Dr. Kelly McCann:
Welcome to The ASCO Post Roundtable Series on Managing Cardiovascular Risk in Metastatic Breast Cancer: Clinical Insights on CDK4/6 Inhibitors. I'm Dr. Kelly McCann. I'm a breast medical oncologist and Assistant Professor at UCLA. Joining me today are Hope Rugo and Dr. Avi Guha.
Dr. Hope Rugo:
Hi, I'm Hope Rugo, a breast medical oncologist and Director of the Women's Cancers Program and the Division of Breast Medical Oncology at the City of Hope Comprehensive Cancer Center. It's a pleasure to be here.
Dr. Avirup Guha:
Hi everyone. My name is Avi Guha. I'm the Director of Cardio-Oncology at Medical College of Georgia and Georgia Cancer Center. I'm also Assistant Professor in the Division of Cardiology and Department of Medicine at Medical College of Georgia. It's great to be here.
Dr. Kelly McCann:
Today we'll be discussing the role that cardiovascular risk factors play in the management of metastatic breast cancer using three patient cases. Our second installment will focus on the use of CDK4/6 inhibitors in medically fragile patients with heart failure.
C.H. is a 41-year-old premenopausal woman with congenital heart disease status post multiple neonatal and pediatric cardiac surgeries, paroxysmal supraventricular tachyarrhythmias status post numerous ablations, congestive heart failure, and pulmonary arterial hypertension, who is diagnosed with de novo metastatic ER-positive, HER2-negative invasive ductal carcinoma in the bones and the liver.
Her past medical history is significant for asthma, hypothyroidism, and migraines. Her medications are extensive and include albuterol as needed, apixaban at 2.5 mg, budesonide, digoxin, fluticasone-salmeterol inhaler, levothyroxine, losartan, oxycodone, metoprolol, potassium, spironolactone, and tadalafil. Her genetics show a germline pathogenic mutation in BRCA2.
In the past year, she's been admitted six times to the cardiac intensive care unit for causes including arrhythmia, hypotension, dyspnea, abdominal pain, and infection. She has declined ICD placement numerous times in the past, but she is agreeable to ovarian function suppression and aromatase inhibitor and a CDK4/6 inhibitor for her breast cancer.
What are your considerations for CDK4/6 inhibitor choice in this patient in this very medically complex patient with heart failure?
Dr. Hope Rugo:
Well, I'll start out and I'm interested in your thoughts too, Kelly. This is a little bit of a balance between how long you're going to live with your various problems. She wouldn't be really a candidate for anything very aggressive in terms of her management.
You couldn't really tolerate any volume shifts and now that she has metastatic disease, you're not going to do a heart transplant, which presumably was discussed before and rejected. And maybe her other vascular issues like pulmonary hypertension made her less of a good candidate. And so then in thinking about ribociclib, she's on a whole bunch of drugs. I don't want to really worry about the QT interval.
And also I think any kind of perturbations like liver enzyme elevations where she might have some degree of right heart failure also would be problematic. So I think in thinking through all of those things, I would use palbociclib and see how she did with it. And I think normally, I would start palbociclib at full dose because it's very well tolerated in general, but this person is really pretty sick and pretty borderline.
So, I figure she's had arrhythmia, hypotension, she is short of breath, she's got abdominal pain, and she's had infections. So, I think I would start her at 100 mg for no rhyme or reason except for that she seems like you're treating a very much elderly person who's not going to tolerate things well. What would you do, Kelly?
Dr. Kelly McCann:
Oh, this was complicated because it's based on a patient case that I saw. She had her own concerns. One of them was becoming anemic because she could end up in the hospital. Nobody wants diarrhea, but at least that can be managed.
I was worried about putting her on abemaciclib and having her become dehydrated. So that was a consideration too. Ultimately, she decided to go on abemaciclib. But over time, that changed as she was hospitalized with diarrhea.
Avi, anything you would add to this case? Is this someone that you would see as a cardio-oncologist in your office?
Dr. Avirup Guha:
Yeah, so this is as I would even say this is a very complex patients, especially whenever somebody has a congenital condition for which they have pulmonary hypertension now, which means their surgeries worked but didn't work quite as well to prevent the eventual outcome, which happens in complex congenital heart disease.
So they should always be seeing a congenital heart doctor. So I would be co-managing the patient with them. Obviously, wouldn't have stepped into the picture until they developed cancer. So I would often take the help of my oncology and have a congenital person guide me as well.
But straight off the bat, just thinking about the volume status, I think diarrhea would make them a little bit drier, which is fine probably for somebody who has volume which they retain. So I would try to reduce some of the antihypertensives or heart failure medications for her.
She would likely have a right heart catheterization done right before initiation of any new therapy just to see what we are working with to guide everyone better. And I think this is a very good case of team approach where you would likely have to have a very close, not just a tumor board of oncologists, but a tumor board of cardiologists, oncologists, a real congenital and various providers, which includes pharmacists because of the polypharmacy she's dealing with at this young age.
So, I think that would be the approach I would take to make sure all our steps are safe and has somewhat of an approach toward prolonging life in a meaningful manner because she's right up in a tight spot.
Dr. Hope Rugo:
What dose did you start her on, Kelly? Because I would be nervous just because you said she was admitted with, I understand the neutropenia, that makes me concerned too, but at a lower dose maybe, and she was admitted with hypotension and things like that always makes me nervous.
Dr. Kelly McCann:
So her big concerns were about neutropenia after past hospitalizations for infections, concerned about anemia because she's dyspneic at baseline. And so I started an abemaciclib with a slow up titration. That was before-
Dr. Hope Rugo:
You think you started at 50 twice a day?
Dr. Kelly McCann:
Yes, I did.
Dr. Hope Rugo:
I think that's a really nice example of shared decision-making.
Dr. Avirup Guha:
Totally.
Dr. Kelly McCann:
So, let's say she comes into clinic 7 months later and she presents to clinic for a routine follow-up with worsening of dyspnea and let's say she's being seen in oncology clinic. What is your workup strategy as the oncologist. And then we'll throw it to cardiology, what's her workup from the cardiology perspective?
Dr. Hope Rugo:
Well, of course, it's going to depend on when her last scan was. So, you want to make sure she had liver and bone mets and we don't really know what's happened with her liver or bone, but you definitely want to make sure that she's not having progressive disease.
You want to make sure she didn't have a PE, which she would be at risk for. I don't know if she was on anticoagulation maybe, but even so I would get a CTPE and then that gives you some information about whether she's got a big pleural effusion also. And then of course, I would call the cardiologist and say, can you get her in for an echo really fast?
Dr. Kelly McCann:
Avi?
Dr. Avirup Guha:
So, as I said, I think I gave a little bit of a clue earlier. So I do a full cardiac exam. This is somebody you try to listen to. One thing, which I always tell all my colleagues who are, it's really cool, something I learned with a congenital doctor, they can tell what congenital disease a person has by the scars they have on their chest.
One of those times when you actually can open up their shirt and see the scars and that scar will tell you if you don't already know all their history in the chart as to what surgery they had. It has saved me a lot of trouble while finding somebody out in a non-adult congenital center, which ours is right now, where I can actually answer this question without calling my pediatric colleagues.
Then echo right away for LV/RV function and RV function more than LV function honestly, because that is going to be a lot of trouble with the volume, especially having the hypotension issue which she had. I measure peer pressures with an invasive right heart cath because we need to know that now even though she's on tadalafil and probably reasonably compensated given that I didn't see a pH admission, although she had the hypotension and volume, maybe that's not working as well.
And then a Holter event monitor because arrhythmias can really create a problem in this patient given history of supraventricular tachycardia. Also with the fact that once one of the CDK4/6 inhibitor goes in and Dr. Rugo mentioned that we can actually see arrhythmias even with palbociclib sometimes.
So it's not just a ribociclib issue. So that's something which we need to make sure we take care of and then just go back and forth with your oncology colleagues to tell them what you're doing because I think that communication is paramount in this situation.
Dr. Hope Rugo:
I have arrhythmias with palbociclib, but there is no association of arrhythmias with palbociclib per se. Just like with ribociclib, even though we see these QT prolongations that are enhanced in certain settings, there hasn't been any patient with Torsades at least documented.
So I think, I don't know that there is any association specifically with arrhythmias and they don't have primary cardiac toxicity. So that's helpful as well.
Dr. Kelly McCann:
I think for her in the setting of dyspnea, the CDK4/6 inhibitors, besides having a thrombotic risk, can also have risk too. So that was also on the differential for her when we were thinking about her being dyspneic.
For oncologists who don't have access to cardio-oncology providers, what would your recommended strategy be to manage this patient?
Dr. Avirup Guha:
So I'll go first and I'd want to see what Hope thinks as well. And also you, because this patient might not have had a little congenital cardiologist. So what I would do is just have a standardized CV screening tool, like the ABCDE approach. Like I said, it applies to everyone including her.
So I would do that, get it out of the way. And then early referred to general cardiology because general cardiology would be the keeper to a cardio-oncology mainly, sometimes some places at least. Then protocolized dyspnea workup, which has nothing to do with cardio-oncology, like you said, rule out PE, a chest x-ray for congestive heart failure.
The CT scan would also tell you about lung infection, anemia, if that needs treating. And then progression of the cancer, like the scan, which Hope mentioned. And then I think one of the very important things is Lexicomp or similar agents people use to quickly identify cardiovascular toxicities of agents and have that reference at hand so that while all this is happening and we are getting hold of a real human being, you can troubleshoot as in you see trouble coming through.
So that's what I would recommend, but you have actually lived it, so probably know what you would do when you don't have access to a cardio-oncologist.
Dr. Hope Rugo:
Lexicomp, not ChatGPT, really? There's a million of these now you can just talk into your phone and say, "What are the drug interactions here? What's the initial diagnosis for this?" And it’ll give you the references too.
But I think somebody has shortness of breath on a CDK4/6 and it was the one thing I didn't mention, you get the CTPE, you're also going to find out if they have ground glass opacities and have a pneumonitis interstitial lung disease. Very rare, less than 1% for the majority, maybe a little more common with the abemaciclib, but it's hard to know because that was really reported in the Japanese population that we know has a higher risk of drug-induced ILD/pneumonitis anyway.
And I have seen, I'm sure you have too, Kelly, a handful, 2-3 people who had a CDK4/6 inhibitor ILD. We don't hold for asymptomatic ILD though, only for symptomatic. So it's different from what we do for trastuzumab deruxtecan and generally it's reasonable to control.
I've skipped around between different drugs in those settings also, but you want to rule out all the different kinds of issues that can occur. And other than the cardiac, getting the CTPE gives you lots of information. So that's helpful. And I think without having a cardio-oncologist, these are situations where you have cardiology to help and that's what really you would contact in that setting.
Dr. Kelly McCann:
And ideally they would be seeing her fairly frequently. This is a patient that I would see at a minimum every 4 weeks, maybe even more often than that because she's so fragile. So, let's say her dyspnea is due to community-acquired pneumonia.
She gets treated with antibiotics and then several days later she comes to the clinic with severe diarrhea, her abemaciclib is held and she's sent to the hospital for hypotension, electrolyte repletion, and she tests positive for C. diff. So being unfamiliar with abemaciclib, the industrious intern on the cardiac care unit researches abemaciclib side effects and finds diarrhea to be very common.
The intern calls the first-year oncology fellow and the fellow has no experience with the abemaciclib either, having only been on the inpatient service for the past 6 months. What do you think that cardio-oncology could do in this situation? Do you think this is an area where they could be bridging the gap?
Dr. Avirup Guha:
Yes. One of the tenets of what we do is to enable cancer treatment, which will prolong life from the standpoint of the disease we're dealing with, which is the cancer without shortening the life from the standpoint of cardiovascular disease. So first thing first is diarrhea. We have got a cause of diarrhea, now we have two causes of diarrhea.
So while there's no imminent risk or threat to the cardiovascular system, why don't we treat the diarrhea with oral vancomycin and minimize electrolyte loss, which will then be a problem for arrhythmia. And then see what happens while keeping on perhaps a lower dose of abemaciclib while that's happening.
And once we keep, she's inpatient so once we keep getting EKGs monitoring and if the diarrhea goes away with just oral vancomycin, then we are done and then they can continue abemaciclib. Another key principle is don't be an alarmist. We have to ensure that we look at the overall picture. It's very hard to get inpatient cardio-oncology counsel, especially at our place.
So what I do is every person would know their go-to cardio-oncologists. Most of us are few and far between and they would just text me or call me, and you should just be available to answer these for us. Very simple questions and go from there. And in this situation, I wouldn't have stopped the medication and just treated the C. diff.
Dr. Kelly McCann:
I think that's very important because even today I was talking to a patient who was surprised to even know that the cardio-oncology field exists. So sometimes that's a surprise. So going on to the key clinical takeaways, treatment of metastatic HER2-negative breast cancer in the first-line setting is endocrine therapy plus a CDK4/6 inhibitor.
Even in patients like this with a germline BRCA mutation. Estrogen deprivation and CDK4/6 inhibitors can exacerbate preexisting cardiovascular issues in many ways, including fluid shifts, electrolyte imbalances, QTc prolongation, and increase venous thrombosis risk. Close collaboration is essential in medically complex patients.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in breast cancer or visit ascopost.com.
