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 two of my colleagues, and I'll allow them to introduce themselves.
Dr. Hope Rugo:
I'm Hope Rugo, Director of the Women's Cancers Program and Division Chief 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 am a cardio-oncologist and Assistant Professor of Medicine at Medical College of Georgia at Augusta University. It is great to be here.
Dr. Kelly McCann:
Thank you both. Today we will be discussing the role that cardiovascular risk factors play in the management of metastatic breast cancer using three patient case studies.
Our first installment will focus on the management of cardiovascular risk factors. E.C. is a 47-year-old woman who is diagnosed with stage III ER-positive, HER2-negative invasive ductal carcinoma of the left breast 10 years ago at the age of 37. Her past medical history is only significant for migraines and she's had no surgeries to that date. Gyn history is G2P2, regular menses, first childbirth at 33, and most recent childbirth at 37. She is not of Ashkenazi Jewish descent, and her family history is negative for breast, ovarian, prostate, and pancreatic cancer. It is positive though for diabetes and a stroke in her father at 62 years old. She's not on any medications at the time of her diagnosis.
On physical exam, her vital signs are normal. Her BMI is 26, and she has a 4-cm oblong mass in the left breast with at least three palpable lymph nodes in the left axilla. Her labs are all within normal range. Breast imaging shows a 5.1-cm mass with at least 4 abnormal lymph nodes. PET/CT shows no evidence of metastatic disease and her genetics is negative for germline pathogenic mutations.
Her treatment course includes surgery with bilateral mastectomies with a left axillary lymph node dissection. And pathology shows a 5.1-cm invasive ductal carcinoma with 6 out to 12 lymph nodes positive for carcinoma. For chemotherapy, she receives adjuvant doxorubicin plus cyclophosphamide x 4 cycles followed by paclitaxel weekly x 12 weeks. She also receives adjuvant radiation therapy, and then she has started on endocrine therapy with ovarian function suppression with goserelin and letrozole x 5 years. And this was before we had our CDK4/6 inhibitors approved in this setting.
Ten years after her original diagnosis, she presents with slowly progressive back pain and right hip pain that is worst at night. Past medical history now includes hypertension. Surgical history is significant only for the bilateral mastectomies. Her gyn history includes now menses that returned after discontinuation of ovarian function suppression. Her medications are amlodipine and metformin for an elevated hemoglobin A1c.
On physical exam, her blood pressure is 139/90, BMI is 29, and she's had bilateral mastectomies with implant reconstruction. Her labs are in the normal range, but her HbA1c is 6.4%. PET/CT shows osseous metastasis in T12, L2, the right acetabulum, and the pleura. Plural biopsy shows ER-positive HER2-negative breast carcinoma.
Her cardiovascular risk factors now include the family history of stroke in her father, a history of anthracycline exposure, hypertension, borderline diabetes, and a BMI of 29. So I think if we start there, what are some of the ways that estrogen deprivation therapy can affect cardiovascular risk?
Dr. Avirup Guha:
This is a great question, and I think something we get asked for in various situations. In this case, this lady is a little younger, so that's always on a positive side because age being the strongest risk factor, we have that on our side. However, when you have a combination of OFS plus aromatase inhibitors, you generally have an increase in LDL, decrease in HDL, which is worsening lipid profile, increase in insulin resistance, which can cause worsening diabetes.
This patient obviously ended up having significant diabetes for which she was taking medication, and well controlled. She has increased central adiposity, which is basically a part and parcel of metabolic syndrome if you add up the blood pressure she has and also the cholesterol, which she will eventually develop. And increase in nitric oxide, which is sort of a scientific mechanism through which endothelial dysfunction and future cardiovascular disease can develop.
And obviously as we talked about, she already has worsening hypertension despite being on good antihypertensive. And then sort of an increased inflammation and prothrombotic state, often noticed more with aromatase inhibitors, which has shown to be increasing the risk of stroke in older women with breast cancer, let alone metastatic breast cancer, which is a prothrombotic state.
And then obviously with the loss of estrogen once she reaches the age where she's no longer menstruating, that leads to, obviously, accelerated high atherosclerosis, which is sort of beyond the scope of just this disease state.
Dr. Kelly McCann:
Dr. Rugo, Hope, what do you think the role of oncology should be? We make a lot of patients postmenopausal and put them on these therapies. What should we be doing as oncologists?
Dr. Hope Rugo:
It's such a good question, Kelly, because we, as oncologists, I mean I think maybe one of the things that attracted many of us who are clinical oncologists is that we are the overall physicians for the patient. You can't just look at an organ, for example. And I think that's really represented nicely in this situation where, as a very young woman, she has a bad cancer, so her risks of recurrence are quite high. But she also now 10 years later and 5 years off of her ovarian function suppression, has substantial cardiovascular risk, as was addressed by Avi.
And so I think that our proactive approach is to say, wow, you have metastatic breast cancer, and we're going to need to treat you with drugs that could potentially affect your heart. I need to talk to a cardiologist and if you're fortunate, a cardio-oncologist, somebody who's a cardiologist who's really focused on this. And even if not, for example, if you don't have somebody who's really focusing on this like our guest Avi is today, you can also just, as long as you communicate with your colleague, the cardiologist, about what the issues are, I think that really helps a lot.
I've been participating in the guidelines for how we manage and monitor patients on breast cancer treatment as part of my role with the Multinational Association for Supportive Care in Cancer. And I think it's really fascinating to think about when we refer and how we co-manage. So here, I think what's really important is for the oncologist to communicate with the cardiologist, whether it's a cardio-oncologist or general cardiologist to say, "These are the issues the patient's going to face moving forward. This is what I need." Because I think we've all had this experience where we're trying to control glucose with PI3 kinase inhibitors. And the endocrinologist said to me, "But a glucose of 200 is fine." I said, "No, not in this case." So communication is key here and I think that's really what we're doing proactively for this patient.
Dr. Kelly McCann:
And I think that primary care can also be very helpful, but it's all about communication. Am I going to be the one managing lipids? Probably not, but I can draw the lipids at least. I don't know. What do you recommend? Do you manage those, the metformin, the cholesterol medications, yourself or do defer that?
Dr. Hope Rugo:
I do the same. I mean I'm happy to. We are checking the labs, so that helps. But I have to say I have relied on the cardio-oncologist even more. If the patient has a primary care physician, absolutely. But in today's world, a fair number of our patients may not be able to get a primary care doctor for 3 months or longer. And so we do need to be sort of balancing who we're reaching out to for managing these issues. And so I think that that helps a lot.
Dr. Kelly McCann:
Avi, when this patient was diagnosed, she was 37, so she wouldn't have had cardiac risk stratification necessarily other than recording her family history. Is there something that you would've done differently during those years that she is on estrogen deprivation?
Dr. Avirup Guha:
So, I think first of all, congratulations to both of you for doing an amazing job of managing diabetes, which I often end up managing myself. So I actually want to make two quick points. One point is sort of the whole ABCDE approach, by which I make it simple for every cancer, every issue where you manage risk factors. Awareness of what these risk factors can do, B is for blood pressure management, C is for cholesterol management, smoking cessation comes over there. The C stands for the cessation, diet, diabetes and exercise. So that's like the ABCDE, which I sort of use for all cancers, all medications because it is the bread and butter of what we do in cardio-oncology and should be the bread and butter for the point two, which is onco-primary care, which is a cool concept, which is I would say a necessity more than be cool.
It's something which we need to have is to have a strong foundation of their primary care so that even things beyond cardiovascular risk can be mitigated. For example, a lot of secondary cancers can appear in patients who are the appropriate age not getting screening for their cancer. So things like that, which primary care would take care of, and be it all and catch it all for situations like these. But I agree with Hope about difficulty in getting these patients.
Going back to your question about what I would do at the age of 37 is essentially trying to answer the last question we have, is what do we do with patients who are getting on CDK4/6 inhibitors? And you get a baseline EKG least. And obviously with the labs you'll have electrolytes. That way you know that if they have a genetic predisposition of QT prolongation, it would be right there in front of our eyes. That's what I would generally do, is at least a baseline EKG at that age. Based on the age and based on primary care guidelines, you would also likely at 37 get a baseline lipid panel.
Dr. Kelly McCann:
That's very helpful. So, let's say this patient, she gets restarted on ovarian function suppression with the goserelin and letrozole, and then we add in ribociclib, a CDK4/6 inhibitor at 600 mg daily. So that's the dose that was approved in the metastatic setting. And her baseline QTc is 440 ms. We could both probably, or all speak to how should QTc be monitored in this patient.
Dr. Hope Rugo:
No, we usually follow the FDA guidelines and the label for ribociclib. Interestingly, for early-stage disease, 400 vs 600 mg of ribociclib seems to have reduced the extent of QTc prolongation that we saw. Interestingly, it did not impact the liver enzyme elevations, which was interesting, or less neutropenia. So, 600 mg, you know that if the QTc does go up, you can reduce the dose, hold and reduce the dose, so that's good.
But the label now says to do a baseline 2 weeks, 4 weeks, and then I think you're done if you don't have a long QTc. But if you have concerns or you change the cardiac medication or give a medicine which could cause QTc prolongation, then we all have to remember to check again, which is a really complicated thing for oncologists since we don't generally know the non-cancer drugs that cause QT prolongation.
Dr. Avirup Guha:
And I would second that, a very important last point which you made. In fact, we just did a study where we looked at a large registry and essentially showed that, of the 6,500 patients which we looked at, about a third of them were on some agent which have a potential, not obviously QT prolonging. So working with the pharmacists who work alongside you in clinics would be very helpful to identify how to mitigate those issues, and if they're at any risk beyond the EKGs and the electrolytes of having further deterioration of QTc. Also educating patients about, "Hey, you shouldn't be taking these," or, "If you're going to start an antibiotic, please call your oncologist or cardiologist."
Dr. Kelly McCann:
So, let's say she comes back for her day-14 labs and her ECG, and her electrolytes are normal, potassium 3.5, mag 1.8, but her ECG shows a QTc of 510 ms. What would you do? I think we talked a little bit about going down on the dose, holding the dose and restarting, but when would you start to get worried about QTc prolongation?
Dr. Avirup Guha:
So, what I have done, as part of standard guidelines at our institution, is if the QTc is more than 500 ms, and again to ensure the QTc is corrected, I'm just going to get in a little bit of details of how we calculate the QTc. So if the patient has normal sinus rhythm and we get a QT interval measured manually between the QRS complex, and the end of T, and then we use a Fridericia correction formula for getting a QTc. And if that is more than 500, you hold ribociclib, correct electrolytes and repeat an EKG right then.
If the QTc then returns at less than 481 ms, you can resume at a lower dose, as Hope was mentioning about efficacy. And then if it remains above 500 ms and associated serious arrhythmias, then you have to change medications. There's obviously the option of switching to an abemaciclib or palbociclib if recurrent QT prolongation happens, and this sort of phenomenon keeps repeating. But that is more of a decision which I'll leave with you, Kelly and Hope, as to when you think your threshold is crossed of doing the same thing.
Dr. Kelly McCann:
Yes, I think we have very different gestalts about these patients and when we would switch, and everybody's probably doing something a little bit different. But now that ribociclib has got overall survival data, it's in the adjuvant setting, and abemaciclib also in the adjuvant setting. We have a lot of choices. Sometimes I worry about putting patients on abemaciclib because they can have more electrolyte abnormalities with diarrhea, but I would potentially consider switching a patient over if they have significant QTc prolongation.
Dr. Hope Rugo:
If maybe there's a medication they can't stop or maybe it's just inherent. I mean interestingly, we haven't seen Torsades from this QT prolongation, but you don't want to have one.
Dr. Kelly McCann:
Yes, you don't want to see that.
Dr. Hope Rugo:
And I haven't had problems with QT in people who are on abema, interestingly. You wonder here, and maybe Avi, this is something you would normally do, is just push the potassium up. Does it help to be higher than 3.5? I don't know.
Dr. Avirup Guha:
So the standard teaching has been potassium above 4, less than 5. If they have heart failure, close to 5.5 is also acceptable because sometimes some of the heart failure medicines can do that. And then mag above 2. And then we keep the calcium, the ionized calcium based on whatever the oncologist really is comfortable with because that changes a lot more with some of the oncology medicines. So that's essentially what we do with electrolytes. I would eventually leave the decision about switching to you all.
Dr. Kelly McCann:
In this patient who had a potassium of 3.5 and QTc prolongation, would you start with trying to replete her potassium or would you just hold the drug?
Dr. Avirup Guha:
No. So basically when I say hold it, you would repeat the potassium as an outpatient, likely not. I mean it depends on the cancer center really. If you can send them for an infusion, to the cancer infusion suite, get them the 50 mEq of potassium that way, and then repeat an EKG and it's gone below 481, you can continue going the next day. But most places, practically speaking, you would give them oral potassium, repeat, and they come back the next day and get an EKG. So they probably miss a dose of ribociclib at that point.
Dr. Kelly McCann:
So for this overall case, I'll give you some key clinical takeaways. Breast cancer treatment with anthracyclines and estrogen deprivation can affect cardiovascular health, both directly and indirectly. Ribociclib can prolong QTc and ECG should be monitored prior to the initiation of treatment and at day 14. But additional ECG monitoring might be advised if the QTc prolongation occurs. If a patient is switching from one medication to another, that could cause QTc prolongation. So it really depends on the patient.
And then in these patients who have an ECG before they start, you should only initiate treatment with ribociclib in those patients who have a QTc less than 450 ms. And check the package insert for ribociclib to see what are those cutoffs for when you should interrupt the dose or resume at the next lower dose. If a patient has a QTc prolongation of greater than 500, or greater than 60 ms change from baseline with signs or symptoms of a series of arrhythmia, then ribociclib should be permanently discontinued. Should also be discontinued if the QTc prolongation greater than 500 ms recurs.
Finally, avoid combination of ribociclib with other QTc prolonging medications. One of those medications could include a drug like tamoxifen, which is also known to cause QTc prolongation.
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.
