Research With Immediate Impact at 2023 SABCS

This podcast episode is made possible in part by a grant from Lilly.

Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here's your host, Breastcancer.org Senior Editor, Jamie DePolo. 

Jamie DePolo: Hello. I’m Jamie DePolo, senior editor at Breastcancer.org. I’m podcasting live from the 2023 San Antonio Breast Cancer Symposium. I’m joined by Dr. Matthew Goetz, a noted breast cancer researcher who is professor of oncology at the Mayo Clinic where he also holds the Erivan Haub Family Professor of Cancer Research Honoring Richard F Emslander, MD. He is also enterprise deputy director of translational research and director of Mayo Breast SPORE [specialized programs of research excellence].

He's going to tell us about the most applicable research that was presented at this year’s conference. Dr. Goetz, welcome to the podcast. Thank you for helping us put all this information into context.

Dr. Matthew Goetz: Jamie, thank you very much. 

Jamie DePolo: So, to start, when you start seeing patients tomorrow, Monday, did anything you heard here this week, is it going to change what you do and say to your patients?

Dr. Matthew Goetz: There was a number of presentations that I think are very, very important. Testing new drugs, and I think those drugs are going to clearly make their way into the clinic, but it’ll take some time.

So one of the very important presentations was with regard to the checkpoint inhibitors, pembrolizumab [brand name: Keytruda] as well as nivolumab [brand name: Opdivo}. And these are drugs that have been studied extensively in triple-negative breast cancer, but thus far when they’ve been tested in patients with ER-positive breast cancer or estrogen-receptor positive breast cancer, there’s been some uncertainly about their benefits. Certainly really no real evidence of benefit in the patient’s metastatic disease. 

So, what they did in these trials was they studied these drugs in patients who have a new diagnosis of breast cancer but very high-risk features. So, ER-positive breast cancer where the tumor grade was very high, grade three, or perhaps in patients where grade two where the Ki-67 was high, and in general many of these patients had very low amounts of estrogen-receptor.

And essentially what was found, and this was presented originally at ESMO and updated here, was that we’re seeing that the addition of these checkpoint inhibitors such as again, pembrolizumab or nivolumab, are leading to very large improvements in what we refer to as pathological complete response. That is, complete eradication of the cancer in the breast and in the lymph nodes.

And so, now as we think about this, one of the questions, of course, is will this translate into better long-term outcome? Not all drugs that improve pCR actually eventually reduce the chance of breast cancer coming back, and so, this is something that we will anxiously wait as time goes on.

Another study that was presented today, which was a late-breaking, was a drug that is called inavolisib, and this particular drug is a PI3 kinase inhibitor, and this drug has kind of been a little bit under the radar. We’ve known about it for a while, and the trial that was reported today was a trial that focused on a group of very high-risk patients. So, these are patients that had received an aromatase inhibitor or tamoxifen as adjuvant therapy. So, this is typically a woman who’s taking tamoxifen or an aromatase inhibitor after a diagnosis of breast cancer, and of course, the goal is to reduce the chance of breast cancer coming back.

So, these are women that are actually progressing on the aromatase inhibitor so, they’re taking the drug and the tumor is growing. And so, in this trial these patients received a standard of care approach which would be the drug palbociclib along with fulvestrant, and then they were randomized to either receive this PI3 kinase inhibitor or not. And what was reported today was a remarkable improvement in what we refer to as progression-free survival.

And I do want to clarify, in order to get onto the trial women had to have a PIK3CA mutation. Their tumor had to have that PIK3CA mutation, and most of these patients had the tumor detected in the blood stream through something we call circulating tumor DNA, a very standard test that we do right now in the clinic. And we know probably about 30, maybe 30, 40% of patients in this situation will see this alteration in the blood stream.

And so, there was a couple things I would note about this. Number one was, when patients have this alteration and they’re progressing on the aromatase inhibitor, their treatment with the fulvestrant and palbociclib was just not nearly as good as we’d like it to be. It was in that range of somewhere between seven, eight months or something like that in terms of time before the cancer progressed. But what we saw was that the addition of this drug, inavolisib actually more than doubled progression-free survival. And there’s an early trend towards we’re seeing slight improvement in overall survival. 

So, wow, was this exciting because now what we’ve done is we’ve identified a really high-risk group of patients and not getting the standard benefit from the treatments that we use right now, and this looks like it’s going to be a really important addition to our armamentarium.

Jamie DePolo: I did want to ask you a question about that because right now we have Piqray, and I cannot say the chemical name for that so, I’m going to call it by its brand name, that’s approved in that, for those tumors with the same kind of mutation. But from the patients I’ve talked to, the side effects are really kind of nasty, and I noticed in the presentation, it sounds like the mechanism of action for this new inhibitor makes it that the side effects are not quite as severe like, there’s still rash, there’s still diarrhea, but it’s not quite as severe as it is with Piqray. Is that correct?

Dr. Matthew Goetz: Yeah. That’s a really good point. And so, this drug because it has a little bit of a different mechanism of action, actually can lead to degradation of the p300 protein which is the mutated PIK3CA protein, and so, it also inhibits the kinase but it also has this additional mechanism of action. Maybe at least one of the reasons why there is exactly as you said, a little bit less toxicity, and certainly we know that alpelisib is a good drug from the standpoint of efficacy, but you’re absolutely right. It’s a hard drug for most of our patients to take, and if you have any tendency towards fasting hyperglycemia or, you know, type one or type two diabetes, it’s just a no go for many of our patients.

And even for patients who don’t have that, you know, if you don’t run into problems with hyperglycemia, you run into problems with the rash as you mentioned, or the issues with diarrhea. So, it’s not that we didn’t see those side effects with the inavolisib, but what appears that it was number one, it was much more tolerable, and patients were staying on the drug. So, that’s I think all that being said, this looks to be like, a very important finding, both from efficacy but also tolerability as you said. 

Jamie DePolo: Great, and then so, what else really caught your eye or ear here at the conference this year?

Dr. Matthew Goetz: So, I think a very important study that was presented yesterday was the NSABP or NRG B-51 trial, and this gets into the whole issue of de-escalation. And by the way, I think this is just as an important question for our patients as is escalation. And one of the things I’m so excited about from being in the area of cancer research is, you know, it’s not always about escalating therapy. De-escalating therapy is also important. 

Let me just explain what was done in this trial. These are patients who have a diagnosis of breast cancer who are receiving a standard neoadjuvant-based chemotherapy, and we know that we’re seeing many people actually achieve what’s called a pathological complete response. And what we know, of course, is that in the past when patients would present with a diagnosis of breast cancer in the breast, let’s say it involved the lymph nodes, that the decision to give radiation or not has always been based on the initial stage. 

And so, what this trial was looking at is well, let’s not base it on the initial stage, let’s base it on what’s left after those 20 weeks of chemotherapy. So, patients with this complete pathological response were randomized to receive radiation therapy, and specifically to the regional nodes. Now, if a woman had a breast conservation she would have received standard radiation, but the idea here was, do you need to actually give, you know, nodal irradiation? 

And of course, then there was a group of patients that did not receive radiation therapy, and again, just thinking about my patients, and I think the bravery for enrolling in these trials, you know, because you don’t know, right? And I think we have to convince our patients, and it’s difficult to say, listen, we think that this is an open question, we’re not sure. We’ve been doing this but we’re not sure. And again, what the data showed was as of right now there was just a… Dr. Terry Mamounas presented these data. There’s just no evidence right now that this regional nodal irradiation is actually leading to improved outcomes.

Now, I would say that the follow-up for this study is still early, but I would also say that, you know, for patients who have a diagnosis of triple negative breast cancer, most of the events are occurring in the first three to four years. So, I feel very confident about that group. I think it’s going to be the ER-positives where we’ll probably need a little bit more data before we feel more comfortable. But again, a very important finding and something that definitely affects how we practice on Monday morning. 

Jamie DePolo: Excellent. What else caught your eye?

Dr. Matthew Goetz: Well, something that definitely caught my eye because I had to present it, was something that I really enjoyed presenting, was actually the final overall survival analysis of the MONARCH 3 trial. And the MONARCH 3 trial was evaluating the drug abemaciclib so, one of the three CDK4/6 inhibitors. Many of you know that this drug is approved not only in patients who have metastatic disease, but also in the adjuvant setting to be able to prevent recurrence.

And so, this trial actually started a while ago, actually in 2014, 2015. In 2017 we got a very early, very strong signal that this drug had really an incredible result in terms of prolonging progression-free survival, and that ultimately led to the FDA approval of this drug and ultimately global regulatory approval. But we’ve been waiting for the final survival analysis, and what I presented was the final overall survival analysis. So, 493 patients that were randomized to receive either abemaciclib plus an aromatase inhibitor, or a placebo plus an aromatase inhibitor. 

Again, I think about the women that go onto these trials and their bravery for doing this. I mentioned a trial where the intervention didn’t help, here’s a trial where the intervention did help. 

So, the final overall survival demonstrated that the addition of abemaciclib prolonged overall survival by about 13 months, it was actually 13.1 months. It didn’t quite meet statistical significance, so what does that mean? It means that in the trial we’re seeing a very large, in fact, the largest difference in overall survival of all the CDK4/6 inhibitors, but the trial was underpowered. What does that mean? It means it was relatively small. And so, we saw an approximate 20% improvement in overall survival, and in patients specifically with visceral disease, these are patients that tend to have worse outcome, we saw almost a 15-month improvement in overall survival.

So, the take home point from this I think, from my perspective is, this study didn’t quite meet statistical significance, but I also can say, we can look at the flip side and say, how confident are we that this 13-month difference is actually true? And it’s a nearly 95% chance that we think that that is true. There’s a small chance that it may not be.

But then I also tell, I’ll look at the data and I look across all the studies and so, I will say, okay, how has abemaciclib performed in the second-line setting? Same thing, it improved overall survival. How does it perform in the adjuvant setting? Well, it substantially reduces the risk for recurrence.

So, I think what we can say with this presentation and from the data I showed is that there is a very consistent effect of the drug overall. And again, it provides, from my standpoint, a lot of reassurance, and certainly continues to reinforce the notion that these drugs are a very important part of the armamentarium for our patients with breast cancer, and I’m excited to tell my patients that, you know, we’re giving drugs now that are improving survival by well over a year now compared to where we were when we started this back in 2015. So, it’s really good news for patients.

Jamie DePolo: Absolutely. And as you say, overall survival is so important because we do…sometimes the study results come in and we have, you know, two years of data, five years of data, the overall survival data isn’t ready yet, and you know, improved progression-free survival, the time until the cancer grows, that’s great. But if it doesn’t improve overall survival I think sometimes patients are like, well, you know, I don’t know.

Dr. Matthew Goetz: You know, I think this is right, and ultimately, you know, if I were to sit with a patient in the office and say to a patient that I have a drug that’s going to prolong the time until the cancer progresses but it’s not going to make you live any longer, she might be saying, what’s the value of that drug, especially as you know, these drugs are very expensive. 

So, I think what we can see very consistently now is that with the drug ribociclib and with the drug abemaciclib that we’re seeing that these drugs are improving overall survival. I would say this. I think as the outcomes improve for our patients, which is a really good news, it becomes harder and harder to be able to show overall survival differences, and people always say well, why is that? And it’s because, you know, it takes very, very large numbers of patients. In this case, this was a nearly 500-patient trial, and technically if we were to do that same trial again and we were to think back and say we’re going to specifically look at survival, we probably would have enrolled more like, 700 or 800 patients. And so, the number that’s needed to be able to show these difference becomes very, very large and so, it’s one of the challenges that we have. 

And I would say also, our job as researchers is to do exactly what was just done today in that inavolisib trial, which is to focus on the highest-risk patients, those patients who are, you know, clearly no matter what we do they’re doing poorly, and I think if we do that we’re going to be able to show improvements just like, was shown today, and I think that’s really exciting for patients. 

Jamie DePolo: Dr. Goetz, thank you so much. This has been really helpful.

Dr. Matthew Goetz: You’re welcome. Thank you.

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