Case 5

Dr. Matthew Goetz:

We have one more case and this is a quite interesting, partly because of the fact that the patient presented with all the right, if you will, prognostic factors. This was a 50-year-old female, who presented to my clinic with a history 5 years prior. So she would've been 45 at the time when she presented with a 1.4 cm invasive ductal carcinoma grade 2, ER and PR was strongly positive, HER2 was negative. She underwent lumpectomy locally at her clinic, a small town in Minnesota, and a lymph node biopsy was performed, it was negative.

And so she had a T1cN0 breast cancer, ER/PR strongly positive, HER2 -egative. Her physicians appropriately obtained an Oncotype recurrence score and that was 9. And she was actually treated, I would think fairly, quite aggressively with this recurrence score, in terms of systemically endocrine therapy, she was treated with ovarian functional suppression and letrozole. And Sara, for a 45-year-old premenopausal patient, T1cN0 breast cancer, would you treat all patients with a recurrence score of 9 with OFS and AI, or do you think there are other alternatives?

Dr. Sara Chumsri:

Yeah, I think based on the data we saw in the SOFT and TEXT trials, I think in the low-risk category like this patient had a low Oncotype score do not require chemotherapy. I think in this case, I might have gone with tamoxifen alone, and I do agree that aromatase inhibitor with the ovarian function suppression that in this case that had the bilateral salpingo-oophorectomy might be a little bit much because of the side effects. And there's also some concern about putting them on the menopause early. There's always a concern about cardiovascular risk and other things later on too.

Dr. Matthew Goetz:

Yeah, so she certainly received, you might say, maximal endocrine therapy in this situation. And interestingly, despite really an aggressive endocrine course, she got right at the end of her 5-year course, so she was right around the age of 50 when she presented while still taking letrozole, she'd had a prior salpingo-oophorectomy to a local ER with upper abdominal pain and some fluidic-type chest pain. And she had a workup there that demonstrated multiple hypodense liver lesions, the largest measuring 5 cm, and she did have a PET scan that demonstrated the aforementioned disease in the liver as well as uptake in the right ileum as well as the left femoral head. Biopsy of this confirmed a moderately differentiated adenocarcinoma consistent with breast primary, ER-positive, PR-negative, HER2-negative. And so she now presents with essentially progression on an aromatase inhibitor. Kevin, your thoughts about how you would approach this patient in 2022?

Dr. Kevin Kalinsky:

Yeah, I mean I think that with progression on an aromatase inhibitor, I think it's entirely appropriate to utilize, outside of a clinical trial, fulvestrant. I do think fulvestrant plus abemaciclib is appropriate, right? That is an appropriate approach, as is something like fulvestrant plus ribociclib. I think it's just a bit of a conversation just in terms of the side effect profile, things of that nature. I would say my default still tends to be ribociclib in this setting, given what we talked about in the other cases, the side effect profile, tolerability, etc. But fulvestrant-based therapy I do think is entirely appropriate.

Dr. Matthew Goetz:

Okay. So actually, it turns out she was enrolled on a clinical trial, abemaciclib and fulvestrant. It was actually a clinical trial that was testing an additional agent along with abemaciclib and fulvestrant, but she was actually treated on just these two drugs and had a fantastic response to therapy. She had a near-complete response to therapy within the liver with only very several small liver lesions that were really too small to characterize a complete, really, a complete PET response with all resolution of all FDG-avid lesions. However, she did have quite a bit of problems with diarrhea and so I remember seeing her back with, even after the first cycle of therapy, substantial diarrhea that was interrupting and causing some issues with quality of life. And we did reduce the dose of abemaciclib per the instructions of the protocol from 150 mg twice daily to 100 mg twice daily; obviously, initiated Imodium. Sara, have you seen something similar? And what is your approach to management of diarrhea in this situation?

Dr. Sara Chumsri:

Yeah. I think diarrhea, it's one of the most troublesome side effects of abemaciclib. I think that in this case in particular because she had liver metastases and there's some subset analysis from the MONARCH trial in patients with liver mets, I normally try to get abemaciclib in, but with the side effects with the diarrhea, I think it's more of the counseling of the patients. I think early prophylactic use of Imodium is very important. I normally also use Lomotil. I normally try to have them alternate the two. The other thing I normally counsel patients is that if you look at this clinical trial with the diarrhea in MONARCH, the diarrhea seems to be more common in the first few months. So I normally try to encourage them to try to keep going and if you pass a couple months, first months of the drug, diarrhea tends to get better.

And once in a while. I also use some other medication like cholestyramine and other things that help with the diarrhea too. And dose reduction, early dose reduction is very important and normally encourage the patient that we do still see the response and the disease control even with the lower dose. So try to get them keep going with the drug and reduce the dose early.

Dr. Matthew Goetz:

Great. Thank you. That's an excellent response. I think as time has gone on, I think all of us are getting a bit more astute, perhaps better able to manage the diarrhea that we see in patients with abemaciclib. Certainly, it's common, but I think early intervention is clearly the key here. And in this particular patient, the patient actually did have early intervention with Imodium, did require dose reduction, actually required a second dose reduction, which in my case in my clinic, is fairly unusual. Most patients, if they do require a dose reduction, oftentimes, do well with just the first dose reduction. But she did have two dose reductions with abemaciclib and actually remained on the drug for 3 1/2 years so that she was remained on the combination of abemaciclib and fulvestrant for over 3 1/2 years with really overall excellent quality of life once the diarrhea was managed well. Kevin, any additional pearls on how you manage diarrhea in patients treated with abemaciclib?

Dr. Kevin Kalinsky:

No, I think that was perfectly said. And I also think that when we are treating patients in the adjuvant setting with abemaciclib, my anecdotal experience is that a number of patients do require dose reductions, whether it's due to the gastrointestinal issues or fatigue, that's something that we have seen. I mean, I think the other thing just to highlight is that we do have data with ribociclib from the MONALEESA studies that the patients who required dose reductions did just as well as the patients who started out, who remained on the 600-mg dose. So that does give us some evidence that if you require dose reduction, you'll still have benefit as is also seen anecdotally in this particular case.

Dr. Matthew Goetz:

Yeah, that's an excellent point. And really, the same observations were made in the MONARCH 2 and MONARCH 3 studies is those patients who required dose reductions really had no difference in progression-free survival than those who did not require dose reduction. So I think we can confidently tell patients that they don't need to suffer in silence, if you will, but we can offer them dose reductions. Certainly, I know one of the first things they say is, well, will it compromise the efficacy of the drug? And apart from, of course, randomized trials and of course, we have Hope Rugo's study which was testing a lower dose of palbociclib a few years ago as well. The early overall data suggest that finding the right dose for our patients, that we have a little bit of flexibility and we can feel confident that we're not compromising efficacy. All right. Well, that brings us to the end of this discussion of these cases in the adjuvant and metastatic settings. Kevin and Sara, any closing thoughts you would like to make before we depart?

Dr. Kevin Kalinsky:

The only comment I was just going to make is just how quickly these data are evolving that what we're talking about now is likely to be somewhat different than if we meet again in 2 years or even a year. I think things are just constantly shifting. And so I think that that's really highlighted in the cases that we've discussed.

Dr. Matthew Goetz:

Yeah, it's a fantastic point and obviously, it's an incredibly good thing for our patients that we have more and more drugs that are being developed and we're able to address what are sometimes some very challenging situations, which I think in the post-CDK4/6 space has been certainly quite challenging because we haven't had a defined winner. But we are seeing glimpses right now, whether it be the data from the DESTINY-04 study, whether it be some of the early data from the ELAINE-2 trial, whether it be the anecdotal data in my clinic of combining abemaciclib post palbociclib. I think we're going to have much more data in the next few months to years that, and things are going to continue to change. So Sara, any other thoughts from you?

Dr. Sara Chumsri:

I totally agree. I think the landscape is changing and that's good for the patient because we have a lot of these new agents and things coming out, a lot of new oral SERDs that are quite interesting. So I think we have to stay tuned and then see those data and it is exciting time.

Dr. Matthew Goetz:

All right. Well, thank you. Well, on behalf of Dr. Sara Chumsri, Dr. Kevin Kalinsky, again, I'm Dr. Matthew Goetz and thank you for being with us today.