The Peter Attia Drive - #278 ‒ Breast cancer： how to catch, treat, and survive breast cancer

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.580 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:53.260 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.080 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Harold

00:01:05.960 Bernstein, who goes by Hal. Hal is currently a professor of medicine at Harvard Medical School.

00:01:11.100 He earned his MD and PhD in cellular immunology from Harvard Medical School, as well as a master's

00:01:15.520 degree in history of science from Harvard University. Hal trained in internal medicine

00:01:20.080 at the Massachusetts General Hospital before his medical oncology fellowship at Dana-Farber

00:01:25.040 Cancer Institute. He joined the staff of Dana-Farber, and he is also on staff at Brigham

00:01:30.040 and Women's Hospital, where he is a clinician and the clinical investigator in the Breast Oncology

00:01:35.540 Center. His research interests include therapy for early stage and advanced stage breast cancer,

00:01:41.780 healthcare for breast cancer survivors, and quality of life and psychological issues among women

00:01:46.500 with histories of breast cancer. This is an episode I have wanted to do for a very long time. As you

00:01:52.580 know, I've already done an episode or two on prostate cancer, and while prostate cancer is the second

00:01:58.640 leading cause of cancer death for men, it's no surprise that breast cancer is the second leading

00:02:03.840 cause of cancer death for women, and therefore this episode is long overdue. In this episode,

00:02:09.740 we talk about all things related to breast cancer, beginning with, of course, the anatomy of the breast

00:02:15.740 and the endocrinology of the breast. We speak about the increasing rate of breast cancer over the past

00:02:21.200 decades. We speak about the changes to a woman's breast throughout her life and how that relates

00:02:25.880 to understanding the pathology of breast cancer. We talk about the different kinds of breast cancer,

00:02:30.580 including the precancerous lesions of ductal carcinoma in situ and lobular carcinoma in situ,

00:02:37.140 DCIS and LCIS, and all the way to invasive breast cancer in the various stages. We talk about the

00:02:43.680 different ways that you would classify these things, and I think Hal does a masterful job

00:02:48.100 of taking it into the three categories of breast cancer. This was an obvious thing that I hadn't

00:02:55.300 really considered until the discussion, and I find it to be now a much more helpful framework for

00:03:01.080 myself. We speak about the different types of breast cancer screening available, including the utility of

00:03:05.960 self-exams, mammograms, ultrasounds, MRIs, and more. And we talk about the importance of early

00:03:11.100 screening and detection as it relates to breast cancer. This is, interestingly, still a very

00:03:16.420 controversial topic. We then talk about the available treatments for the different types of

00:03:21.840 breast cancer, and again, we'll go into much greater detail about how someone listening to this

00:03:27.180 with breast cancer can understand which bucket they're in of the three and what the implications

00:03:32.960 are. We end the discussion by speaking about the role of genetics in breast cancer. Of course,

00:03:38.560 many people have heard of the BRCA mutations. We talk about the role that they play, but they're

00:03:43.260 not the only genes involved in breast cancer, so we have a more thorough discussion about that.

00:03:48.400 We also touch on male breast cancer. This is something that many people are surprised to learn

00:03:52.580 exists, but I personally have a very close friend who was diagnosed with breast cancer. Fortunately,

00:03:58.300 it was caught at an early enough stage, and he's doing fine, but this is never something that

00:04:02.880 should be too far off your radar. So, without further delay, please enjoy my conversation

00:04:08.000 with Dr. Harold Bernstein.

00:04:14.780 Hey, Hal. Thank you so much for joining me today. This is a topic I've been really wanting to do a

00:04:20.540 deep dive on for quite some time. We've done a deep dive on prostate cancer a couple of times.

00:04:25.780 I think we're long overdue to talk about the second leading cause of cancer death for women,

00:04:30.800 which is, of course, breast cancer. But maybe just briefly give listeners a little bit of a

00:04:34.980 sense of your background, the post you sit in, and the work you do.

00:04:38.680 Well, first, thanks for being here. I want to learn how to live longer,

00:04:41.320 so I'm hoping that we'll have a two-way conversation here. It's great to be able to

00:04:45.320 speak with you and your audience. I'm a professor of medicine at Harvard Medical School and a medical

00:04:50.200 oncologist here at Dana-Farber Cancer Institute, where I specialize in breast cancer.

00:04:54.680 I trained in medical school as an MD-PhD student, and I got a PhD in immunology. Following that,

00:05:01.380 I was a house officer studying internal medicine at Mass General and came over to Dana-Farber to do

00:05:07.000 medical oncology, where I've been for the rest of my career. In my day-to-day work, I see a lot of

00:05:12.440 patients who run a very active and busy clinic here at Dana-Farber. I'm involved in a lot of teaching

00:05:17.080 at the medical school and for our fellows. I do a lot of both clinical research and clinical

00:05:22.360 education, including guidelines work with ASCO, the NCCN, the St. Gallen Pathways, and other

00:05:28.260 international and national groups interested in breast cancer care.

00:05:32.560 Let's just give people a little bit of a sense of the magnitude of breast cancer.

00:05:36.940 What is a woman's lifetime incidence of breast cancer?

00:05:40.560 So the famous statistic is that American women have about a one in eight lifetime risk, or 12%

00:05:46.580 lifetime risk of developing breast cancer.

00:05:49.040 What fraction of those cases will be fatal?

00:05:50.880 The good news is that only a small fraction of those will be fatal.

00:05:55.640 The fatality or the mortality associated with breast cancer depends on the stage at which it is caught,

00:06:01.140 and it also depends on the subtype of breast cancer because we have different treatment programs for

00:06:06.200 each of the different subtypes of breast cancer. So if you look very broadly across the board,

00:06:11.720 there are roughly 275,000 cases of breast cancer in the United States every year,

00:06:17.400 and there are roughly 38,000 deaths. So if you assume a steady state, we are curing 80% to 85%

00:06:24.520 of women with breast cancer, but roughly 15% to 18% are still at jeopardy for recurrence and death

00:06:30.540 from the disease.

00:06:31.800 Okay. I'd like to start kind of at the beginning with a little bit of the anatomy.

00:06:36.280 I think one of the challenges, of course, of diagnosing breast cancer is that you don't get

00:06:42.680 to look directly at the place where the tumor arises the way you do, for example, with colon cancer

00:06:47.780 or skin cancer or cervical cancer for that matter. So it probably behooves us to spend some time

00:06:53.940 explaining everything from the embryology to the prepubescent anatomy to the maturation process of

00:07:01.920 the breast and then perhaps even what happens during menopause. So how would you describe the

00:07:07.140 development and changes of a breast during a woman's life with a specific nod to how this will

00:07:12.080 factor into helping us understand the pathology of breast cancer development during some of those

00:07:16.300 stages?

00:07:17.260 The breast is a gland. It is fundamentally a sweat gland if you look at the pure embryology of it,

00:07:24.500 and it is the defining feature of what it is to be a mammal. And as you alluded to,

00:07:30.200 the breast goes through different stages of maturation and development in the life of a

00:07:35.940 woman. It begins as a quiescent area of tissue, and then during puberty, because of the hormonal

00:07:42.980 changes, develops enlargement and maturation of the glands such that they become able to eventually

00:07:49.280 secrete milk if the woman becomes pregnant. And the breast is largely composed of two types of tissue.

00:07:55.360 The majority of the volume is actually just fat and non-specific stromal elements. And the thing

00:08:02.000 that determines the size of the breast in a woman is just really how much non-glandular tissue there

00:08:07.840 is. All women more or less have the same amount of glandular tissue in the breast, the milk-generating

00:08:14.020 component of the breast, if you will. And those ducts radiate from the various breast tissues into the

00:08:20.780 nipple, which has multiple orifices. And the God-given purpose here, of course, is to nurse

00:08:26.020 the child. Breast cancers largely arise from the ductal or the glandular tissue. And in this respect,

00:08:34.240 breast cancer shares its origins with almost all common cancers, prostate cancer, colon cancer,

00:08:40.560 lung cancer, where it is the glandular part of the organ from which arises the malignant cell.

00:08:47.340 One of the interesting things about breast cancer and normal breast development is that there has

00:08:54.200 been over the past decades a rise in the incidence of breast cancer, the rate of breast cancer.

00:09:00.540 And one of the likely contributors relates to both the early puberty that we are now seeing in women.

00:09:08.400 Girls are starting to menstruate at a far younger age in the 2020s than they were 100 years ago,

00:09:14.660 or certainly 150 years ago, owing probably to better nutrition and better general health. And that

00:09:20.980 means that the breast development and the exposure of the breast to estrogens starts earlier. And women

00:09:27.040 are also menstruating for longer, again, largely owing to better health. And women are having, at the

00:09:33.940 population level, in the developed countries at least, fewer children, and they tend to nurse those

00:09:39.280 children for a shorter duration of time. Again, this rarely describes an individual patient, but at the

00:09:44.920 population level, the rates of breast cancer are highest in the most developed societies. And many

00:09:50.140 people think it relates to these issues of childhood nutrition, pubescent nutrition, number of pregnancies,

00:09:57.180 duration of nursing. And that accounts for a lot of the difference in the incidence rates that we see

00:10:02.340 between, say, the United States and other parts of the world. Interestingly, as people shift societies,

00:10:08.520 because they move, or as other societies become more developed, their rates of breast cancer tend

00:10:13.060 to go up to mirror those of the U.S. or Western European populations.

00:10:17.400 I remember one of the discussions we had in first-year medical school coming up on 30 years ago

00:10:22.080 was the study of Japanese women who moved to the United States and within a generation went from

00:10:29.200 very, very low rates of breast cancer to assuming the same rate, the same high rate of breast cancer as

00:10:35.760 American women. And of course, I think, at least for me, the takeaway of that was we could never know

00:10:40.920 what the causative driver was, given that there are so many things that are happening. But clearly,

00:10:45.620 there's an environmental component to this, whether it's some combination of food, exercise, hormones,

00:10:53.360 stress levels, pollution. I don't know what the answer would be, of course, but you would have a very

00:10:58.320 long list of things that could change that could amount for such a dramatic shift, as opposed to saying,

00:11:03.520 for example, there's genetic differences that are accounting for this. We're obviously going to

00:11:07.960 talk at length about the genetic drivers of this, but that wouldn't explain the one-generation shift,

00:11:12.480 of course.

00:11:13.260 Well, that's right. Back to the 19th century, one of the first cancer epidemiological findings was that

00:11:19.580 nuns who never became pregnant were at greater risk for developing breast cancer. And along with the

00:11:24.980 discovery of scrotal cancers in chimney sweeps, it was one of the first real steps forward in the

00:11:30.720 epidemiology of cancer biology to help people begin to get a sense of what was causing cancer.

00:11:37.060 And so I think you make a good point that the environment, by which I don't specifically mean

00:11:41.920 like the atmosphere or the pollutants or all those kinds of things, but the environment in which a

00:11:45.700 person grows up is going to have an impact on their breast cancer risk. Now, the dilemma here is that

00:11:51.300 for any given individual, we almost never have a good sense of what their intrinsic risk of breast

00:11:57.900 cancer is aside from, and I'm sure we'll get to this, the family history and genetic cancers and

00:12:02.840 why they get breast cancer now and why they got it in one breast and not the other breast and all

00:12:08.040 those things remain very mysterious. And for someone who takes care of breast cancer patients,

00:12:12.820 it's a source of real frustration. There are some tumors where we really think we understand why

00:12:17.840 they're at greater risk. You know, the smoking and lung cancer, at least you can imagine how this

00:12:22.900 arose. Whereas breast cancer is often a disease of very healthy women, women who have gone to great

00:12:28.640 lengths to care for themselves. And despite that, they are encountering a breast cancer diagnosis,

00:12:33.580 which is often frustrating.

00:12:35.660 Do you recall, I wasn't actually aware of the epidemiologic studies in the early parts of the

00:12:41.260 20th century that identified nuns as higher risk. I'm very familiar with the work on scrotal

00:12:46.200 cancer and chimney sweeps. The hazard ratios there were alarmingly high. I mean, they were hazard ratios of

00:12:52.360 four and five, six. It was very easy to make the causal link. Do you know how high the hazard ratios

00:12:57.420 were for nuns versus non-nuns in breast cancer? To be honest, I'm not sure they even articulated

00:13:03.060 as hazard ratios back in the day. And just to be clear for your audience, I wasn't there when these

00:13:07.680 studies were being done, but it was seen that these nuns were at a greater risk of developing breast

00:13:12.820 cancer. And again, we're talking about a time that predates radiology. One of the reasons you could do

00:13:17.400 epidemiology on scrotal tumors or breast tumors is because you could see the cancer.

00:13:22.360 And in fact, breast cancer was known to the ancients. It is described in Hippocratic-type

00:13:28.000 writings and other documents from antiquity. And it was the one cancer that would commonly be

00:13:34.560 visually seen. People undoubtedly had other kinds of cancers in the era, but in a time before you had

00:13:40.460 imaging, there were rather few that you would actually visually encounter. So breast cancer is a very

00:13:46.160 ancient disease in that respect. And it was one of these things that people appreciated that,

00:13:50.140 for whatever reason, nuns were at greater risk. And so nowadays we would say it's because they

00:13:56.320 were not pregnant and were not nursing and all those kinds of things, which clearly change

00:14:00.340 the risk. The interaction between pregnancy and breast cancer risk is both very interesting and

00:14:04.760 complicated. So multiple pregnancies lower the risk of breast cancer. One pregnancy transiently

00:14:10.840 increases the risk, and then it comes down as time goes by. And no pregnancies are associated with a

00:14:15.780 slightly higher risk of developing breast cancer. And that's not related to the in vitro fertilization

00:14:21.700 or other hormonal supplements. They've looked at that with a lot of rigor, particularly the Scandinavian

00:14:26.700 databases where they have outstanding public health registries of all the patients in the

00:14:31.180 Scandinavian countries. Infertility, for instance, is a slight risk for breast cancer, but the treatments

00:14:36.800 for infertility per se are not. The other thing, and I don't want to get too far ahead of ourselves,

00:14:41.320 but the other thing to say is when we talk about increased risk, there's a huge difference between

00:14:45.240 a population increased risk and the risk for a given patient. So at the outset, we said one in

00:14:50.700 eight lifetime risk in the United States, that's 12, 13%. A woman who has early onset of menarche,

00:14:57.700 menstruation, or hormone replacement therapy, such that they have longer estrogen exposure or shorter

00:15:03.840 period of nursing or fewer pregnancies, they might have a 25 or 30% greater risk of breast cancer,

00:15:09.100 but that only moves the needle from around 12% to around 15%. The risk at the population level is

00:15:16.560 big. The risk for an individual is still pretty small for these kinds of factors.

00:15:21.160 Do we have a sense of the difference between things that drive the increase in risk versus things that

00:15:25.260 drive an increase in mortality? So for example, in prostate cancer, it's generally well understood

00:15:29.680 that the prevalence of prostate cancer approximates the decade of life of the male. So basically half of

00:15:37.760 men in their 50s have some prostate cancer. Gleason 3 plus 3, that's not a prostate cancer you would

00:15:43.420 take out, but on autopsy, you would find it. By the time a guy is in his 70s, you might expect there's a

00:15:49.340 70% chance he has prostate cancer. And of course, the challenge then of the urologist is understanding

00:15:54.460 which man is going to die from versus with prostate cancer. A moment ago, you gave the example of

00:16:00.660 hormone replacement therapy. And of course, that's a topic we've covered in such alarming detail here

00:16:05.120 that it needs no further rehashing. But the punchline is while the Women's Health Initiative

00:16:10.580 demonstrated that women taking conjugated equine estrogen plus MPA had a 25% increase in the risk

00:16:17.720 of breast cancer, it never translated to an increase in mortality. And similarly, the women who took

00:16:23.040 conjugated equine estrogen alone saw 24% decrease in breast cancer. So a point there being, do we have a

00:16:30.600 sense of which risk factors are driving mortality versus just incidents?

00:16:36.380 No and yes. Again, population level, this gets us into the subsets of the different cancers that we

00:16:42.100 speak about. So there are really three major flavors of breast cancer. There is estrogen receptor

00:16:47.420 positive, so-called HER2 or HER2 negative breast cancers. And those are the most prevalent kinds of

00:16:53.600 breast cancer. They account for 70 to 75%, if not more, of all breast cancers.

00:16:59.300 They are the tumors most likely to be found on screening mammography, as opposed to presenting

00:17:04.360 with a lump in the breast. They tend to have, ounce for ounce, size for size, the most favorable

00:17:09.620 prognosis in most, but not all instances. And they peak in incidence at around age 65 in the United

00:17:16.820 States. So that is the sort of public health face of a lot of breast cancer. But there are other types

00:17:23.520 of breast cancer as well, presumably which have some different epidemiologic risk factors. And those

00:17:29.040 include what's called triple negative breast cancer, which is lacking estrogen receptor,

00:17:34.680 progesterone receptor, and HER2, hence triple negative. Those tumors have an earlier onset,

00:17:40.460 are more common in younger women, are more common to the population level in African-American women,

00:17:46.280 are less likely to be the kind detected on a screening mammogram, as opposed to a clinical finding,

00:17:52.100 and are a riskier flavor of breast cancer. And similarly, HER2 positive breast cancers,

00:17:58.600 which were tumors that have an amplification of the HER2 new oncogene and account for about

00:18:03.660 10 to 15% of all breast cancers. Those tumors were classically described in younger women. And

00:18:08.900 again, there's the epidemiology of HER2 positive breast cancer, as opposed to ER positive breast

00:18:13.800 cancer is not really well described. So in general, older women are more likely to have

00:18:19.540 better prognosis breast cancers at diagnosis because of the subset that arises in them.

00:18:24.480 And younger women tend to have more aggressive flavors of breast cancer, again, in rod strokes.

00:18:31.300 Hal, I want to go over that again, because I think that's just a fantastic overview of basically the

00:18:35.280 three subtypes. I also want to point out that you did not talk about progesterone receptor,

00:18:39.380 except in the negative, when you talked about the triple negative case. Let's go back.

00:18:43.000 Case one is, I'm assuming it's ER positive, PR agnostic, HER2 negative, correct?

00:18:49.540 That's correct. Though the vast, vast majority of those tumors also express progesterone receptor.

00:18:54.260 You made the case again, these are the ones that are showing up more likely on mammography.

00:18:57.940 They're also showing up in older women, median age, I think you said about 65.

00:19:02.420 Across the whole age spectrum, but the peak is at 65, and that's correct.

00:19:06.740 Obviously, we're going to dive into the therapeutic options, prognoses, etc. You then talked about triple

00:19:11.920 negative, though you didn't give a distribution or a number on that. I'm just doing the math in my head.

00:19:15.700 That seems to be about 10% to 15% of the population?

00:19:18.980 Correct.

00:19:19.720 Okay, so 10% to 15% are triple negative. Again, that's ER negative, PR negative, HER2 new negative.

00:19:26.100 These skew younger?

00:19:28.040 Again, you can see them anywhere. I see 80-year-olds who have triple negative breast cancer,

00:19:32.160 but they tend to skew younger. There is an interesting relationship between race and triple

00:19:37.320 negative breast cancer, and there's been a lot of really excellent studies to suggest that there may be

00:19:41.860 some real demographic genetic differences that predispose. We tend to see triple negative

00:19:47.160 breast cancers also in BRCA1 mutation carriers, so there's a clear link between specific genetic

00:19:52.620 syndromes such as BRCA and triple negative disease. But they also tend to be more virulent,

00:19:59.100 so they're more likely to present as a lump in the breast or a physical exam finding as opposed to

00:20:03.560 readily being identified on a screening mammogram.

00:20:06.060 You mentioned a higher prevalence in African American. Where do Asian women fit into this?

00:20:10.720 Do they skew to any more than others?

00:20:13.080 They don't have any enrichment in general over the U.S. distribution.

00:20:17.080 The last one you talked about was all the HER2 new positives, which includes your triple positives

00:20:21.940 and, frankly, agnostic of ER, PR, but HER2 new positive.

00:20:26.220 Correct. And that's collectively about 15% of all breast cancers split half and half between those

00:20:31.800 that are ER positive, HER2 positive, and ER negative and HER2 positive.

00:20:35.480 Okay. So, again, that includes all of your triple positives. And is the distinction there a

00:20:40.720 biologic one, Hal, or are you making that distinction more because of Herceptin? I guess

00:20:45.760 I should just clarify for the listener, because there's a targeted therapy for the HER2 new receptor

00:20:50.720 positive cancer.

00:20:52.140 You're exactly right. So trastuzumab or Herceptin is the target of therapy, and that has been

00:20:55.760 the revolutionary treatment in the management of HER2 positive tumors. So there is a biological

00:21:01.520 difference. There is a specific region of the chromosome 17 that's amplified, giving

00:21:06.380 overexpression of the HER2 new oncogene that's presumably a driver for a fraction of these

00:21:11.240 breast cancers. But it's also very important because it allows us to bring a specific targeted

00:21:16.160 therapy to play.

00:21:17.520 Let's talk a little bit about what happens to a breast during or post-menopause. Obviously,

00:21:22.860 we understand some things that are happening during menopause. So estrogen and progesterone

00:21:26.460 levels are falling dramatically. Presumably, there are anatomical changes occurring in the

00:21:32.260 breast as the breast no longer needs to maintain the infrastructure for lactation. Anything worth

00:21:37.420 talking about there specifically as it pertains to increasing risk?

00:21:41.460 Only indirectly. So estrogenization of the breast does account for breast density, which is something

00:21:47.200 that is often seen on a mammogram. And there is a relationship between more breast density and a

00:21:54.140 slightly greater risk of developing breast cancer. Presumably, that relates somehow to the woman's

00:22:00.100 lifetime exposure to estrogen. And so post-menopausal women who have more dense breast tissue on

00:22:05.260 mammogram are at slightly greater risk of developing breast cancer. And it's not simply that the density

00:22:10.700 makes it harder to see the breast cancer.

00:22:13.140 Just to interject, Hal, to make sure I understand, is estrogen controlling ductal density?

00:22:18.960 It's more about the soft tissue component of the breast.

00:22:22.920 The actual fatty tissue?

00:22:24.600 In a pre-menopausal woman, obviously, with the monthly cyclical variation,

00:22:28.200 the breast will have changes in both the ductal tissue and the other tissues. And I want to be

00:22:32.900 clear, if anybody listening to this is an embryologist or a breast surgeon, they're rolling their eyes

00:22:37.660 here because I'm not going to get all the details correct. But in broad terms, there is monthly

00:22:42.200 change in the breast architecture and tissue. But for post-menopausal women on the screening mammogram,

00:22:46.580 that density reflects the fibrous tissue, the fatty tissue in the breast, not specifically the

00:22:53.540 glandular tissue.

00:22:54.860 Okay. And then just kind of bringing it back to a point full circle, you mentioned at the outset that

00:22:59.340 regardless of the size of a woman's breast, so if you compare a woman with an A cup to a D cup,

00:23:05.340 the glandular tissue is still relatively consistent. I actually took that to mean the risk of breast

00:23:11.380 cancer by breast size was also relatively similar, given that they're dealing with the same amount of

00:23:17.640 glandular tissue. Is that an incorrect assumption?

00:23:20.020 That's a correct assumption.

00:23:20.980 It is. Okay.

00:23:21.840 Breast size at the extremes tends to correlate with obesity. There is a weak but detectable link between

00:23:27.800 obesity and breast cancer risk. So perhaps a slight, slight increased risk.

00:23:33.120 That's confounded to your point.

00:23:34.600 We don't fundamentally think that breast size affects risk.

00:23:38.000 Okay. But density per se does, and not just from a detection standpoint.

00:23:44.480 Correct. Density is a marker that is associated with a slightly increased risk again. But all of these-

00:23:48.940 We're talking small risks. Yeah.

00:23:50.480 One in eight to a one in seven or six lifetime risk. So it's the kind of thing that from the public health

00:23:55.540 point of view is very important for any given woman, rarely is a huge driver. And I just point that

00:24:01.880 out to draw a distinction between a genetic syndrome or specific behaviors like smoking that we know

00:24:08.300 are clearly a dominant risk factor for many different kinds of tumors and things like that.

00:24:13.040 Let's talk a little bit about some of those other modifiable risk factors then. So we know that,

00:24:17.020 I guess the WHO would say that the top two environmental triggers for cancer are in order smoking and

00:24:24.140 obesity. Now, I've always thought that obesity is just a proxy for insulin resistance and that it's

00:24:29.160 really the hyperinsulinemia, the excess growth factors and the inflammation that track with obesity rather

00:24:35.500 than the adiposity per se that is driving that risk. How much do those two factors, smoking and call it

00:24:43.040 obesity and right up to type two diabetes, how much are those moving the needle at the individual level

00:24:48.260 for risk?

00:24:49.660 So smoking really is not a major risk factor for breast cancer. My shorthand, you know, it's simply a matter of

00:24:55.100 the smoke affects the aerodigestive tract and some of the internal organs like the kidneys that end up

00:25:00.220 filtering out some of the carcinogens and stuff, but it's really not part of the breast story, if you

00:25:04.600 will. Obesity, as we mentioned, is a relatively weak risk factor relative to many others and certainly

00:25:11.880 not one that has allowed us to, say, for instance, stratify patients for high-risk screening versus not or

00:25:19.260 offer reassurance to a woman that she is not at jeopardy for breast cancer because of lean body mass

00:25:26.160 or things like that.

00:25:28.140 Okay. Let's talk a little bit about the types of lumps that can show up in a breast and let's start

00:25:33.540 at the benign end of the spectrum. So how often will a woman either doing a correct self-exam, and by the

00:25:41.720 way, I'm so far from this myself in my current practice that I don't know if it's still in vogue or not

00:25:48.000 in vogue to teach women how to do a self-exam of the breast, but maybe you could clarify that for

00:25:52.700 me. But if a woman is doing a self-exam of the breast, and then if she's also getting an exam

00:25:56.660 from, say, someone like yourself who knows what they're doing, what's the probability that a woman

00:26:01.420 in her lifetime is going to feel a lump? And then what fraction of those lumps turn out to be benign?

00:26:07.580 Most women have variations in the texture of the breast. And so almost all women have breast tissue or

00:26:14.840 other things that one can feel, and they can appreciate that vary. And in younger women,

00:26:20.420 these may change with the monthly cycle. And in postmenopausal women, they may represent just

00:26:25.460 residual breast tissue. If you lose weight, you might feel some of that architectural tissue more

00:26:31.060 readily than other times. And so there's a lot of normal lumpiness, if you will, to the breast.

00:26:37.980 In our advice to patients, I think it's worth that they have an awareness of their body and a general

00:26:43.740 sense of what feels normal to them and what feels different from normal to them. It's been pretty

00:26:48.900 hard to show that a regular monthly breast self-exam or a rigid approach to self-palpation

00:26:56.740 adds that much. There have been some studies in China where they literally had tens of thousands

00:27:02.940 of patients who were taught how to do a breast exam versus not. It really didn't change the mortality

00:27:08.000 from breast cancer. But what does change the mortality is a real awareness of the body and

00:27:13.800 of the breast. And our message to women is, if you feel something different, suspicious, concerning,

00:27:20.360 seek evaluation. Because nowadays, we can usually get people imaging studies, whether it's mammography

00:27:27.220 or ultrasound, combined with an exam by a breast surgeon or a breast expert, and usually do a quick

00:27:33.800 evaluation that most of the time reassures the patient that this is a benign finding in the

00:27:39.760 breast itself. Some patients may need further evaluation, either with follow-up imaging or even

00:27:45.040 with some kind of a needle biopsy. But the majority of these findings are not going to be breast cancer.

00:27:51.980 Again, having said that, the most important thing is if a patient does appreciate a change in the

00:27:57.040 breast or a lump in the breast, certainly if a physician or other clinician provider feels something

00:28:02.960 suspicious, it is very important to get appropriate imaging and, if necessary, a tissue biopsy to make

00:28:08.840 sure we understand exactly what's going on. Now, if a woman ends up having a lump and the lump is

00:28:14.960 suspicious enough that it requires more than just reassurance that it's nothing, the next step is

00:28:20.400 going to be what? So if a woman has a mammogram that shows a lump that is suspicious with or without

00:28:28.020 calcification, what is the algorithm for evaluating that lump? And when does it go down the path of

00:28:33.620 more imaging versus a needle biopsy versus an excisional biopsy?

00:28:38.400 Again, the key takeaway is if people feel a lump, they should seek medical evaluation.

00:28:42.940 For patients who have findings either on physical exam or on imaging, the imaging team, the quality of

00:28:49.180 radiology has become really terrific at most places around the country. And they can often look at

00:28:54.440 findings and say, yeah, you know, this looks like a benign change or yeah, this same thing was seen

00:29:00.100 a year ago and five years ago when the patient had a mammogram and it hasn't evolved in any way, so it's

00:29:05.260 reassuring. Or they can say, I'd like to get more imaging. So sometimes patients are referred for

00:29:11.860 additional ultrasound or MRI imaging to be sure. And sometimes it's necessary to get a tissue biopsy

00:29:18.820 to really understand what exactly is going on. And nowadays that usually begins with an image-guided

00:29:25.540 needle biopsy or core needle biopsy where using an ultrasound or other imaging device, the radiology

00:29:32.720 team knows exactly sort of where to pinpoint the lesion within the breast. They use a very fine gauge

00:29:38.160 needle to extract a tissue biopsy that's around the width of a pencil lead. And with that, they can look

00:29:44.780 under the microscope and usually make a clean diagnosis about what's going on within the breast

00:29:50.340 itself. So do you have a sense of the number of, if we go to the point where we're actually getting

00:29:55.440 a biopsy, what fraction of those turn out to be a benign lesion such as a fibroadenoma?

00:30:00.680 I don't have an immediate answer. I will follow up with you and try and get you the answer. But

00:30:05.140 I would guess that the majority of these do. And for most women, it turns out to be very reassuring

00:30:11.500 that either it is a benign lesion like a fibroadenoma or a pre or even a pre-pre-cancerous

00:30:18.800 change in the breast that might warrant additional follow-up or surveillance, but is not truly breast

00:30:25.560 cancer.

00:30:26.780 Got it. Which would be the analog of finding a polyp in the colon which gets removed, which

00:30:31.680 puts you on alert for more screening, but of course is not cancer itself.

00:30:36.140 That's correct. And in fact, we may get to the point of talking about ductal carcinoma in

00:30:40.460 situ or DCIS, which is a pre-cancerous lesion where the cells are beginning to accumulate

00:30:47.020 within the duct, but have not penetrated into the rest of the breast tissue. And the analogy

00:30:52.740 I give to patients all the time is this is like a colon polyp. It's a growth. It is a

00:30:57.480 pre-cancerous growth. We treat it so that it doesn't blossom into a full-blown cancer, but

00:31:03.860 in and of itself, it is not a cancer lesion.

00:31:07.220 That's a great pivot to that. I do want to talk about DCIS and LCIS. So maybe first explain

00:31:13.840 it going back to the anatomy, the difference between ducts and lobules, and then how does

00:31:19.180 that factor into ductal carcinoma in situ versus lobular carcinoma in situ?

00:31:24.840 The ductal tissue of the breast includes sort of a highway, if you will, where the milk would

00:31:31.120 come out of the breast. And then at the end of it, a parking lot, if you will, where the

00:31:34.780 sort of terminal lobule, where the gland terminates and the milk would be generated,

00:31:40.000 if you will. And again, my breast cancer surgeon friends are rolling their eyes, but that gives

00:31:44.900 you a flavor of what we're talking about.

00:31:46.860 We'll include in the show notes a great figure of this. Figures tend to be easier to follow,

00:31:51.280 I think, sometimes than the words here.

00:31:53.060 The relationship between lobular carcinoma or lobular carcinoma in situ and ductal carcinoma

00:31:58.660 or ductal carcinoma in situ really don't exactly correlate to the architecture of the normal

00:32:04.260 gland itself. It's really how the cells look under the microscope, if you will. You can

00:32:09.140 see changes in these cells that are staged along the way towards cancer. So one of the

00:32:17.000 things that is associated with an increased risk of breast cancer is if there are prior changes

00:32:22.720 in the breast that suggest abnormal amounts of proliferation or atypical appearing cells,

00:32:29.080 which are sort of the pre-pre-cancerous stages. So oftentimes a woman might have a biopsy that shows

00:32:35.880 what's called atypical hyperplasia. There are too many cells present. That's the hyperplasia.

00:32:42.700 And those cells don't look exactly normal. The nucleus begins to look a little more aggressive

00:32:47.400 and things. And if you're familiar with talking about Gleason scores, the Gleason score is beginning

00:32:51.640 to drift up there. And ADH, atypical ductal hyperplasia, or ALH, atypical lobular hyperplasia,

00:32:59.460 are lesions that put a woman at slightly greater risk for developing breast cancer in the decades

00:33:04.360 to follow. The numeric risk is still pretty small, probably only about a half to one percent per year

00:33:10.680 risk of developing breast cancer and follow-up. But it's one of those precursor lesions that begins to

00:33:15.960 flag a patient as being at greater risk for developing breast cancer.

00:33:19.320 And then the next step along the way would be in situ carcinoma. So these are cells that have

00:33:25.420 taken one more step towards looking like cancer. And if you were to look under the microscope,

00:33:30.720 the cell itself looks like it's almost a cancer cell, but it is respecting some of the normal

00:33:35.960 membranes of the breast gland. It's not penetrating into the breast tissue. It hasn't gone through

00:33:41.680 whatever the final steps of full-blown carcinogenesis are, such that that cell can now persist, thrive

00:33:48.520 outside of that gland and begin to develop its own blood supply or even metastasize somewhere else in

00:33:53.860 the body, which is how we think of breast cancer. So you will encounter those lesions along the way.

00:34:00.860 Many women have been diagnosed with these precursor lesions, particularly ALH, ADH. They can show up as

00:34:07.180 architectural changes in a mammogram. They can show up as calcifications in a mammogram. It's rare to find

00:34:12.500 that you actually can feel these things, though sometimes it's an incidental finding if you're evaluating a

00:34:17.000 lump in the breast. And those are things that warrant regular surveillance. And in some instances,

00:34:22.000 we can actually now use anti-estrogen medicines like tamoxifen to help slow the development of any

00:34:27.880 malignant cells in a patient with those problems.

00:34:31.140 Do we have a sense of how often those things exist? For example, we know from autopsy studies,

00:34:37.540 as I said, the prevalence of low-grade prostate cancer that is not causing any other issue.

00:34:44.160 Do we have similar autopsy studies in women where we're looking at women who have died from some

00:34:49.660 other cause and examining breast tissue and looking for the prevalence of all of these associated

00:34:55.740 changes up and to DCIS and LCIS?

00:34:59.160 I don't have a good answer for you. It's certainly a common enough problem that it wouldn't surprise me

00:35:05.060 if someone's done a study of this and reported on it. The distinction I would draw is those classic

00:35:10.280 autopsy studies of men, I believe they were from automobile accidents back when I used to read

00:35:14.800 these papers, finding that they had prostate cancer. We're still talking about something a little

00:35:19.400 different in the breast. So these are pre-cancerous changes. They're not uncommon. Many of them will

00:35:25.540 never move further. And that's different from breast cancer, where the tumor can be indolent,

00:35:32.880 it can grow slowly. But we're not so sanguine that these are tumors that would sort of never

00:35:38.280 require treatment or never be a clinical problem for a patient.

00:35:42.200 Does every breast cancer start as a ductal carcinoma or lobular carcinoma in situ?

00:35:49.100 Many do, particularly hormone receptor positive breast cancers, triple negative breast cancers,

00:35:54.100 which probably have something of a different cell of origin within the duct channel,

00:35:59.140 a little less of the glandular component and a little more of the sort of architectural stromal

00:36:04.000 element of the gland. You will often encounter triple negative tumors that do not have DCIS

00:36:10.200 associated with it. But probably the vast majority of hormone receptor positive, ER positive breast

00:36:15.700 cancers emerge from these multi-stage evolution of these precancerous lesions.

00:36:21.300 So is the majority of DCIS then captured through screening mammography and or other forms of

00:36:28.120 screening in higher risk women where you're using more than mammography, such as ultrasound or MRI?

00:36:32.980 That's right. 70 years ago, DCIS would present as a lump in the breast because the cells would

00:36:38.300 just kind of keep accumulating within the duct or Paget's disease of the breast, where the cells would

00:36:43.660 literally creep out of the nipple and sort of form what looked like a crust on the surface of the

00:36:48.280 nipple or the breast, which was again, the growth of these precancerous cells. But in modern

00:36:54.740 practice, those still exist, but they're really rare. The vast majority of the time, DCIS is identified

00:37:00.700 following a mammogram because of calcifications or other subtle changes that appear on the mammogram.

00:37:06.680 How is DCIS staged? Isn't there actually an invasive DCIS, which would be the closest thing

00:37:11.880 to an actual cancer? Am I making that up or misremembering that?

00:37:15.180 Well, DCIS by definition lacks an invasive component. So DCIS is stage zero breast cancer,

00:37:20.860 or as I like your nomenclature earlier, I call it a colon polyp of breast cancer. It really is

00:37:25.980 a benign growth that we want to treat so that it does not become an invasive cancer. The difference

00:37:32.520 between the colon polyp, if people can sort of picture the little mushroom growing sort of in

00:37:36.440 the lumen of the colon and the DCIS, is that the DCIS cells are not as mushroom forming, if you will,

00:37:43.520 and they can creep and crawl through the ductal space. So you can end up with a more diffuse distribution

00:37:49.580 of the DCIS cells in the breast than you might encounter from an isolated colon polyp.

00:37:55.140 So once DCIS is identified, and assuming it's done through a core biopsy, what are the next steps?

00:38:01.200 So this is actually a really interesting area of research. So I'm going to start by just saying

00:38:05.140 what we typically do for most cases, and then we can talk about some of the areas of controversy.

00:38:09.880 For most women who have DCIS diagnosed on a core biopsy because there were calcifications or other

00:38:15.120 changes in the breast, the first step is to do an excisional biopsy, a surgical biopsy where the

00:38:20.100 area of tissue is surgically removed. And we do that for two reasons. One is we want to remove the

00:38:26.800 affected portion of the breast to remove the area of the breast that has DCIS. And secondly, because

00:38:32.740 there is some upstaging that happens. So about 15% to 20% of the time when a woman has the surgical

00:38:38.980 excision of an area of DCIS, there will actually be a small component of invasive breast cancer

00:38:45.180 adjacent to that space or nearby that's removed as well, which upstages the diagnosis from stage zero

00:38:52.280 or DCIS to an early stage breast cancer. And it's important to know that and to remove that affected

00:38:58.500 portion of the breast. So that's almost always the first step in treatment.

00:39:02.520 In that case there, do you also do a sentinel node biopsy if you discover that? I know we'll

00:39:09.660 come back to that and talk about it in detail, but I just want to ask the question before I forget.

00:39:13.140 So the sentinel node biopsy we do routinely in invasive breast cancers because we want to find

00:39:17.860 out if the cancer is spread to the axillary, the armpit lymph nodes. And we can, by we here,

00:39:23.620 I mean, again, my surgeon friends who are still rolling their eyes as we're talking here,

00:39:27.200 but they can inject a radioactive tracer and blue dye into the breast tumor. They track that into the

00:39:32.300 armpit. It allows them to identify the so-called sentinel lymph node or lymph nodes, which are hot

00:39:37.720 from the radioactivity and blue from the contrast dye. And you can find out by removing a couple of

00:39:42.780 those nodes, whether the cancer has spread to the armpit, which is really important staging

00:39:46.960 information. That's going to be done in those 15 to 20% of women who are getting upstaged. You're

00:39:51.400 going to get a wet read in the operating room. You might, but usually not. Okay. Got it.

00:39:56.080 If you're just having that lumpectomy where the portion of the breast is being removed

00:39:59.460 and it's not known to have invasive cancer ahead of time, if there is a finding of invasive cancer,

00:40:04.920 then the patient would need to go back for a second operation to do the sentinel lymph nodes.

00:40:09.000 So the exception to this is sometimes there's a lot of DCIS in the breast, or for whatever reason,

00:40:15.720 the patient has chosen to have a mastectomy for DCIS. So this is necessitated sometimes by the extent

00:40:21.160 of the affected area relative to the size of the breast. Some women will have diffuse changes in the

00:40:25.660 breast that require a mastectomy. Others might have a personal preference for it. And if the

00:40:30.820 whole breast is being removed for DCIS, then they will also do sentinel lymph node mapping of the

00:40:36.920 lymph nodes in the armpit, because once you remove the breast, you can't go back post hoc and do the

00:40:42.420 sentinel node mapping if there is an occult area of cancer found within that area of DCIS.

00:40:48.800 And I'm guessing though, after they've had the excisional biopsy of the DCIS, you get the pathology back a

00:40:54.080 week later and it says, you know, in fact, there is some invasive component here. You still have a

00:40:58.560 compromised sentinel node biopsy at that time, I assume, because you've actually taken the tumor

00:41:03.560 out, right? Presumably the sentinel node is doing its thing and it's still very feasible to do

00:41:07.340 sentinel node mapping after an initial lumpectomy biopsy. But you don't have a tumor to inject into.

00:41:13.040 They know where the tumor bed was. You don't have to inject the tumor itself. You're tracking the

00:41:17.480 lymphatic channels in that portion of the breast. So you can use the bed or the area.

00:41:22.180 All right. So the other 80 to 85% of women will emerge from surgery. They'll be told,

00:41:28.420 good news, there was no invasive cancer there. So this was neither diffuse DCIS nor invasive cancer.

00:41:35.640 What is the standard of care today?

00:41:37.780 For DCIS, so following DCIS removal, if you've had a mastectomy, usually that's all you need. And

00:41:44.560 there is no further treatment for DCIS. For women who have had a lumpectomy, then there are a couple of

00:41:50.540 options that they can think about. One is to do radiation therapy. So one of the interesting

00:41:56.340 things about DCIS, as we noted earlier, is the cells tend to creep along the ductal channels,

00:42:00.660 and these all arborize out throughout the breast space. And the cells can kind of sneak around in

00:42:05.660 there. So radiation therapy has been shown in many, many studies to lower the risk of in-breast

00:42:11.780 recurrence, including both more DCIS and including the development of invasive breast cancer.

00:42:18.900 So for younger, healthy women, 65, 70, and younger who have DCIS, it's pretty standard to give a course

00:42:25.820 of radiation therapy to the breast to lower the risk of recurrence of DCIS within the breast itself.

00:42:33.440 And then there's another option of adding an anti-estrogen therapy. So medicines like tamoxifen

00:42:39.600 or aromatase inhibitors, both of which work by depriving the tumor area of estrogen,

00:42:47.160 can also lower the risk of in-breast recurrence of DCIS or lower the risk of developing invasive

00:42:54.120 cancer after DCIS. The downside to those treatments is we usually recommend many years of therapy.

00:42:59.800 They have a lot of side effects that are manageable for most women. But when you're talking about a DCIS

00:43:04.900 lesion, which isn't a full-blown cancer, a lot of women wouldn't be sufficiently interested in the

00:43:10.360 couple of percentage points reduction in the risk of recurrence or more DCIS for having to take a

00:43:16.240 medicine for many, many years that has side effects related to its anti-estrogen effects.

00:43:20.700 So typical would be lumpectomy, strong consideration of radiation therapy, and then above and beyond that,

00:43:27.680 discussing whether or not to offer anti-estrogen treatments. And with that, most women do very,

00:43:32.260 very well. When you get the pathology back, you're also getting the receptor status back on the DCIS?

00:43:37.500 They will test it for estrogen receptor. And as with invasive cancer, the vast majority of DCIS

00:43:43.320 lesions are estrogen receptor positive because it's the precursor lesion for most breast cancers.

00:43:48.420 There's no HER2-new status on a DCIS or there is?

00:43:52.000 It can be tested, but we don't usually do so because clinically it's not actionable. We don't

00:43:56.560 offer treatment. That's right.

00:43:58.780 Let's talk about risk reduction. So if you took all women who had DCIS, who underwent a lumpectomy

00:44:05.840 and were found to only have DCIS, had no invasive cancer, and you did nothing, how many of those

00:44:13.000 women will go on to get invasive breast cancer?

00:44:16.300 With breast cancer, so the thing you want to know is what does the DCIS look like under the microscope?

00:44:21.400 Because one of the really important prognostic markers for both DCIS and for invasive breast

00:44:26.260 cancer is what we call GRADE. So higher GRADE, GRADE 3 DCIS lesions, often associated with what's

00:44:33.680 called necrosis, which just means the cells are kind of dying in the ductal space because they're

00:44:38.360 sort of outstripping the oxygen supply. There's no blood vessels that feed DCIS. Those lesions have

00:44:44.100 a slightly greater risk of in-breast recurrence than would lower GRADE, typically more estrogen

00:44:50.040 receptor positive, less comedonecrosis type lesions. And so the span ranges from 5% to 10% at the low

00:44:56.800 risk end to 20%, 25% at the higher risk end without further treatment. With treatment, with radiation

00:45:03.820 therapy, you bring way down the risk of recurrence of DCIS or of new breast cancer for both those kinds

00:45:10.260 of lesions, such that it's usually into the low single digits nowadays.

00:45:14.240 Does that reduce mortality also or just recurrence?

00:45:16.820 No. The interesting thing about DCIS is treating DCIS has actually never been shown to affect

00:45:21.880 mortality because you're so far ahead of the diagnosis that there probably isn't a survival

00:45:27.380 benefit. And this is what's led to some really interesting trials looking at if we can do less

00:45:31.960 for DCIS. So Shelly Wong, who's a very distinguished breast surgeon down at Duke, has really been a force

00:45:38.700 in the development of these trials where they are doing more or less what you proposed, which is,

00:45:42.560 what if you just took it out and followed it and see what happens? In some instances,

00:45:47.500 they're not even doing that excisional biopsy. They're doing a core biopsy and saying,

00:45:50.580 oh, it's just DCIS. We're just going to follow you.

00:45:53.000 So that's interesting though, because then they're willing to miss the 10% to 15% of women

00:45:57.100 that have invasive cancer.

00:45:58.800 Correct. That's an ongoing study in the NCI-led cooperative groups. And one of the things that

00:46:02.740 can be really interesting is to see, is that really adequate? The other thing that comes into play

00:46:07.200 here is one's perception of risk. Because for some women, having a 10% to 15% risk over the next

00:46:13.720 decade of having a recurrence or a breast cancer in the breast is a very low risk. 85%, 90% chance

00:46:20.020 they would be fine. They're not eager to have more surgery or to have radiation therapy. And so they're

00:46:25.520 comfortable with that. Other women will look at the same number and say, gosh, I don't really want

00:46:30.160 to deal with this. If you're telling me that three to four weeks of radiation can lower my risk down

00:46:34.240 to 1% to 2% chance of having a problem, I'm willing to sign up and do the radiation treatment.

00:46:39.800 So these become very nuanced discussions that have to reflect both the magnitude of the risk,

00:46:45.680 as we've been discussing, the possible benefit, and the patient preferences become real important here.

00:46:51.660 How well are radiation oncologists able to shield the heart, for example? Do you find women making

00:46:56.220 a different decision if this is left side versus right side DCIS? Or is the amount of radiation

00:47:01.700 that's delivered in this for DCIS so low compared to, say, invasive breast cancer that it's a

00:47:07.400 non-issue? So the radiation treatments are fundamentally the same for invasive cancer and

00:47:12.640 for DCIS. In fact, one of the things that's been persistently a confounding part of the discussion

00:47:18.380 about DCIS is that treatments for DCIS look almost identical to the treatments for invasive breast

00:47:23.240 cancer. So if it's a lumpectomy, it's the same kind of surgery. You're looking for negative margins.

00:47:27.220 You're talking about radiation therapy afterwards. It's all very similar to if you were being treated

00:47:32.080 for an early stage invasive breast cancer. So the issue of left and right, what you're alluding

00:47:37.440 to is the historic experience, which is that radiation therapy to left-sided breast cancers

00:47:42.020 in the past, important point, was associated with a greater risk of coronary artery disease.

00:47:47.860 And that is because in the early days of breast radiation, they would radiate the breast straight

00:47:53.920 on, if you will, as though someone was standing in front of you, shooting an arrow right at your

00:47:57.700 heart, and that's where the beam of radiation was going. Nowadays, and for the past 18 to 20 years

00:48:04.300 or more, 30 years almost now, we don't do that. And by we, I mean my radiation oncology friends and

00:48:09.940 colleagues. What they do is called tangential field radiation for most things, where they very

00:48:15.000 carefully map out the anatomy of the chest and the breast, and they use the radiation coming in from

00:48:20.280 the sides in what are, if you were drawing a circle, sort of tangent lines to the circle to irradiate

00:48:26.880 the breast tissue while sparing the underlying chest wall, lung, and particularly heart. So while

00:48:34.200 any patient who gets breast radiation will be counseled as part of the decision-making process

00:48:39.560 that there is a risk of accelerated coronary disease, in modern contemporary practice, that risk

00:48:45.480 is incredibly low. And not just do they set up the fields differently, but now there are a lot of

00:48:50.900 other tricks, including specific blocks that radiation doctors can use, and what's called a

00:48:56.080 breath-holding technique, where they synchronize the radiation treatment to holding the breath.

00:49:00.940 So if you exhale, the heart moves closer to the breast, if you will. If you take a big breath in,

00:49:06.260 the chest expands, the heart falls back, and you have more space between the breast and the heart.

00:49:11.600 And so they nowadays synchronize the radiation beam, which is a zap that moves at the speed of

00:49:17.220 light, to your breath-holding. So they say, take a big breath in, and so the risk to the heart is

00:49:24.140 extraordinarily low. What about other risks, just briefly, in terms of skin damage or other risks,

00:49:30.740 sickness, any persistent damage from radiation under the current way it's done? It depends a little bit

00:49:36.180 on how much radiation is done and where they have to go. So if you have a breast cancer, particularly a

00:49:41.080 large breast cancer with extensive regional lymph nodes, then that's where you start talking about

00:49:45.640 doing more extensive radiation to the chest wall, the regional lymph nodes, sometimes even the internal

00:49:50.120 mammary nodes. And there, while they can still spare the vast majority of the heart, it becomes a little

00:49:55.760 trickier to fully avoid the heart. There is a risk of so-called pneumonitis, inflammation of the lung from

00:50:01.980 some of the radiation scatter. There is a risk of secondary skin cancers, which you can rarely see after the

00:50:07.640 radiation. And there's a lot of short-term side effects. Getting the radiation treatment is like

00:50:12.060 having a bad sunburn, or as we say in Boston, a wicked bad sunburn on the breast tissue itself,

00:50:18.140 where the breast gets red, sore, swollen. It accumulates during the course of the radiation,

00:50:22.440 just as a sunburn accumulates during your day at the beach. That can be very physically uncomfortable.

00:50:27.760 Over time, that resolves. The skin heals. The tissue sort of fades from a lobster red to a pink,

00:50:34.880 and then to a tan color, and eventually back to normal skin tone.

00:50:38.620 What percentage, again, of DCIS are estrogen receptor positive?

00:50:42.440 Something like 80 plus percent, the vast majority.

00:50:45.420 Got it. So then to the next question, which is, what is the natural history of DCIS,

00:50:53.240 ER positive DCIS, with and without estrogen blockade in terms of recurrence?

00:50:59.140 Yes. Estrogen blockade helps lower the risk further beyond what radiation does. One of the cleanest

00:51:04.920 studies we have of this is a study called NSABP B24, which is an old study. And in that study,

00:51:11.620 it built on a previous study called B17. So in B17, they randomized patients to surgery alone for DCIS,

00:51:18.980 lumpectomy alone, versus lumpectomy plus radiation. And in that study, at 10 years, about 25 or 30 percent of

00:51:25.680 the women who had surgery alone had had a recurrence or second cancer of DCIS or invasive cancer in the

00:51:32.120 breast. Radiation cut that in half to about 12 to 15 percent. And then in the follow-on study, B24,

00:51:39.380 they did, okay, lumpectomy plus radiation with or without tamoxifen. And again, it lowered the risk

00:51:45.540 further by about half again. The dilemma there is that that study is old enough that we've gotten

00:51:52.560 much more sophisticated in terms of the imaging we offer to the breast, looking at the margins very

00:51:57.380 carefully, making sure there's no extraneous calcifications. So most people think that the

00:52:02.800 baseline risk after surgery alone nowhere approximates that 25 to 30 percent kind of number

00:52:08.500 anymore. It's much lower for most patients who have mammographically detected DCIS. And so

00:52:14.560 the rules apply. So it drops it by half, drops it by half. But the absolute benefit is a lot smaller

00:52:19.780 because the baseline risk is no longer way up here. It's kind of down here. And so for that reason,

00:52:24.760 the marginal benefits of the anti-estrogen approaches are something on the order of three

00:52:28.860 to 5 percent in terms of preventing a recurrence. And some of that benefit actually relates to the

00:52:34.980 prevention of a second problem in the opposite breast because the drug therapy obviously affects

00:52:39.740 both breasts. And so you can help prevent a new cancer in the opposite breast, which adds a percentage

00:52:44.680 point or two of the benefit. So it's a relatively small gain to be using anti-estrogens after DCIS.

00:52:51.660 Some patients, it clearly makes sense because of the extent or other features of the tumor.

00:52:56.160 Some will pursue it because they like the idea of the secondary benefit of the opposite breast.

00:53:00.600 Many women will pass on the anti-estrogen therapies even as they receive other treatments for DCIS.

00:53:06.860 One of the academic questions is, can you use the anti-estrogens instead of the radiation?

00:53:12.340 And that's part of other studies that are going on where women might get surgery for the DCIS and

00:53:18.020 then be put on anti-estrogens without the radiation. And we're going to see in the modern

00:53:22.420 era if that's an acceptably beneficial approach. I think a lot about hormone replacement therapy and

00:53:28.140 what tamoxifen does to women, especially pre-menopausal. I'm amazed that that's the more

00:53:34.000 interesting academic question when the radiation, as you point out, is getting safer and safer and

00:53:39.220 more and more efficacious. It seems to me that the real jugular question is, how long can we justify

00:53:45.060 giving tamoxifen to women with DCIS given the really devastating consequences? If you think about,

00:53:53.960 it's basically putting women into menopause at a young age, depriving them of estrogen. We think

00:53:59.000 about the long-term consequences on their bones, the vasomotor symptoms, the sexual side effects.

00:54:03.820 Your calculations are sort of the same as where I'm coming out when I do the math on the NSABP

00:54:08.600 24 study, which is we're talking about a 3% to 5% reduction of recurrence over a decade with no

00:54:14.620 change in mortality. It's interesting to hear that the majority of women do not elect for that.

00:54:20.400 If I'm hearing you correctly, it sounds like the majority of women say,

00:54:22.820 I'll take my lumpectomy, I'll do a little bit of radiation, but I'm not going to take tamoxifen for

00:54:27.260 five years.

00:54:27.800 It's part of a comprehensive discussion, but I think you've done the analysis the way many women

00:54:32.960 would and say, you know, I'm not sure that really adds up for me. And one of the other things,

00:54:37.860 in addition to the safer features of the radiation therapy, we're now offering shorter durations of

00:54:42.000 radiation treatment. Historically, the standard was 25 fractions. We're now down to 16 fractions for

00:54:48.440 most women. And in Europe and increasingly in the U.S., there's interest in looking at yet shorter

00:54:53.800 courses of radiation down to about five days of treatment. So at some point, that becomes a very

00:54:59.020 compelling option, I think. And for many women, that would be great news.

00:55:04.200 Now, Hal, when I was in medical school and maybe a little bit beyond, the traditional thinking,

00:55:09.820 so I know this can't be right anymore, but was that with LCIS, which was much less frequent than DCIS,

00:55:17.260 it was more of a systemic concern. And that your risk of contralateral breast cancer was sufficiently

00:55:25.520 high that, my gosh, were they at one point recommending bilateral mastectomies for LCIS?

00:55:32.760 Am I making that up?

00:55:34.360 I don't think you're making it up, but that's not an approach we would endorse today. So LCIS

00:55:38.200 is probably best thought of as a field risk marker. It's one of those things that you

00:55:44.440 might have talked about in other contexts, like leukoplakia in the throat, which increases the

00:55:50.220 risk of developing head-neck cancers or other field defects. Clearly, the diagnosis is saying

00:55:57.540 this patient is at greater risk for developing cancer. And historically, the teaching was that

00:56:01.680 actually the risk was the same in each breast. With very large studies, there's probably a slightly

00:56:06.040 greater risk in the affected breast itself. There's probably something specific and a little bit

00:56:10.860 clonal going on there, but it can increase the risk of a second breast cancer as well.

00:56:14.440 So what we usually offer patients like that is, in fact, very close monitoring. And many of those

00:56:21.100 women will consider anti-estrogen therapy to lower their risk of developing breast cancer. However,

00:56:27.860 LCIS is not a lesion that is readily thought of as one you treat with surgery alone or surgery plus

00:56:33.280 radiation. So that's an area where LCIS sort of management diverges from DCIS management.

00:56:39.280 And for all radiographically suspicious lesions that go down this pathway,

00:56:44.440 what's the distribution of LCIS versus DCIS? How much less is the LCIS?

00:56:49.940 I would say it's about 20% of the diagnoses compared to DCIS, but I'm ballparking that.

00:56:56.660 But roughly four to one. Any differences there demographically? Are we seeing more LCIS in older

00:57:03.960 women, younger women, different changes in estrogen receptor status, anything like that?

00:57:08.400 No, LCIS is almost universally a hormone receptor positive, estrogen receptor positive

00:57:13.620 lesion. There's a rare entity called pleomorphic LCIS, which is a pathologic diagnosis. That's a

00:57:20.400 more virulent flavor of perhaps LCIS and certainly of lobular breast cancer, pleomorphic lobular breast

00:57:26.580 cancer. But otherwise, it's the same kinds of demographic trends that we've been alluding to.

00:57:30.880 Okay. When a woman has LCIS, do we know the natural history of that as a progression to invasive

00:57:38.940 cancer and how it differs? In other words, I realize that it's more of a global marker of

00:57:44.340 risk within the breast as opposed to a local marker, but is it also a higher risk that breast

00:57:49.120 cancer will occur? Yeah. So LCIS, along with those things we alluded to earlier, like atypical

00:57:55.320 ductal hyperplasia, atypical lobular hyperplasia, sort of a pre-pre-cancerous lesion. And it does

00:58:02.240 increase the risk of eventually developing breast cancer. We have some very good data,

00:58:07.620 again, from the NSABP. And just by way of disclosure, I work with the NSABP as a chair of

00:58:13.000 one of their data safety and monitoring boards. So I know their data really well. I don't have any

00:58:17.300 other commercial conflicts of interest, but I do work with the NSABP. So they did a study called

00:58:21.540 the P1 study, which was a prevention study. The goal of this study, which was published over 20

00:58:26.700 years ago, was to see if tamoxifen could lower the risk of breast cancer diagnosis in women who

00:58:31.660 were at intermediate to moderate risk of developing breast cancer. And so in that trial, they included

00:58:37.820 a lot of women who had lobular carcinoma in situ. And those women were at greater risk of developing

00:58:46.000 breast cancer. So that risk, just to be quantitative, so I'm looking this up as I speak to you, was

00:58:51.180 there was a rate of 13 per 1,000 women, 13 per 1,000 women per year. And tamoxifen cut that in

00:58:59.500 half, down to about 5 or 6 per 1,000 women per year. So it makes a few percentage points difference

00:59:06.580 as a preventative agent. Again, the key point here is the absolute risk for developing breast

00:59:11.880 cancer in any given span of time is still pretty low following a diagnosis of LCIS. But those patients

00:59:17.940 do warrant monitoring, obviously mammography, and they should consider or they can consider

00:59:23.700 antiestrogens to help lower that risk. So this study took women who were at high risk who had

00:59:29.600 been diagnosed or had not yet been diagnosed with LCIS? Not yet diagnosed with breast cancer. Yeah,

00:59:34.200 they had higher risk because of family history or because of atypical hyperplasia. There was a whole

00:59:38.680 algorithm that went into the risk assessment. These women took tamoxifen for how long?

00:59:42.980 Five years versus a placebo. It reduced by less than 1% in absolute risk the occurrence of breast

00:59:52.060 cancer? So the overall diagnosis of breast cancer in that study was about 4% through five years of

01:00:01.860 follow-up and tamoxifen cut that in half to about 2%. So the drug, quote, works, unquote. And so for women

01:00:10.340 who are at higher risk or who are very motivated, tamoxifen and subsequently other antiestrogens have

01:00:15.560 been shown to lower that risk of diagnosis. But for most ordinary risk women, that risk is

01:00:22.280 sufficiently low that the relative reduction only amounts to a percentage point or two. And so it's

01:00:28.040 not an approach that has been enthusiastically embraced by most general population patients.

01:00:33.600 Did that reduction in risk translate to a survival benefit or just an incidence?

01:00:37.740 It did not for a couple of reasons. One is obviously the risk is really low.

01:00:41.480 Second, we have good treatments for those women who do develop breast cancer. And third,

01:00:46.820 if you're using tamoxifen as a preventative, arguably you're preventing the most treatable

01:00:52.360 types of breast cancer from arising. So you're pulling out the better actors, if you will. And what's left

01:00:58.960 are tumors that remain somewhat resistant to the antiestrogens and therefore more worrisome.

01:01:03.760 Yeah. I might not have a dog in this fight because I'm not a woman, but boy, the thought that 98 out of

01:01:10.360 100 women are unnecessarily exposed to tamoxifen for five years to save two cases of breast cancer that

01:01:17.640 doesn't translate into any survival benefit. My goodness.

01:01:21.440 One of the frustrations for people who are really interested in cancer prevention

01:01:24.520 has been that for most people in any given span of time, the risk of developing a cancer is pretty

01:01:31.800 low. Even in that study, which sought to enrich for a group of women who are at slightly greater

01:01:37.400 than average risk of breast cancer, the absolute benefit turns out to be modest. And it's been

01:01:42.320 a drug that only the most motivated patients would be inclined to pursue.

01:01:47.500 Yeah. God, I think it really places the onus of really capturing a great consent with the

01:01:53.140 physician. I worry that some of those women might not know what they're signing up for when they do

01:01:58.080 it. I know a number of women who have taken tamoxifen for DCIS, wives of friends, for example,

01:02:03.800 and a year in, they're sort of calling me saying, what the hell is going on? Is this really necessary?

01:02:10.300 And then I kind of walk them through the math and I say, look, I think you ought to talk to your

01:02:14.080 oncologist because no doctor can predict how badly you will have side effects. Some women

01:02:20.000 probably take tamoxifen and it goes off without a hitch. But I think it's worth revisiting that

01:02:25.020 discussion with your physician and saying, look, I'm one year into a five-year course. I'm premenopausal

01:02:29.740 and this drug has ruined my life. I don't think any doctor would advise that woman to keep taking the

01:02:35.340 drug. So you make a couple of really great points here. The first is it is a nuanced conversation.

01:02:40.380 We're living at a time when it's often hard for clinicians to find that time to have these kinds

01:02:46.360 of very detailed conversations with patients. And so it's really important that they talk to

01:02:50.340 people who will invest the time to speak about that. Secondly, there will be patients for whom

01:02:56.120 taking this medicine is really important and they feel very reassured by it. And for many,

01:03:00.400 it will be a different decision. And third is I don't want us to demonize the anti-estrogen medicines

01:03:04.880 too much. They clearly have side effects. I'm sure we'll get to a discussion of those.

01:03:08.660 But in terms of global health, tamoxifen and other anti-estrogens have cured more people of cancer

01:03:16.160 than anything else we do in oncology, aside from surgery itself. So these are really important

01:03:22.560 medicines from the global battle against breast cancer. And while there are legion side effects,

01:03:28.600 and we spend a lot of time in clinic addressing those and talking about them and alerting patients

01:03:33.120 to them and managing them, these remain really important medicines for invasive breast cancer.

01:03:37.380 For pre-invasive cancers like DCIS and for pre-cancerous lesions, it's been a more complicated

01:03:44.520 area to discuss because the benefits look pretty small to most people.

01:03:49.240 Anything else you want to say about, by the way, DCIS or LCS before we start to talk about

01:03:52.340 invasive breast cancer?

01:03:53.740 The shared element here is mammography. And we're going to get to invasive breast cancer momentarily,

01:03:59.200 but the reason we make diagnoses of DCIS and LCIS is often because of mammography. So one of the

01:04:06.160 critiques of mammography, which I think is important to acknowledge, is that when you have a national

01:04:11.920 screening mammography program, you're going to see an upsurge in the cases of DCIS and LCIS. And this

01:04:17.680 has led some to question whether we are over-diagnosing cancer on mammography. It's part and parcel of the

01:04:24.360 same thing. For the cancers where we have successful screening programs, one way they work is because

01:04:30.700 they allow you to diagnose pre-cancerous conditions. So fundamentally, that's what a pap smear does.

01:04:36.300 So a pap smear is looking for obviously cervical cancer, but it's also looking for the pre-cancerous

01:04:41.760 changes that you can identify on the pap smear. A colonoscopy is a very effective screening tool

01:04:47.220 for colon cancer because it allows you to both treat the lesion, the polyp, which is the pre-cancerous

01:04:52.520 one, and identify those who are at risk for more of them so they get more frequent screening.

01:04:57.500 You do diagnoses of skin lesions, your dermatologist's office, and some of them will be benign and others

01:05:03.320 will be skin cancers, but you're going to have an uptick in these pre-cancerous findings as well.

01:05:07.840 So that is the nature of a successful screening program. You are finding pre-cancerous lesions.

01:05:13.040 The debate as it relates to breast cancer is how much treatment should we offer in these

01:05:17.380 pre-cancerous instances. But that's why there's more DCIS and LCIS, and it is a natural consequence

01:05:24.260 of a successful screening tool for the tumor.

01:05:27.720 Before we leave that, let's add in a word on ultrasound and MRI. So again, bringing it back to

01:05:34.580 our prostate analogy, the workhorse of prostate cancer screening is the PSA, so not an apples-to-apples

01:05:40.940 comparison because it's not an imaging test, but by itself really lacks the specificity

01:05:46.340 to be a high-yield tool. And so in many cases, actually, as you probably know, the PSA is being

01:05:52.280 abandoned, which is unfortunate because it can be used, provided you look at the density and the

01:05:57.240 velocity of the PSA. But instead, of course, higher-risk patients are being evaluated and being

01:06:02.880 more quickly sent for MRI, and it's a multi-parametric MRI. We can explain what that means, but I assume

01:06:10.120 it's a very similar phase of MRI that's being done in breast cancer where it's looking at a high-quality

01:06:16.600 image, T1 and T2-weighted image, along with diffusion-weighted imaging and the use of contrast

01:06:23.540 as well. In the case of prostate, this is scored with a RADS score that ranges from 1 to 5, and

01:06:29.700 that's where the radiology can sort of assign a probability of suspicion. So can you talk a little

01:06:34.160 bit about how ultrasound and MRI work for breast cancer and how they sharpen the resolution in the

01:06:41.740 screening stage? The screening tool that's most important is the mammogram, and that is supplemented

01:06:47.660 by sort of an awareness of one's own body. Interestingly, we may get to this later on when we talk about

01:06:52.760 global impact of breast health interventions, but just teaching women to find a lump and go see a doctor

01:06:58.440 has, in many developing countries, actually lowered the fatality rate of breast cancer because it allows

01:07:03.800 early detection. So there is awareness of the body matters. When we're talking about screening

01:07:07.880 mammography, what they're looking for are architectural changes, irregularities, calcifications

01:07:13.380 that might be a sign of an invasive cancer, and that's the gold standard for most folks.

01:07:19.180 The mammogram is not a perfect tool. Any woman who's had a mammogram will tell you what an imperfect

01:07:22.840 tool it is. It's hard to exactly position the breast correctly. It depends a lot on a radiology

01:07:28.660 technician to do a good image, the mammography radiologist to interpret it correctly, a correct

01:07:34.140 comparison back and forth from the older images to the newer ones, and sometimes the breast itself can

01:07:40.120 be difficult to view because of breast density or other features in the breast, and that's where other

01:07:44.940 imaging can be helpful. So occasionally, people may need an ultrasound to support a mammogram finding.

01:07:52.480 It's not a reflex per se, and it's not universally recommended. In fact, studies have not really shown that

01:07:58.180 ultrasonography dramatically improves the outcomes if you are found to have breast cancer, but in some

01:08:03.480 women who have denser breast tissue or other suspicious findings, it's a pretty routine thing.

01:08:07.900 MRI is a very sensitive tool for finding abnormalities in the breast. It does not replace the need for a

01:08:14.780 mammogram, but for women who are at very high risk of getting breast cancer, classically, these are women

01:08:20.080 who have strong family histories or who have a known hereditary predisposition, like a BRCA1 or 2 mutation.

01:08:26.320 MRI is very important for early detection of cancers and is routine for those women, but not for the

01:08:33.000 general population. Does the mammogram have a similar score to radiographic scoring where you have a RADS

01:08:39.160 score of 1, 2, 3, 4, 5? Correct. So these are definitions put forward by the academic radiology

01:08:45.340 community, and they're widely used in clinical practice. They call it a BI-RAD score, and they range

01:08:51.560 from 0, which is there's nothing of concern, to 5, which is, oh my gosh, that looks like a cancer,

01:08:57.320 and in between is a gradation. And there are very well-done standards of what those gradations mean.

01:09:03.980 The breast imaging has become very sophisticated, and at large centers, they focus a lot on the

01:09:10.520 quality of the imaging and the review, and all of them are required to maintain their data. And they know

01:09:15.320 if you had a BI-RADS-3, how many of them eventually became a breast cancer within a couple of years

01:09:20.500 versus not? And there are accepted standards for what all this should mean. It's sort of like the

01:09:24.860 aviation industry. They've gotten really good at quality control and safety measures, and it's really

01:09:31.320 a very refined and sophisticated field of clinical care.

01:09:34.520 So given how much MRI has changed prostate cancer diagnoses, and I keep drawing this analogy,

01:09:41.240 but I think they're very similar, those data exist, for example, where if you know the PSA,

01:09:47.380 and you know the PSA density, and you know the BI-RADS score, you have a complete distribution of

01:09:54.440 whether or not there's no cancer present, a Gleason 3 plus 3, which you'll watch and wait,

01:09:59.480 a Gleason 3 plus 4, which needs to come out, or a 4 plus 4, which should have come out last year.

01:10:04.520 You know that a priori before you biopsy. Does that level of resolution exist with the combination

01:10:11.120 of BI-RADS and any other factor that you can put in, for example, the mammographic insight or other

01:10:17.600 parameters of family history?

01:10:19.500 The short answer is no. The guiding force of breast cancer management is really what the tissue biopsy

01:10:25.280 defines. And the finding on the mammogram screening, the imaging itself, doesn't tell you as much as you

01:10:32.440 would like to know. There are a few overarching pearls, you can say. Slowly evolving lesions tend

01:10:40.240 to be hormone receptor positive, and those tend to have a better prognosis. Things that pop up

01:10:44.660 quickly tend to be more virulent or proliferative lesions, which have a less good prognosis. But

01:10:50.080 those are not standard markers of risk that you would use to judge what therapy a patient needed.

01:10:56.360 All right. So let's now talk about what fraction of women that show up with something suspicious,

01:11:05.620 either they present with something suspicious or they're undergoing screening and on mammography and

01:11:11.800 or follow-up imaging, there's something suspicious enough to warrant that needle biopsy. What fraction

01:11:17.760 of those needle biopsies turn out to be invasive cancer on contact?

01:11:22.060 Well, it depends a lot on what the abnormality is. So in other words, if you have a BIRADS 4 lesion,

01:11:29.820 the radiology team is signaling that's a very suspicious lesion. That should have a high chance of being

01:11:34.420 DCIS or invasive breast cancer. BIRADS 3, it's probably, I forget the exact number, but I want to say like

01:11:40.620 a less than 5% chance that that's a malignant lesion. There's that gradation within there. And different

01:11:46.940 groups have then different thresholds internally and about what gets biopsied. Having said that,

01:11:52.220 I think the message to share with patients or people in the general audience would be that a lot

01:11:57.720 of the time, even if there's a so-called callback for a mammogram finding and the mammogram team wants

01:12:03.880 to do additional imaging, or there's even a recommendation for a biopsy, a lot of the time,

01:12:09.000 these will still be for precancerous or even benign lesions. And it doesn't automatically mean

01:12:14.240 that the patient has breast cancer. When you quoted, obviously, the numbers at the beginning

01:12:18.620 of the episode about the number of cases of breast cancer in the U.S. per year, I don't recall the

01:12:23.320 number. Was it about 250,000? Yeah, I said 275, I think, but it's about 250 to 300,000.

01:12:29.840 That's just invasive. Obviously, that doesn't include any of those DCIS, LCIS cases, correct?

01:12:35.200 Correct. There's ballpark another 50 to 60,000 cases of DCIS.

01:12:39.080 Walk us through the diagnostic and staging procedure for a woman who on that core biopsy

01:12:47.780 comes back. A couple of weeks later, pathologist says, I'm sorry, the news is bad. We have invasive

01:12:53.800 cancer. So first of all, what news is coming back with that in addition to the obvious, which is what

01:12:59.560 I just said, coupled with receptor status? What other information is coming back with respect to grade

01:13:04.560 or other cellular machinery and then walk us through the completion of staging?

01:13:11.160 Yeah. So the core biopsy is very helpful for both defining what the diagnosis is. Is it

01:13:16.260 precancerous? Is it DCIS? Is it invasive breast cancer? And then they would also comment on the

01:13:23.000 grade. So the grade is judged as grade one, grade two, or grade three. Grade three, the cells are kind

01:13:27.700 of growing wildly and sort of all over the place. Grade one, the cells tend to still form structures that

01:13:33.600 are recognizable as glandular structures. And the analogy here would be to a Gleason score. It's not

01:13:38.820 quite a one-to-one analogy, but, you know, the higher the number, the more sort of abnormal the

01:13:42.780 cells are. And they would also do biomarker testing for those three markers we alluded to at the

01:13:47.800 beginning, estrogen receptor, progesterone receptor, and HER2 or HER2. Is there anything else that they

01:13:52.840 look at there or is it just those?

01:13:54.320 There are a lot of things they can look at. So they also sometimes comment on the proliferation rate by

01:13:59.700 using a test called the KI-67, which is a proliferation measure. They can also comment on

01:14:05.280 whether or not tumor infiltrating lymphocytes or TILs are present. That is a prognostic marker in

01:14:12.120 triple negative breast cancers in particular. Presumably a favorable prognostic sign, I'm assuming.

01:14:17.260 It's a favorable marker in triple negative. That's right. They will comment if they can see any on

01:14:21.840 whether or not lymphovascular invasion is present. Sometimes they can see the cancer cells sort of

01:14:26.660 burrowing into a blood vessel or a lymphatic channel, and that is a marker of somewhat greater

01:14:32.220 risk of the breast cancer. So those are things you can all see on the core biopsy. And then those

01:14:37.200 same tests are typically redone, especially if you're at a different institution, they're redone

01:14:42.340 at the time of the definitive surgery.

01:14:44.140 And the definitive surgery here is always going to be a modified radical mastectomy, or is there

01:14:50.720 any situation where the lump is small enough that you will just do a lumpectomy with sentinel

01:14:55.940 lymph node?

01:14:56.620 The good news here is that for women who have early detection of breast cancer, the majority

01:15:01.000 are going to be candidates for so-called breast conserving surgery, also known as a lumpectomy.

01:15:05.500 So in that instance, only the affected portion of the breast is removed. The rest of the volume

01:15:10.800 of the breast is left intact. So the next definitive surgery for most women would be a lumpectomy,

01:15:16.980 where the affected portion of the breast is surgically removed. And at the same time,

01:15:21.120 the surgeon would typically do a sentinel lymph node biopsy. So they would look into the armpit,

01:15:25.600 remove a couple of lymph nodes, one, two, three, and see if there's cancer in those lymph nodes.

01:15:30.300 And then you'll have the full stage information. Now, for some women, there is still discussion

01:15:35.440 about a mastectomy. That may be because of family history or genetics. It might be because

01:15:41.580 of personal preference. It might be because of the size of the tumor relative to the size of the

01:15:46.340 breast is such that a lumpectomy isn't adequate for achieving a cosmetic result that people would

01:15:51.820 think is acceptable. Or maybe that there's sort of diffuse changes throughout the breast that require

01:15:56.600 it. So it's very individualized at that point. But with early detection, most women are going to

01:16:02.680 be candidates for a lumpectomy. Maybe walk through the TNM staging just so people get a sense of what

01:16:08.500 are the three big things that are driving prognosis? Because now we're going to put people into four

01:16:13.120 stages, one, two, three, four, with some A's and B's thrown in there.

01:16:16.660 So as with all cancer staging, stage four is metastatic or cancer that is spread beyond the

01:16:22.580 tissue of origin. So in breast cancer, that means there's a breast cancer, but it is spread to

01:16:27.200 the bone, the lung, the liver, those kinds of organs, metastatic disease. Stage one at the other

01:16:33.860 end of the spectrum is a tumor that is two centimeters or smaller. So that's about the size of a nickel

01:16:39.540 or smaller. And the lymph nodes are negative. Stage two includes slightly bigger tumors, bigger than two

01:16:46.700 centimeters, and or involvement of some of the axillary, the armpit lymph nodes. Stage three is a

01:16:53.680 progressively larger cancer and similarly affecting more lymph nodes. Lymph node involvement is the biggest

01:17:00.820 single prognostic marker for early stage breast cancer, by which we mean not involving some other

01:17:07.440 organ elsewhere in the body. And there's sort of a relatively sharp cut between sort of node

01:17:13.220 negative tumors and node positive cancers. All of it's really a spectrum. So breast cancer is really

01:17:18.680 interesting. If you have big enough study, a one centimeter cancer is less risky than a one and a

01:17:23.280 half centimeter, which is less risky than a two centimeter, which is less risky than a two and a

01:17:26.700 half centimeter and so forth. There's another axis that goes by nodal status. Node negative is less

01:17:32.900 risky than one, two, three, four. It's all very linear. And then finally, there's a third dimensional

01:17:38.660 access about the biology of the tumor, where triple negative cancers, again, ounce for ounce, size for

01:17:44.500 size, will have a more aggressive natural history. HER2 positive tumors historically were also a very

01:17:50.500 aggressive tumor. Now we have some of our most successful outcomes with treatment of HER2 positive

01:17:54.920 cancers. Within this large group of ER positive HER2 negative cancers, the risk depends on some of these

01:18:02.100 biomarkers like grade. So low grade, intermediate grade, higher grade, how robust the expression of

01:18:08.200 the estrogen receptor is. And nowadays, we also use so-called genomic tests like the Oncotype DX

01:18:13.280 recurrence score to understand for that large group of cancers how risky they are and whether they warrant

01:18:18.780 chemotherapy. So I tend to describe it, as would many others, as sort of a three-dimensional axis of

01:18:24.760 the tumor size, the nodal status, and then these biological features as well, all of which are likely to

01:18:31.640 affect risk of recurrence. And just to be clear for the listener, Hal, it's important that they

01:18:35.740 understand that all of that is in the M0 case, the non-metastatic case. So all bets are off. When

01:18:41.960 we have metastatic disease, the prognosis is awful. No, the prognosis is different, but it's not awful.

01:18:47.200 There are women who are living a long time nowadays with metastatic disease. We even occasionally think

01:18:52.220 we might cure some people with metastatic disease, though that's not usually the goal going

01:18:56.560 into it. It's only in the fullness of time. What fraction of women today would live 10 years?

01:19:01.680 Very small percentage and largely in this group of HER2-positive breast cancers where we think we

01:19:06.460 have very effective therapies these days. Big difference is, is the tumor still confined to

01:19:11.620 the breast and the lymph nodes so that with a combination of surgery and radiation therapy to

01:19:17.440 the chest and then drug therapy to prevent recurrence either in the chest or anywhere else in the body,

01:19:23.000 we can cure the cancer or at least aim to achieve a cure for the cancer as opposed to that stage four

01:19:30.740 distinction where it has spread to other important organs where usually we don't actually speak of

01:19:35.720 curing the cancer. We speak of managing it, treating it, keeping it at bay for a long time. And there

01:19:40.700 will be women who will live for years and years and years with advanced or metastatic breast cancer.

01:19:45.480 That's the separation between functionally stage three and four.

01:19:49.080 What is the median survival today for stage four breast cancer?

01:19:52.400 Sure. It's about five years and it depends again on the subtype of the breast cancer.

01:19:57.820 Triple negative breast cancers, it's more modest. HER2-positive breast cancers,

01:20:01.940 actually it's moving further and further out beyond that.

01:20:04.740 Can you tell me again the distinction between the stage two and the stage three? Is it more

01:20:09.220 separated by the number of lymph nodes or the size of the primary?

01:20:12.140 It's both. If you have a large tumor bigger than five centimeters, that becomes a so-called

01:20:17.580 T3 cancer. And if you have T3 cancer with any degree of nodal involvement, that becomes a stage

01:20:23.960 three breast cancer. If you have four or more positive nodes, regardless of the extent of the

01:20:31.060 size of the tumor, that's stage three. If you have involvement of the supraclavicular nodes,

01:20:35.480 that's stage three. And so you got to sort of get the grid out and look up all the criteria.

01:20:40.360 Can you give me full survival, so not five-year, not median, but 10-year actual cure rate for stage

01:20:47.260 one, two, and three?

01:20:48.620 Well, if you look at the American Cancer Society statistics, they update them every year. And I

01:20:53.060 can look up the numbers and give them the fingertips. But in ballpark terms, stage one,

01:20:57.120 isolated to the breast, 10-year cancer-free survival. Nowadays, often on the order of 90% or more.

01:21:04.060 Stage two, more like, and I'm ballparking here, but 75% to 80%. Stage three, more like 65% to 75%.

01:21:13.960 And again, it depends a lot on not just the stage, but on the biology of the tumor and the kinds of

01:21:19.560 treatments that people get.

01:21:21.260 Now, the grade, the 1-2-3 grade on pathology, that doesn't factor into any of the staging. Is it

01:21:27.660 more of a subtle issue that comes in when you are thinking about different chemo regimens?

01:21:32.260 I'm not trying to mince words. There is a staging criteria that factors in things like grade,

01:21:37.660 and that can be used in some of the more up-to-date American Joint Commission on Cancer

01:21:43.260 staging criteria. They do look at some of the things like grade. Usually, though, it's less

01:21:48.580 discussed because it mostly relates to the outcomes in ER-positive breast cancer. So triple negative

01:21:54.700 breast cancers are almost always grade three. Most HER2-positive breast cancers are grade two or three,

01:22:00.680 and they all get treated with the trastuzumab drug. And it's really in that gradation of the

01:22:06.600 vast majority of cancers, the ER-positive ones, where low-grade clearly does a lot better than

01:22:12.920 higher-grade cancers and needs different treatment approaches.

01:22:16.240 I guess before we go on to treatment, I've had many disagreements with people over the years

01:22:21.140 when it comes to arguments around aggressive screening. To me, one of the most compelling arguments

01:22:27.000 for aggressive screening of breast cancer, let's just limit it to breast cancer,

01:22:31.220 really is explained by what you just said, coupled with another observation, which is if you catch a

01:22:39.080 breast cancer that is two centimeters or smaller without lymph node involvement, the chances that

01:22:46.420 you will be cured, which we use as 10-year remission, is 90 to 95 percent. And without exception,

01:22:55.840 the larger the tumor is at presentation and the greater the lymph node involvement,

01:23:00.620 the lower your survival. And of course, if it spreads beyond the breast, let's not mince words,

01:23:07.800 there is no long-term survival. We also know that when we give women chemotherapy in the adjuvant setting,

01:23:16.460 I'll let you explain what that is in a moment, and we give virtually the identical chemotherapy for

01:23:22.300 women in the metastatic setting, the survival difference is profound. It's a huge difference.

01:23:29.160 Suggesting that tumor burden must matter. All of this is a long-winded way of saying,

01:23:34.420 the better we're able to identify breast cancer early on seems to me our best bet at curing cancers,

01:23:43.080 which acknowledges you will catch more cancers. In other words, you will increase the size of the

01:23:47.980 pool of women who have cancers. There will be lead time bias. All of those things will be true. But

01:23:52.480 ultimately, it seems to me mathematically, by definition, you are also going to cure more women

01:23:57.880 of cancer because you will shift the risk pool towards stage one tumors. Do you agree with that?

01:24:04.420 I do. And I think most people who take care of breast cancer patients would very much agree with

01:24:08.420 that. As you may know, there is still debate as to how valuable screening could be. It's a complicated

01:24:14.960 subject in the sense that most of the studies that were done showing screening was valuable were

01:24:21.360 concluded by the late 1980s. They showed that screening did contribute to improvements in

01:24:27.460 mortality. Since then, the therapy for breast cancer has gotten a lot better, which arguably cuts both

01:24:33.820 ways. On the one hand, it means that it minimizes some of the benefits of early detection because you're

01:24:39.780 not just cutting it out and you are able to treat metastatic or systemic disease, which is ultimately

01:24:45.480 the life-threatening part of breast cancer and prevent recurrence, which on some level diminishes the

01:24:50.380 value of early detection. On the other hand, early detection is clearly still associated with a better

01:24:55.560 long-term prognosis. The drugs are more effective or you can use the same drugs or fewer drugs when the

01:25:02.220 tumor is smaller to get better results. So I think all of us who are in the cancer community feel

01:25:08.200 strongly that mammography is a very important tool, not to take us away from thinking about how we

01:25:13.820 treat in the United States. But as you may know, breast cancer is now the most common diagnosis of

01:25:19.200 cancer, aside from non-melanoma skin cancer. It's the most common cancer diagnosis in the world

01:25:24.000 for almost all countries on earth. I didn't know that, Hal. You're saying it's more common than lung cancer?

01:25:30.400 More commonly diagnosed than lung cancer. Because the outcomes are better, there's still more fatalities

01:25:35.060 from lung cancer. But it's the most common diagnosis of cancer in women in almost every

01:25:41.620 country on earth. There are still some places in sub-Saharan Africa where their cervical or other

01:25:46.940 gynecologic tumors outpace breast cancer. But almost everywhere else, it's the number one diagnosis of

01:25:52.920 cancer in women. And in total, it's the largest cancer diagnosis. So the point of this story is to say

01:25:59.520 that from a global health point of view, it's becoming a huge issue for countries that historically

01:26:04.940 we've not thought of cancer as a big driver of mortality in. And this relates to the welfare

01:26:10.940 advances in many countries around the world as they've been becoming more affluent, better nourished,

01:26:16.320 and becoming more Western in that sense that they now have cancer problems that are looking more and

01:26:22.000 more like the kinds of cancer issues that we see in the United States and Western Europe and other

01:26:25.780 developed countries. So the importance of mammography globally is growing, not shrinking. And one of the

01:26:34.100 challenges is there is simply insufficient medical manpower, woman power, to adopt widespread screening

01:26:42.160 programs in many parts of the world right now. And there's been a lot of really cool artificial

01:26:46.560 intelligence research to suggest that you can look at breast imaging, perhaps even in the future,

01:26:51.440 without a radiologist to begin to identify women who warrant either more detailed evaluation or other

01:26:58.700 diagnostic workup. But this is going to be a huge problem in the coming decades as breast cancer

01:27:05.060 spreads, if you will, to really become a global disease.

01:27:09.440 So let's talk a little bit about the treatment and we'll go back and do it through the lens of the

01:27:13.000 staging. So a woman comes out of the definitive procedure, which again is going to be a lumpectomy

01:27:18.020 with a sentinel node biopsy. The sentinel node is negative. They will not undergo a formal lymph

01:27:22.840 node dissection. She will be told she had stage one breast cancer. Is she receiving effectively the

01:27:28.900 same treatment as the DCIS woman where she's going to get radiation for local control? And then depending

01:27:34.940 on the receptor status, she'll either get tamoxifen if it's ER positive, her septent if it's HER2 new

01:27:40.540 positive. Is there any treatment beyond that?

01:27:42.700 So the first thing to say is that's a very common problem. In the United States, the most common

01:27:48.560 presentation of breast cancer is a stage one breast cancer found on a mammogram, which has a very good

01:27:54.220 prognosis after surgery. But almost all patients will be candidates for some type of what we call

01:27:59.760 adjuvant therapy. So adjuvant therapy are treatments that are designed to help prevent a recurrence after

01:28:05.540 surgery. It's not unique to breast cancer. We use adjuvant therapy in colon cancer and in some sarcomas

01:28:11.360 and in certain prostate cancers and in other kinds of cancers as well. And sometimes patients

01:28:17.140 ask, well, why do I need extra therapy after all the surgeon got rid of the tumor? It's a good

01:28:21.700 question when you think about it. And the answer is that we worry about the possibility of microscopic

01:28:26.340 disease that might be somewhere either in the breast or chest area or might have snuck away somewhere

01:28:31.480 else in the body itself. And so we use additional therapies to mop up those microscopic bits of cancer.

01:28:37.640 So one of those is the radiation therapy. We've talked about that. The majority of women who are

01:28:42.700 70 and younger and who are vigorous and healthy who have early-stage breast cancer are going to be

01:28:48.160 advised to get radiation therapy. Many women in their 70s and even older will have to think about

01:28:53.160 radiation treatment. Depends on the type of cancer they have, their overall health status,

01:28:57.920 and fundamentally, as a ballpark term, you might say whether they have a 10-year life expectancy or not,

01:29:02.420 such that radiation is likely to be of some value to them in preventing recurrence over the next decade.

01:29:07.820 And also, the vast majority of patients are going to be candidates for some form of drug therapy.

01:29:12.980 And in terms of what has really changed the mortality from breast cancer, it's two fundamental

01:29:18.620 things beyond the surgery itself, which is obviously the sine qua non. One of them is early

01:29:24.040 detection through mammography, and that's reduced the risk of breast cancer over the past 30, 40 years by

01:29:28.200 about half mortality from breast cancer. And the other is effective systemic therapy. And that has given us

01:29:34.200 the other half of improvements in mortality that we're seeing in the United States over the past 30

01:29:39.680 years. And so for cancers of almost any size that are estrogen receptor positive, we think about

01:29:45.700 anti-estrogen medicines like tamoxifen or aromatase inhibitors. For tumors that are as small as a half

01:29:51.600 a centimeter or more in size, we think about drugs like trastuzumab that target HER2. And similarly,

01:29:57.340 for very small triple-negative breast cancers, we often think about chemotherapy.

01:30:00.440 And then there's a discussion. Most women with HER2-positive cancers also get chemotherapy with

01:30:06.880 that trastuzumab. And then as the tumor gets bigger and riskier, we amp up with more anti-HER2 drugs

01:30:12.540 and more chemotherapy. If the tumor is estrogen receptor positive, we go through a process where

01:30:19.080 we decide whether or not the patient needs chemotherapy. And that usually involves an oncotype

01:30:25.100 DX recurrence score or similar genomic test done on the tumor itself, where they look at the patterns

01:30:31.260 of gene expression in the tumor. And those studies have shown us that the majority of women who have

01:30:37.640 low risk scores on this genomic test, and there are several commercially available. There's one called

01:30:42.580 the recurrence score from Exact Sciences. There's one called the mammoprint assay from Agendia and there

01:30:46.620 are others. Those have been shown to be very powerful at figuring out who does, and more importantly,

01:30:51.220 who does not need chemotherapy. So there's been a huge shift in how we use chemotherapy in ER-positive

01:30:59.200 breast cancers over the past 25 years. From the time in 1999 when the NCI said every woman who had

01:31:05.000 a one-centimeter cancer needed chemotherapy, to a time nowadays when we frequently can avoid chemotherapy

01:31:11.120 for most ER-positive breast cancers, but certainly those that are node-negative and many of the ones that

01:31:17.120 are node-positive as well, because we understand that based on this genomic test, the chemotherapy

01:31:22.520 is just not going to help them do better in the long run. So circle back. Surgery is the sine qua non.

01:31:29.160 Following the surgery, we use radiation therapy to sterilize the breast and chest area. And then the

01:31:34.940 majority of women will need to think about some kind of drug treatment, which could be chemotherapy,

01:31:40.480 anti-estrogen therapy, targeted drugs, sometimes immunotherapy, to help prevent a recurrence

01:31:46.060 anywhere else in the body. Just spend a moment there explaining to people the distinction between

01:31:51.460 chemotherapy and some of these other therapies, because I think a lot of people sort of hear any

01:31:55.480 systemic therapy is quote-unquote chemotherapy, but you've made a great point to distinguish between

01:31:59.740 the anti-estrogen therapy and tamoxifen and astrazole, things like that. Herceptin, which is a

01:32:05.160 targeted therapy versus quote-unquote chemotherapy. So what are the things that you put in that bucket?

01:32:10.100 How are you defining that? And specifically, what are some of the chemotherapies and what are their

01:32:13.500 side effects? We've talked about the several different kinds of breast cancer. And nowadays,

01:32:18.760 we have a different treatment paradigm, really, when it comes to the drug therapy for each of these

01:32:23.980 different types of tumors. So for ER-positive HER2-negative breast cancer is the most common

01:32:28.900 kind. The most important drug therapy relate to anti-estrogen medicines. So there are two basic

01:32:34.580 flavors in the early stage. One is called tamoxifen. The other is called an aromatase inhibitor.

01:32:39.300 These are each pills. They work by different mechanisms. Tamoxifen sort of blocks estrogen's

01:32:45.620 ability to reach the estrogen receptor in the cancer cell. The aromatase inhibitors only work

01:32:50.860 in post-menopausal women, and they block the production of estrogen by non-ovarian tissue.

01:32:57.620 So a post-menopausal woman still makes a little bit of estrogen in tissues like the liver, the adrenal

01:33:02.240 gland, the fat, and normal body stores of fat. The aromatase inhibitors block that production of

01:33:07.500 estrogen. So the consequence is estrogen deprivation, which again, starves on the vine. These cancer

01:33:12.820 cells that we think depend on estrogen for their growth and development. So that's a very important

01:33:18.700 medicine. And again, globally, hugely important, has saved more lives than bone marrow transplant or

01:33:24.140 Gleevec or immunotherapy or whatever of the sexy new approaches in cancer. But the statistics are all in

01:33:31.560 favor of these hormone manipulations as being globally of huge importance. Now, in addition to that,

01:33:36.080 we also have a whole closet full of different types of drugs that we use. So some of them are

01:33:42.240 traditional chemotherapy drugs. And patients may sort of have a cultural sense of what these drugs

01:33:47.300 are. They tend to be rather nasty IV medicines. They make you sick to your stomach. They can make

01:33:52.860 your hair fall out. They lower your blood counts. They make you tired. On the one hand, our supportive

01:33:58.080 care in oncology has gotten vastly better in recent decades. So we have very powerful anti-nausea medicines.

01:34:03.960 We have medicines to goose the white blood cells to come back faster so you're not at risk for

01:34:09.200 infections. We have cold caps these days that allow women to often not experience hair loss during

01:34:16.040 chemotherapy. So on the one hand, the supportive care has really transformed our ability to give

01:34:21.760 chemotherapy drugs, drugs such as doxorubicin or what's also known as adriamycin, the red devil,

01:34:27.440 taxane type drugs called paclitaxel or taxol, alkylator drugs like cyclophosphamide or carboplatin,

01:34:34.820 very widely used chemotherapy drugs.

01:34:37.220 And maybe just for folks to understand how these things all have something in common,

01:34:40.700 which is they're basically anti-proliferative drugs. As you said, they're old school dirty drugs.

01:34:46.680 These are drugs that have been around for many, many decades, and they target dividing cells.

01:34:52.440 And that's why these side effects exist. Hair falls out because hair is dividing. You get

01:34:57.160 sores in your mouth because the epithelial cells in your mouth are dividing. And so

01:35:00.540 they're very nonspecific, but on balance, they are going after cancer cells in the sense that cancer

01:35:07.020 cells are going to be dividing more frequently than non-cancer cells.

01:35:11.880 That's exactly right. And so they're rather blunt instruments, but sometimes it's really helpful to

01:35:15.660 have a wrecking ball, if you will. So that's where things stood for a long time. But in the past

01:35:21.200 two decades, we've really transformed how we think about this because of some newer drugs that have

01:35:25.940 come along. So in the different subtypes, we have different approaches. Triple negative breast cancer

01:35:32.500 had historically been one of the most difficult to treat types of breast cancer where we didn't

01:35:36.920 really have a targeted therapy. And so we used a lot of chemotherapy and there were dozens of trials

01:35:42.160 optimizing chemotherapy and triple negative disease. But the biggest new thing has been immunotherapy.

01:35:47.360 And I'm sure in other cancer podcasts, you've talked about the so-called checkpoint inhibitors,

01:35:51.780 drugs like pembrolizumab and others that have proven very active in a lot of different tumor types.

01:35:56.960 In breast cancer, the data are most compelling for these drugs in triple negative breast cancers,

01:36:02.220 where we have shown that they can reduce the risk of cancer recurrence. And interestingly,

01:36:07.300 we usually use them before the surgery. We can come back to talking about that in what we call a

01:36:11.800 neoadjuvant approach, which is the same idea as adjuvant therapy, drug therapy to mop up cancer

01:36:17.360 everywhere in the body, but actually given before the surgery to shrink the tumor and to allow the

01:36:23.040 patient to get the effective treatment that goes everywhere in the body. For the HER2 positive,

01:36:26.720 the transformative event was the development of trastuzumab or Herceptin, which the data came

01:36:31.000 forward in 2005 for early stage breast cancer, that adding trastuzumab dramatically improved the chances

01:36:38.460 of never hearing from the cancer again. And that became totally standard for HER2 driven breast

01:36:44.000 cancers. Nowadays, for higher risk ones, we add a second anti-HER2 drug called pertuzumab or

01:36:49.020 perjeta. Now, interestingly, we're still giving chemotherapy with those anti-HER2 drugs, but we've

01:36:54.400 completely flipped the outcomes for HER2 positive breast cancer, where it has gone from one of the most

01:37:00.020 feared types of breast cancer to one of the most successfully treated types of breast cancer.

01:37:04.520 And finally, with estrogen receptor positive breast cancer, there have been two narratives.

01:37:08.480 One has been a narrative about using less chemotherapy. So the good news is we are able

01:37:13.100 to figure out a lot of women don't actually need chemotherapy for ER positive HER2 negative breast

01:37:19.040 cancers. There's this genomic test we get to help us decide whether chemotherapy is going to be

01:37:24.180 valuable. And with that, about two-thirds of the women who were previously offered chemotherapy can now

01:37:29.720 avoid chemotherapy. At the same time, we're amping up some of the hormonal axis manipulation. So we are

01:37:35.920 using ovarian suppression, which means for younger women going into premature menopause to help

01:37:41.160 prevent the cancer from coming back. We're using longer durations of anti-estrogens for higher risk

01:37:46.120 tumors. And there's a very exciting new class of drugs called CDK4-6 inhibitors, which are oral

01:37:51.120 medicines given for a couple of years now. They are targeted drugs that, again, slow down the

01:37:56.680 proliferation of tumors. And for very high-risk cancers, we're now looking at using them in addition

01:38:01.420 to all the other kinds of medicines that we're talking about. So each type of breast cancer has

01:38:06.780 its own paradigm of treatment, and each group is doing incrementally better and better because of

01:38:11.580 those innovations. What are the indications for neoadjuvant therapy? Which tumors on imaging and

01:38:18.980 biopsy are deemed cancers where they're going to get all that systemic therapy before surgery? And my

01:38:24.900 recollection is the pathological response that you see to the neoadjuvant therapy is also a great

01:38:31.240 prognostic indicator. That's exactly right. So for larger tumors, we have been moving more and more

01:38:37.320 towards a paradigm of what we call neoadjuvant treatment, where the usual sequence of diagnosis

01:38:42.740 of cancer, surgery, chemotherapy if you're going to get it, radiation therapy if you're going to get it,

01:38:47.500 hormonal therapy out back. We're kind of moving it all around. And I often describe this as sort of

01:38:51.960 freight train. It's a cassette of treatment, and we're just kind of giving the same kind of therapy,

01:38:57.020 but we're switching the order. And we're switching the order for very specific reasons. One of those

01:39:02.620 reasons is that by giving the drug therapy first, we usually can shrink the tumor either in the breast

01:39:09.060 or particularly in the lymph nodes as well. And so that means we can offer very good outcomes, the same

01:39:15.320 good outcomes, but with less surgery. So women who might have needed a mastectomy might now be able to

01:39:20.460 have a lumpectomy if the tumor shrinks. Or women who might have been obliged to undergo a so-called

01:39:25.540 axillary lymph node dissection where all the lymph nodes in the armpit are removed, that carries a

01:39:29.980 greater risk of limited range of motion in the arm or lymphedema in the arm, now might be a candidate

01:39:34.980 for a sentinel node biopsy by shrinking those tumors ahead of time. So that's one big advantage of

01:39:40.400 neoadjuvant therapy. It gives the same treatment, but it makes the surgeon able to do a lesser operation

01:39:46.460 so there's less morbidity from the operation and a better cosmetic result. The second big reason is

01:39:52.200 that we learn while giving this neoadjuvant treatment how well the tumor responds. And if

01:39:58.060 the cancer totally disappears, intuitively obvious, that's a really favorable prognostic finding. And we

01:40:03.780 call that a pathologic complete response. It just means the pathologist looks under the microscope at

01:40:08.620 the end of that treatment course at the time of the surgery and says, there's no cancer left.

01:40:12.800 That's a really good finding and puts the patient into a much lower risk category, a much better

01:40:17.640 prognostic group.

01:40:19.060 Do those patients get adjuvant therapy or is therapy done?

01:40:22.100 They often get something. It depends, again, on the specific flavor of where you're at. But

01:40:26.260 the prognosis goes way up. Conversely, if there's some residual cancer, it's a less favorable prognostic

01:40:32.200 finding. But in many instances, we actually have drugs that we're now using to overcome that residual

01:40:38.300 disease. So for instance, in HER2-positive breast cancer, we give chemotherapy and

01:40:42.740 trastuzumab up front. If there's residual disease out back, we can use a derivative of

01:40:47.700 trastuzumab called trastuzumab mtansine, which improves the prognosis for those patients who

01:40:52.280 have residual cancer. And there are many instances of this throughout the spectrum of breast cancer

01:40:57.060 treatment. So we use neoadjuvant therapy for larger tumors to shrink the tumor in the breast,

01:41:02.400 shrink the tumor burden in the lymph nodes, and to individualize or tailor treatment on the

01:41:08.020 backside based on how much response there is.

01:41:10.600 Let's talk about prostate cancer again as an analogy. So again, I think here's a great analogy,

01:41:14.940 right? We know that in the case of prostate cancer, testosterone is not causing prostate cancer,

01:41:19.680 but it's a growth factor for the cancer. So once a man has prostate cancer, if he has metastatic

01:41:25.600 disease, androgen therapy is the standard of care, removing the androgen. If he has surgical disease,

01:41:30.840 you remove the tumor. But men are able to go back on testosterone replacement therapy if they need

01:41:36.980 it, provided the PSA stays low. So is there an analogy here in breast cancer where obviously if

01:41:42.260 a woman has ER positive breast cancer and it's metastatic, well, unfortunately, you're going to

01:41:46.520 be dealing with anti-estrogen therapy indefinitely. But if you're talking about a stage one cancer or a

01:41:52.040 stage two cancer or even a stage three where you have neoadjuvant treatment, you have a pathologic

01:41:57.440 CR. As far as you're concerned, there's no evidence of disease. Are those women still told to forego

01:42:05.720 estrogen replacement therapy in postmenopause? And if so, why the difference from the biology of

01:42:10.780 prostate cancer?

01:42:12.100 So as we've said a couple of times in the course of the session, the anti-estrogen medicines,

01:42:16.600 which are very common, remember 80 plus percent of tumors are estrogen receptor positive, and nearly

01:42:20.540 all those patients would be advised to have anti-estrogen medications. So the side effects all relate to

01:42:25.620 the estrogen deprivation, hot flashes, night sweats, bone and joint stiffness and achiness, hair thinning,

01:42:31.300 not hair loss, but thinning finer hair, somewhat of a receding hairline, vaginal dryness and sexual

01:42:37.380 health issues or frequent urinary tract infections related to changes in the epithelial of the genital

01:42:42.940 tract, osteoporosis, all these things are related to the loss of estrogen. Now, the upside of the

01:42:48.760 treatment is sufficiently important that we encourage patients to strongly consider those treatments

01:42:53.780 nonetheless. But managing those side effects is a part of the work of what oncology teams do.

01:42:59.420 For women who've had complete pathologic response, one asks, do I really need all the therapy out

01:43:04.940 back? And it's a great question. At the moment, we don't usually omit the anti-estrogens if the tumor

01:43:09.800 is ER positive. Parenthetically, it's rather rare for ER positive tumors to have that complete pathologic

01:43:15.740 response because there's sort of an inverse relationship between the effectiveness of hormone

01:43:20.540 treatment and the effectiveness of chemotherapy. The more hormone sensitive the tumor is, the less

01:43:25.660 role there is for chemo and sort of vice versa in the space of ER positive disease. For women who have

01:43:30.860 triple negative breast cancers, in theory, you could say, gosh, it would be okay to take anti-estrogens,

01:43:37.320 but we don't stylistically endorse that too often. I think what we really focus on is what's the symptom

01:43:44.600 that we're trying to address with the hormone replacement therapy. And in those instances,

01:43:49.940 we have important conversations with patients. So, for instance, patient has osteoporosis. We have

01:43:55.080 very good non-hormonal options to treat osteoporosis. Patient has hot flashes and night sweats. There are

01:44:02.340 non-hormonal options to address those. In fact, the FDA just approved a drug a few months ago to try and

01:44:07.520 treat hot flashes. Genital symptoms, genital urinary symptoms, sexual health issues were actually rather

01:44:13.400 liberal about using genital preparations of estrogens, so vaginal estrogen creams and things

01:44:20.560 like that that can alleviate some of the discomfort or other symptomatology without giving significant

01:44:25.360 systemic absorption. For most breast cancer patients, we stay away from oral hormone replacement therapy,

01:44:31.620 looking whenever possible to use non-hormonal or tapered or tailored hormonal manipulations that don't

01:44:38.440 offer systemic exposure. Now, having said all that, everyone who sees a lot of breast cancer patients

01:44:42.640 knows there's a few women who are really just so uncomfortable without the hormones that they

01:44:48.020 really need that to have a valuable quality of life. And then you have a unique conversation with

01:44:52.620 the patient about those issues. Let's talk a little bit about the genetics of this. So,

01:44:56.640 I think there can't imagine there's anybody listening to this who hasn't heard of the BRCA genes.

01:45:00.580 So, let's start with those. They're clearly not the only genes that are responsible. And when we talk

01:45:04.700 about cancer, of course, everybody understands cancer is a genetic disease in the sense that there are

01:45:09.600 mutations that are the sine qua non of the cancer. Most of those mutations are somatic. They're

01:45:15.200 mutations that occur during our life, but a handful of them are germline. And clearly, the BRCA mutations

01:45:21.360 are the most noteworthy. So, what can we say about inherited risk of breast cancer through either single

01:45:29.080 genes or polygenic? How much do we know? What's the prevalence? What else can you tell us about those?

01:45:34.880 Family history is obviously a powerful marker for greater risk of breast cancer recurrence.

01:45:41.160 If you look at large populations, roughly 8% to 10% of all breast cancer diagnoses are related to a

01:45:48.880 specific hereditary gene mutation. So, BRCA1, BRCA2, BRCA1, BRCA2 account for about half or 5 of that 10%

01:45:58.000 of all hereditary breast cancer. So, these often are families that have particular histories of

01:46:04.920 ovarian cancer and breast cancer. BRCA1 and BRCA2 are very high penetrant genes. That means there's a

01:46:11.520 pretty high lifetime risk of developing breast cancer or ovarian cancer if you have a BRCA1 or BRCA2

01:46:17.440 mutation. So, if the average, again, we've talked about this number at 1 and 8, instead of 1 and 8,

01:46:22.360 we're talking about a 1 and 2 or even a 2 and 3 chance lifetime of developing breast cancer for women

01:46:28.480 who harbor those gene mutations. The genetic testing for that now has become very standard.

01:46:34.500 And increasingly, what we're seeing is that when one member of a family is identified as having a

01:46:39.520 BRCA1 or BRCA2 mutation, we can help that patient in several ways. First, they might consider mastectomy

01:46:46.080 because of the risk of a second breast cancer. Some women who've not been diagnosed with cancer will

01:46:51.200 consider prophylactic mastectomy. Second, we think about prophylactic oophorectomy, removing the

01:46:56.380 ovaries once that patient is done with childbearing because we don't really have a good screening tool

01:47:00.740 for ovarian cancer. And so, once women have finished having their families, they often think about having

01:47:06.520 their ovaries removed to lower their risk of ovarian cancer, which also traffics with a BRCA1 and BRCA2

01:47:12.040 mutation. And finally, for women who choose to retain the breast, we offer more intensive screening.

01:47:16.900 Usually, it's an annual MRI staggered every six months with an annual mammogram.

01:47:21.980 We've learned a lot about those particular mutations. We also talk to extended family members

01:47:27.780 because, as you know, BRCA1 and BRCA2 increase the risk of prostate cancer in men. They also increase

01:47:32.740 the risk of male breast cancer. And they also increase the risk of pancreatic cancer, though the

01:47:37.600 numerical issues there are all smaller than the risk of breast or ovarian cancer. So, these are a really

01:47:43.860 evolving space in our management of cancers. And we have a whole team of genetic counselors

01:47:48.540 and genetic specialists who both do the genetic testing and then advise patients very carefully on

01:47:54.220 what the particular findings mean for their own care and how they should think about that

01:47:58.200 in their breast cancer or other cancer management.

01:48:01.940 Can you say a little more about those as far as BRCA being gain-of-function, loss-of-function? How is

01:48:06.060 it transmitted? Is it autosomal dominant? Does it matter if a male knows that he has it with respect

01:48:11.740 to his female offspring, et cetera? Yeah. So, these are, as you said, autosomal

01:48:15.500 dominant transmitted. That is to say, a man can transmit it to his offspring just as easily as

01:48:19.960 a woman can. They are loss-of-function mutations. The normal biological role of these proteins that

01:48:26.900 are encoded by the BRCA1 and 2 genes seems to be to help repair the DNA in a normal cell. Every time

01:48:32.560 a cell divides, there's all this fine print editing, if you will, of the genome. And they're

01:48:37.940 constantly replacing base pairs to correct the genome so that it stays perfect, if you will,

01:48:43.780 through the thousands of divisions that a cell might undergo in a lifespan of a person.

01:48:48.260 When you have a deficiency in BRCA1 or BRCA2 or other genes in this space, that repair mechanism

01:48:54.480 is much less precise. And so, mutations begin to accumulate. And if you have further loss of DNA repair,

01:49:01.080 that can then predispose to giving rise to cancers. And the ones we've talked about, breast,

01:49:06.180 ovarian, prostate, pancreatic are the most common ones that we see with BRCA1 and 2.

01:49:11.700 What makes up the other half?

01:49:13.320 The other half has actually become very interesting as well. So, the other half

01:49:16.500 includes other proteins in the same pathway of the BRCA1 and 2. So, in particular, PALB2,

01:49:23.180 which is a partner of the BRCA2 protein. And about 1% of all breast cancers will have a PALB2 mutation,

01:49:31.000 which is a mutation that also substantially increases the risk of developing lifetime breast cancer,

01:49:36.080 but a little bit less than BRCA1 or 2. About 1% to 2% will be related to a gene called CHEK2,

01:49:42.540 C-H-E-K-2, which also increases the risk of colon cancer. And about 1% to 2% will be related to

01:49:49.300 mutations in the ataxia telangiectasia gene, the ATM mutations, which can give rise to several

01:49:55.360 different kinds of cancers, though they're less common. But that's something that we are now

01:49:59.380 encountering. Because here's the key takeaway. For many, many women now, we are recommending that

01:50:04.900 following a breast cancer diagnosis, they do have genetic testing so that we can understand

01:50:09.620 if we need to think about their tumor differently, or if we need to think about their surveillance or

01:50:14.200 prevention approaches differently. And so, we're doing a lot more genetic testing than we used to

01:50:18.700 do. And with that, we're finding these other mutations. Now, most women still don't have a

01:50:24.560 mutation. Most women who have first-degree relatives, mom or sisters who have breast cancer,

01:50:30.080 don't have a hereditary mutation. And the obverse of this is that many women can be reassured that

01:50:36.720 they have not transmitted an undue risk to their offspring, which is a real concern amongst many

01:50:43.020 patients diagnosed with breast cancer. And so, a negative genetic test result can also actually

01:50:47.520 be very reassuring for a family, even as a positive finding can allow us to act differently in their

01:50:53.020 management. So, BRCA1 and 2, PALB2, check 2, ATM account for 10% of breast cancer cases.

01:51:01.740 At the most.

01:51:02.520 These are the exception and not the rule, but they are germline mutations. They're single gene

01:51:08.140 mutations, and they're worth screening for. Is there any reason a woman with a questionable family

01:51:15.500 history, I mean, one first-degree relative should be checking this? Or if a woman has a sufficient

01:51:21.620 enough family tree, mom does not have it, no grandparents have it, no parents have it,

01:51:27.820 would that be dispositive to say, I don't need genetic testing?

01:51:30.840 There's a growing recognition that, so these different genes have different sort of familial

01:51:35.540 patterns. And because many of them are so-called less penetrant.

01:51:39.520 Because it's not fully penetrant, you can be fooled by a relative not having it.

01:51:45.480 It's not so full-blown. I think that one of the things that happens following a breast cancer

01:51:50.120 diagnosis is a lot of other family members might be tested as well. I think we're getting closer to

01:51:55.220 the time when there will be universal genetic testing following a breast cancer diagnosis,

01:51:59.140 and that will have a cascading effect into the families of affected individuals. And for women who

01:52:05.060 have a strong family history of cancers, it's certainly very appropriate to meet with genetic

01:52:09.340 counselors, talk about the testing options, and in many instances pursue that testing, both

01:52:14.200 because they want to know if they should be more aggressive about their screening and

01:52:17.420 surveillance, but also looking for the reassurance that that isn't something they have to be unduly

01:52:21.840 concerned about. So this is another part of the revolution of our breast cancer treatment,

01:52:26.540 which has been very exciting to see mature over the past 20 years.

01:52:30.360 Are there any commercial tests that you can point people to where they can ask their doctor or go

01:52:37.000 directly over the counter and get a test done that looks specifically for those five genes?

01:52:42.360 There are tests. There are many commercial assays from many different companies that

01:52:46.000 typically look nowadays at larger panels of genes, often up to about 100 genes on a rather regular

01:52:52.480 basis. These are usually done with a specific purpose of looking for hereditary cancer risk.

01:52:57.760 While the over-the-counter kind of things like the 23andMe things can, in theory, pick these up,

01:53:02.720 we don't usually lean on them as clinically actionable tests. And I think if there's a real concern about

01:53:08.360 family history, probably better to seek out a genetic counselor or a cancer center in the community where

01:53:14.920 you can talk more about this and get specific tests from different companies.

01:53:19.400 Yeah, that actually leads me to another question, which is the importance or lack of importance

01:53:24.680 of multidisciplinary care. So obviously you're at Dana-Farber, which is probably one of the top

01:53:29.880 three cancer centers globally, certainly in the United States, which would be the epicenter of

01:53:35.440 multidisciplinary care. Maybe tell folks what multidisciplinary care means, what the benefits are,

01:53:41.740 but given that most people are not going to go to Dana-Farber or Memorial Sloan Kettering for their

01:53:47.200 breast cancer care, how important is it? And what should they be looking for in their local hospital

01:53:53.340 when they are diagnosed?

01:53:55.280 It's a really great point about helping patients get excellent breast cancer care. And it's not,

01:54:00.900 of course, unique to breast cancer, but many, many cancers require, as you said, multidisciplinary

01:54:06.680 care. Fancy way of saying you're going to need to think about surgery, radiation therapy, medical

01:54:12.400 oncology management with drug therapy. You want to have outstanding pathology. You want to have

01:54:17.340 genetic counselors. You want to have great imaging teams. And what cancer centers do is they bring all

01:54:22.580 those people together under one roof. These days it's sometimes, you know, with satellites, but they all

01:54:27.120 collaborate together and work together. And that is really why care in a major cancer center can be

01:54:33.600 so effective because you have a team of people who are working together every day to make sure that

01:54:40.360 things get done the right way. And sometimes I draw an analogy about the airline industry. As a passenger,

01:54:47.080 you want an invisible experience with the airline, but what makes it all work? Well, you got to have a

01:54:52.340 great maintenance team. You got to have an air traffic controller that knows what they're doing. You got to have

01:54:56.820 pilots who understand how things work. You need the food delivery trucks to arrive at the right time

01:55:02.500 at the right moment. You need gate agents to keep people moving through the whole thing. And you get

01:55:07.580 that at airports that are good because they all work together constantly and they know exactly what

01:55:11.940 they're doing. They communicate with each other regularly. That's what makes for a very uneventful

01:55:16.520 flying experience, we hope. And for cancer care, you want the same thing. The way you figure this out

01:55:22.560 if you're a patient is, are the providers talking to each other? You don't have to see them all the

01:55:27.100 same day, though of course it's nice if you can do that. And we try to do that. They don't have to

01:55:31.200 all be under the same roof because again, we try and do that, but it's not essential. What's essential

01:55:35.700 is that they function as a team because almost every patient with breast cancer is going to need to think

01:55:40.700 about surgery, radiation therapy, medical oncology care. Many will also need to think about plastic or

01:55:47.480 reconstructive surgery. Many will need to think about quality of the imaging they get down the road.

01:55:52.520 They might need genetic testing. You want folks who are working together all the time, communicating

01:55:57.460 with each other, and handing the baton back and forth as necessary. So one of the conversations we

01:56:04.080 frequently have when we meet a new patient is, which modality of therapy is going to come first? Is it

01:56:09.220 going to be surgery and then medical oncology and radiation afterwards? Or do we actually want to flip

01:56:14.580 the sequence as we talked about in neoadjuvant treatment and give medical oncology treatment

01:56:18.840 first? That's where you want a group that works together, talks effectively and regularly so that

01:56:25.480 they're all on the same page. And we all say things like, okay, you're going to have surgery first.

01:56:30.180 I'm going to let my surgical team take you through that next lap on this relay race. Then we're going

01:56:34.860 to have the radiation team grab the baton. They're going to take you on a lap. And then I'm going to pick

01:56:39.260 it up and take you through another lap as we talk about the medical oncology therapy.

01:56:43.180 That kind of collaboration and teamwork is really important for women who have been diagnosed with

01:56:48.360 breast cancer. How important do you think it is for a woman to undergo her therapy at home versus

01:56:55.100 coming somewhere else? If a woman listening to this lives in, I'm going to offend whoever lives in that

01:57:01.180 city, but the implication is not that the cancer care in city X, so I won't even name a city, but they

01:57:06.260 live in city X. They're listening to this podcast and they just got diagnosed with breast cancer and they

01:57:10.900 say, well, I want to go to Dana-Farber. The way that he's describing that sounds like exactly the

01:57:15.460 care I want to be. But the reality of it is city X is a two hour flight from Boston. They came out and

01:57:21.160 they saw you for a consult. Are you going to say to them, look, city X might not have a place as good

01:57:26.680 as Harvard, but it's pretty darn good. And I think you're better off staying there because you at least

01:57:32.980 can go home every night as opposed to having to stay in hotels and things like that.

01:57:36.940 How do you help patients navigate that? And what fraction of the patients who come to Dana-Farber

01:57:42.580 don't live in Boston? We're very fortunate to have a terrific reputation such that we see patients

01:57:48.260 from obviously New England, all across the country, and really all across the world who will come to

01:57:53.180 a cancer center like Dana-Farber for exactly that kind of multidisciplinary care. And in the management

01:57:58.720 of metastatic disease, they might also come for clinical trials, actually both in the early and in the

01:58:03.340 advanced stage disease where the next wave or the future of innovative treatment is going to emerge.

01:58:08.780 Having said that, breast cancer is a very common problem. It is the most common cancer diagnosis in

01:58:14.560 the country, as we've mentioned. And you can get great breast cancer care in many, many parts of the

01:58:19.560 country. There are very few parts of the United States where people really don't live within reasonable

01:58:25.060 access distance of really good breast cancer care. It's a common problem. Now, having said that,

01:58:31.320 I think it is important to make sure that you're dealing with people who specialize in cancer care.

01:58:37.020 There's been a big push to professionalize the issues of radiation oncology and surgery,

01:58:41.760 to subspecialize those areas just as we subspecialize medical oncology, and that you have that team

01:58:47.540 presence. And I think those are things to very much seek out as part of your treatment program.

01:58:53.400 And most people, again, will live within distance of getting a second opinion. That's always a good idea.

01:58:58.920 If there's any ambiguity or if you're looking for reassurance, because hopefully by making the

01:59:04.440 effort once perhaps to go to a place where you can get external validation of the plan,

01:59:09.380 it offers a lot of reassurance and comfort.

01:59:12.440 Where would you say is the greatest variability of care across the medical oncology, surgical

01:59:18.780 oncology, radiation oncology, when you compare, say, the top flight, if you took the top 20 institutions

01:59:24.920 in the United States and compared them to the median institutions of the country, where will you see

01:59:32.020 the most disparity? Will it be in the radiation side, the surgical side, the post-operative side?

01:59:37.840 Like, where's the greatest variability?

01:59:39.620 I don't think there's one specific area that jumps out. I think that the value added of some of the cancer

01:59:46.200 centers that we've been discussing, a really thoughtful review of the pathology and radiology.

01:59:52.120 These are things that are not often visible to patients, but the experience of the radiology

01:59:59.120 team working with the surgeons, they really satisfied that that little ditzel doesn't need

02:00:03.460 to be biopsied. Is the pathology first rate? Did they really make sure that the grade was called

02:00:09.540 correctly, that the estrogen receptor studies were correctly done? Those are incredibly important

02:00:14.840 things. And while most places do it very well, those are things that can really alter longer-term

02:00:21.500 outcomes. Another area is judicious use of treatment. So there are a lot of drugs that we can use in

02:00:29.060 early-stage breast cancer, and dialing in the right amount is a bit of an art form. Again, it's a common

02:00:35.940 disease. Most places do it very well. But there are sometimes nuanced questions about, is this a case

02:00:40.340 where we want to add more, or is this a case where we're comfortable doing a little bit less? That's an

02:00:44.460 important part of the discussion. Other areas that matter a lot, again, not always so obvious to

02:00:50.500 patients, but plastic and reconstructive surgery. Tremendous variation in approaches and in the

02:00:56.580 teamwork and collaboration between the breast surgeon and the plastic and reconstructive

02:01:00.960 surgery teams. Those things can also have a big impact on how people look and feel years after the breast

02:01:08.140 cancer diagnosis. So making sure that you have high-quality access to plastic and reconstructive

02:01:13.700 surgeons, if that's part of the treatment plan, is really critical. So I think that, again, the good

02:01:19.480 news is that you can get excellent breast cancer care at many, many places around the country. And

02:01:23.560 the test, if you will, for most patients is, are these folks used to working together? Are they

02:01:29.160 talking to each other, collaborating with one another, coming up with a unified plan that makes sense?

02:01:34.220 That's really what you want to see happen. Yeah. And if that's not happening, if they don't have a

02:01:39.240 monthly tumor board, those would be kind of signs, a meeting where all these people, the pathologists,

02:01:44.640 the medical oncologists, surgical oncologists, radiation oncologists get together. If you don't have a tumor

02:01:48.720 board, that might be a sign that says, hey, I'm going to travel a little bit further to the next city or see

02:01:53.560 what I can do. Also seems to me that one of the most high-yield investments, if you're going to seek that

02:01:59.400 second opinion, sending a block of pathology slide to the A-plus center is really valuable. I think

02:02:07.060 that's something that patients don't always know. And I hope that people listening, we can now make

02:02:10.620 this a really good public service announcement, which is make sure when you have your tissue specimen

02:02:16.860 taken that you understand you have a right to request a section of that tissue be sent to another

02:02:22.700 pathologist of your choosing. And that can be, as you said, I think a very important determinant of

02:02:27.880 outcome. That's an easy place to make a mistake or overlook something if a less experienced center

02:02:34.320 is viewing a tumor that happens to be not a run-of-the-mill tumor.

02:02:38.960 It's a great point, Peter. The quality of pathology is the foundation for all of cancer care. And again,

02:02:46.840 breast cancer, very common, usually begins in the breast. It's usually not so mysterious, but

02:02:51.220 oftentimes a pathology review is vital importance. Are the margins adequate? Is this

02:02:56.600 DCIS or invasive cancer? It can sometimes be hard to know. Is this a favorable prognosis tumor under the

02:03:03.240 microscope or not? And then if you take a bigger step back, we occasionally see things that aren't even

02:03:09.360 breast cancer. There are other tumors that can be there. They can be reclassified. And then when you start to

02:03:13.460 imagine other kinds of cancer, sarcomas and lymphomas and leukemias, where there's a real art to the

02:03:20.360 pathology, that's an unappreciated vital part of the cancer care process that everyone has access to

02:03:28.960 with consultations on pathology and is part of what great cancer centers really deliver.

02:03:34.280 Just for the sake of completeness, although most people probably aren't aware of this,

02:03:37.640 you've already alluded to it twice, men can develop breast cancer as well. Can you say a little bit

02:03:42.560 about what the incidence is and do we know anything about the risk factors?

02:03:45.760 Yeah. So it's an absolute truism that men can get breast cancer. Fortunately,

02:03:50.220 the incidence is pretty low. For every 200 cases of female breast cancer, there's one case of male

02:03:55.900 breast cancer. The risk factors are not particularly well known, but they do include genetic predisposition

02:04:02.560 as part of it. They include certain hormonal conditions that men can rarely get. But what's

02:04:08.780 interesting is men are often unaware that they can get breast cancer. And so it is not uncommon that men's

02:04:15.480 diagnoses are actually at a higher stage than women's because they weren't really paying a lot

02:04:20.600 of attention to the chest or the breast or they noticed some nodularity and didn't really think

02:04:24.400 much of it. And so if men are found to have on exam any changes around the breast tissue, that should

02:04:30.620 be evaluated as well. And I've actually had the experience over the years of a woman who was

02:04:36.540 diagnosed with breast cancer and then her husband was poking around his chest like, wait a second, and they

02:04:41.620 have husband and wife breast cancer. So it happens once in a while. It's a small area of overlapping

02:04:47.140 Venn diagrams there. It is something to be aware of. And the treatment principles for male breast

02:04:52.580 cancer are fundamentally the same as for female breast cancer, though nearly all breast cancers in men are

02:04:59.360 estrogen receptor positive. It's very rare to get a triple negative breast cancer in a man.

02:05:04.200 And what about HER2 receptor?

02:05:06.120 Uncommon, but not unheard of.

02:05:07.660 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

02:05:13.280 you do see men from time to time.

02:05:15.360 We do. And we actually have a program here for men with breast cancer headed by Pablo Leon and several other

02:05:21.720 cancer centers around the country also have this. There are issues that arise. Historically, men have been

02:05:26.560 offered mastectomy because the aesthetic virtues of breast preservation have not been thought to be so

02:05:31.580 important in men. That's kind of changing nowadays for some men. Most men will be candidates for

02:05:36.220 anti-estrogen medicine as their tumors are estrogen receptor positive. The genetic piece is very

02:05:41.100 important. So there are clinics that specialize in the care of men with breast cancer as well.

02:05:46.320 Well, Hal, this has been a really interesting discussion. It's been a whirlwind tour of all

02:05:50.740 things breast cancer. I want to thank you very much for sharing your time. I know how busy you are.

02:05:56.180 So I want to thank you again. And I know that we'll link to a lot of the stuff that we've talked

02:05:59.820 about, including some of the trials, so that people can understand this. I hope that people come away

02:06:03.500 from this with a really good sense of how to ask the right questions to be better advocates for

02:06:08.200 themselves as they're going through therapy. And of course, ultimately, if they are diagnosed with

02:06:12.320 breast cancer, to understand what the critical questions are that should be asked of the team

02:06:18.160 that's going to be charged with their care. It's a treat to be with you. And I hope it's been helpful.

02:06:23.960 And I don't want to sound too rose-tinted glasses here. But the fact is, women are doing better and

02:06:31.760 better following a diagnosis of breast cancer. And early detection is really important.

02:06:36.480 Multimodality therapy, as we've discussed, is really important. The drugs are getting better

02:06:40.660 and better for both early and for advanced or stage 4 breast cancer. So there's a lot of tremendous

02:06:46.180 optimism in the care of breast cancer patients right now, even as it remains a public health challenge

02:06:51.700 and obviously a personal challenge for hundreds of thousands of women around the country.

02:06:55.740 Great. Well, thank you very much, Hal.

02:06:57.280 Thank you.

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The Peter Attia Drive - November 06, 2023

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

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