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

25:27Okay, 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 and my current practice, that I don't know if it's still invogue or not invogue 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?

26:04And 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 very, and in younger women these may change with the monthly cycle. And in post -menopausal women, they may represent, you know, just residual breast tissue. If you lose weight, you might feel some of 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 a regular monthly breast self -exam or a rigid approach to self -palpation adds that much.

26:58There 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.

27:40Some 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 of 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?

28:22So if a woman has a mammogram 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 make seasonal biopsy. Again, the key takeaway is if people feel a lump, they should seek medical evaluation. For patients who have findings on their own 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.

28:58Or yeah, this same thing was seen a year ago and five years ago when the patient had a 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 cord 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 head.

29:43And 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, but is not truly breast cancer.

30:25got 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 pre -cancerous 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 poly. It's a growth, it is a pre -cancerous 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.

31:07That'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 ductile carcinoma and situ versus lobular carcinoma and situ. The ductile 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.

31:46We'll include in the show notes a great figure of this. figures tend to be easier to follow, I think sometimes in the words here. The relationship between labyrinthic arsonoma or labyrinthic arsonoma and cyto, and ductal arsonoma or ductal arsonoma and cyto, 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 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 -pre -cancerous stages.

32:32So 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 in things. And if you're familiar with talking about gleecin scores, the gleecin score is beginning to drift up there. And ADH, atypical ductile 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.

33:12and follow -up, but it's one of those precursor lesions that begins to flag a patient as mean a 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 the 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.

33:57So, 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 the judgment. 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 tomoxifen to help slow the development of any malignant cells in a patient with those problems.

34:30Do 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.

35:18We'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 never require treatment or never be a clinical problem for a patient. Does every breast cancer start as a ductal carcinoma or lobular carcinoma inside you? 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.

36:06You will often encounter triple negative tumors that do not have 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 pre -cancerous 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, which is kind of keep accumulating within the duct, or pageant's 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 pre -cancerous cells.

36:53But 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 zero 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.

37:32The 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 the DCIS cells are not as mushroom forming, if you will, and they can creep and crawl through the ductile 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.

38:09For 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 surgical exision 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.

38:55And 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 in 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 is 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.

39:33It 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 percent 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 lump back to me 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 sense and alimuth notes.

40:09So the exception to this is sometimes there's a lot of DCIS in 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 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 post -hoc and do the Sentinel node mapping if there is an occult area of cancer found within that area of DCIS.

40:48And 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 mapping after an initial lump back to me by accident. But you don't have a tumor to inject into. But 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.

41:22All 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. 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 lump back to me, 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 ductile channels, and these all arborize out throughout the breast space.

42:04And 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 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 to Moxifen or aromatase inhibitors, both of which work by depriving the tumor area of estrogen, can also lower the risk of inbreast recurrence of DCIS or lower the risk of developing invasive cancer after DCIS.

42:55The downside to those treatments is we usually recommend many years of therapy, they 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 lump back to me, strong consideration of radiation therapy, and then above and beyond that, discussing whether or not to offer anti -estrogen treatments.

43:30And 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. 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 her two new 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 wouldn't offer treatment. That's right. Let's talk about risk reduction. So if you took all women who had DCIS, who underwent a lump -back to me, and were found to only have DCIS, had no invasive cancer, and you did nothing.

44:12How 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 cancers, what we call grade. So, higher grade, grade three 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 or subterpositive, less comedonecrosis type lesions.

44:53And so the span ranges 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 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.

45:33So, 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 biops. They're doing a core biopsy and They're not, it's just DCIS, we're just going to 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.

46:02And 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 one to two percent chance of having a problem, I'm willing to sign up and do the radiation treatment.

46:39So 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 our radiation oncologist is 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 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.

47:23So if it's a lump back to me, 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 cancers in the past, an 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 some who is standing in front of you, shooting an arrow right at your heart, and that's where the beam of radiation was going.

48:01Nowadays, 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 their decision -making process that there is a risk of accelerated coronary disease in modern contemporary practice, that risk is incredibly low.

48:47And 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 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.

49:22And so the risk of the heart is extraordinarily low. What about other risks just briefly in terms of skin damage or other other risks of sickness? Any persistent damage from radiation under the current way it's done? It depends a little bit on how much radiation is done and where they have to go. So if you have a breast cancer, or 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.

49:58There is a risk of so -called pneumonitis, inflammation of the lung from some of the radiation's 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 so that it fades from a lobster red to a pink and then to a tan color and eventually backed in a normal skin tone.

50:38What percentage again of DCIS are estrogen receptor positive? Something like 80 plus percent, the vast majority. Got it. But so then to the next question, which is, what is the natural history of DCIS, ER positive DCIS with and without estrogen blockade 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 NSABPB24, 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, lump -backedomy alone, versus lump -backedomy plus radiation.

51:22And 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, lump -backedomy plus radiation with without tomoxifen, 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.

52:01So 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 baseline risk is no longer way up here. It's kind of down here. And so for that reason, the marginal benefits of the antiestrogen approaches, or something on the order of three to five percent 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.

52:46So it's a relatively small gain to be using anti -estrogens 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 of the opposite breast. Many women will pass on the anti -estrogent therapies even as they receive other treatments for DCIS. One of the academic questions is, can you use the anti -astrogens instead of the radiation? And that's part of other studies that are going on where women might get surgery for the DCIS and then be put on the anti -astrogens without the radiation.

53:21And 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 Tommoxifen 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 to Moxifen 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 the vestrogen.

53:58we 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 NSA BP24 study, which is we're talking about a three to five percent 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 lumpec to me. I'll do a little bit of radiation, but I'm not going to take to Moxif in 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, that I'm not sure that really adds up for me.

54:36And 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 were 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 radiation down to about five days of treatment. And so at some point that becomes a very compelling option, I think, and for many women, that would be great news. Now, how 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?

55:32Am I making that up? I don't think you're 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 Leucoplegia in the throat, which increases is the risk of developing head neck cancers or other field defects. Clearly the diagnosis is saying this patient is a 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.

56:08There'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 antiestrogen 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 is 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?

56:47How 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 four to one. 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 hormonal receptor positive, estrogen receptor positive. Legion, there's a rare entity called pleomorphic LCIS, which is a pathologic diagnosis. That's a more virulent flavor of perhaps LCIS and certainly a lobular breast cancer, pleomorphic lobular breast cancer. But otherwise, it's the same kinds of demographic trends that we've been alluding to.

57:31Okay. 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 ductile hyperplasia, atypical labyrinthipraplasia, 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 a chair of one of their data safety and monitoring board.

58:15So I know they're data -pidly well. I don't have any other commercial conflicts of interest, but I do work with the NSABP. 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 Tomoxovin could lower the risk of breast cancer diagnosis and 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 a lobular carcinoma in situ. And those women were at greater risk of developing breast cancer. So that risk, just to be quantitative, so I'm looking this up as I speak to you, was there There was a rate of 13 per thousand women, 13 per thousand women per year.

58:58And Tomoxin cut that in half down to about five or six per thousand women per year. So 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 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.

59:34Yeah, they had high risk because of family history or because of atypical hyperplasia. There was a whole algorithm that went into the risk assessment. These women took Tamaxifen 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 Tomoxivan 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, Tomoxivan and subsequently other antiestrogens have been shown to lower that risk of diagnosis.

1:00:18But for most ordinary risk women, that risk is sufficiently low, that the relative reduction only amounts to a percentage point or two. 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 of 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 tamoxin as a preventative, arguably you're preventing the most treatable types of breast cancer from arising.

1:00:54So you're pulling out the better actors, if you will, and what's left are tumors that remain somewhat resistant to the antiestrogens and therefore more worrisome. Yeah. I might not have a dog in this fight because I'm not a woman, but boy, the thought of that 98 out of 100 women are unnecessarily exposed to Tamaxifen 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.

1:01:32Even in that study, which sought to enrich for a group of women who are slightly greater than average risk of breast 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 to Moxifen for DCIS, wives of friends, for example, and a year in, they're sort of calling me saying, what the hell is going on?

1:02:08Is 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 to Moxifen 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 pre -manopausal and this drug has ruined my 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.

1:02:40We'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, tomoxid and other anti -estrogens have cured more people of cancer than anything else we do in oncology, aside from surgery itself.

1:03:21So 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 in 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?

1:03:53The shared element here is mammography. And we're going to get to invasive breast cancer momentarily, but the reason we make diagnoses of DCIS 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're 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 pre -cancerous conditions.

1:04:33So, fundamentally, that's what a pap smear does. So, 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 pre -cancerous 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 pre -cancerous findings as well.

1:05:07So that is the nature of a successful screening program. You are finding pre -cancerous lesions. The debate as it relates to breast cancer is how much treatment should we offer in these pre -cancerous instances, but that's why there's more DCIS and LCIS, 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 Apple's Apples comparison because it's not an imaging test. But by itself really lacks the specificity to be a high yield tool.

1:05:49And 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 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.

1:06:32So 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, 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 matters. 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.

1:07:16And 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 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.

1:07:52It's not a reflex per se, and it's not universally recommended. In fact, studies have not really shown that ultrasoundography 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 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 BRCA 1 or 2 mutation.

1:08:26MRI is very important for early detection of cancers in his routine for those women, but not for the general population. Does the mammogram have a similar score to radiographic scoring where you have a rad's 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 by -read 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 there are very well -done standards of what those gradations mean.

1:09:04The 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 by -rads -3, 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.

1:09:42Those data exist, for example, where if you know the PSA, and you know the PSA density, and you know the high -rad score, you have a complete distribution of whether or not there's no cancer present, a gleece in 3 plus 3, which you'll watch and wait, a gleece in 3 plus 4, which needs to come out, or a 4 plus 4, 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 of family history? The short answer is no.

1:10:20The 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.

1:11:12There'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 Byreds 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. Byreds 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 and about what gets biopsyed.

1:11:51Having 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 imaging, or there's even a recommendation for a biopsy, a lot of the time these will still be for pre -cancerous 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.

1:12:23Was it about 250 ,000? I said 275, I think, but it's about 250 to 300 ,000. That's just invasive. Obviously, that doesn't include any of those DCIS, LCIS cases, 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 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 grade or other cellular machinery and then walk us through the completion of staging.

1:13:10Yeah, 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. And the analogy here would be to a gleece in score. It's not quite a one -to -one analogy, but the higher the number, the more 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 HGR2.

1:13:51Is 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.

1:14:24Sometimes they can see the cancer cell sort of burrowing into a blood vessel or a lymphatic channel and that is a marker of some of the 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 lumpectomy.

1:15:05So 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 one, two, three, 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.

1:15:40It might be because of personal preference. It might be because of the size of the tumor relative to the size of the breast, such that a lumpectomy maybe isn't adequate for achieving a cosmetic result that people would think is acceptable, or maybe 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 lump back to me. 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, one, two, three, four with some A's and B's thrown in there.

1:16:16So, 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 is spread to the bone, the lung, the liver, those kinds of organs metastatic disease. Stage one, at the other end of the spectrum, is a tumor that is two centimeters or smaller. So that's about the size of a nickel or smaller, and the lymph nodes are negative. stage two includes slightly bigger tumors, bigger than two centimeters, 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.

1:16:58Lymph 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 no negative tumors and no positive cancers. All of it's really a spectrum. So breast cancer is really interesting. If you have a 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 risky than a two and a half centimeter, and so forth. There's another axis that goes by nodal status.

1:17:32No negative is less risky than one, two, three, four. It's all very linear. And then finally, there's a third dimensional access about the biology of the tumor, where triple negative cancers, again, ounce -for -ounce size for size, will have a more aggressive natural history. Hereto -positive tumors, historically, were also a very aggressive tumor. Now we have some of our most successful outcomes with treatment of hereto -positive cancers. Within this large group of ER positive, hereto -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.

1:18:09And nowadays we also use so -called genomic tests like the Onkotide DX recurrence score to understand for that large group of cancers how risky they are and whether they weren't chemotherapy. So I tend to describe it as, with 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 how it's important that they understand that all of that is in the M zero case, the non -metastatic case. So all bets are off. When we have metastatic disease, the prognosis is awful.

1:18:45No, 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 her two 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.

1:19:27cancer. 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'll be women who will live for years and years, with advanced or metastatic breast 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 too positive breast cancers, actually, it's moving further and further out beyond that.

1:20:04Can 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 five centimeters, that becomes a so -called T3 B cancer, and if you have T3 cancer with any degree of nodal involvement, that becomes a Stage 3 breast cancer. If you have four or more positive nodes, regardless of the extent of the size of the tumor, that Stage 3, if you have involvement of the superclivicular nodes, that Stage 3. And so you got to sort of get the grid out and look up all the criteria.

1:20:40Can 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 American Cancer Society statistics, they update them every year, and I can look up the numbers and give them the finger tips, but in ballpark, stage one, isolated to the breast, 10 year, cancer -free survival. Nowadays, often on the order of 90 % or more, stage two, 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.

1:21:21Now, the grade, the one, two, three 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 chemoregiments? 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. Triple negative breast cancers are almost always grade three.

1:21:57Most HER2 positive breast cancers are grade two or three, and they all get treated with the TREAS2ZAMAB 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. Really is explained by what you just said, coupled with another observation, which is if If you catch a breast cancer that is two centimeters or smaller without lymph node involvement, the chances that you will be cured, which we use as 10 -year remission, is 90 -95%.

1:22:53And without exception, the larger the tumor is at presentation and the greater the lymph node 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. It's a huge difference. Suggesting that 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.

1:23:45In 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, 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 the late 1980s.

1:24:24They 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, And early detection is clearly still associated with better long -term prognosis.

1:24:56The 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 may know, breast cancer is now the most common diagnosis of cancer aside from non -melonomal skin cancer, it's the most common cancer diagnosis in the world. For almost all countries on Earth. I didn't know that. How you're saying it's more common than lung cancer? More commonly diagnosed lung cancer.

1:25:32Because the outcomes are better, there's still more fatalities from lung cancer. But it's the most common diagnosis of cancer in women, almost every country on Earth. There are still some places in Sub -Saharan Africa where there's cervical or other gynecologic a tumor's 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.

1:26:08And this relates to the welfare advances in many countries around the world as they've been becoming more affluent, better 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 are simply insufficient medical manpower, womanpower or 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.

1:27:00But this is gonna 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 lump back to me with a sentinel node biopsy. The sentinel node is negative. They will not undergo a formal lymph node dissection. She'll be told you 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?

1:27:33And then depending on the receptor status, she'll either get to Moxifen if it's ER positive. Herceptin, if it's her two new positive, is there any treatment beyond that? So the first thing to say is that's a very common problem. In the United States, the most common presentation of breast cancer is of a Stage 1 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.

1:28:07We use adjuvant therapy in colon cancer and in some sarcomas and in certain prostate cancers 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.

1:28:39We'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 radiations 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 drug therapy.

1:29:12And 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 cyniquan known. One of them is early detection through a 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 seen in the United States over the past 30 years. And so for cancers of almost any size that are estrogen receptor positive, we think about antiethrogen medicines like tomoxifen or aromatase inhibitors, for tumors that are as small as a half a centimeter or more in size, we think about drugs like Tres Tuzamab that target her two.

1:29:56and similarly for very small triple negative breast cancers, we often think about chemotherapy. And then there's a discussion. Most women with her two positive cancers also get chemotherapy with that Trestusamab. And then as the tumor gets bigger and riskier, we amp up with more anti -herchew 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 recurrent score or similar genomic test done on the tumor itself, where they look at the patterns of gene expression in the tumor.

1:30:33And 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 mammoprintasse from Agendia and there 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 one centimeter cancer needed chemotherapy, to a time nowadays, when we frequently can avoid chemotherapy for most ER positive breast cancers, but certainly those that are no negative and many of the ones that are known 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.

1:31:25So, circle back. Surgery is the cyniquanone. Following the surgery, we use radiation therapy to sterilize the breast and 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 antiestrogen therapy and to Moxifen and AstraZol, things like that.

1:32:04Herceptin, 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, her two 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.

1:32:36One is called tomoxifen. The other is called an aromatase inhibitor. These are each pills. They work by different mechanisms, tomoxifen sort of blocks estrogen's ability to reach the estrogen receptor and the cancer cell, the aromatase inhibitors, only work in postmenopausal 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 consequences estrogen deprivation, which again, starves on the vine, these cancer cells that we think depend on estrogen for their growth and development.

1:33:17So that's a very important medicine. And again, globally, hugely important has saved more lives than bone marrow transplant 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.

1:33:52They can make your hair fall out. They lower your blood counts. They make you tired. On the one hand, our supportive care and oncology has gotten vastly better in recent decades. So we have very powerful anti -nauseumeticons. 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 drugs, drugs such as doxarubicin or what's also known as adriamisin, the red devil, taxine type drugs called packletaxle or taxile, alkylator drugs like cyclophosphamide or carboplatin, very widely used chemotherapy drugs.

1:34:37And maybe just for folks to understand how these things all have something in common, which is they're basically anti -proliferative drugs. As you said, they're old school dirty drugs, these of drugs that have been around for many, many 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, 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.

1:35:11That'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 and triple negative disease.

1:35:45But 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 Pembrolyzumab and others that have pruned 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 neo -adjuvant approach, which is the same idea as 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.

1:36:25For the HER2 positive, the transformative event was the development of Tres Tuzamab, or her septin, which the data came forward in 2005 for early stage breast cancer, that adding Tres Tuzamab dramatically improved the chances of never hearing from the cancer again. And that became totally standard for HER2 driven breast cancers. Now it is for higher risk ones, we add a second anti -her2 drug called Pertuzamab or Purgetta. Now interestingly, we're still giving chemotherapy with those anti -hereto drugs, but we've completely flipped the outcomes for hereto -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.

1:37:04And finally, with estrogen receptor positive breast cancer, there have been two narratives. One has been a narrative about using less chemotherapy. So the good news is we are able to figure out a lot of women don't actually need chemotherapy for ER positive hereto -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 two -thirds 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.

1:37:42We're using longer durations of anti -estrogens for higher risk tumors. and there's a very exciting new class of drugs called CDK46 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're 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 neoagevent 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 neoagevent therapy is also a great prognostic indicator.

1:38:32That's exactly right. So for larger tumors, we have been moving more and more towards a paradigm of what we call neo -adjuvant 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 freight train. It's a cassette of treatment and we're just kind of giving the same kind of therapy, but we're switching the order. 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.

1:39:11And 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 lump back to me 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 are removed. That carries a greater risk of limited range of motion in the arm or lymphedema in the arm. Now, it might be a candidate for a sensinal node biopsy by shrinking those tumors ahead of time. So that's one big advantage of neoagevent 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.

1:39:50The second big reason is that we learn while giving this neoagevent treatment how well the tumor responds. And if the cancer totally disappears intuitively obvious, that's a really favorable prognostic 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. Did those patients get adjuvant therapy or is therapy done? They often get something.

1:40:23It 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 her two positive breast cancer we give chemotherapy and trastuzum ab up front. If there's residual disease out back we can use a derivative of trastuzum ab called trastuzum ab m -tancing which improves the prognosis for those patients who have residual cancer and there are many instances of this throughout the spectrum of breast cancer treatment.

1:40:57So we use neoadjotherapy 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, if he has metastatic disease, androgen therapy is the standard of care, removing the end region. If you have surgical disease, you remove the tumor, but men are able to go back on testosterone replacement therapy.

1:41:36If 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 antestrogen 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 neoagevent treatment, you have 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?

1:42:11So as we've said a couple times in the course of the session, the anti -estrogen medicines, which are very common. Remember 80 plus percent of 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.

1:42:47Now 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 anti -estrogens if the tumor is ER positive. Perinthetically, it's rather rare for ER positive tumors to have that complete pathologic response, because there's sort of an inverse relationship between the effectiveness of hormone treatment and the effectiveness of chemo therapy.

1:43:23The more hormone -sensitive the tumor is, the less role there is for chemo and sort of vice versa and 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.

1:43:59Patient 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, genital hearingarious symptoms, sexual health issues were actually rather liberal about using general preparations of estrogen. So vaginal estrogen creams and things like that that can alleviate some of that is comfort 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.

1:44:39Now, 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 Braca 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.

1:45:08in the sense that there are mutations that are the synchronon of the cancer. Most of those mutations are somatic. They are mutations that occur during our life, but a handful of them are germline, and clearly the brachy 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 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 percent of all breast cancer diagnoses are related to a specific hereditary gene mutation.

1:45:51So BRCA1, BRCA2, BRCA1, BRCA2 account for about half or five of that 10 percent of all hereditary breast 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 and 8, instead of 1 and 8, we're talking about a 1 and 2 or even a 2 and 3 chance lifetime of developing breast cancer for women who harbor those gene mutations.

1:46:30The 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 BRCA and one of BRCA to 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 not been diagnosed with cancer will consider prophylactic mastectomy. Second, we think about prophylactic u forectomy, removing the ovaries. Once that patient is done with child barring because we don't 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.

1:47:13And 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 to extended family members, because as you know, BRCA -1 and 2 increased the risk of prostate cancer, and men, they also increased the risk of male breast cancer, and they also increased 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 to both do the genetic testing and then advise patients very 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.

1:48:01Can you say a little more about those as far as Braca being gained a function, loss a 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, etc? Yes, 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 woman can. They are loss of function mutations. The normal biological role of these proteins that are encoded by the BRCA and one of two genes 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.

1:48:37They'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 a lifespan of a person. When you have a deficiency in BRCA1 or BRCA2 or other 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 BRCA1 and What makes up the other half? The other half has actually become very interesting as well.

1:49:15So the other half includes other proteins in the same pathway of the BRCA1 and 2. So in particular palbi2, which is a partner of the BRCA2 protein, and about 1 % of all breast cancers will have a palbi2 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 CHEK2, which also increases the risk of colon cancer. And about 1 to 2 % will be related to mutations in the ataxia -talanjectasia gene, atymutations, which can give rise to several different kinds of cancers, though they're less common, but that's something that we are now encountering.

1:50:00Because here's the key takeaway. For many, many women now, we are recommending that following a breast cancer diagnosis, is 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.

1:50:44So 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 Bracka wanted to palbi to check to 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.

1:51:26No 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 breast cancer diagnosis, and that will have a cascading effect into the families of affected individuals.

1:52:04And 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 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?

1:52:42There 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 that over the counter kind of things like the 23 and me things can theory pick these up. We don't usually lean on them as clinically actionable tests. 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.

1:53:18Yeah, 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 Telphokes, 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?

1:53:55It's a really great point about helping patients get excellent breast cancer care. It is not, of course, unique to breast cancer, but many, many cancers require, as you said, multi -disciplinary care. Fancy 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.

1:54:29And 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.

1:55:03You 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 into the same roof, because again, we try and do that, but it's not essential.

1:55:35What'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 as 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?

1:56:08is it going to be surgery and then medical oncology and radiation afterwards? Or do we actually want to flip the sequences we talked about in neo -adjuvant 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 grabbed 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.

1:56:43That kind of collaboration and teamwork is really important for a woman 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 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.

1:57:22Are you gonna say to them? Look city X might not have a place as good 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 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 multi -disciplinary care.

1:57:58And 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. You can get great breast cancer care in many, many parts of the country. There are very few parts 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.

1:58:29Now, 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 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.

1:59:12Where 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 is the greatest variability? I don't think there's one specific area that jumps out. I think that the value added of some of the cancer centers that we've been discussing, a really thoughtful review of the pathology and radiology.

1:59:52These 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 biopsyed. Is the pathology first rate? Did they really make sure that the grade was called correctly, that the estrogen receptor was studied was were correctly done? Those are incredibly 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.

2:00:31And 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 new ones 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, 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.

2:01:09So 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 of a meeting where all these people, the pathologist, the medical oncologist, surgical oncologist, radiation oncologist get together.

2:01:48If you don't have a tumor board, that might be a sign that says, hey, I'm going to 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 plus 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 announcement, which is make sure when you have your tissue specimen taken that you understand you have a right to request the section of that tissue be sent to another pathologist of your choosing.

2:02:24And 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 mill 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 of the microscope or not?

2:03:04And 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 an unappreciated vital part of the cancer care process that everyone has access to with consultations on pathology and as part of what great cancer 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.

2:03:39Men 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.

2:04:25And so if men are found to have on exam, any changes around the breast tissue, that should be evaluated 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 was poking around his chest. I think, 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 vent 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 receptor positive, it's very rare to get a triple negative breast cancer in a man.

2:05:04And what about her two receptor? Uncommon but not unheard of. So one 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 Leon 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 or receptor positive.

2:05:39The genetic piece is very important. So there are clinics that specialize in the care of men with breast cancer as well. Well, how 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 for sharing your time. 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.

2:06:10And 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. So, it's a treat to be with you and I hope it's been helpful and I don't want to sound two rose tinted glasses here, but the fact is women are doing better and better following the diagnosis of breast cancer and early detection is really important. Multimodality therapies we've discussed is really important. The drugs are getting better and better for both early and for advanced or stage 4 breast cancer. So there's a lot of 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.

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