Management of Breast Cancer: Information for Cardiologists
Dr. Shah: Joerg, you have been a leader in this emerging field of cardio-oncology, and I wanted to get a sense from you because it seems like quite a few breast cancer therapies have implications for the cardiologist. Could you give us an overview of which therapies have what kinds of implications for the heart?
Dr. Herrmann: Yeah. Thank you, Aman. I would be more than happy to provide this information because, looking back, a history of chemotherapeutics and the waves of attention cardiotoxicity has received. It started out in the 70s with anthracyclines and then at the turn of the millennium, we had a second wave and that really drove the entire field which was driven by the observation that trastuzumab, an antibody directed against a human EGF receptor 2, when given in close temporal proximity to anthracyclines, led to heart failure. Not just cardiac dysfunction, heart failure rate of nearly 30 percent at times, life-threatening.
That was a major game changer in especially the breast cancer group and ever since, now, for any HER2-directed therapy trial, there had to be echocardiograms to follow patients along and that was for the first time we were included, the cardiologists, in monitoring these patients and that really as indicated was a huge boost to this whole cardio-oncology concept and field, cardiologists working with oncologists, and vice versa.
Now, what was found to be the case or conceptualized, I should say, early on was that anthracyclines and trastuzumab would lead to two different types of chemotherapy-induced cardiotoxicity. With anthracyclines, it would be damage to the heart. True injury. With trastuzumab, it would be a dysfunction. So, no structural injury, no permanent damage, and the thought that was once you hold the drug, their cardio function would recover, no permanent damage, you could re-stress them, and these patients would be just fine. Limited to the time of exposure would only be the cardiac risk.
Dr. Shah: And did that turn out to be true?
Dr. Herrmann: Yeah, so in the randomized clinical trials, for instance, there was the HERO trial, that was true there. The event rate in the sub-studies for cardiac events plateaued. At the time, the trastuzumab therapy was completed, but that was in marked contrast to what we’ve seen now in multiple registry-based studies. It started out with the SEER database. That was a few years ago, published in JACC, and I remember how angry our oncology colleagues were with those data showing that the risk of heart failure over the 3 years to follow was marked higher with trastuzumab than with anthracyclines, and was highest in the combination group, and they argued that this was claims data and who knows how accurate this was. But then, surprisingly, the cancer research network forwarded an analysis that showed the same. And anthracyclines were on the same level as just other chemotherapies. Trastuzumab alone had a higher risk and the highest was, again, in the combination anthracycline/trastuzumab therapy group.
And now, just last week, as we report in PracticeUpdate, a registry study from Denmark showed the same, that a much higher risk over time persisting twofold after 18 months and 9-fold higher risk within the first 18 months after diagnosis for patients treated with trastuzumab and anthracyclines versus just chemotherapy alone. So, that is in a marked contrast to the initial concept in that the type 2 injury with trastuzumab with dysfunction would really be a benign version and not to worry about. So, we’re now entering a stage where we have to rethink this.
Dr. Shah: So, that’s the clinical trial data. Now, at this point, if you were to just give a sort of bulleted instruction, for which breast cancer patients should a cardiologist be part of the care team? And second, what should the cardiologist be doing in terms of monitoring those patients? What’s the simple instruction that we can pass on to our community?
Dr. Herrmann: Yes. So, what I pass on to the oncology community is that underneath the breast is the heart on the left side on the chest, so it’s right there even if you don’t see it, and you should start thinking about it even before therapy. And I think a useful concept here is the multiple hit theory. And as far as underlying baseline cardiovascular risk factors, hypertension, diabetes, as you add all of these up, they can all reduce the cardiovascular reserve of the patient as they then undergo cancer therapy. So, that’s, I think, is the first step. To think about the patient-related risk factors and do they bring a lot to the table, and then what kind of therapies are we giving? Are we giving anthracyclines? Are we giving trastuzumab? So that’s the first important step. And if the risk factors add up, maybe not just by themselves but if they add up, then these patients should be followed with echocardiograms.
They should have a baseline echo so we know what the reference is because sometimes we’re in these scenarios where, lo and behold, the patients may develop symptoms or someone decides to check an echo right into the course of the chemotherapy and then it’s reduced and we don’t know, was that preexisting or not. And particularly for trastuzumab, we’ve tried to define those young, healthy females with no other risk factors who can forego these kinds of surveillance recommendations, but it’s really hard to do so.
So, we really feel that someone who goes on trastuzumab therapy, they should have a baseline and 3 months of the echocardiograms until they are completed with the chemotherapy. And then the American Society of Echocardiography would also recommend a 6-month follow-up in patients who had anthracyclines and trastuzumab, but then after that, after the 6- to 12-month period, there is really no guidance. And we do need these data as how to follow these breast cancer patients long term.
Dr. Shah: And we have the data for trastuzumab, but I expect that you would say be conservative. And also for patients who are only getting pertuzumab, still follow them with echocardiograms?
Dr. Herrmann: Yeah. It’s usually given in combination.
Dr. Shah: So, virtually all HER2-positive patients should get baseline echocardiograms and be followed up. And that seems like a big change.
Dr. Herrmann: Yeah, and it’s also, we’re integrating in these echocardiograms, strain analyses. And there is some data showing that this would indicate at least three months earlier if someone is in the direction a drop of ejection fraction. And obviously, the goal is to detect this, and to avoid that they progress further to heart failure symptoms but no one knows how to react to an abnormal strain.
So, what do you advise? So, if you’re in that situation, would you say stop therapy, start cardiovascular medications, or just don’t do anything? Just wait until EF drops?
We’re now starting a clinical trial, NIH funded, at Mayo. It’s called TACTIC because we really don’t know the right tactic for these patients. It will have three arms. One will be the standard, which is wait and see right now until the EF drops. The comparator group, one comparator group is reacting to an abnormal strain or high sensitive troponin elevation. And the first arm is to use just a preemptive approach, to assume that these patients are at risk and we’re not really able to accurately tell. So, carvedilol is the intervention. And then we also try to address not only these two questions, do we need prevention for trastuzumab cardiotoxicity as that reached more attention now, and when do we start it, but also when do we stop it because patients ask.
I mean, I’m done with my cancer therapy, presumably, what I’ve told you earlier, the risk period is over, but can we stop it, but then we have all these other registry-based data indicating that the risk might persist. So, the study will also look at another year or not of carvedilol therapy after everything is said and done and thought to be good.
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