High-Risk HR-Positive, HER2-Negative Early-Stage Breast Cancer: Bridging Evidence, Risk Identification, and Real-World Practice

Dr. Sara Tolaney:

Welcome to High-Risk HR-Positive, HER2-Negative Early-Stage Breast Cancer: Bridging Evidence, Risk Identification, and Real-World Practice, a JADPRO Virtual Roundtable. My name is Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute, and today I'm very lucky to be joined by my two colleagues, Dr. Erica Mayer, who leads clinical research in breast oncology at Dana-Farber, and Dr. Elahe Salehi, a very well-experienced breast nurse practitioner. So thank you both for joining us today.

For our third and final case today, we're going to discuss the management of toxicities that can arise in high-risk hormone receptor–positive breast cancer patients who are getting CDK4/6 inhibitor therapy. So just to put this into context, this is patient P.F., who is a 58-year-old woman who has a T2N1 high-grade hormone receptor–positive, HER2-negative early-stage breast cancer. She was started on endocrine therapy abemaciclib, with abemaciclib having been started at a dose of 150 mg twice daily.

She started treatment and began to experience pretty persistent diarrhea with three to four bowel movements a day starting around day 10 after initiating her abemaciclib, and this sort of persistent diarrhea has been going on for about 7 days, at this point in time. So, Elahe, I'll start off with you. You obviously have treated a lot of patients on abemaciclib and have seen this before. So, one, how common is this for you to be seeing someone having persistent diarrhea at around this time point and how would you monitor and manage this patient?

Dr. Elahe Salehi:

We do see quite a good amount of diarrhea in our patients on abemaciclib, specifically for the first 8 to 12 weeks in starting abemaciclib. We're making sure that they are actually using the appropriate management for antidiarrhea medication, optimizing. So in this setting, she has three to four stools a day, which basically puts her on grade 1. So with grade 1 toxicity of diarrhea, one, we need to identify what is the normal bowel movement, what's the baseline for this patient, whether a patient had comorbidities such as colitis that has started on abemaciclib and now exacerbated with diarrhea, and making sure that the patient optimizing over-the-counter medications such as loperamide in this setting.

And with a grade 1 well-controlled using the management of antidiarrhea medication, we tend to not really interrupt the dosing unless this is becoming consistent for the patient and causing the patient to have difficulty in their daily activity that one can consider stopping the medication. And we already know that dose reduction is a possibility for grade 2+ diarrhea in the setting of abemaciclib, but we have seen that the efficacy does not decrease with the dose reduction.

Dr. Sara Tolaney:

I think that's a really important point, because I will say, and in this case, I would agree that one could work on supportive care if she's not doing it appropriately and seeing if you can optimize it. But if you held therapy and it recurred again, you probably would consider dose modification. And as you point out, it's important for patients to realize if we did go, let's say, from 150 mg twice a day to 100 mg twice a day, that it's not likely to have any impact on the benefits that they're gaining from therapy because, as you point out, there have been analyses that have been done, for example, in monarchE where they looked at relative dose intensity of treatment during the trial where patients were getting 2 years of abemaciclib, and, in fact, found that the invasive disease–free survival was similar based on different relative dose intensities. They also did a time-dependent analysis where, again, the benefits were also seen irrespective of a dose over time. So I think, again, patients worry about this when we start lowering dose and it's nice that that data is available.

Erica, you obviously have paved the way in this field, thinking about how to optimize administration of abemaciclib, and one question that comes up is should we actually be starting patients at 150 mg twice a day? We just talked about that we could go down in dose and it would maintain efficacy, but would we ever think about escalating dose, maybe starting low and going high? Would that be better for the patient? Maybe you could tell us about that strategy

Dr. Erica Mayer:

Yeah, this is a topic that we've thought about a lot and much of it has been inspired by what we all see in clinics, starting patients at what we might call target dose, 150 mg twice a day, and then seeing patients experience diarrhea, which, honestly, for someone starting a 2-year course of drug is challenging and discouraging. And we know from monarchE that although the diarrhea is front-loaded and for many patients, once they get over the hump, things quiet down and they carry on without as much difficulty later, that the majority of the dose reductions, and importantly, discontinuations were related to toxicity, specifically diarrhea.

We also know that about half of the discontinuations for toxicity, patients didn't even use a dose reduction, they just experienced the toxicity and then stopped, which makes you think that person must have had diarrhea and it was just not good in their life and they said, "I've had it with this drug." So they miss all that benefit.

So we wanted to think about are there ways to onboard a patient to a medication that will make it easier for them so they can get used to it and stay on the medicine and ultimately achieve the benefit. We have had experiences with other targeted therapies where this has been successful, for example, with neratinib or with everolimus, and so we wanted to try this with abemaciclib. So we designed the investigator-initiated phase II TRADE study, which was a single-arm study looking at adjuvant abemaciclib in a dose-escalated fashion. The patients who entered TRADE were all candidates for adjuvant abemaciclib, there was about 90 people, and they started at the lowest dose, 50 mg twice a day for 2 weeks. And if that was well tolerated, they escalated to 100 mg for 2 weeks. And if that was well tolerated, then at the beginning of Cycle 2, Day 1, they went to the target dose 150 mg twice a day onward for the goal 2-year course.

The primary endpoint of the study, which was designed to be measured at 12 weeks, so covering that early higher-risk period of time, was looking at whether patients could reach the target dose of 150 mg, maintain the dose, and not discontinue the therapy, so stay on therapy.

What the study showed was about 30% of patients met the endpoint, meaning that they couldn't reach or maintain the dose or they had to stop early, but this number was significantly lower than what was seen in monarchE. So this was very successful. This showed us that by doing the dose escalation, this allowed fewer patients, in particular, to discontinue therapy. And at 12 weeks, we saw 93% of people were still on drug, which is a much higher number than what was seen in monarchE.

Now, interestingly, when you look at each individual patient, not everybody is at 150. Some people end up at 100, some people end up at 50, but each person's different, each person's body is different, and as we just talked about, even though they have a lower dose, this does not interrupt dose efficacy. Importantly, though, they are on drug and we hope that they will then be able to complete the 2 years. We're still monitoring the patients in TRADE to provide long-term outcomes, but this has been a very successful strategy and I'm really gratified to hear people from all over the world who have been using this in their patients very successfully.

Dr. Sara Tolaney:

Yes, it's great, Erica, and certainly it's really nice for physicians to have this as an option. I think, very commonly, we tend to get a little nervous, maybe, if someone's older, has comorbidities. And I think before this data came out, maybe we would just start a little low because we were getting anxious and just wanted to make sure they could tolerate it. But now we actually have good data to suggest that we can escalate patients and start low and go high, and it seems to lead to lower discontinuation rate, which I think is really important and allows patients to accommodate to the dose. So great to have that as an option and a strategy to think about.

So thinking about dose modification is important, thinking about dose escalation is another alternative. Another potential side effect, or not maybe side effect, but a thing that comes up in clinic, at least that I find, is that sometimes I'll notice that someone's creatinine is elevated when they're on abemaciclib. That can be confusing because certainly we just talked about how abemaciclib can cause diarrhea. It could make you think, "Oh, is that patient prerenal? Are they dehydrated? Do I need to hydrate them?" But on the other hand, we also know that the abemaciclib can impair creatinine excretion in the renal tubules and can cause this elevation of creatinine, which may not actually be reflective of any renal impairment. And so, Erica, if you see this in clinic, do you order an additional test? What do you do to help sort this out?

Dr. Erica Mayer:

Yeah, it definitely can be tricky in clinic. I think a good test to send is a cystatin C test, which provides a more accurate determination of renal function in that setting where the abemaciclib might be competing with creatinine for clearance. And when we see the normal cystatin C level, that helps provide reassurance that renal function is fine, it's just an artifact that we're seeing. But certainly in a patient having diarrhea who risks dehydration, it's a very real concern whether there's an impact on renal function. So if we begin to see a situation where the patient's coming in with a persistently-elevated creatinine, we will sometimes have a standing cystatin C order just to make sure that we know each time that renal function is okay.

Dr. Sara Tolaney:

Yeah, that's good. I think sometimes people forget about that. I'll say it also throws off our radiologists sometimes because they see the elevated creatinine and then they're like, "Oh, we can't give contrast," if they needed a scan for some reason. But if you can show the GFR is actually normal with a cystatin C, that's actually super helpful.

Another thing that sometimes may come up is let's say you had this patient on an aromatase inhibitor and abemaciclib, and let's say that patient hates the aromatase inhibitor. They get tons of arthralgias, you've tried changing the AI up, it's not working. Would you ever consider switching them to tamoxifen? And, Elahe, is there anything you're worried about by giving concurrent tamoxifen and abemaciclib or anything that comes to mind with that?

Dr. Elahe Salehi:

I definitely would worry about switching to tamoxifen with abemaciclib, because in the trial, in the monarchE trial, they did actually see that patients who were receiving tamoxifen with abemaciclib had a higher chance of blood clot formation. So this will be really something that I personally will not feel comfortable doing and I'll try every management to keep the patient on aromatase inhibitor. That would be how I will be comfortable with the management.

Dr. Sara Tolaney:

I think it's tricky. As you point out with tamoxifen and abemaciclib, the rate of VTE is around 4%, so it's almost double what you'd see with an AI and abemaciclib. So definitely something to be cognizant of.

On the other hand, you actually cannot give tamoxifen with ribociclib. That is contraindicated given prolongation of QTc with both agents, so leading to too much prolongation when you give them both together, so that is not something that can be done.

Here, I think the question is if you're really stuck and you just can't give the AI, obviously I think we'd go to tamoxifen and abemaciclib over nothing, right? But I think the question that sometimes comes up is, would you ever think about doing something to prevent clot, which is sometimes a discussion we think about. So I think one thing to just keep in mind is that if someone has a very high risk, for example, of developing VTE and you're going to tamoxifen, it's something that it's worth having a little bit of a discussion maybe with your hematologist about is whether or not you try like a prophylactic DOAC, for example, in that particular situation. This is not data-driven by any means that was not required in someone on tamoxifen on abemaciclib, it was fine to give in monarchE, but as Elahe points out, it does have a 4% VTE rate.

For example, I had a 75-year-old male patient who did not want to use Lupron but had 19 positive nodes and I definitely was going to give endocrine therapy and abemaciclib in this situation and we did end up having a discussion with hematology, and did put this patient on low-dose DOAC with tamoxifen and abemaciclib because we felt that the risk of clot would be higher in this particular individual than the average patient. And so, I think just a little bit of a reminder to keep in mind if you really do need to turn to tamoxifen, again, technically fine to do, but, again, there is some risk of a VTE that shouldn't be overlooked in assessing clot risk in that patient's probably important to think about.

So I think the key takeaways from this particular case is when you are starting a CDK, as we heard very nicely from Elahe, the patients do really need to be seen every 2 weeks for the first 2 months after starting therapy. They do need to be monitored. Doses can be adjusted to deal with toxicities and that seems not to have an impact on efficacy, so important to let your patients be aware of that. And that, on the other hand, we can also think about a dose escalation strategy with abemaciclib based on the data that Erica had previously presented from the TRADE trial, showing that taking this strategy does seem to lead to lower rates of discontinuation, and so can be an alternative approach when initiating abemaciclib therapy.

Thank you so much for this great discussion. This brings us to the end of our case. Please do see the other two videos for further discussion about the latest research in breast cancer at JADPRO.com.