, well, why do I need extra therapy? After all, the surgeon got rid of the tumor. It's a good question when you think about it. And the answer is that we worry about the possibility of microscopic disease that might be somewhere either in the breast or chest area, or might have snuck away somewhere else in the body itself. And so we use additional therapies to mop up those microscopic bits of cancer. So one of those is the radiation therapy. We've talked about that the majority of women who are 70 and younger and who are vigorous and healthy who have early stage breast cancer are going to be advised to get radiation therapy. Many women in their 70s and even older will have to think about radiation treatment. Depends on the type of cancer they have, their overall health status, and fundamentally, as a ballpark term, you might say whether they have a 10 year life expectancy or not, such that radiation is likely to be of some value to them in preventing recurrence over the next decade. And also the vast majority of patients are going to be candidates for some form of drugs therapy. And in terms of what has really changed the mortality from breast cancer, it's two fundamental things beyond the surgery itself, which is obviously the sine qua non. One of them is early detection through mammography. And that's reduced the risk of breast cancer over the past 30, 40 years by about half mortality from breast cancer and the other is effective systemic therapy. And that has given us the other half of improvements in mortality that we're seeing in the eye United States over the past 30 years. And so for cancers of almost any size that are estrogen receptor positive, we think about anti estrogen medicines like tamoxifen or aromatase inhibitors. For tumors that are as small as a half a centimeter or more in size, we think about drugs like trastuzumab that target HER2. And similarly for very small triple negative breast cancers, we often think about chemotherapy. And then there's a discussion. Most women with HER2 positive cancers also get chemotherapy with that trastuzumab. And then as the tumor gets bigger and riskier, we amp up with more anti HER two drugs and more chemotherapy. If the tumor is estrogen receptor positive, we go through a process where we decide whether or not the patient needs chemotherapy. And that usually involves an oncotype DX recurrence score or similar genomic test done on the tumor itself, where they look at the patterns of gene expression in the tumor. And those studies have shown us that the majority of women who have low risk scores on this genomic test and there are several commercially available. There's one called the recurrent score from exact sciences, there's one called the mama print assay from agenda, and there are others. Those have been shown to be very powerful at figuring out who does and more importantly, who does not need chemotherapy. So there's been a huge shift in how we use chemotherapy in ER positive breast cancers over the past 25 years. From the time in 1999 when the NCI said every woman who had a 1cm cancer needed chemotherapy, to a time nowadays when we frequently can avoid chemotherapy for most er positive breast cancers, but certainly those that are node negative and many of the ones that are node positive as well. Because we understand that based on this genomic test, the chemotherapy is just not going to help them do better in the long run. So circle back surgery is the sine qua non. Following the surgery, we use radiation therapy to sterilize the breast and chest chest area. And then the majority of women will need to think about some kind of drug treatment which could be chemotherapy, anti estrogen therapy, targeted drugs, sometimes immunotherapy to help prevent a recurrence anywhere else in the body.

Just spend a moment there explaining to people the distinction between chemotherapy and some of these other therapies. Because I think a lot of people sort of hear any systemic therapy is quote unquote chemotherapy. But you've made a great point to distinguish between the anti estrogen therapy and tamoxifen anastrozole, things like that, Herceptin, which is a targeted therapy versus quote unquote chemotherapy. So what are the things that you put in that bucket? How are you defining that and specifically what are some of the chemotherapies and what are their side effects?

We've talked about the several different kinds of breast cancer and nowadays we have a different treatment paradigm really when it comes to the drug therapy for each of these different types of tumors. So for er, positive HER2 negative breast cancers, the most common kind, the most important drug therapy relate to anti estrogen medicines. So there are two basic flavors in the early stage. One is called tamoxifen, the other is called an aromatase inhibitor. These are each pills, they work by different mechanisms. Tamoxifen sort of blocks estrogen's ability to reach the estrogen receptor in the cancer cell. The aromatase inhibitors only work in postmenopausal women women and they block the production of estrogen by non ovarian tissue. So a postmenopausal woman still makes a Little bit of estrogen in tissues like the liver, the adrenal gland, the fat and normal body stores of fat, the aromatase inhibitors, block that production of estrogen. So the consequence is estrogen deprivation, which again starves on the vine. These cancer cells that we think depend on estrogen for their growth and development. So that's a very important medicine. And again, globally, hugely important, has saved more lives than bone marrow transpl or gleevec or immunotherapy or whatever of the sexy new approaches in cancer. But the statistics are all in favor of these hormone manipulations as being globally of huge importance. Now, in addition to that, we also have a whole closet full of different types of drugs that we use. So some of them are traditional chemotherapy drugs. And patients may sort of have a cultural sense of what these drugs are. They tend to be rather nasty IV medicines. They make you sick to your stomach, they can make your hair fall out, they lower your blood counts, they make you. On the one hand, our supportive care in oncology has gotten vastly better in recent decades. So we have very powerful anti nausea medicines. We have medicines to goose the white blood cells to come back faster so you're not at risk for infections. We have cold caps these days that allow women to often not experience hair loss during chemotherapy. So on the one hand, the supportive care has really transformed our ability to give chemotherapy drug drugs. Drugs such as doxorubicin or what's also known as adriamycin, the red devil, taxane type drugs called paclitaxel or taxol, alkylator drugs like cyclophosphamide or carboplatin. Very widely used chemotherapy drugs.

And maybe just for folks to understand, Hal, these things all have something in common, which is they're basically antiproliferative drugs. As you said, they're old school dirty drugs. These have drugs that have been around for many, many decades, decades. And they target dividing cells. And that's why these side effects exist. Hair falls out because hair is dividing. You get sores in your mouth because the epithelial cells in your mouth are dividing. And so they're very non specific. But on balance, they are going after cancer cells in the sense that cancer cells are going to be dividing more frequently than non cancer cells.

That's exactly right. And so they're rather blunt instruments. But sometimes it's really helpful to have a wrecking ball, if you will. So that's where things stood for a long time. But in the past two decades, we've really transformed how we think about this because of some newer drugs that have come along. So in the different subtypes we have different approaches. Triple negative breast cancer had historically been one of the most difficult to treat types of breast cancer where we didn't really have a targeted therapy. And so we used a lot of chemotherapy. And there were dozens of trials optimizing chemotherapy in triple negative disease. But the biggest new thing has been immunotherapy. And I'm sure in other cancer podcasts you've talked about the so called checkpoint inhibitors, drugs like pembrolizumab and others that have proven very active in a lot of different tumor types in breast cancer. The data are most compelling for these drugs in triple negative breast cancers where we have shown that they can reduce the risk of cancer recurrence. And interestingly, we usually use them before the surgery. We can come back to talking about that in what we call a neoadjuvant approach, which is the same idea as adjuvants, adjuvant therapy, drug therapy to mop up cancer everywhere in the body, but actually given before the surgery to shrink the tumor and to allow the patient to get the effective treatment that goes everywhere in the body. For the HER2 positive, the transformative event was the development of trastuzumab or herceptin, which the data came forward in 2005 for early stage breast cancer, that adding trastuzumab dramatically improved the chances of never hearing from the cancer again. And that became totally standard for HER two driven breast cancers. Nowadays, for higher risk ones, we add A second anti HER2 drug called pertuzumab or perjeta. Now, interestingly, we're still giving chemotherapy with those anti HER2 drugs, but we've completely flipped the outcomes for HER2 positive breast cancer, where it has gone from one of the most feared types of breast cancer to one of the most successfully treated types of breast cancer. And finally, with estrogen receptor positive breast cancer, there have been two narratives. One has been a narrative about using less chemo. So the good news is we are able to figure out a lot of women don't actually need chemotherapy for ER positive HER 2 negative breast cancers. There's this genomic test we get to help us decide whether chemotherapy is going to be valuable. And with that, about 2/3 of the women who were previously offered chemotherapy can now avoid chemotherapy. At the same time, we're amping up some of the hormonal axis manipulation. So we are using ovarian suppression, which means for younger women going into premature menopause, to help prevent the cancer from Coming back, we're using longer durations of anti estrogens for higher risk tumors. And there's a very exciting new class of drugs called CDK4.6 inhibitors, which are oral medicines given for a couple of years now. They are targeted drugs that again slow down the proliferation of tumors. And for very high risk cancers, we're now looking at using them in addition to all the other kinds of medicines that we talking about. So each type of breast cancer has its own paradigm of treatment and each group is doing incrementally better and better because of those innovations.

What are the indications for neoadjuvant therapy? Which tumors on imaging and biopsy are deemed cancers where they're going to get all that systemic therapy before surgery. And my recollection is the pathological response that you see to the neoadjuvant therapy is also a great prognostic diagnostic indicator.

That's exactly right. So for larger tumors, we have been moving more and more towards a paradigm of what we call neoadjuvant treatment, where the usual sequence of diagnosis of cancer surgery, chemotherapy, if you're going to get it, radiation therapy, if you're going to get it, hormonal therapy out back, we're kind of moving it all around. And I often describe this as sort of a freight train. It's a cassette of treatment and we're just kind of giving the same kind of therapy, but we're switching and we're switching the order for very specific reasons. One of those reasons is that by giving the drug therapy first, we usually can shrink the tumor either in the breast or particularly in the lymph nodes as well. And so that means we can offer very good outcomes, the same good outcomes, but with less surgery. So women who might have needed a mastectomy might now be able to have a lumpectomy if the tumor shrinks. Or women who might have been obliged to undergo a so called axillary lymph node dissection, where all the lymph nodes in the armpit that carries a greater risk of limited range of motion in the arm or lymphedema in the arm now might be a candidate for a sentinel node biopsy by shrinking those tumors ahead of time. So that's one big advantage of neoadjuvant therapy. It gives the same treatment, but it makes the surgeon able to do a lesser operation. So there's less morbidity from the operation and a better cosmetic result. The second big reason is that we learn while giving this neoadjuvant treatment how well the tumor is responds. And if the cancer totally disappears. Intuitively obvious, that's a really favorable prognostic finding. And we call that a pathologic complete response. It just means the pathologist looks under the microscope at the end of that treatment course, at the time of the surgery and says there's no cancer left. That's a really good finding and puts the patient into a much lower risk category, a much better prognostic group.

Do those patients get adjuvant therapy or is therapy done?

They often get it depends again on the specific flavor of where you're at, but the prognosis goes way up. Conversely, if there's some residual cancer, it's a less favorable prognostic finding. But in many instances, we actually have drugs that we're now using to overcome that residual disease. So for instance, in HER2 positive breast cancer, we give chemotherapy and trastuzumab up front. If there's residual disease out back, we can use a derivative of trastuzumab called trastuzumab emtansine, which improves the prognosis for those patients who have residual cancer. And there are many instances, instances of this throughout the spectrum of breast cancer treatment. So we use neoadjuvant therapy for larger tumors to shrink the tumor in the breast, shrink the tumor burden in the lymph nodes, and to individualize or tailor treatment on the backside based on how much response there is.

Let's talk about prostate cancer again as an analogy. So again, I think here's a great analogy, right? We know that in the case of prostate cancer, testosterone is not causing prostate cancer, but it's a growth factor for the cancer. So once a man has prostate cancer cancer, if he has metastatic disease, androgen therapy is the standard of care. Removing the androgen if he has surgical disease, you remove the tumor. But men are able to go back on testosterone replacement therapy if they need it, provided the PSA stays low. So is there an analogy here in breast cancer where obviously, if a woman has, er, positive breast cancer and it's metastatic, well, unfortunately you're going to be dealing with anti estrogen therapy indefinitely. But if you're talking about a stage one cancer or a stage two cancer, or even a stage three where you have neoadjuvant treatment, you have a pathologic cr, as far as you're concerned, there's no evidence of disease. Are those women still told to forego estrogen replacement therapy in postmenopause? And if so, why the difference from the biology of prostate cancer?

So, as we've said a couple times in the Course of the session. The antiestrogen medicines, which are very common. Remember, 80 plus percent of tuna tumors are estrogen receptor positive and nearly all those patients would be advised to have anti estrogen medications. So the side effects all relate to the estrogen deprivation. Hot flashes, night sweats, bone and joint stiffness and achiness, hair thinning, not hair loss, but thinning, finer hair, somewhat of a receding hairline, vaginal dryness, and sexual health issues or frequent urinary tract infections related to changes in the epithelial of the genital tract, osteoporosis, all these things are related to the loss of estrogen. Now, the upside of the treatment is sufficiently important that we encourage patients to strongly consider those treatments nonetheless. But managing those side effects is a part of the work of what oncology teams do for women who've had complete pathologic response. One asks, do I really need all the therapy out back? And it's a great question. At the moment, we don't usually omit the antiestrogens if the tumor is ER positive. Parenthetically, it's rather rare for ER positive tumors to have that complete pathological response because there's sort of an inverse relationship between the effectiveness of hormone treatment and the effectiveness of chemotherapy. The more hormone sensitive the tumor is, the less role there is for chemo and sort of vice versa in the space of ER positive disease. For women who have triple negative breast cancers, in theory, you could say, gosh, it would be okay to take anti estrogens, but we don't stylistically endorse that too often. I think what we really focus on is what's the symptom that we're trying to address with the hormone replacement therapy. And in those instances, we have important conversations with patients. So for instance, patient has osteoporosis, we have very good non hormonal options to treat osteoporosis. Patient has hot flashes and night sweats, there are non hormonal options to address those. In fact, the FDA just approved a drug a few months ago to try and treat hot flashes, genital symptoms, genitourinary symptoms, sexual health issues were actually rather liberal about using genital preparations of estrogens. So vaginal estrogen creams and things like that that can alleviate some of the discomfort or other symptomatology without giving significant systemic absorption. For most breast cancer patients, we stay away from oral hormone replacement therapy, looking whenever possible to use non hormonal or tapered or tailored hormonal manipulations that don't offer systemic exposure. Now, having said all that. Everyone who sees a lot of breast cancer patients knows there's a few women who are really just so uncomfortable without the hormones that they really need that to have a valuable quality of life. And then you have a unique conversation with the patient about those issues.

Let's talk a little bit about the genetics of this. So I think there can't imagine there's anybody listening to this who hasn't heard of the BRCA genes. So let's start with those. They're clearly not the only genes that are responsible. And when we talk about cancer, of course, everybody understands cancer is a genetic disease in the sense that there are mutations that are the synchronon of the cancer. Most of those mutations are somatic. They're mutations that occur during our life. But a handful of them are germline. And clearly the BRCA mutations are the most noteworthy. So what can we say about inherited risk of breast cancer through either single genes or polygenic? How much do we know? What's the prevalence? What else can you tell? Tell us about those.

Family history is obviously a powerful marker for greater risk of breast cancer recurrence. If you look at large populations, roughly 8 to 10% of all breast cancer diagnoses are related to a specific hereditary gene mutation. So BRCA1, BRCA2, BRCA1, BRCAsA2 account for about half or five of that 10% of all hereditary breast cancer cancer. So these often are families that have particular histories of ovarian cancer and breast cancer. BRCA1 and BRCA2 are very high penetrant genes. That means there's a pretty high lifetime risk of developing breast cancer or ovarian cancer if you have a BRCA1 or BRCA2 mutation. So if the average, again, we've talked about this number at 1 in 8 instead of 1 in 8. We're talking about a 1 in 2 or even a 2 in 3 chance lifetime of developing breast cancer. For women who harbor those gene mutations, the genetic testing for that now has become very standard. And increasingly, what we're seeing is that when one member of a family is identified as having a BRCA1 or BRCA2 mutation, we can help that patient in several ways. First, they might consider mastectomy. Because of the risk of a second breast cancer, Some women who've not been diagnosed with cancer will consider prophylactic mastectomy. Second, we think about prophylactic oophorectomy, removing the ovaries once that patient is done with childbearing, because we don't really, really have a good screening tool for ovarian cancer. And so once women have finished having their families, they often think about having their ovaries removed to lower their risk of ovarian cancer, which also traffics with a BRCA1 and BRCA2 mutation. And finally, for women who choose to retain the breast, we offer more intensive screening. Usually it's an annual MRI staggered every six months with an annual mammogram. We've learned a lot about those particular mutations. We also talk about, talk to extended family members because, as you know, BRCA 102 increase the risk of prostate cancer in men. They also increase the risk of male breast cancer, and they also increase the risk of pancreatic cancer, though the numerical issues there are all smaller than the risk of breast or ovarian cancer. So these are really evolving space in our management of cancers. And we have a whole team of genetic counselors and genetic specialists who both do the genetic testing and then advise patients very carefully, carefully on what the particular findings mean for their own care and how they should think about that in their breast cancer or other cancer management.

Can you say a little more about those, as far as BRCA being gain of function, loss of function, how is it transmitted? Is it autosomal dominant? Does it matter if a male knows that he has it with respect to his female offspring, et cetera?

Yeah. So these are, as you said, autosomal dominant, transmitted, that is to say, a man can transmit it to his offspring just as easily as a, a woman can. They are loss of function mutations. The normal biological role of these proteins that are encoded by the BRCA102 gene seems to be to help repair the DNA in a normal cell. Every time a cell divides, there's all this fine print editing, if you will, of the genome, and they're constantly replacing base pairs to correct the genome so that it stays perfect, if you will, through the thousands of divisions that a cell might undergo in the lifespan of a person. When you have a deficiency in BRCA1 or BRCA genes in this space, that repair mechanism is much less precise. And so mutations begin to accumulate. And if you have further loss of DNA repair, that can then predispose to giving rise to cancers. And the ones we've talked about, breast, ovarian, prostate, pancreatic, are the most common ones that we see with BRCA 1 and 2.

What makes up the other half?

The other half has actually become very interesting as well. So the other half includes other proteins in the same pathway of the BRCA1 and 2. So in particular pathways, PALB2 which is a partner of the BRCA2 protein. And about 1% of all breast cancers will have a PAL B2 mutation, which is a mutation that also substantially increases the risk of developing lifetime breast cancer, But a little bit less than BRCA1 or 2. About 1 to 2% will be related to a gene called Chektoo C H E K2, which also increases the risk of colon cancer. And about 1 to 2% will be related to mutations in the ataxia telangiectasia gene, the ATM mutations, which can give rise to several different kinds of cancers, though they're less common. But that's something that we are now encountering because here's the key takeaway for many, many women now we are recommending that following a breast cancer diagnosis, they do have genetic testing so that we can understand if we need to think about their tumor differently, or if we need to think about their surveillance or prevention approaches differently. And so we're doing a lot more genetic testing than we used to do. And with that we're finding these other mutations. Now, most women still don't have a mutation. Most women who have first degree relatives, mom or sisters who have breast cancer don't have a hereditary mutation. And the obverse of this is that many women can be reassured that they have not transmitted an undue risk to their offspring, which is a real concern amongst many patients diagnosed with breast cancer. And so a negative genetic test result can also actually be very reassuring for a family, Even as a positive finding can allow us to act differently in their management.

So BRCA 1 and 2 pal B2 check 2 atm account for 10% of breast cancer cases at the most. These are the exception and not the rule, but they are germline mutations, they're single gene mutations, and they're worth screening for. Is there any reason a woman with a questionable family history, I mean, one first degree relative should be checking this? Or if a woman has a sufficient enough family tree, mom does not have it, no grandparents have it, no parents have it. Would that be dispositive to say I don't need genetic testing?

There's a growing recognition that so these different genes have different sort of familial patterns. And because many of them are so.

Called less penetrant, because it's not fully penetrant, you can be fooled by a relative not having it.

It's not so full blown. I think that one of the things that happens following a breast cancer diagnosis is a lot of other family members might be tested as well. I think we're getting Closer to the time when there will be universal genetic testing Following a breast cancer diagnosis, and that will have a cascading effect into the families of affected individuals. And for women who have a strong family history of cancers, it's certainly very appropriate to meet with genetic counselors, Talk about the testing options, and in many instances, pursue that testing, Both because they want to know if they should be more att aggressive about their screening and surveillance, but also looking for the reassurance that that isn't something they have to be unduly concerned about. So this is another part of the revolution of our breast cancer treatment, which has been very exciting to see mature over the past 20 years.

Are there any commercial tests that you can point people to where they can ask their doctor or go directly over the counter and get a test done that looks specifically for those five genes?

There are tests. There are many commercial assays from many different companies that typically look nowadays at larger panels of genes, Often up to about 100 genes, on a rather regular basis. These are usually done with a specific purpose of looking for hereditary cancer risk. While the over the counter kind of things like the 23andMe things, can, in theory, pick these up, we don't usually lean on them as clinically actionable tests. And I think if there's a real concern about family history, probably better to seek out a genetic counselor or a cancer center in the community where you can talk more about this and get specific tests from different companies. Yeah.

That actually leads me to another question, which is the importance, or lack of importance of multidisciplinary care. So obviously you're at dana farber, which is probably one of the top three cancer centers globally, Certainly in the united states, which would be the epicenter of multidisciplinary care, Maybe tell folks what multidisciplinary care means, what the benefits are. But given that most people are not going to go to dana farber or memorial sloan kettering for their breast cancer care, how important is it, and what should they be looking for in their local hospital when they are diagnosed?

It's a really great point about helping patients get excellent breast cancer care. And it's not, of course, unique to breast cancer, but many, many cancers require, as you said, multidisciplinary care. Fancier way of saying you're going to need to think about surgery, radiation therapy, Medical oncology management with drug therapy. You want to have outstanding pathology, you want to have genetic counselors, you want to have great imaging teams. And what cancer centers do is they bring all those people together under One roof these days, it's sometimes, you know, with satellites. But they all collaborate together and work together. And that is really why care in a major cancer center can be so effective, because you have a team of people who are working together every day to make sure that things get done the right way. And sometimes I draw an analogy about the airline industry. As a passenger, you want an invisible experience with the airline. But what makes it all work? Well, you got to have a great maintenance team. You got to have an air traffic controller that knows what they're doing. You got to have pilots who understand how things work. You need the food delivery trucks to arrive at the right time, at the right moment. You need gate agents to keep people moving through the whole thing. And you get that at airports that are good because they all work together constantly, and they know exactly what they're doing. They communicate with each other regularly. That's what makes for a very uneventful flying experience, we hope. And for cancer care, you want the same thing. The way you figure this out, if you're a patient, is, are the providers talking to each other? You don't have to see them all the same day, though, of course, it's nice if you can do that. And we try to do that. They don't have to all be under the same room, because, again, we try and do that, but it's not essential. What's essential is that they function as a team. Because almost every patient with breast cancer is going to need to think about surgery, radiation therapy, medical oncology care. Many will also need to think about plastic or reconstructive surgery. Many will need to think about quality of the imaging they get down the road. They might need genetic testing. You want folks who are working together all the time, communicating with each other and handing the baton back and forth at necessary. So one of the conversations we frequently have when we meet a new patient is which modality of therapy is going to come first. Is it going to be surgery and then medical oncology and radiation afterwards? Or do we actually want to flip the sequence as we talked about in neoadjuvant treatment and give medical oncology treatment first? That's where you want a group that works together, talks effectively and regularly so that they're all on the same page. And we all say things like, okay, you're going to have surgery first. I'm going to let my surgical team take you through that next lap on this relay race. Then we're going to have the radiation team grab the baton. They're going to take you on A lap and then I'm going to pick it up and take you through another lap. As we talk about the medical oncology therapy. That kind of collaboration and teamwork is really important for women who have been diagnosed with breast cancer.

How important do you think it is for a woman to undergo her therapy at home versus coming somewhere else? If a woman listening to this lives, lives in, I'm going to offend whoever lives in that city. But the implication is not that the cancer care in City X, so I won't even name a city, but they live in City X. They're listening to this podcast and they just got diagnosed with breast cancer and they say, well, I want to go to Dana Farber. The way that he's describing that sounds like exactly the care I want to be. But the reality of it is City X is a two hour flight from Boston. They came out and they saw you for a consult. Are you going to say to them, look, City X might not have a place as good as, as Harvard, but it's pretty darn good. And I think you're better off staying there because you at least can go home every night as opposed to having to stay in hotels and things like that. How do you help patients navigate that? And what fraction of the patients who come to Dana Farber don't live in Boston?

We're very fortunate to have a terrific reputation such that we see patients from obviously New England, all across the country and really all across the world who will come to a cancer center like Dana Farber for exactly that kind of multidisciplinary care and in the management of metastatic disease. They might also come for clinical trials, actually, both in the early and in the advanced stage disease where the next wave or the future of innovative treatment is going to emerge. Having said that, breast cancer is a very common problem. It is the most common cancer diagnosis in the country, as we've mentioned, and you can get great breast cancer care in many, many parts of the country. There are very few parts the of of the United States where people really don't live within reasonable access distance of really good breast cancer care. It's a common problem. Now, having said that, I think it is important to make sure that you're dealing with people who specialize in cancer care. There's been a big push to professionalize the issues of radiation, oncology and surgery to subspecialize those areas, just as we subspecialize medical oncology and that you have, have that team presence. And I think those are things to very much seek out as part of your treatment program. And most people again will live within distance of getting a second opinion. That's always a good idea if there's any ambiguity or if you're looking for reassurance, because hopefully by making the effort once, perhaps to go to a place where you can get external validation of the plan, it offers a lot of reassurance and comfort.

Where would you say is the greatest variability of care across the medical oncology, surgical oncology, radiation oncology. When you compare, say the top flight, if you took the top 20 institutions in the United States and compared them to the median institutions of the country, where will you see the most disparity? Will it be in the radiation side, the surgical side, the post operative side? Like, where's the greatest variability?

I don't think there's one specific area that jumps out. I, I think that the value added of some of the cancer centers that we've been discussing, really thoughtful review of the pathology and radiology. These are things that are not often visible to patients. But the experience of the radiology team working with the surgeons, they really satisfied that that little ditzel doesn't need to be biopsied. Is the pathology first rate? Did they really make sure that the grade was called correctly, that the estrogen receptor studies were correctly done? Those are incredib important things. And while most places do it very well, those are things that can really alter longer term outcomes. Another area is judicious use of treatment. So there are a lot of drugs that we can use in early stage breast cancer and dialing in the right amount is a bit of an art form. Again, it's a common disease. Most places do it very well. But there are sometimes nuanced questions about is this a case where we want to add more or is this a case where we're comfortable doing a little bit less? That's an important part of the discussion. Other areas that matter a lot, again, not always so obvious to patients, but plastic and reconstructive surgery, tremendous variation in approaches and in the teamwork and collaboration between the breast surgeon and the plastic and reconstructive surgery teams, those things can also have a big impact on how people look and feel years after the breast cancer diagnosis. So making sure that you have high quality access to plastic and reconstructive surgeons, if that's part of the treatment plan, is really critical. So I think that again, the good news is that you can get excellent breast cancer care at many, many places around the country. And the test, if you will, for most patients is Are these folks used to working together? Are they talking to each other, collaborating with one another, coming up with a unified plan that makes sense, that's really what you want to see happen.

Yeah. And if that's not happening, if they don't have a monthly tumor board, those would be kind of signs, a meeting where all these people, the pathologists, the medical oncologist, surgical oncologist, radiation oncologists get together. If you don't have a tumor board, that might be a sign that says, hey, I'm gonna travel a little bit further to the next city or see what I can do. Also seems to me that one of the most high yield investments, if you're going to seek that second opinion, sending a block of pathology slide to the A center is really valuable. I think that's something that patients don't always know and I hope that people listening. We can now make this a really good public service cent announcement which is make sure when you have your tissue specimen taken that you understand you have a right to request a section of that tissue be sent to another pathologist of your choosing. And that can be, as you said, I think, a very important determinant of outcome. That's an easy place to make a mistake or overlook something. If a less experienced center is viewing a tumor that happens to be not a run of the mil tumor.

It's a great point, Peter. The quality of pathology is the foundation for all of cancer care. And again, breast cancer, very common, usually begins in the breast. It's usually not so mysterious. But oftentimes a pathology review is vital importance. Are the margins adequate? Is this DCIS or invasive cancer? It can sometimes be hard to know is this a favorable prognosis tumor under the microscope or not? And the. And then if you take a bigger step back, we occasionally see things that aren't even breast cancer. There are other tumors that can be there, they can be reclassified. And then when you start to imagine other kinds of cancer, sarcomas and lymphomas and leukemias, where there's a real art to the pathology that's unappreciated vital part of the cancer care process that everyone has access to with consultations on pathology and is part of what great cancer center centers really deliver just for the sake of completeness.

Although most people probably aren't aware of this, you've already alluded to it twice. Men can develop breast cancer as well. Can you say a little bit about what the incidence is and do we know anything about the risk factors?

Yeah. So it's a absolute truism that men can get breast cancer. Fortunately, the incidence is pretty low. For every 200 cases of female breast cancer, there's one case of male breast cancer. The risk factors are not particularly well known, but they do include genetic predisposition as part of it. They include certain hormonal conditions that men can rarely get. But what's interesting is men are often unaware that they can get breast cancer. And so it is not uncommon that men's diagnoses are actually at a higher stage than women's because they weren't really paying a lot of attention to the chest or the breast or they noticed some nodularity and didn't really think much of it. And so if men are found to have on exam any changes around the breast tissue, that should be evaluated on as well. And I've actually had the experience over the years of a woman who was diagnosed with breast cancer and then her husband, like, was poking around his chest like, wait a second. And they have husband and wife breast cancer. So it happens once in a while. It's a small area of overlapping Venn diagrams there. It is something to be aware of. And the treatment principles for male breast cancer are fundamentally the same as for female breast cancer. Though nearly all breast cancers in men are estrogen receptors receptor positive, it's very rare to get a triple negative breast cancer in a man.

And what about HER2 receptor?

Uncommon, but not unheard of.

So 1 in 200 cases. So there's not a lot of men in your care, but given the size of your practice, I'm sure you do see men from time to time.

We do. And we actually have a program here for men with breast cancer headed by Pablo Leone. And several other cancer centers around the country also have this. There are issues that arise. Historically, men have been offered mastectomy because the aesthetic virtues of breast preservation have not been thought to be so important in men. That's kind of changing nowadays for some men. Most men will be candidates for anti estrogen medicine as their tumors are estrogen receptor positive. The genetic piece is very important. So there are clinics that specialize in the care of men with breast cancer as well.

Well, Hal, this has been a really interesting discussion. It's been a whirlwind tour of all things breast cancer. I want to thank you very much, much for sharing your time. I know, I know how busy you are, so I want to thank you again. And I know that we'll link to a lot of the stuff that we've talked about, including some of the trials so that people can understand this. I hope that people come away from this with a really good sense of how to ask the right questions to be better advocates for themselves as they're going through therapy and of course ultimately if they are diagnosed with breast cancer, to understand what the critical questions are that should be asked of the team that's going to be charged with their care.

It's a treat to be with you and I hope it's been helpful. And I don't want to sound too rose tinted glasses here, but the fact is women are doing better and better following a diagnosis of breast cancer and early detection is really important. Multimodality therapy, as we've discussed, is really important. The drugs are getting better and better for both early and for advanced or stage four breast cancer. So there's a lot of tremendous, tremendous optimism in the care of breast cancer patients right now, even as it remains a public health challenge and obviously a personal challenge for hundreds of thousands of women around the country.

Great.

Well, thank you very much Hal.

Thank you.

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