Samira (00:01.08)
Good morning. I'm Samira Daswani, the host of the podcast, The Patient From Hell. We're recording on a rather special day. It's Sunday here. It's a Sunday after SABCS. And I have Dr. Doug Blayney who is a very well-respected, world-renowned medical oncologist, who also is the chief medical officer of Manta Care's and is going to be helping us summarize the key insights from SABCS.

Hi Dr. Blayney, thank you for taking time on Sunday morning.

Dr. Blayney (00:32.268)
Hi, Samira. Yeah, no, it's fun to be here. It's cold outside, so it's nice to be warm and cozy inside. And it was a great meeting in San Antonio. I think there were almost 10,000 people there. San Antonio was a great host city, host site. The people were very nice. And it struck me, and contrary-wise to many scientific meetings I go to,

There were a lot of patient advocates, women and men with breast cancer who were there, who were listened to and engaged and made very thoughtful contributions to the discussion. So I think for our audience, it's important to make that point.

Samira (01:25.772)
Thank you, Dr. Blayney Can we actually start with what S-A-B-C-S is? I think you alluded to it, but maybe just a quick... This is what this conference is about.

Dr. Blayney (01:32.632)
Sure.

So San Antonio Breast Cancer Symposium is held in San Antonio. It's been going on for as long as I've been a medical oncologist. Yes, it started slow. It was organized by two breast medical oncologists in the days when there was not a lot of differentiation around what breast cancer was.

Bill McGuire, was one of the founders of the symposium. started, and he was responsible largely for sort of differentiating estrogen receptor positive breast cancer from others. Anyway, the symposium started in San Antonio, grew, grew, grew. And now it's co-sponsored by UT Southwestern, a major cancer center in Texas.

and also the American Association for Cancer Research, a major professional society geared more toward basic science and translational research than is ASCO or some of the other more purely clinical societies. AACR sponsors several scientific meetings, the San Antonio Breast Cancer Symposium.

is one of them. it starts Tuesday afternoon, goes through Friday afternoon. There's various scientific symposia, plenary lectures, tumor boards where typical patient cases are discussed by leading experts and docs who both do clinical trials, clinical research, and patient care.

Samira (03:29.4)
Thank you for that. That was super, super helpful. So this year, 2024, if you had to summarize the four days of information insights into, I don't know, four points, well, what are they?

Dr. Blayney (03:46.2)
Well, let me say yes, I'll try four, but those are four that are of interest to me. I will leave out many things, I think four things that maybe your readers or our readers and listeners should be aware of. One is the...

progress that's being made in the so-called CDK 4/6 inhibitors. Second is what about antibody drug conjugates? I learned a lot about antibody drug conjugates. We're also, as a clinical doctor, I'm interested in, gee whiz, are we over treating some patients? Where are we?

Where are we gonna get the Goldilocks? Not too much treatment, not enough, but right in the middle. And actually there are clinical studies, maybe we can talk about that, address that. And finally, artificial intelligence, which is us fusing much of what we do, whether we know it or not. So I think those are the three things I want to talk about.

Samira (05:06.136)
Alright, let's start with the first one, CDK 4/6s

Dr. Blayney (05:09.602)
Well, so CDK 4/6 inhibitors, are three on the market now. Palbociclib or Ibrance Ribociclib or Kisqali and Abemaciclib Ribociclib and Abemaciclib are indicated in adjuvant, meaning right after surgery, breast cancer, that is.

ER or estrogen receptor positive and the two CDK 4/6, Abemaciclib and Ribociclib are indicated in addition to endocrine therapy. Typically, it would be one of the aromatase inhibitors, letrozole anastrozol or goodness, the other one.

Samira (06:01.378)
lovestrine

Dr. Blayney (06:02.606)
No, Fulvestrant is a third, so letrozole, anastrozol the third one, whose name I'm forgetting, I'm sorry. But anyway, so they're indicated and they have both shown benefit in terms of progression-free survival. So in other words, having the cancer come back after it is all gone, after.

Samira (06:15.224)
We'll find out.

Dr. Blayney (06:31.85)
surgery and radiation and also in overall survival, which is a good thing. So I think we have, as a clinical doctor and patient, we have two choices that will never be compared head to head, but they will be, they're roughly equivalent. think most doctors and experts think they're roughly equivalent. So if side effects are too much with one, there's probably

a good reason to adjust the dose or change the drug. So it's good to have choices. So anyway, that's in the adjuvant setting. The ribocyclic or casqually approval came within the last few months after the ASCO annual meeting in June of 2024.

news out of San Antonio was that the Ibrance or Palbociclib was studied and shown to be beneficial after in metastatic cancer. In other words, cancer that has come back and has a demonstrable lesion or spot on the CT scan or others. But Palbociclib was shown to help patients by reducing tumors in

even though they had already seen or already been treated with another CDK 4/6 inhibitor. So that again gives patients with hormone receptor positive recurrent metastatic breast cancer another treatment option. Even though it's Sunday, I got a call this morning from an old family friend and we're able to talk about, you know,

Gee whiz, this new friend had a new diagnosed breast cancer. Gee whiz, what do I do? Is this the end of things? And I said, I'm not your doctor because you're 2,000 miles away. But I think when you do talk to your oncologist, there's a lot of things that can be helpful for you. So again, having options and not only having options, but also having

Dr. Blayney (08:57.55)
clinical trials that show they work in a setting or can work in a setting where we didn't think they did before. So I think that's one of the salient important things to come out of the last week.

Samira (09:11.544)
All right, so was theme number one. Should we switch?

Dr. Blayney (09:17.036)
Yes.

Samira (09:19.39)
Alright, theme number two, ADCs.

Dr. Blayney (09:22.592)
ADCs, antibody drug conjugate. So antibody drug conjugate, there was one large session well attended on antibody drug conjugates. Antibody drug conjugates are useful in treating breast cancer, but also in treating other kinds of cancers, including lymphoma, bladder cancer, and gastric cancer.

So it's one of those treatment modalities that we have that can be useful in a lot of different cancers. focusing on breast cancer, there are three, and we'll talk to them in a minute, but antibody-drug conjugates are antibodies joined to a drug. So, okay, fair enough.

So antibodies, you and I, everybody makes antibodies when we get exposed to the pneumococcus or get exposed to pneumococcal pneumonia or we get a strep throat or a variety of infections. We make antibodies that recognize various sites or they're actually called antigens on the cell surface of these bacteria. And our immune system is

is designed to mount a variety and make a variety of these antibodies. One of the Nobel Prize winning discoveries in the 1970s was how to trick a cell into making not multiple antibodies, but one antibody. And that's one clone or monoclonal antibody.

Those antibodies were made initially in mice or hamsters, I forget. But if a normal person gets injected with a mouse protein, which a mouse antibody is, our immune system will gobble that up and digest that protein and it will be useless. So the next big advance was taking a monoclonal antibody that was made in a mouse.

Dr. Blayney (11:46.314)
and cutting off a part of it and joining a human piece of the human immunoglobulin. So the human body would not recognize that as foreign and would not chew it up. And that antibody would persist in the circulation for actually a month or so. The first monoclonal antibody that was approved

for cancer treatment was Rituximab, which is for lymphoma. It was largely developed by one of my colleagues, former colleagues at Stanford, Ron Levy, and it's been used widely now, not only to treat lymphoma, but for a variety of autoimmune diseases as well. So monoclonal antibody conjugated or joined to a drug.

So one of the useful things about the discussion we had last week was that the why, what about these drugs? Why were they picked? I always thought that if you went to had a monoclonal antibody joined to a chemotherapy drug that most of the antibody, most of the antibody drug conjugate would end up in the tumor. Well, turns out that's not true.

Only about when you squirt in or inject a monoclonal antibody drug conjugate, only about 1 % of that antibody ends up in the tumor. And that means that the rest of it needs to be metabolized or detoxified or have the body get rid of it, which has some implications for these.

antibody drug conjugates as drugs. So stepping back a bit from the antibody drug conjugate has a monoclonal antibody, a linker, which is a short piece of protein. And then that protein is attached to a chemotherapy. there are two chemotherapy type drugs that are attached that have

Dr. Blayney (14:12.514)
found used in breast cancer. There's emtansine drugs, are known as spindle poisons or tubulin agents, much like Vincristine or perhaps taxanes are tubular poison. emtansine is a potent tubulin agent that is attached to an antibody drug conjugate. And the TDM-1

or the TDM1 or Kadcyla has the tubulin agent, antitubulin agent, and Trastuzumab deruxtecan has a tubulin type agent. And the third monoclonal antibody, Sacituzumab govitecan or Trodelvy which is easier to say, has an arenaticin-like.

drug, which means its efficacy, meaning the anti-tumor benefit as well as its toxicity is more like a renatikan than some of the others. So anyway, long way around saying I learned something new that not all the, in fact, very small minority of the antibody-drug conjugate gets to the tumor.

The rest is circulating. And that the poisons, the chemotherapy-like poisons, have certain properties, including both benefit and toxicity. So that was an interesting finding. Yes.

Samira (15:55.416)
Can I interrupt really quickly?

Can I interrupt? So one of the things I remember you teaching me, and I think you said this in our ASCO recap, if I remember right, is the bystander effect of an ADC.

Dr. Blayney (16:18.285)
Yes.

Samira (16:19.33)
Can you talk about that in conjunction with the 1 % penetration? wonder, and this is the open question, I wonder how much of it is designed.

Dr. Blayney (16:24.503)
Dr. Blayney (16:29.678)
Yeah, so the bystander effect, just to recap, so some of these poisons, one of the particular, the TDM, I'm sorry, no, the deruxtecan leaks out of the cell and goes into surrounding cells.

whether they have the HER2 overexpression or not. So it doesn't have a whole lot to, the bystander effect depends on that 1 % of the ADC that gets to the antigen bearing target. In this case, the HER2, it gets ingested, the whole complex.

antibody linker and poison get ingested into the cell, the antibody gets degraded just like a cell degrades protein, the linker gets degraded, and then the deruxtecan leaks out of the cell into the surrounding environment, doesn't penetrate very far, but leaks out of the cell into the surrounding environment. Now that has, so that's one effect.

The other circulating antibody drug conjugate also gets metabolized normally, just like anything, Any protein that gets injected into the body, gets metabolized. It also leaks some of the, or don't know, frees up some of the protein that it acts, or not protein, some of the chemotherapy.

And that acts as a slowly releasing cells, a slowly releasing chemotherapy. it, unlike if you inject a small molecule chemotherapy like cytoxan or like taxane into the blood, most of it's gone within 24 hours. This tubulin protein sort of leaks slowly and retains in the body for a long time.

Dr. Blayney (18:48.12)
Now that may be part of the therapeutic effect. It's certainly why some of the off-target toxicities like hair loss and like bone marrow or white blood cell suppression occur. anyway, so they're two relatively unrelated phenomenon.

Samira (19:13.474)
Can you talk a little bit about the balance between efficacy and toxicity? Because unlike

Dr. Blayney (19:20.172)
Yes, so I think.

Go ahead.

Samira (19:25.28)
I was just going to compare contrast really quickly, CDK4-6 and ADC, because in the CDK4-6s, it's almost like the lens we were looking at that class of drugs is progression free survival, overall survival, reduction of risk of recurrence in the early stage setting, metastatic setting slightly different. It's about choice combinations, extension. ADCs, the decision-making feels a little different. It feels...

a bit about toxicity versus efficacy.

Dr. Blayney (19:57.56)
Well, yes, if you include toxicity, not only what we might think of what I mentioned about hair loss or white blood cell lowering counts, et cetera, and neuro neuropathy or numbness, but also time toxicity. So gee whiz, would I rather take a pill one day a week or show up and get an infusion once for half an hour or?

two hours or so every month. So there's other toxicities. I think maybe step back a little bit and talk about antibody drug conjugates in breast cancer. think it...

It's a statement that may be a little bit out there, but everybody with metastatic breast cancer should probably get a trial, at some point, should probably get a trial of one of the antibody drug conjugates. And we can run down the list of the three types of, subtypes of breast cancer and where that might fit, if that's where we want to go. we talk about toxicity too.

Samira (21:11.457)
interesting.

Dr. Blayney (21:15.0)
So in.

Samira (21:15.448)
I would like to go there. Can I summarize really quickly? Because I think you said something really important that I want to make sure we highlight. Because I think you said some version of, regardless of subtype of breast cancer, if you're metastatic and have breast cancer, at some point along the treatment continuum, ADCs may be playing a role. Is that a fair summary?

Dr. Blayney (21:39.342)
Yes, and some of that is very defensible and some of that is sort of out there. And let me, we can talk about, or we should talk about it. So the very defensible part is that the trastuzumab or herceptin-related antibodies. So trastuzumab, deruxtecan.

Samira (21:48.568)
you

Dr. Blayney (22:06.744)
HER2 and trastuzumab emtansine or Kadcyla are targeted to the HER2 protein on the cell surface. historically and practically, they form a very

large pillar, big pillar of metastatic treatment. So, Trastuzumab, Hertuzumab, Magnetuxumab even, and then the ADCs, Trastuzumab, Deroxytan, and Trastuzumab, Amantazine. Guess what? All Trastuzumab-like or anti-HER2 agents have a role in that being more and more refined in the clearly HER2 over-expressing.

patient with overexpression HER2 in their metastatic cancer. The triple negative breast cancer, triple negative meaning not expressing or overexpressing HER2 protein on the cell surface, not expressing the estrogen and progesterone receptor so-called. So that's the triple negative. The triple negative cancers often expand.

almost always express a protein on their surface called TROP-2. That TROP-2 antibody has been developed against TROP-2 that is tagged to a drug, a renotecan-like drug. And so the triple negative breast cancer, almost all of those women should, and men too, should have

Trodelvy or Sacituzumab govitecan-hziy unpronounce-a-man as part of their treatment paradigm. So that's the HER2 overexpressors, the triple negative. Where it's controversial is in the estrogen receptor positive cancers. So I'm sure your...

Dr. Blayney (24:24.236)
our audience is familiar with estrogen receptor positive cancers. There's a lot of steps that can be taken. Anti-estrogen, if the tumor grows, more different anti-estrogen than one or more of the CDK 4/6, then the PI3 kinase inhibitors, mTOR inhibitors, all, you know, lot of steps in the way, on the way. And...

And again, all of those put off cytotoxic chemotherapy. We have evidence now that many of the estrogen receptor positive cancers also express either high, low, medium, or low level, or ultra low levels of HER2 on their cell surface.

Samira (25:22.456)
Hmm.

Dr. Blayney (25:22.946)
You read it, our audience might be familiar with the HER2 3 +, which is conventionally said, yeah, those women are HER2 positive. Okay, they should get trastuzumab-based treatment and treatments. The 1 and 2 +, it's been shown that those women can also bind, the HER2 antibody can bind to those.

Samira (25:40.056)
Okay.

Dr. Blayney (25:51.468)
lower expressing and have a beneficial therapeutic effect or those women with those characteristics on their tumor can benefit. Ultra low and maybe, know, IHC zero doesn't mean there's no, it means there's normal amount of HER2. normal breast tissue has some low or HER2 zero level of expression. So those women...

patients, women with those characteristics should get a trial. So I think it came out this last week that the more HER2 expression one has, the higher the chance of the antibody drug conjugate working. But even if it's one plus or zero and the situation is not dire, meaning demands immediate.

response of one should be given a couple of months to see a couple of months worth of therapy to see if it works. Now that's out there. think there's going to be one of the things that did come out this week was the biomarkers need to get better. So IHC was developed to be three plus and to be a relatively convenient.

lab tests that could be applied in most pathology labs. And it's been shown to be relatively reproducible with accuracy. So it's a useful test to HER2, you know, Herceptin or not. But now with these HER2 low, ultra low, it's really breaking down as a predictive marker of benefit for anti-HER2 treatment. So...

stay tuned. But again, I think that as long as the situation is not dire and as long as the treatment is available, meaning paid for or available by insurance, it should be something to use, something worth a try.

Samira (28:08.92)
Super, super helpful. Just in the interest of time, should we go to topic number three?

Dr. Blayney (28:15.918)
which was, I got so excited and I plumb forgot. I'm like...

Samira (28:19.416)
De-escalation in DCIS, I think.

Dr. Blayney (28:26.356)
Okay, yeah, so good. So DCIS, ductal carcinoma in situ. Editorial comment, many of my colleagues are interested in taking the C, ductal carcinoma in situ, out of the name because it's more, I think, more descriptive and possibly more helpful.

as panic-inducing to patients to regard this as what's called a pre-malignant lesion, or it's formerly a stage zero cancer, but it's an abnormality that could but doesn't always progress into cancer, much like a colon polyp. cancer can develop in a little polyp in the...

a little outpouching or wart-like structure that no one sees in colonoscopy, or a melanoma that's in situ on the skin is not necessarily an invasive melanoma, but a superficial spreading melanoma can be just shaved off before it develops into an invasive, potentially fatal cancer.

And certainly in the prostate, which is more akin to what we're talking about, there are low-grade prostate cancers that develop, do not kill a patient, and never cause a problem. So I think we're coming to terms with that concept in breast cancer. But again, these slow-moving, slow-growing cancers. And I think it's worth

highlighting that the DCIS slowly changes. So that has two implications. One, if you're going to do clinical studies where development of cancer is an outcome, it's going to take years and maybe decades to do a study. Secondly, if it's a slow growing, you have a a patient, an individual patient has some time to thoughtfully consider what to do.

Dr. Blayney (30:48.984)
about ductal carcinoma in situ. So having said that, that's a good segue into what's called the COMET study. This got picked up by news media, the New York Times, Wall Street Journal, and others picked this up because it said, well, wait a minute, this ductal carcinoma in situ can be observed. And OK, that's what the study shows.

It only had two years of follow-up was the first thing. So God knows what's going to happen in five, 10, 20 years. So that's one thing. Secondly, the ductal carcinoma in situ cancers that were included in the study were very low grade and very small. and obviously most of these were picked up by mammogram. They were too small to actually.

be felt with a mass that was an abnormal screening mammogram and lo and behold, low-grade ductal carcinoma in situ. Patients were randomized for surgery or not and followed. if something changed, they could have surgery or they got said, no, I'm tired of waiting. Let's just get rid of this.

That was an indication for surgery. Most of the women did get anti-hormone treatment, Tamoxifen, if they were ER positive. And it turned out that the invasive, there was no difference in development of invasive cancer over the two years, and importantly, no difference.

in quality of life, whether women got surgery immediately or observation. So that, I think, we need more follow-up. And certainly, there needs to be digestion on the field when this study is published.

Samira (33:04.866)
Dr. Blayney, can I summarize something really quickly and then I have a question for you. So the summary is, it sounds like the very first thing with DCIS is de-escalation. Can you help us explain that? What does that mean in the context of the study?

Dr. Blayney (33:19.043)
Well.

Yeah, mean, it means something to a doctor, which means not as a treatment with as many side effects. In this case, we don't have to give side effect producing radiation right away or side effect producing surgery right away.

So, you know, de-escalation may have some negative connotations or negative meaning to a patient. Gee whiz, you we don't care. We're going to, you you're 70 years old. We don't, you know, no one cares kind of thing. Maybe it's right sizing is a better term. For the tumor, for the DCIS, equally in a 40-year-old woman who,

Doc, I've got 50 years more to live. I don't want to have this little thing always there. Maybe taking the surgery route is appropriate for a 40-year-old woman. Contrary wise, for a 70, 75-year-old woman, Doc, I've got 10 or 20 years, or especially if you've got other causes of sickness.

you know, doc, I'm content to watch this thing. I'm coming to the doctor every three to six months to get my blood pressure and other things checked. It's no big deal. it, you know, I would think of this as a de-escalation strategy. The 40 year old woman would say, right, right sizing this for me, maybe the 70 year old woman and you know, every, everybody's different. So the, so I think the point is that there's options and it's.

Dr. Blayney (35:09.846)
It's right-sizing or personalizing the treatment given the whole scheme of things. Is that a fair statement? that?

Samira (35:23.852)
That is, can I, in hearing you talk about the three classes, classes is the wrong word, but three sort of themes, have CDK46 is, CD4, I keep mispronouncing this, don't I? The CDK is, I'm go with that. The ADCs and then DCIS, the thing that strikes me is right sizing seems to be a theme kind of across all three.

but the way you write size is a little different. Because in the CDK, CD4, I can't say that, I just cannot. The CDK, in that class, it's about optionality. It's about trying one profile, side effect profile is different. If it doesn't work, maybe switching and try. There's like trial and error almost to find what works. In the ADC, it's about the expression of proteins.

Dr. Blayney (36:02.604)
You're doing well. You're doing great.

Samira (36:22.316)
HER2-low, HER2-intermediate, TROP-2 and the subtype of breast cancer in terms of our own confidence in terms of the efficacy of the ADCs. So it's like the biology of the cancer is kind of deciding a little bit the choice of therapy in ADCs, at least today it sounds like. And then some of those choices, you have a bit more optionality in the HER2 space than the TROP-2 it sounds like there's one of them right now. Is that fair?

Dr. Blayney (36:52.024)
Yeah, and so the missing word, I think maybe that ties this all together is biomarkers. In the most familiar, perhaps, biomarker is ER, or estrogen receptor, on a breast cancer cell. An estrogen receptor is a biomarker.

that not only talks about prognosis, so estrogen receptor positive breast cancers have a relatively good prognosis compared with estrogen receptor negative, that's also a predictive biomarker. So it can predict that anti-estrogen treatments like tamoxifen and like the aromatase inhibitors predict for better outcomes when applied.

So the ADCs were learning that as 20 years ago, HER2-IHC, you know, 3, 2, 1, or 0 was a prognostic and predictive biomarker. So if it was 3 +, that was a bad prognosis tumor, but also predicted that trastuzumab or herceptin or...

like drugs would lead to a better outcome. So in the Trebeldi or Sosatuzumab example, TROP-2 is not a prognostic, but it is a predictive biomarker perhaps. In the DCIS, we don't have as good biomarkers. saw there's a company

Samira (38:28.596)
interesting.

Dr. Blayney (38:37.998)
now that has a panel of gene expression panel that may predict, and it looks like it does predict, whether radiation treatment after standard treatment for DCIS is beneficial. So if this predicted biomarker of benefit for radiation pans out, and I think it probably will, that

means that we can deescalate or personalize or fit in a weather radiation treatment. And its side effects are likely to be beneficial to that patient. it's much about developing biomarkers. Oncotype and others like oncotype, mammoprint, et cetera.

Samira (39:18.402)
Thank you.

Dr. Blayney (39:37.056)
are some biomarkers for prognosis and prediction of early stage, in early stage estrogen receptor positive breast cancer. where, you again, the problem, not the problem, the problem, well, a problem from a scientist or experimentalist point of view is that it takes a long time for these things to show a benefit, you know, years and probably half decades or decades.

to get these sorted out and by that time often the fields moved on, treatments are better, different kind of thing. So it's a conundrum.

Samira (40:19.256)
Dr. Binney, I really like you tying it together with a biomarker, but I think there's a second thing that ties all classes together, and that's choice from the patient. Because what struck me, and I think it strikes me mostly in the DCIS setting, but I do believe it translates across all three, is in the DCIS setting, if you're younger, getting diagnosed in 30s, 40s, 50s, have a long potential lifespan, your choices may be...

from a clinical perspective, more aggressive. If you are, I see the expression, I know you well enough to know that I should pause.

Dr. Blayney (41:00.024)
Well, aggressive means in many people's mind, both patients and their caregivers, something that has more side effects, regardless of the potential anti-cancer benefit. So aggressive, I think a more.

Samira (41:20.504)
Hmm.

Dr. Blayney (41:24.866)
precise and maybe useful term is something with a higher side effect and a slightly potential higher benefit. Going back 40 or 50 years, aggressive breast cancer surgery was mastectomy. Doc, let's do this mastectomy. want these. I don't want any chance of this coming back.

Samira (41:36.214)
Hmm. Hmm. Hmm.

Dr. Blayney (41:52.3)
Well, when the studies were done comparing mastectomy or taking the breast off and lumpectomy, meaning just taking out the lump, the survival was equal. And yet the women who had mastectomy, it was the right thing to do at the time. But now we know it may still be the right thing to do. But there are.

and mastectomy is viewed as aggressive, but it does have side effects. And so long as a person is aware of the potential side effects and not just reading through them, but really understanding what the side effects are. Okay, lymphedema, okay, that's trivial. I don't want this cancer. But again, 25, 10, 20 years down the road,

if your rings don't fit on that side or you can't make a complete fist or maybe play the piano quite as well or finger the violin, lymphedema can be a big deal. And maybe it's I'll give 2 % potential survival benefit if in 20 years I can play a duet with my granddaughter kind of thing.

So, choices. I think part of the thing that drives me and I know that drives you is making patients as aware as we possibly can of not only what their choices are, but why they might choose something completely different than their sister or their neighbor in the precise same.

cancer situation.

Samira (43:45.496)
I think that was a phenomenal summary of what I was trying to get at. So thank you. That was very, very helpful. And yes, you're totally right. think it is, I've been thinking about this a little bit recently about, it's almost like gas. That's what I'm looking for. You know, in a car, you have your little indicator and you have a gas tank and you have sort of zero and a hundred. Whatever, not a hundred, I'm sure our cars have more. I don't know what the metric here is, but zero hundred.

Dr. Blayney (44:07.33)
Yes. Yes. Yeah. Empty. Cool.

Empty, full. Okay.

Samira (44:17.058)
for our purpose. There we go. Thank you for all right. Empty and full. And in this case, I think there's something about low and high, because I think if patients are thinking about side effect profile impact on quality of life, just to be sort of comprehensive and the impact that treatments can have. So impact on quality of life and then impact on quantity of life as almost two gas tank gauges, right?

and giving a patient some sense of where they are on each of those things at any point in time, because they can be dependent variables. But from a patient perspective, it's hard to understand the dependency and it's hard to communicate the dependency. But if we were able to communicate to the clinician, Dr. Blayney, I really want to optimize quality of life more than quantity. That's one thing. If I want to optimize quantity over quality, one thing, if I am somewhere in the middle on both,

then that becomes a bit of a Goldilocks principle of like, how do we balance impact on quality of life and the survival benefit? And I almost want patients to have those little like, I need a better word than I guess, fuel gauges. I think, think, at least I see you smiling. So I think I'm at least communicating this enough for you.

Dr. Blayney (45:40.974)
Yeah, no, it's a struggle. And quality of life, OK, can that be answered by a nine question questionnaire? Well, maybe. I mean, if you can't get out of bed, your quality of because something hurts or if your arm doesn't work because they're so swollen, that's one extreme. that's, I don't know.

awful, but and certain, you know, certainly to be avoided, I think most people would say. But usually the distinctions are not on that scale. You know, trying to say, well, I don't want to, I want to be able to play a duet in 20 years. I need to be alive in 20 years and I need not to have lymphedema.

Well, what about 15 years playing that duet? What about three? It's those kind of subtleties that that are That we that we need to take account of and I think the first step is making Patients aware is sort of what you said was, you know, we can we want to think about Or ask people to consider what's important to you

I don't play the piano, I'm never going to, so that's not important. Okay. But, you know, I need to take care of, I need to not be a burden on my mother because she's ill and I got to take care of her, be around her, can't travel or, you know, I want, you know, having four bowel movements a day with this treatment, which is a, you know, a grade or five, which is a grade two toxicity. Okay, trivial.

But if you're a outside salesperson or you're a waitress or you're a, you know, you can't do that. I mean, you can, but you can't live your life effectively. So maybe a drug that has that kind of toxicity, which, you know, on the big scheme of things, if it's going to save your life, well, maybe it's worth it.

Dr. Blayney (47:55.534)
If there's a choice that has equal benefit, you may want to avoid the diarrhea kind of drug.

Samira (48:03.64)
That's super, super, I think you're totally right. I think the subtleties and the nuance of what is important is I think what patients and families need to be able to communicate to the doctor and nurse of six and synthesized fashion. And yes. Yes, sir. I was just going to go there. Yes.

Dr. Blayney (48:16.598)
Now, do we have time to talk about AI? Because I think that that so anyway. OK, good. mean, know, AI drives me crazy when it autocorrects spelling when I text people and autocorrects their name or the autocorrection feature of AI. But there were several.

of papers that are several presentations that talked about the use of artificial intelligence and large language models in cancer care. One of them, a couple that really struck me were use of artificial intelligence in the diagnosis of cancer and in screening through imaging, know, imaging mammography, MRI scans of the breast.

and ultrasound. So that's one sort of piece. And that, guess, to summarize, AI can, artificial intelligence can interpret mammograms. The images from a mammogram 20 years ago, there were four, top, bottom, side, side, and maybe another oblique. And now there's 60 images from a mammogram.

So that means that a radiologist, a human radiologist, whether it's next door or around the world, somebody needs to look at those. AI can help. trying to, I think the radiologists and imagers are trying to figure out exactly how to use it. When AI has been compared with radiologists, the accuracy is measured by sensitivity and specificity.

area under the receiver operating curve, if you will, AI is not quite as good as the test data sets in that radiologist. So if you take 50 mammograms and get a radiologist to look at them and take those same 50 mammograms and get an AI to look at them, the AI is not quite as good as the test.

Dr. Blayney (50:38.392)
Contrary-wise, when you look at the day-to-day operations of a radiologist, AI is just as good, or maybe a touch a small amount better, than a day-to-day radiologist. radiologists, and we all get into this, I think Hawthorne effect is maybe familiar to some people. When the Hawthorne effect was...

discovered when they made measurements at the Western Electric Telephone Assembly Plant and noticed that when assemblers who put telephones together were more accurate when somebody was watching them than when they did it just routinely. So similar effect is now with radiologists and their day-to-day work, AI, because it

doesn't get tired because it doesn't get bored maybe a slight amount better. I think the issue is these edge cases, something that is really obvious to a radiologist that AI has never seen before or seen rarely are the things where it's working out. So I think where our colleagues in diagnostic imaging are going is how to get

the two things to work together to be effective, not only in the well-curated 50 cases, but in what walks in the door every day. So that's one application of AI. And the other thing that I think is fascinating is, again, it comes back to the personalization. They're looking at

mammograms and there's more information in the mammogram than just what looks like a cancer. So for instance, dense breasts have always been a problem for, a problem. So to step back a bit, just as a reminder that as women and men age, there's more fat that accumulates in the breast.

Dr. Blayney (53:03.542)
natural process of aging. Diagnostic mammograms, x-rays, detect the contrast between fat and either calcium or connected tissue, gristle or cartilage, or connected tissue in the breast. So when there's less fat and more connected tissue in the breast, small cancers can easily hide and not

be seen as well by the naked eye, if you will. And that has played itself out. In many states, there's legal obligation for the mammographer to include in the report patient or subject. You have dense breasts. OK. What does that mean? Well, now with AI, they

They are getting techniques to be more sophisticated to say, you're at high risk for because of dense breasts and other characteristics. You're at high risk. And you should be screened every, I don't know, six months or 12 months rather than the one year or maybe two years or three years, which is standard in Europe. So there's an opportunity.

using more information that's present in the mammogram that I or a chain radiographer can't see, but that an AI training itself on millions of mammograms can see and work itself out. So I think that's a, again, it's going to be a little more personalized and ability to...

personalize right size and hopefully make mammograms, I mean, they're more beneficial and get us more bang for our, more bang, if you will, for our screening buck. And buck, not only direct costs, but time and anxiety, et cetera, screening. So I think that's cool. And I think that bears on what you and I have been talking about in...

Dr. Blayney (55:31.32)
where we hope to go with Manta in terms of patient reported outcomes. Gee whiz, can we personalize some of the questions we ask of patients who use our platform, you know, who may benefit from a query every six weeks or some of it may benefit from a query from every three days or something like that. So I thought that was proof of principle.

in a related but different area of cancer care.

Samira (56:06.284)
I mean, that was phenomenal. mean, this episode we had sort of spoken about a couple of days ago. And what I didn't fully appreciate was how beautifully the four seemingly distinct areas of innovation insights actually have a pretty common thread about right sizing, about the personalization of.

oncology treatment today and personalization happening kind of across many, dimensions. There's personalization happening around technology and the use of AI in radiology screening. There's personalization happening along choice within relatively comparable drugs in a class. There's choice and personalization on biomarkers and the new tests and diagnostics required, but also the new biomarkers that are coming out.

Then there's personalization around patients on goals and the subtleties around side effect profile and overall benefit. So there's personalization happening kind of across many, many dimensions and we're just talking breast cancer. So at some point we would, I imagine that we'd need to replicate this conversation across the different types of cancers because many of these themes most likely got across all cancers as well.

Dr. Blayney (57:31.182)
Yeah, right. I agree. So the metaphor, I'm on this side and I'm excited about the progress we've made and the potential for future progress in right sizing. And you're on the other side and a recipient or representing a potential recipients of advice and thinking about what

the considerations that are. So, you know, it's really cool. Some of these are ready for prime time. Some of these will be in the next few years. I think the CDK 4/6 that we talked about, the antibody drug conjugates we've talked about, and the deescalation, again, in the right patient. So the deescalation is not applicable to every woman with DCIS. Yeah, so some of these are...

not applicable to everyone, again, it's a finer and chopping up's the wrong metaphor, but divide into smaller and smaller subsets.

Samira (58:48.274)
beautiful. Thank you Dr. Blayney. That was such an incredible episode. As usual, I'm walking away learning a lot. So thank you.

Dr. Blayney (58:50.401)
All right, Samir.

Dr. Blayney (58:54.914)
Me too. Thanks. It was great to interact with you and I hope our viewers get to give out as much as I did. So thanks and goodbye.