Dr. Iyengar:
Welcome to Balancing Benefit and Burden: Managing Toxicities in HR-Positive/HER2-negative Metastatic Breast Cancer, an ASCO Post Roundtable. I'm Dr. Neil Iyengar, Associate Professor of Hematology and Oncology, Co-Director of Breast Medical Oncology, and Director of Cancer Survivorship Services at the Winship Cancer Institute of Emory University. Joining me today are two of my friends and colleagues, Dr. Bill Gradishar and Dr. Sara Tolaney. I'd like each of them to go ahead and introduce yourselves. Dr. Tolaney, why don't we start with you?
Dr. Tolaney:
Thanks, Neil. So I'm Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute in Boston, and thanks so much for having me today.
Dr. Gradishar:
And I'm Bill Gradishar from Northwestern University, a breast medical oncologist, and happy to be here.
Dr. Iyengar:
Wonderful. So let's get into the first case here. Our first case will focus on the management of PIK3CA-altered hormone receptor–positive, HER2-negative metastatic breast cancer. So our first patient, we'll call her HK, is a 64-year-old post-menopausal female with a history of primary hormone receptor–positive, HER2-negative breast cancer diagnosed in 2011. I'll just briefly review her primary treatment and then we'll get into her metastatic presentation.
She underwent breast conservation surgery with a lumpectomy, and this yielded a PT1bN0 invasive ductal carcinoma. The tumor was estrogen receptor–positive at 80%, progesterone receptor–positive at 60%, and HER2 nonamplified, with an IHC score of 1+. Germline genetic testing showed that she was BRCA1/2 wild-type, and genomic testing with the Oncotype DX platform revealed a recurrence score of 29. She then went on to get adjuvant therapy with four cycles of docetaxel and cyclophosphamide. This was followed by radiation and then subsequent endocrine therapy with ovarian suppression and aromatase inhibitor for 10 years. She completed this therapy in 2021. I'll just note that she also had hypertension and a body mass index of 28.
So now fast-forward to 2023, she presents to clinic with pubic pain. This prompted a workup, including imaging, and a PET/CT scan revealed an FDG-avid lesion in the pubic symphysis as well as several small hepatic lesions. And this represents about a 2-year disease-free interval with now a presumed radiographic diagnosis of metastatic disease. This was next confirmed by tissue biopsy of a liver lesion, and this was consistent with her primary breast cancer, with an ER-positive expression of 80%, progesterone receptor at 55%, and again, HER2 nonamplified at 1+. She also had next-generation sequencing performed on the tumor tissue, and this revealed a PIK3CA mutation, specifically an H1047R mutation. Subsequently, she underwent ctDNA testing, which also showed that PIK3CA alteration, the H1047R lesion, with a variant allele fraction of 1.8%.
So I'll just pause there. You can see her cross-sectional imaging on the slides there, highlighting the FDG-avid lesion in the pubic symphysis, which is causing her some pain, as well as some small lesions in her liver, which are also enhanced. So let's start by talking about our first-line treatment selection for a patient who presents like this. Maybe, Dr. Tolaney, I'll start with you. How would you approach this patient now presenting with metastatic disease?
Dr. Tolaney:
Yeah. So usually in the first-line setting, when someone presents with metastatic disease, I think we're trying to understand, if this is a recurrent cancer, what was their disease-free interval from prior endocrine therapy? In this case, it sounds like it was about 2 years, and so that makes you try to figure out what the optimal endocrine backbone would be. Usually if someone recurs within a year or on an aromatase inhibitor, then I tend to think about fulvestrant. If it's greater than a year, 2+ years, then I'm thinking about maybe reusing the AI.
And then we try to understand whether or not that patient should get endocrine therapy with a CDK4/6 inhibitor, or if they should get a triplet combination of endocrine therapy, CDK, and a PI3 kinase inhibitor. And so getting genomic information in this setting is now important. Although I will say she kind of falls outside of what would be considered a classic candidate for a triplet combination strategy.
So we have the data from the INAVO120 trial that had looked at giving fulvestrant plus palbociclib plus inavolisib, but it was in patients who recurred on or within a year of endocrine therapy. And again, she's just falling outside of that range. And so I will say she is kind of on the border, though. 2 years is on the shorter side, and so one could be creative and consider it.
And so I think the classic thing in this case would be probably to give an aromatase inhibitor and a CDK4/6 inhibitor as my first-line strategy. Though one I think could debate if you wanted to use a triplet. I probably would think about a triplet in someone who had a lot of visceral involvement. So someone who maybe I was worried about disease burden, maybe that would sway me a little bit towards the Inavo triplet, but for the most part, in this case, it sounds like bone-only recurrence, and I probably would stick with the AI plus CDK4/6, in this case.
Dr. Iyengar:
Thanks for walking us through that. Makes a lot of sense. Dr. Gradishar, let me ask you first if you have anything further to add. And then we saw with this patient several approaches to genomic and genetic testing. Do you agree with that? What's your approach for genomic testing for a patient presenting initially with metastatic disease?
Dr. Gradishar:
Sure. So the only comment I would make in addition to Sara's framework for thinking about this, which I agree completely, is just to sort of quickly say that we wouldn't necessarily use chemotherapy. And just that dogma that, if you've got liver metastases, you got to think about chemotherapy. We have now trials that have looked at endocrine therapy with a CDK4/6 inhibitor compared to chemotherapy either as monotherapy, as combination therapy, and optimal endocrine therapy is better. So there would be no reason to think about that.
With respect to the issue of how do we assess whether or not there are actionable mutations, we oftentimes would think about delaying doing that until the second-line setting. But now, as Sara already pointed out, we have trial information that suggests, in certain patients, knowing whether or not they have a PI3 kinase mutation and they fit INAVO120 may lend itself to considering a triplet. So I think we're doing it earlier.
And then the only other point I would probably make is, this issue, do we rely on ctDNA? Do we get tissue for the analysis? Do we do both? They're not perfect in terms of perfect overlap. Again, the ctDNA may give a more holistic picture of what's going on, whereas if you do a single tissue biopsy, you may or may not see that entire picture of what's going on in the body in the setting of metastatic disease. If given the opportunity to do both, which this patient presented with because you had to confirm the diagnosis of metastatic disease, I would get both. But thereafter, I would be doing ctDNA.
Dr. Iyengar:
Great. A lot of important points there. Thank you for that outline there and also for highlighting the RIGHT Choice trial amongst other trials, showing superiority of CDK4/6 plus endocrine therapy over chemotherapy, even in the setting of visceral metastasis like this patient.
Let's go on to what happened next. And she did in fact receive first-line treatment with endocrine therapy, specifically an AI, letrozole, plus CDK4/6 inhibitor with ribociclib. And she did fairly well on that. For about 21 months, her disease was under control. She symptomatically improved. That pain in her pubic symphysis improved as well. There were some discussions about whether or not to pursue palliative radiation or not, but she had a very favorable response to first-line systemic therapy and her pain improved as well.
So now at 21 months, however, her imaging showed several new small hepatic lesions on the PET scan, and you can see that a representative image there on the slide, and this, unfortunately, was consistent with progressive disease. Though that being said, her liver function remained normal at this time. She did have some further testing, which included a reassessment of ctDNA, which again identified or showed the PIK3CA alteration, now with a variant allele frequency of 4.9%. And in preparation, and this is a bit of foreshadowing here, I'll just mention here that her hemoglobin A1C was 5.9%.
So we have now this patient who's progressed on first-line AI plus CDK4/6 inhibitor. We know the tumor has a PIK3CA alteration. Her comorbidities include hypertension and a BMI of 28 and a hemoglobin A1C of 5.9%. Dr. Gradishar, could you walk us through how you think about her next line of therapy?
Dr. Gradishar:
Sure. So in this patient, again, I think it's important to recognize, going back a bit, as Sara pointed out earlier, in patients who had PI3 kinase mutations in the first-line setting who've got a CDK4/6 inhibitor, they still benefited from the CDK4/6 inhibitor, but the magnitude of benefit may not have been the same.
Now, contrary to that statement, this patient's had 21 months, which is looking not so dissimilar from the early registration trials with an optimal result. So I say all that to suggest that this patient probably is still endocrine sensitive. You don't see that very short PFS interval that we might be looking for if you were looking for resistance. So I would still think about endocrine therapy, and your foreshadowing would suggest that the next step would probably be a PI3 kinase inhibitor, an AKT inhibitor, which we'll talk about. And I would feel very comfortable in doing that in this patient because her LFTs are normal and you have a window to still explore whether endocrine therapy may be helpful.
Dr. Iyengar:
Great. Dr. Tolaney, anything to add there?
Dr. Tolaney:
Yeah, no, I very much agree. Here, it sounds like she did not have an ESR1 mutation, where we see maybe 40% or so of people by ctDNA will have ESR1 at the time of progression on first-line AI therapy. So really it is just a PIK3CA mutation. And so I would agree that the standard approach really is fulvestrant plus capivasertib in this setting for someone who's progressed on AI CDK with a PI3K mutation.
It always does beg the question, does everyone need a PI3-kinase inhibitor? Are there other alternatives in someone as a second-line option? Certainly there are. There is some data for continuation of CDK beyond progression. For example, could one use fulvestrant plus abemaciclib? There was benefit irrespective of PI3 kinase mutation status. We saw some intriguing data from EMBER-3 looking at imlunestrant plus abemaciclib. Obviously not technically FDA approved as a combination in the second-line setting, but that benefit was seen irrespective of ESR1 and PI3K mutation status. And sometimes people will even use fulvestrant plus everolimus in a second-line setting, where everolimus benefit is also seen irrespective of a PI3K mutation status.
So there are lots of choices here, which always makes it so complicated, but I think the most straightforward thing is usually to hit the specific mutation with an inhibitor. In this case, I prefer using the AKT inhibitor over using alpelisib, for example. You did mention some risk factors for hyperglycemia, including BMI and sort of the borderline A1C. And with capivasertib, at least, we see less in the way of hyperglycemia than we would with alpelisib. So also favoring that as your favorite choice here. Although I will note, maybe consideration of clinical trials should also be made given the newer PI3K mutant-specific inhibitors, which do seem to have a lot less toxicity. So obviously always important to consider that as well.
Dr. Iyengar:
Yeah. Thank you, both of you, for highlighting that. And certainly huge proponent of clinical trials for that reason, also for the novel antiestrogen combination strategies as well. And so this patient did indeed go on to get capivasertib and fulvestrant, as you highlighted, Dr. Tolaney. Let's just take a minute there and talk a little bit about management and monitoring strategies for our patients treated with an AKT inhibitor or PI3 kinase inhibitor, and we'll talk specifically in this case about capivasertib with fulvestrant. Dr. Tolaney, you mentioned or highlighted some of the risk factors in this patient. What's generally your approach to monitoring patients that you start on capivasertib, and do you use any prophylactic strategies for these patients?
Dr. Tolaney:
Yeah. So I think in my head, I try to think of what are the most common toxicities and what am I worried about? So with capivasertib, one of the things we worry about, certainly, is risk of hyperglycemia. And so, as appropriately was done here, usually we like to understand what their baseline hemoglobin A1C is, understand fasting glucose levels. And then there was an update to the guidance for monitoring with capivasertib, where they now do recommend finger sticks being checked. So it's a complicated schedule, but it is needed to be checked on three different days. And so we've had to put in place glucometer teaching every time we prescribe capivasertib now because it's just too complicated for them to be coming into clinic with those guidelines. And so I give them a glucometer and teach them how to do finger sticks at home.
The other thing that I think about is risk of rash. And so, unfortunately, rash is a fairly common toxicity with capivasertib, not dissimilar to what we see in terms of rates with alpelisib. So I do give prophylactic antihistamine with capivasertib, usually starting them either the day before or the day of. If I remember, the day before, but usually it's often the day of starting the capivasertib, so they're taking it daily. And then the other common side effect is diarrhea. So unfortunately rates of grade 1 diarrhea are quite high. And so I do make sure patients have loperamide on hand to use as needed, and that typically works very well.
Dr. Iyengar:
Great. Thank you for walking us through that. And for those of you that are looking at the slides, I'll walk you through some of the monitoring. As Dr. Tolaney mentioned, it can get a bit complicated here. So this patient did undergo glucose monitoring, as we just heard about. And she started off fairly well, I would say. Her day 3 fasting glucose at home was 110. On day 7, a week into treatment, it was 132. And she was brought in for lab testing, this is now at week 1, which sort of confirmed that range, with a fasting glucose of 140. And this is where we start to think about initiating metformin.
So she was, indeed, started on metformin extended-release at 500 mg daily. I tend to like the extended-release formulation a little better than the immediate-release. It's fewer pills, usually one time a day. And from an adverse effect profile, I find it to be a bit more tolerable than the immediate-release. But you could certainly use the immediate-release metformin as well. This did help her glucose control. You can see her fasting ranges went back into optimal range, at least for week 2. But now into week 3, she's, again, creeping up there a bit. So her metformin ER dose was increased to 1,000 mg daily and endocrinology was brought on board at this point.
Despite that increase in her metformin, her glucose continued to creep up, now at 164 at week 5, and this does require a dose hold. So capivasertib was held for that reading and her endocrinologist started her on an SGLT2 inhibitor in addition to the metformin, specifically canagliflozin at 100 mg daily for a week, which was then escalated to 300 mg daily. This is generally the approach for initiating an SGLT2 inhibitor.
And then week 5, you can see that her fasting glucose was now under better control at 114, so capivasertib was resumed at the same dose. Maybe I'll start with Dr. Gradishar, see if you have any comments about the prophylactic strategies or management strategies that Dr. Tolaney just mentioned. And in this patient specifically, after seeing how her glucose fluctuated and how it was managed, any additional comments or do you agree with this management?
Dr. Gradishar:
No, I completely agree with how it was done. I think that you just have to be vigilant about the early start and make sure you understand what their glucose trajectory is. And then the only other comments I would make with respect to, say, GI symptoms, specifically diarrhea, we try to give it actually with food. It might actually decrease the diarrhea. There's been studies that look at that and doesn't affect the PK in any way. So concurrent with food is fine and may actually decrease some of the GI symptoms. So those are about the only points I would add.
Dr. Iyengar:
Great. All right. So that takes us to the summary and clinical takeaways from this case. And so I'll comment here. And we heard from both Doctors Tolaney and Gradishar with regard to the clinical trial data demonstrating that for patients with PIK3CA/AKT/PTEN-altered tumors in the hormone receptor–positive, HER2 negative setting, AKT inhibitors, specifically capivasertib, has been shown to extend progression-free survival in this setting.
And then in terms of prophylaxis and management, one of the strategies that I certainly advocate for is that we try and identify candidates who will be using an AKT or PI3 kinase inhibitor, try to identify these candidates early. Particularly, like in this patient, we knew at the onset that her tumor harbored a PIK3CA alteration, so that gives us that time on first-line treatment to optimize her glycemic status in preparation for an AKT or PI3 kinase inhibitors. We do need to screen for hyperglycemia risk factors, which primarily include hemoglobin A1C and BMI at baseline, and provide glucose monitoring education. We heard about glucometer education from Dr. Tolaney, that aligns with your clinic team's workflow and so forth.
We also heard from Dr. Gradishar about dietary modifications. Certainly for glycemic control, a low-carbohydrate diet can be helpful. A high-fiber diet can be helpful as well. On the other hand, if a patient is experiencing diarrhea, giving capivasertib with food can be helpful, and actually lowering the fiber intake can be helpful as well. Certainly physical activity can be helpful for glycemic control. And then finally, we heard about hyperglycemia monitoring, both at home and in the lab. This slide summarizes the time points that are optimal for this monitoring and to increase monitoring if fasting hyperglycemia develops to monitor at least twice a week.
So we'll end the case there. That brings us to the end. Please see the other segments of this round table for further discussion about the latest research in breast cancer, or you can visit ascopost.com. I want to thank Drs. Gradishar and Tolaney for this excellent discussion, and thank you for viewing.
