2022 SABCS Key Takeaways

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Jamie DePolo: Hello. Thanks so much for listening. The 2022 San Antonio Breast Cancer Symposium featured five days of research presentations, educational sessions, and posters. The amount of research presented is a little overwhelming, which is why we've asked Dr. Stephanie Graff to help us break down the key take-aways for people who've been diagnosed with breast cancer.

Dr. Graff is the director of the Breast Oncology Program at the Lifespan Center Institute at Brown University and co-leader of the Breast Cancer Translational Research Disease Group. In addition, she serves as a medical adviser to the Dr. Susan Love Foundation for Breast Cancer Research. Dr. Graff, welcome to the podcast. 

Stephanie Graff: Thank you. It's so good to be here.

Jamie DePolo: So, from your perspective, what was the most applicable research presented at this year's conference?

Stephanie Graff: So, San Antonio Breast Cancer Symposium 2022 is sort of the year of updates. I can't tell you that there's a big standing ovation moment like we had at ASCO 2022, but years like this are really important as well. Because things that are important to us treating breast cancer is not just that we get a great first response, but that we get durable responses, that what we do lasts, and that what we do is safe, not just today, but for a long time. So, we're getting like 12-year follow up on studies, and that's exciting. It's cool that in breast cancer, we follow people for 12 years because not all cancers can say that. But it also doesn't make for a big splash.

Jamie DePolo: But still, if you want it...so what was, I guess, rather than most applicable, what was most interesting? Yeah, let’s go with that one. 

Stephanie Graff: Yeah, I think...so I think maybe the biggest splash or the biggest practice-affirming, practice-changing, is just updates on the monarchE study.

MonarchE is a trial that randomized patients with hormone receptor-positive, so estrogen receptor-positive, or estrogen and progesterone receptor-positive, early-stage, but high-risk breast cancer. So, patients treated with the goal of curing their cancer, many had positive lymph nodes, most had larger tumor sizes, most received chemotherapy. And those patients were randomized to either receive endocrine therapy, like we would give patients normally, or endocrine therapy plus abemaciclib. Abemaciclib as a CDK4/6 inhibitor, that's our standard of care, so you, the CDK4/6 inhibitors are a standard of care in metastatic breast cancer. 

So, this is asking, does giving these drugs earlier make a difference? They’re oral. Abemaciclib's brand name for those that are following the TV commercials is Verzenio, and in the monarchE study, patients took Verzenio for two years. And we've already seen the results of this study, and already have an FDA approval for abemaciclib in this setting, in curative intent, early-stage, high-risk, hormone receptor-positive breast cancer, and...but when we got the approval, the data was still early, so when they approved it, they put some caveats around it, that only certain percentages of the people that were originally on the study got to take the drug, and this gave us this longer term follow up. 

Jamie DePolo: So for the approval, what was the follow up? And then what was this follow-up?

Stephanie Graff: Yeah, so this follow up on the...because you took the abemaciclib for two years, on the first follow up that we had, a bunch of people were still taking the medicine. So, the question was, is it really that the medicine is going to kill cancer, or stop it from coming back, or is it just that we still have our finger in the proverbial dam? And that was one of the big criticisms, was that it was such an early data analysis, that the FDA, when they reviewed it said, well, gosh, maybe the problem here is that the only data that was mature was patients that also had something called a high Ki67. 

A Ki67 is a proliferative rate, it kind of can tell us maybe how quickly that tumor is growing or changing. There’s all sorts of problems with Ki67s. So, that created quite a controversy in the world of breast cancer, and there was a lot of disruption and conversation in the world of breast cancer doctors about whether we should really only prescribe it to people with that high Ki67, like the approval, or whether we should give it to everybody, which is really what the trial was designed to do. So, that first analysis that was reported, was at 24 months, and this longer follow up that they're giving us is at 54 months or 48 months of follow up, so we're getting much longer follow up. 

Right now, as we've seen, we saw an improvement in invasive disease-free survival, which means you are less likely to have your cancer come back anywhere in your body, including in your breast or somewhere else -- which is obviously the really bad things we don't ever want to find -- by 33%, which is huge. A one-third reduction as compared to the other...the patients who did not receive the abemaciclib.

And the nice thing about that invasive disease-free survival benefit was that it was persistent over that longer term of follow up and we actually see the curves continue to separate. And so what we thought was that if it was just that the pill was holding our finger in the dam, the benefit wouldn't keep widening. If anything, it would start to close, or it would stay at exactly the same level as people stopped taking the pill at two years. 

So, this is a really promising sign. The overall survival, which is, you know, the...

Jamie DePolo: Gold standard. 

Stephanie Graff: Gold standard. We're trying to shoot the moon here, that we're reaching for isn't met yet. So, we still need longer follow up to be able to get to overall survival, but the fact that at four years of follow up, we're starting to see those curves divide, tells us that hopefully, we're going to get there. 

The other nice thing that we see on this follow up is that that benefit wasn't just in the high Ki67 set. We start to see the benefit in the whole intention to treat population, so now we'll have to see if we see some change in the way that that approval language was set. But I think that, especially for me as a prescriber, it gives me a lot more comfort in how I'm going to use the medication for my patients.

Jamie DePolo: So, it sounds like it potentially is applicable for anyone diagnosed with high-risk, early-stage hormone receptor-positive disease.

Stephanie Graff: Exactly. Exactly. On the flip side of the hormone receptor-positive breast cancer story, we saw the 12-year follow up on studies like TAILORx, which showed us that tests like the Oncotype DX Recurrence Score, are really, really effective at predicting who does not need chemo, which is awesome. Because a bunch of patients don't need chemo with hormone receptor-positive breast cancer. 

Other updates we got were on the trastuzumab deruxtecan story, the brand name of that is Enhertu. Obviously, that was the standing ovation drug of ASCO Annual Meeting 2022 because it treated HER2-low breast cancer.

Trastuzumab deruxtecan is, also, treated...is also approved for HER2-positive breast cancer, so it’s now kind of running rampant in the world of breast oncology. We’re just giving it to everybody, it's like water, let’s pass it out everywhere, let’s try it everywhere. So, we got longer term follow up both in the HER2-positive metastatic setting and in the HER2-low space. The take-home message of both of those updates was this is a great drug. It's highly effective, the safety signal doesn't change, and I have told, you know, they had hit such a home run with that first data that follow up on their data is like, yeah, well, you know, we already know you were great, so...

Jamie DePolo: But it did suggest...I know that, again, the overall survival, the median wasn't met, but it looks like with the percentages, that it was in favor of Enhertu and it seems like that's going to be there as well.

Stephanie Graff: Yeah, and that really is just sort of the way statistics work. But sometimes when we analyze data, we're just not over the magical threshold that we need to get to that overall survival benefit, but it's hard to imagine that it won't cross that needed threshold statistically. One of the quotes I use all the time in my cancer clinic is Mark Twain's, that there's three kinds of lies: lies, damn lies, and statistics. And we see a lot of statistics here, and that's one of the maybe favorable examples that we'll get there. 

The last hormone receptor-positive story that I thought was really interesting, was the RIGHT Choice study, which looked at ribociclib plus endocrine therapy, as compared to chemotherapy, which is not something we see very often in patients with visceral crisis.

Visceral crisis means that you have breast cancer that has metastasized or spread to organs, like lung or liver, in a way that is threatening that organ to stop working. So, it has made your liver enzymes very high. It has threatened your breathing. It has caused abdominal pain. In 2022, there are some tighter rules around how we use that language than at the time the RIGHT Choice trial was designed. So, they used sort of a looser definition of what visceral crisis meant. There’s no official definition of rapid progression, that is very subjective, so one of my criticisms of this trial is that...my guess is that patients maybe weren't as sick in real life as they potentially sound on paper. 

But nevertheless, when we compare the patients that went on the RIGHT Choice trial, where they were randomized, again, to ribociclib, which is a CDK4/6 inhibitor, plus endocrine therapy, versus chemotherapy, with, you know, bulky, rapidly progressive, potentially visceral crisis, hormone receptor-positive, metastatic breast cancer to these two agents. These aren't patients we've ever given CDK4/6 inhibitors to before. When we look at the CDK4/6 inhibitor trials, historically, we see high numbers of patients that are older, 65-plus. We see high patient numbers of bone-only metastatic disease. We see patients that often are completely asymptomatic from their metastatic breast cancer, eligible and enrolling on those trials, and this RIGHT Choice trial, just by the very presence of bulky, aggressive visceral disease, these are patients that are sick with their breast cancer. 

And what we saw was that the CDK4/6 inhibitors worked. It improved. Their progression-free survival was much better with the CDK4/6 inhibitor than chemo, and although the chemotherapy patients responded a little bit faster. It wasn't faster, dramatically. It was faster, like a few weeks. Not in a way that would have made a difference in that person's long-term outcome, and the patients that got chemo didn't feel as good. So, I think that this tells us that even in visceral disease, even in bulky disease, even in progressive disease, even in young disease, because the average age of patients in the RIGHT Choice was in their 40s. Patients can do great on CDK4/6 inhibitors, and that's really bolstering to see. 

Jamie DePolo: So, can I ask you, there was a whole session, a debate on HER2-low breast cancer. Which I watched. I'm not sure what to think, but I’m not a researcher. You know, I thought very compelling arguments were made on both sides. It is a distinct subtype. It's not a distinct subtype. 

Stephanie Graff: Yeah. 

Jamie DePolo: What's your take?

Stephanie Graff: Yeah, so there was a brilliant, like you said, brilliant debate on the HER2-low entity. And fascinatingly, it was a pro-con debate, and one of the discussants used, actually my data, to support that it is a separate entity. That if you go and look at the poster, I...the conclusion on my poster, is that it's not. So, they did not reach the same conclusion from my own data that I did, which is fascinating.

So, HER2-low is imprecision medicine at its finest, in my and you did not mishear me, I said imprecision medicine, listeners.

So, HER2-low, just to sort of level set so that everybody knows, right now in breast oncology, we use immunohistochemistry, which is my big fancy doctor word that means we dump ink on your tumor and see if it sticks to define HER2 expression. And so we pour some ink on a slide and if there's no ink that sticks, you’re HER2-zero. If there's a little bit of ink, or a lot of ink, or like a whole lot of ink, you're a one, a two, or a three. So, this is like kind of a classic grayscale. And so we say if you're a zero or a one you're negative. If you're a two, you need extra testing done, and if you're a three, you’re positive. 

The extra tests we do for twos is called a FISH or a fluorescence in situ hybridization, and it's either positive or negative. And if you're positive, you're positive, and if you're negative, you're negative. And that creates an entity of HER2-low, where if you're a 2-plus with a negative FISH, or a one, you're HER2-low. And if you're a zero, you're a zero, and if you're a 3-plus you're a positive. So, we've sort of created this kind of middle category that just means you're on the grayscale.

And the truth is that the grayscale is probably much more of a grayscale than even those sort of nominal definitions that I just gave you. Right, and this all came into existence because of trastuzumab deruxtecan. And I think that what we have to understand is that trastuzumab deruxtecan may just be a highly effective drug. Trastuzumab sticks very well to its target, which is HER2. And so if you have just a tiny amount of HER2, which almost all breast cancer has a tiny amount of.

Jamie DePolo: Even if it registers zero?

Stephanie Graff: Even if it's zero. There's one or two freckles on that field of white that it might stick to. So that's the target for trastuzumab deruxtecan, then trastuzumab deruxtecan -- the deruxtecan is the chemo part -- and it's bound to the target, the trastuzumab part, with a linker. And that linker, once it's bound, let's go, which allows the chemo to be deployed to the surrounding area. And so...you know, I think what this tells us is that when the bumper car hits the other bumper car, it lets go, and the deruxtecan is a really powerful chemotherapy. And so, it's hard to know...there was a trial called the DAISY trial that took patients that had HER2 zero and gave them trastuzumab deruxtecan, and a substantial proportion of them did great with that combo. 

So, when we look at HER2-low, and we do all of this work, and the things that we consider are things like, if HER2-low were its own entity, wouldn't drugs, other than trastuzumab deruxtecan stick? Like, wouldn't Herceptin by itself stick? And the answer is no, it doesn't. We did that trial, it was negative. Wouldn't other genomic or biological signatures that we do, the molecular and genomic profiling that we can do, identify a pattern in HER2-low breast cancer in the same way it identifies patterns in HER2-positive breast cancer, in estrogen receptor-positive breast cancer, in triple negative breast cancer? And the answer is no, it doesn't. And that was...my paper looked at thousands of patients, and the answer was no, there's no pattern there. And so, you know, it doesn't have a unique treatment. It doesn't have a unique biological signature. And the next question is, wouldn't it have a different prognosis? 

And we've also seen between ASCO 2022 and now, updates looking back at all these other studies, we've done, looking at the CDK4/6 inhibitor trials, looking at the KEYNOTE studies and saying, well do the HER2-low patients do different with immunotherapy? Do they do different with CDK4/6 inhibitors? And the answer is no. So, if they don't prognostically do different with treatment, they don't respond differently to any drugs other than trastuzumab deruxtecan, they don't have a different biological pathologic signature. Is it that HER2-low is its own entity, or is it that trastuzumab deruxtecan is just a really special drug? And I think that that case is pretty simple, open and shut case for me, and it's not that HER2-low is a new thing. It's that trastuzumab deruxtecan is just special.

Jamie DePolo: Okay. Well, thanks for that, and then one final question. So, I know that...I'm going to call it Enhertu because I always have a hard time saying deruxtecan, but it's called an antibody-drug conjugate. 

Stephanie Graff: Yes. 

Jamie DePolo: So, basically, as you said, the antibody is the Herceptin...

Stephanie Graff: Yeah.

Jamie DePolo: ...that's targeting something in the cancer. 

Stephanie Graff: Yeah. 

Jamie DePolo: So, to me, it sounds like that's what we should be focusing on and making more of those. So is that where you, I mean, are studies looking at that?

Stephanie Graff: Yeah, and we're doing that. Yeah, we're doing that. So, you know, the other antibody-drug conjugate that we're using readily, FDA-approved in two different breast cancers is sacituzumab govitecan, Trodelvy, is the brand name, and that targets Trop2. Trop2 we also don't test for because it's everywhere and it actually doesn't matter if you have it or not, you still respond to Trodelvy, so everyone gets sacituzumab govitecan.

Sacituzumab govitecan is approved both for metastatic, triple-negative and metastatic, hormone receptor-positive breast cancer. There's some differences in response, but there's some differences in response in those diseases, right? So, you know, I think people have some variable enthusiasm for it in different settings. But you know what, their triple-negative breast cancer and hormone receptor-positive breast cancer are different, and so we should temper our expectations differently. And then there's emerging ADCs being developed and explored...most...probably up and coming the quickest through the pipeline is a drug called datopotamab deruxtecan. 

Jamie DePolo: That is a mouthful. 

Stephanie Graff: Right. Yeah, we'll do a spelling challenge at the end of this podcast. And you can call that one Dato-DXd until it gets itself a fancy pronounceable name. Yeah, and Dato-DXd, I keep lovingly calling it the love child of sacituzumab govitecan and trastuzumab deruxtecan. 

Jamie DePolo: So, what is it targeting? 

Stephanie Graff: Yeah. So, it is a Trop2 antibody with deruxtecan as the chemo. So, like sacituzumab govitecan, the antibody is Trop2. 

Jamie DePolo: Which you said is everywhere. 

Stephanie Graff: Which is everywhere, but like trastuzumab deruxtecan, the chemo is the deruxtecan. 

Jamie DePolo: And so, do you think that chemo is...it seems like it anyway, is better than what's attached…than the chemo in Trodelvy? Or more effective or maybe that's not the right question. 

Stephanie Graff: We have never compared...I have no possible way. We don't know. We don’t know. 

Jamie DePolo: Okay. 

Stephanie Graff: Yeah. They're just different. 

Jamie DePolo: Okay. Okay. 

Stephanie Graff: But now I think we'll move into a generation of asking, can we, or how do we sequence antibody-drug conjugates? Can you give target after target, or chemo backbone after chemo backbone? Right? Can you give trastuzumab deruxtecan after Dato-DXd because they're both deruxtecan? Can you give Dato-DXd with sacituzumab govitecan because they both hit Trop2? So, I think that someday we're going to emerge into a world where we're trying to figure out whether or not all of these players can be out on the dance floor together.

Jamie DePolo: And then I have one more question. This may be a dumb question, but I'm going to ask it anyway. Does it make any sense at all to target, say, an estrogen receptor?

Stephanie Graff: That's not a dumb question at all. So, the problem with antibody-drug conjugates is that if the target is highly selective, and you deliver the chemo to it, it's going to go everywhere that target is, so you have to ask where else the target is. 

Jamie DePolo: I see. 

Stephanie Graff: And unfortunately, as women, we express estrogen in lots of places, and you probably don't want chemo to go all of those places. so, it...the selectivity would be a problem. So, with antibody-drug conjugate development, some of our issues are: Is the receptor bindable? Because if it's an internal...like if...for some of our receptors, they're intracellular and we can't bind something that's inside of our cell unless we break the cell open first, and then that doesn't work...I mean, I can't break open a cell with the...we’ve got a problem. And then some of it is the selectivity of that receptor to the cancer, because that's going to change the side effect profile. If it's a receptor that's everywhere, and that moves into the sort of what our problems are with the TKIs [tyrosine kinase inhibitors]. So, medicines like EGFR inhibitors, part of the reasons that patients get terrible rashes, and mouth sores, and high blood sugars, and some of the things that we see with TKIs is that those receptors are everywhere. And so we're getting these very sort of systemic reactions because we're messing with the receptor that's in a lot of places.

Jamie DePolo: Okay. Thank you so much for explaining that and everything else that you did. This is great. 

Stephanie Graff: Yeah. 

Jamie DePolo: We appreciate your time.

Stephanie Graff: No problem. Thanks.