Jose Baselga, MD, PhD: BOLERO-2 Findings Confirm Efficacy of Everolimus Plus Exemestane
Dr. Jose Baselga discusses the exciting data for the HER2-negative breast cancer patient — the BOLERO-2 trial released at the CTRC-AACR 34th Annual San Antonio Breast Cancer Symposium.
Dr. Baselga is the Chief of the Division of Hematology/Oncology, Associate Director of the Massachusetts General Hospital Cancer Center and a Professor, Department of Medicine, Harvard Medical School.
The Group Room at the 34th Annual CTRC-AACR San Antonio Breast Cancer Symposium was made possible by support from:
VIDEO TRANSCRIPT:
Selma Schimmel, Founder & CEO, Vital Options International:
Hello and welcome to the group room where we’re at the 34th Annual CTRC-AACR San Antonio Breast Cancer Symposium. I’m very happy now to be joined by Professor-Doctor Jose Baselga, the Division of Hematology and Oncology and Associate Director of the Massachusetts General Hospital Cancer Center in Boston. You are also a Professor of Medicine at Harvard Medical School. And you are the star at this San Antonio Breast Cancer Symposium. You’ve got some very exciting data to talk about. What have we got going for the Her2-Negative metastasis patient?
Jose Baselga, MD, PhD, Chief, Division Hematology/Oncology, Massachusetts General Hospital:
The work has been done on the estrogen receptor positive patients. So this is the group that we studied in Bolero-2. Now for patients with ER-Positive these are the tumors that express estrogen receptors. The backbone of therapy is hormonal therapy so classically we have inhibitors, we have Tamoxifen, we have Obestrim, so these tumors are sensitive to hormones. Down the line though, once patients failed one line of therapy and then they go to second line, and they fail second line, every time the benefit of therapy is shorter.
And the biggest problem that we had for decades is the issue of endocrine resistance. Those tumors, that did benefit from anti-estrogen therapy for a while, stopped responding. And this was like the Holy Grail, in my mind, of therapy with ER agents. We had made no entrance whatsoever in understanding and applying the mechanisms of resistance to anti-estrogen. And here comes Everolimus. So we had known for a number – Afinitor is the official name…..
Selma Schimmel:
Right, and it has a background as an anti-immunosuppressant agent….
Jose Baselga, MD, PhD:
Correct. It is an immunosuppressant but the [INAUDIBLE] cancer is another one. That is a very important target in the cell that’s called MTOR. Now that is not a god from Scandinavia. MTOR stands for Mammalian Target of Rapamycin. M-tor is a critical note that signals in the cancer cell. Afinitor inhibits MTOR, so Afinitor prevents MTOR from working, if you wish. We had known for years that MTOR had the capacity to activate estrogen receptor and bypass the effects of anti-estrogens in experimental models, we knew that. So then the idea was served if MTOR is responsible, maybe, of resistance to anti-estrogens let’s try to combine a MTOR inhibitor to block that with an anti-estrogen, and that’s the basis behind Bolero.
Selma Schimmel:
If the agent was originally used to prevent the rejection of organ transplants, how does the scientist know the component – the biological component – where you even begin to put the pieces together to know that it could have efficacy in the breast cancer setting? Is it because it has antigenic properties?
Jose Baselga, MD, PhD:
Because in the lab you can really dissect the multiple activities of MTOR inhibitors so you can work in breast cancer models and you can clearly identify and separate the immunosuppressant effects from the growth inhibitor effects from the anti-estrogen effects from the antigenics. We have models that are so good that we can manipulate them to our advantage to understand what is really going on, and this is what happened with MTOR. So we were able to identify in the lab that it did hit the ER-Positive cells.
Selma Schimmel:
Quite brilliant.
Jose Baselga, MD, PhD:
Yeah. I mean this is worked by many people, and this is so absolutely brilliant. I came to this absolutely fascinated; I understood nothing of MTOR but when I saw it I said ‘this is fantastic’. And I was so attracted to this that I did the first in human trial with Everolimus, with Afinitor. I did the phase one study and then I did the phase two study, and now I’m doing the phase three. And the more you know about the molecule and the concept the more attractive it is. It’s a critical mediator of the cell.
Selma Schimmel:
It’s combined yet with another drug, the Aromasin…
Jose Baselga, MD, PhD:
Right.
Selma Schimmel:
…can you expand a little bit on how this combination works?
Jose Baselga, MD, PhD:
In tumors that express the estrogen receptor, the estrogen receptor is what drives growth on those tumor cells, so it’s the driver. For many, many years, the dominant way by which the estrogen receptor becomes turned on is by estrogen binding to the receptor, that’s why it’s called estrogen receptor. So the strategies that we devised – by we, I mean the community – were mostly to prevent, either the protection of estrogen so if you don’t get estrogen you don’t bind into the receptor, and you don’t turn it on – that was our strategy – Or two, and there’s Tamoxifen, lets prevent physically the binding of estrogen to estrogen receptors. So let’s make a physical blockade, and that works.
Selma Schimmel:
And this is an aromatase inhibitor.
Jose Baselga, MD, PhD:
The aromatase increases the levels of estrogen that combines into the receptors, so this works. Now when the tumor stopped responding to the aromatase inhibitors, and to Tamoxifen, we said the tumor was estrogen receptor resistant. That is wrong. The tumor does not any longer respond to estrogen suppression, but the estrogen receptor continues to be working, and it’s working via an alternative patterns. Something else is activating that receptor.
So you see, it was a misconception – these tumors are not estrogen receptors resistant. They are likened, they are estrogen independent, which is something that occurs also in prostate cancer, it’s the same principle. So then the next thing is, if estrogen is not activated in this receptor, what’s activating the receptor? And that’s where MTOR comes in. So MTOR is perhaps the most important – or one of the most important activators of the receptor that is not independent on estrogen. So now, and the last component that we have to understand – to see why the combination is so active – if you block MTOR the receptor signals that MTOR is being blocked and then estrogen signaling gains importance, and estrogen signaling rescues the cell from the depredation of MTOR. So the cells have waste without.
This is like you have a car that is a hybrid – it goes by gas, it goes by electricity – you shut down the gas, no problem, the electricity kicks in. So this is a hybrid system, and the opposite is true. You block estrogen, and MTOR goes up. So we identified that it was this adaptive responses that were playing against – basically in favor of the cancer cell – the cancer cell is very smart. They have ways to reactivate. So that was the moment when the idea came said we are not going to make any headway until we block it together, and that was the basis. And then if you brought them together you’re basically leaving the cancer cell without any repertoire to survive. And that is the principle behind this combination.
Selma Schimmel:
And there are other aromatase inhibitors. How did you come to discover this was the correct combination?
Jose Baselga, MD, PhD:
I’m not sure it’s the correct combination. I think, frankly, that this could apply to the other ones. We use it, this one, because this is the inhibitor that is used most frequently in this clinical setting. But I am convinced, actually I am sure, this would apply into other aromatase inhibitors, and we know for a fact that it also applies with Tamoxifen. It was a small but very important French study that was in San Antonio last year called [INAUDIBLE], in which they also combined Afinitor with Tamoxifen, and they observed very similar data. So I think there’s a universal thing is just a concept that blocking estrogen-dependent receptor activation and non-estrogen dependent, the two things that’s winning formula, if you wish.
Selma Schimmel:
And what’s interesting is in reading the information, the word ‘duo’ keeps coming up. Duo-attack, duo-combination, and this word, ‘duo’ is very significant.
Jose Baselga, MD, PhD:
And that’s going to be the way of the future. It’s unconceivable to me that by just blocking one pathway, you’re going to get rid of the cancer. They are smarter than that. You have to duck more than one way, and the concept of duo-approach, if you’re smart about it – I mean if you’re lucky and you can target two pathways that are important, the results are much better.
Selma Schimmel:
So Cleopatra’s now going to be looking at the use in the adjuvant setting. What’s the next phase for Bolero?
Jose Baselga, MD, PhD:
With Bolero, first of all, the Bolero results are also practice changing because we more than doubled progression-free survival in patients that were in second, third line of therapy. So Bolero on its own it’s again, practice-changing right there. Now with Bolero, we would love to go earlier in the disease, we would love to go to the first line setting, and we would love to go into the adjuvant setting as well. So we are talking about that. But Bolero has another thing, if I may, that to me is more appealing, and this is the first time that we break on estrogen-resistance. So this is the first opening of the door. And this has – scientifically it has the most power because that is telling us that this is a direction that we have to go. And I’m telling you we have drugs that are even more exciting down the line. So now we have PI3-Kinase inhibitors that are perhaps better, we have duo – again PI3-Kinase, MTOR inhibitors, we have AKT inhibitors – so with what we know now that this is functioning, I’m telling you, we will have better drugs, we will have better ideas. So I am very positive these are going to be a sea of change in the way with the things in breast cancer.
Selma Schimmel:
Thank you so much. I mean you’re the lead investigator in all of this for taking the time on such a busy San Antonio meeting to come and even talk to us, but the sense of pride and just your passion and happiness must be quite overwhelming for you right now.
Jose Baselga, MD, PhD:
It is. It’s been the work of the community. There’s been so many people working on this and the struggles, I mean it’s been so global – thousands of women from around the world. It’s really a global effort so it’s a very good time, I think for all of us to celebrate this.
Selma Schimmel:
Well, your reputation is wide and vast. You’re pretty famous guy and you know it’s been a real privilege working with you, former president of ESMO and you’re just one of these non-stop oncology researchers and it’s a real privilege to know you.
Jose Baselga, MD, PhD:
Thank you.
Selma Schimmel:
Professor-Doctor Jose Baselga, Chief of the Division of Hematology/Oncology, Associate Director of the Massachusetts General Hospital Cancer Center in Boston, where you’re also the Professor of Medicine at Harvard Medical School, and I know they must miss you a lot in Europe.
Jose Baselga, MD, PhD:
I miss them too but I go very frequently.
Selma Schimmel:
I would imagine. Thank you, and enjoy the rest of your day.
Jose Baselga, MD, PhD:
Thank you.
END OF VIDEO