Dr. Iyengar:
Welcome to Balancing Benefit and Burden: Managing Toxicities in Hormone Receptor–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 my two colleagues and friends, Dr. Gradishar and Dr. Tolaney. I'll let them introduce themselves. Dr. Gradishar, let's start with you.
Dr. Gradishar:
Sure. Bill Gradishar. I'm a Breast Medical Oncologist at Northwestern University in Chicago.
Dr. Tolaney:
And I'm Sara Tolaney. I'm a Breast Medical Oncologist at Dana-Farber Cancer Institute in Boston.
Dr. Iyengar:
Wonderful. Thank you. So, we'll jump right into our case today. This is a case of a 58-year-old postmenopausal female who presented initially with a breast mass and a persistent cough. Her past medical history includes hypertension, diabetes, hyperlipidemia, and obesity, with a body mass index of 31. Her current medications include lisinopril, hydrochlorothiazide, metformin 500 mg twice a day, as well as atorvastatin.
So, she undergoes a workup, essentially for her breast mass, as well as a staging workup, including a PET scan. We'll just sort of cut to the chase here, and show you on the slides, representative images from her PET-CT. There you can see that she indeed does have an FDG-avid primary breast mass, including uptake in the axillary lymph nodes, the ipsilateral axillary lymph nodes.
But we also see uptake in some pulmonary nodules, highlighted in the image on the bottom there. What's not shown here, is that she also had uptake in some hepatic nodules as well. So she undergoes a biopsy of that primary breast mass, and this indicates invasive ductal carcinoma, ER-positive at 80%, PR-positive at 70%, and HER2-negative, null by IHC.
So, let's pause there and talk a little bit more about her workup. Dr. Tolaney, what additional testing at this point would you order for this patient?
Dr. Tolaney:
So, it looks like she's presenting with de novo metastatic disease, that she had a primary breast mass, and now has some liver and lung metastases. While we've biopsied her breast mass, and we haven't yet biopsied a distant site of disease, and usually I do like to confirm that someone has pathological metastatic disease, and so, I would see what is easiest to biopsy, probably a liver lesion, for example. Get that biopsy, make sure it is consistent with the breast primary.
Also want receptors off of that metastatic site. Additionally, we usually like to get genomic testing done off of the tumor. So, if we're biopsying, for example, the liver, it'd be nice to send that off for next generation sequencing, as well as potentially consider ctDNA testing. I also like to get germline testing in patients who have metastatic disease, so we usually want to understand if they could have, for example, a BRCA alteration. So that would be some of the initial workup that I'd want done.
Dr. Iyengar:
Great. Very comprehensive. And so, we'll go to her workup next. Essentially this is what was done. She had next generation sequencing performed on that primary breast tumor biopsy. This yielded a PIK3CA alteration, specifically an E542K mutation. She also had ctDNA tested, and this was undetectable at this point. Her baseline hemoglobin A1C was 6.9%.
As you mentioned, Dr. Tolaney, she underwent a biopsy of a distant site to confirm metastatic disease, in this case, a biopsy of a liver lesion. This yielded invasive carcinoma that was consistent with her breast primary, also ER-positive, PR-positive, and HER2-null. Next-generation sequencing on the liver lesion also yielded the PIK3CA alteration.
So, Dr. Gradishar, I'll turn to you next, and perhaps you could synthesize this data for us and walk us through how you select your first-line treatment in this patient?
Dr. Gradishar:
Sure. So in this patient, again, the general approach is to try to use endocrine therapy before pivoting to chemotherapy. I mean, that's sort of a dogma we try to educate clinicians on, and I think that's true in this case as well. The next generation information from the NGS testing reveals that she has a PI3 kinase mutation.
We're starting to look at that early and earlier in the cascade of treating patients. It may turn out 2 years from now, that we may be doing something very different in the first line setting. But for most patients today, I would still think about giving a CDK4/6 inhibitor and an endocrine agent as a first-line therapy.
The other thing I think we have to keep in the back of our head, as you describe this case, is this patient has a few comorbidities that could be relevant, not only to choice of therapy, but how she tolerates them. Including hovering at a higher hemoglobin A1C, a BMI that's higher. So, all of these things go into the mix when we're thinking about how we're going to approach the patient.
But although you could perhaps think about a triplet, particularly if they were a rapid progressor after adjuvant AI therapy, I would still be more inclined to use a CD4/6 inhibitor and an AI in this patient.
Dr. Iyengar:
Great. Yes. I think that was the tricky part about this case, is that she would, as you highlighted, technically be someone who might qualify for INAVO120, with the exception of the hemoglobin A1C. And certainly, that A1C and her comorbidities raise her risk of significant hyperglycemia.
And so, in this particular patient, she was indeed started on first-line CDK4/6 inhibition, plus letrozole. So she specifically got ribociclib plus letrozole. Clinically, she noted a response during treatment. She noted reduction in the size of the breast mass, and her cough that she presented with also resolved. Her initial imaging also confirmed treatment response with a partial response.
That being said, now at about 12 months, she noted that her breast mass started to feel larger, and her imaging with a PET-CT at this time showed new uptake in enlarged mediastinal lymph nodes, as well as a new liver lesion. So, she had some additional biomarkers performed at this time. ctDNA was evaluated again. Which again, identified that PIK3CA alteration, an E542K alteration or mutation, with a variant allele frequency of 1.4%. At this point, her hemoglobin A1C was 7.2%.
So now we're thinking about how we select second-line treatment for a patient like this. Dr. Tolaney, let me ask you how you would approach second-line therapy for this patient?
Dr. Tolaney:
Yeah. So, she didn't get a very long time off of her first-line AI CDK. If this is a de novo patient, for example, with a PI3K mutation, it makes you wonder that the PI3K mutation is driving the shorter PFS potentially in this case. We do see that the relative risk reduction from AI CDK is similar with your PI3K mutant or wild type, but you see the absolute PFS numbers with AI CDK tend to be lower in the PI3K mutant patients, which I think is probably a reflection of what's going on in this patient.
So, it does make you interested in trying to turn off that PI3K signaling pathway, thinking that it may be a potential mechanism of endocrine resistance here. So, the challenge, as I think this case is bringing out, though, is that she does have a hemoglobin A1C a little over seven. And so, knowing that agents that hit the PI3K pathway are going to cause hyperglycemia, and this patient already has issues, that is something that is concerning.
Capivasertib has been studied in patients with A1Cs as up to eight, so it can be used in this setting. But I think it does make you cautious. And so, I would want to better understand what her current management is for her underlying diabetes. I probably want to talk to her endocrinologist, assuming she has one, to think about how we could optimize her glycemic control.
As someone who's not on metformin, these are the patients who I typically will put on prophylactic metformin when starting patients on capivasertib, because I am worried about that. So, I think about fulvestrant/capivasertib here, but I would want a discussion with endocrine about optimal ways to prevent high blood sugars.
Dr. Iyengar:
Yeah, absolutely. It turns out that this patient, despite being on metformin, was not seeing an endocrinologist, and that might be reflected in the poor control of her diabetes.
Nonetheless, as you pointed out, capivasertib can be used cautiously in patients with A1C up to 8%. And so, she was started on capivasertib plus fulvestrant as her second-line treatment. Now, in the last case, we spoke a little bit about monitoring and prophylactic strategies for patients being treated with PI3-Kinase or AKT inhibitors.
Now, a patient like this with significant risk factors, metabolic risk factors, Dr. Gradishar, how would you approach monitoring and prophylaxis for a patient like this in whom you're starting capivasertib?
Dr. Gradishar:
Well, this patient is at risk for her glucose really going off the wall. So, I think you have to be even more vigilant than maybe we would typically be, in somebody that was euglycemic right from the get-go.
So, in this patient, again, you'd probably be checking her fasting glucose with a glucometer several times a week, and making sure you understand that you have her under good control, because if it gets up into the 500 or beyond range, then you've got real problems compromising the ability to actually treat her. And of course, she's at risk for other problems related to hyperglycemia.
So, I think vigilance in this case is even more pressing, and the need to get her sugars under control and maybe even transition even more quickly to an SGLT2 drug may be in her future.
Dr. Iyengar:
Yeah, well said. And so, we'll look at her glycemic management here. So, just kind of recapping, her A1C during her first-line treatment was 6.6%, and then at initiation of second-line treatment with capivasertib was 7.2%. She was on metformin immediate release 500 mg twice daily. This was changed.
We did get her in to see an endocrinologist. So, this was changed to metformin extended release 1,500 mg daily, when she started capivasertib. She was monitored with home glucometer testing two to three times per week for the first month, then weekly thereafter.
So let's go through some of her glycemic readings here to get a sense of how she did. So, she started off okay. But as you predicted, Dr. Gradishar, her glucose did start to go on the rise there. She started off at 148 at day 2, which then popped up to 254 by the time she got to week 2, day 5. So she was brought in for labs.
Her fasting glucose at that time was 260. Now she also, when she came in, noted some symptoms. She had dysuria for 2 days, and her UA was positive for nitrites and white blood cells, no ketones in her urine. And so, at this point, capivasertib was held, and endocrinology was consulted again.
This is a little bit of a red herring here, to point out the fact that infections can certainly drive up fasting blood glucose levels. So, she was started on nitrofurantoin for UTI treatment, and she received antibiotics for seven days. By week 5, her fasting glucose came down to 142. So, this is essentially with antibiotic treatment. So, capivasertib was then resumed at the same dose level.
But now in week 6, she pops up again with a fasting glucose of 162. Capivasertib is held at this point, and her metformin extended release increased to 2,000 mg daily. Now, she wasn't able to tolerate that. That's a pretty hefty dose of metformin. So, she was experiencing abdominal cramping, significant abdominal cramping, and metformin had to be reduced back down to 1,500 mg daily.
At this point, an SGLT2 inhibitor with canagliflozin was started. I think to your point, Dr. Gradishar, maybe starting that earlier may have been more beneficial for her. Capivasertib was then resumed at one dose level reduction, given her multiple hyperglycemic events on metformin, and now on canagliflozin. But now at this dose reduction with the two anti-hyperglycemic agents, her blood glucose was now under control. There you can see her fasting plasma glucose ranges are now in range.
So, we'll wrap up this case by highlighting a few key clinical takeaways here. In this particular patient who has high-risk PI3 kinase–mutated metastatic breast cancer, as we discussed, this is a patient who we would consider potentially for triplet therapy, based on the INAVO120 trial.
But in patients like this who have risk factors that would not have, or would have prevented eligibility for trial enrollment and are not suitable for that first-line regimen with inavolisib, then an AKT inhibitor like capivasertib, which allowed for a looser glycemia control at enrollment, might be appropriate. But as I think we've all pointed out here, we have to be very careful about monitoring glycemic index very closely.
So that leads to the second point here, and that is, when you do initiate AKT or PI3 kinase inhibitors, consider hyperglycemia prophylaxis with metformin, especially for our patients at elevated risk that's defined as an A1C of 5.7 or greater, pre-diabetes, a BMI of 30 or greater, or elevated baseline fasting glucose. I would certainly start metformin in those patients.
And then finally, start metformin or escalate the existing dose and add other agents like an SGLT2 inhibitor to treat the hyperglycemia, with one note here is that you do want to avoid, if you can, insulin secretagogues, like sulfonylureas and glinides, because these can actually cause hypoglycemia. But certainly a conversation with our endocrinology colleagues, excuse me, is important there as well.
And then the last thing I'll note here is that prophylactic extended-release metformin initially at 500 mg daily before initiating capivasertib, and then escalating as needed, can be a helpful prophylactic approach as well.
So, that brings us to the end of this case. I want to thank Dr. Gradishar and Dr. Tolaney for their insights and this great discussion here. Please see the other segments for further discussion about the latest research in breast cancer, or visit ascopost.com. Thank you.
