Dr. Adam Brufsky:
Hello everybody. Welcome to The ASCO Post roundtable series on PI3K Inhibition Strategies for Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer. I'm Dr. Adam Brufsky, I'm a breast medical oncologist and Professor of Medicine at the University of Pittsburgh School of Medicine and the UPMC Hillman Cancer Center. And so with me today I have Dr. Heather McArthur. Heather, you want to introduce yourself?
Dr. Heather McArthur:
Certainly. Great to be here with you today. I'm Heather McArthur, I'm the Clinical Director of the Breast Cancer Program and Professor in Internal Medicine and a breast cancer–dedicated oncologist at UT Southwestern in Dallas, Texas.
Dr. Adam Brufsky:
And then we have Dr. Seth Wander. Seth?
Dr. Seth Wander:
Great to be with you both. I'm Seth Wander. I'm a medical oncologist and breast cancer specialist at Massachusetts General Hospital in Boston, and Assistant Professor of Medicine at Harvard Medical School.
Dr. Adam Brufsky:
Great to have you both, and this will be a very lively discussion.
So our second installment will focus on progression after first-line treatment with a CDK4/6 inhibitor in ER-positive metastatic breast cancer. So this is a 58-year-old woman who presented in late 2022 with low back pain for 3 months. She's not had a mammogram for 5 years. On exam, she has a 5-cm fixed left breast mass in the upper outer quadrant. She has a past medical history that includes hypertension, osteoarthritis in the lower back, and is a current smoker. She's currently on omeprazole and ibuprofen. You do a mammogram. She's got a 5-cm irregular spiculated left upper outer quadrant mass. You do an ultrasound of her left breast that confirms a 5-cm irregular hypoechoic mass, with multiple enlarged left axillary lymph nodes.
You biopsy the mass and it's got adenocarcinoma consistent with breast. The ER's 40%, PR's 30%, HER2 is 2+ and her FISH ratio's negative. It's 1.2 with a copy number of 4.1. You do a CT of the chest, abdomen, and pelvis. She's got five mixed lytic and osteoblastic lesions in the thoracic and lumbar spine. Multiple liver lesions in both lobes, the largest being 4 cm, a small right pleural effusion, and her LFTs are normal. You do a bone scan, and she has multiple areas of uptake in the thoracic and lumbar spine. So what do you do now? Seth, I know what you would do, and that's why I'm asking you first. What would you do? NGS?
Dr. Seth Wander:
Yeah, here we have a patient who has de novo metastatic hormone receptor–positive, HER2-negative disease. As we were discussing with the other case, I would typically gather information here and do NGS targeted sequencing. We typically do it on both the solid available tissue and liquid, and then liquid only at progression, unless we're worried about receptor switching or there's some behavior of the tumor that would necessitate additional invasive biopsies.
I think again, this is more about banking information for the future. I don't think in this particular case, in an untreated de novo hormone receptor–positive patient, that the NGS is going to make a dramatic impact. Although we're going to have upcoming data in terms of tracking emergence of ESR1 and other mutations that I think could change this in a really fundamental way for the entire field. But at the moment it would be more about understanding the molecular genomics of the tumor, putting that information away for future use, and we'll get into what we would give this patient in a moment.
Dr. Adam Brufsky:
So when you do NGS, are you going to do it on her primary tumor, her blood, or both?
Dr. Seth Wander:
I would do it on any available metastatic tissue, if possible, if we did a metastatic biopsy per our prior conversation. If we didn't have metastatic tissue, I would think about doing it on the primary tumor, and I definitely would get blood targeted sequencing.
Dr. Adam Brufsky:
Heather, your thoughts on that?
Dr. Heather McArthur:
Even with de novo metastatic disease, we still aim to biopsy a distant site, so that we can determine whether the biomarkers are consistent. I think we could debate whether upfront NGS is meaningful or whether you could delay to a later date, when it might be clinically impactful. I think we have a desire to understand upfront the biologic drivers of disease, but it wouldn't actually change the management at this point, which would be an upfront AI and CDK inhibitor in the first-line setting.
Dr. Adam Brufsky:
Got it. You know, I'm feeling kind of... Seth, that's why I asked you first. I know you love NGS, you love ESR mutations, you're going to love SERENA-6, which is what we're kind of alluding to, which is basically monitoring ESR1 mutations and changing therapy when an ESR1 mutation arises. I think SERENA-6, I don't know when this is going to be presented, but SERENA-6 will be presented at ASCO. I think most of us know this. There was a press release on it at the time of this recording, suggesting that it is clinically significant benefit to that strategy, but nonetheless I think that we're going to see the real results at ASCO.
So the issue though, Heather, is without that, would you treat with an NGS? I probably would. I think that if push comes to shove, I could do it. And I agree, an AI and a CDK4/6 to begin with, and obviously a bone agent, probably zoledronic acid because it's generic. But I think that I could go either way with this. I think it's going to be a moot point, obviously, I think after SERENA-6, I believe. I'm curious to hear what you guys have to say. So let's just say we do it... Well, let's say we don't do it. And so how would you monitor the patient? Okay, so what would you do? How often would you do CTs? I think I remember somebody, I'm forgetting who it was, it may have been from the Harvard system, published a paper a number of years ago suggesting that we only needed to CT scan people serially every 6 months with metastatic disease, and anything less was no good. Do you guys agree with that? How often would you do CTs? Heather?
Dr. Heather McArthur:
I don't agree with that, because I think there's huge variation, and we don't know how this person is going to respond to first-line therapy, and there's prognostic information to be had and an opportunity to pivot in a clinically meaningful way to an alternative therapeutic strategy if you identify people who have primary endocrine resistance.
So I don't agree with that. You know, we would expect the first-line approach to confer about 2 years of durable response to therapy before moving on thereafter. But when you look at the PFS in the second line and beyond after a CDK4/6 inhibitor exposure, they're still in the order of 3 to 6 months. So I don't think, except for our exceptional responders who demonstrate that they have long, durable disease, that we're really at a place where we can really advocate for shorter interval imaging.
Dr. Adam Brufsky:
Fair enough. And so Seth, I know you wanted to answer, and I'll pose the question a slightly different way too. Would you use circulating tumor DNA yet? Would you use tumor markers? Anything else besides CTs at some interval?
Dr. Seth Wander:
I completely agree with Heather. I typically, especially when we're starting a new line of therapy, make the scan interval somewhat tighter. To the point that you just made, some of these patients have intrinsic or upfront resistance. As the patient continues to demonstrate clinical stability, we may space those scans further and further out. Certainly for these excellent long-term responders, maybe small amount of bone-only oligometastatic disease, I might do twice a year or something like that.
To answer your question Adam, tumor markers, I think, can be helpful in a subset of patients, particularly if they're very elevated to begin with. In other patients, due to the biology of the disease, they don't really produce tumor markers in a reliable way. I currently do not use circulating tumor DNA as a metric of response on treatment without clinical progression though I do think that we as a field are moving in this direction. SERENA-6 will be the first of probably a large wave of clinical trials, not just in breast cancer but in any tumor where you have genomically actionable alterations in the blood.
And I do believe to deliver on this really exciting promise of personalized medicine and precision oncology, we are moving into a world where we are getting better and better at understanding and deploying technology like circulating tumor DNA. It will help us understand not just the total burden of disease across the body, but also the emergence of these subclonal resistance drivers. That will allow us, potentially, to change therapy in the absence of overt clinical and radiographic progression, again depending on the data that we see from SERENA-6 and other studies like that. So at the moment I'm not doing it, but I anticipate at some point in the relatively near future that there will be some big paradigm shifts in this area.
Dr. Adam Brufsky:
Great. So let's go on. So she gets ribociclib, letrozole, and zoledronic acid. She gets scanned serially by CT every three months. She does get a CA 27.29 monthly. Her scans initially improve, with sclerosis of her bone lesions, reduction of her largest liver lesion of two centimeters, and her CA 27.29 is uninformative. So this is one of those that made no difference. It was 35 and it didn't change. But her back pain got better.
However, after 9 months of therapy, her liver lesions on her CT start to progress. The largest one is now 6 cm. Her ALT is now a hundred, AST is 300, both of which are a little bit abnormal based on the normal values. But her bilirubin is still normal at 0.8. She remains asymptomatic. So now what do you do? Do you re-biopsy or get an NGS? Do you get an NGS on a biopsy, on liquid? What do you guys do?
Dr. Heather McArthur:
I mean, this is a bad situation, the poor prognosis with progression within 9 months of CDK4/6 and aromatase inhibitors, so that has big prognostic impact in terms of probability of response to subsequent lines of therapy. I would do a liquid biopsy for her at this point. I don't think I'm so much looking for... And that's assuming that I don't have genomics on the original tissue. I'm looking for ESR1 mutation, although I don't think that the ESR1 mutations with progression within 9 months is what's driving resistance to disease, because it's not really an adequate exposure to pivot to an ESR1-mutated driver of disease. So I'm probably more likely looking for PIK3CA mutation that's actionable here.
Dr. Adam Brufsky:
Got it. So Seth, I'll ask the next question to you. So they do a liquid NGS, and it's positive for the Y538S ESR1 mutation, as well as, she's got two mutations, the H1047R PI3K mutation. So Seth, what do you do now?
Dr. Seth Wander:
Yeah, I agree with all the comments that Heather just made, and I think, Adam, this is one of the most challenging situations we're encountering right now in ER-positive second-line metastatic disease. But not for long, because we have lots of prospective large randomized trial data coming with doublet therapy. So right now the challenge that you're alluding to here is, we have monotherapy approval for elacestrant for ESR1-mutant disease in patients that have progressed on prior endocrine and CDK4/6 therapy. We now have a couple of doublet options, fulvestrant plus alpelisib or capivasertib for patients in this situation with a PIK3CA pathway alteration. Nobody on any of those trials got any of the other agents at the time that they were being developed, so we're going to have to use our institutional experiences and real-world data sets to start to look at concrete data sequencing these agents for the time being.
Eventually we're going to come to a place, and I think it's going to be sooner rather than later, where we have good safety data and efficacy data for doublets with a next generation anti-estrogen and a next-generation targeted PI3K pathway inhibitor, so we don't have to make these kind of choices between the two. But for now I think we have to decide for this particular patient which of the two options we would choose. Doublet with a PI3K pathway or AKT inhibitor, vs a single agent, elacestrant in this case given the FDA approval. We now have prospective data for imlunestrant including abemaciclib, but we don't have an approval yet for that.
So Adam, in this patient, where we have two targetable alterations, she has, to Heather's point, fairly high-risk disease. Despite having de novo metastatic disease, the ER and PR levels were moderate at best. She progressed within a year. I personally don't love the idea, in this particular case, of moving from a doublet to a single agent, and so I would probably prioritize targeting the PI3K pathway, and then it comes down to discussions about the toxicity of alpelisib vs capivasertib, the dosing schedule, the patient's comorbidities and A1c. I think this discussion of who would go to an ADC or chemotherapy is another point, although I would try to prioritize all of the available oral targeted agents first. And in any given patient, when you have these two alterations, it's going to come down to cadence of the disease, pattern of disease spread, patient comorbidities, and preferences, and it's a complex decision in today's treatment landscape.
Dr. Adam Brufsky:
Got it. Okay, so let's keep going. So she actually gets capivasertib, 400 milligrams PO BID 4 days out of 7, and fulvestrant 500 IM monthly, and she's continued on her zoledronic acid. So Heather, how do you usually monitor for hyperglycemia in these patients? What do you usually do?
Dr. Heather McArthur:
We do fasting blood glucose weekly at the onset, and intermittently thereafter. In terms of tumor response, we do bloods which are comprised of CBC, CMP, and tumor markers. We do CA 15-3, and you could do CA 27.29 as well. And then we do scans every 3 months to look at response to disease. But with respect to... Fortunately with the capivasertib combination with fulvestrant, the incidence of hyperglycemia and clinically meaningful hyperglycemia is lower than what we previously saw with the SOLAR-1 alpelisib regimen, but it still warrants close monitoring and potential dose adjustments accordingly.
Dr. Adam Brufsky:
Got it. So Seth, now you started, so it's 2 weeks later and you're doing fasting glucoses weekly, and it's 200, and you happen to have a hemoglobin A1c, so it's 5.8, so it's more acute than chronic. So what do you do at this point?
Dr. Seth Wander:
We're all becoming better diabetologists, right, across the board as oncologists, because of these agents. For this patient, obviously to Heather's point, we're watching very closely, and to your point, this is more of an acute rise, not a chronic baseline issue. We would probably think about a drug hold, dose reduction. I would coordinate closely with the pharmacy team to look at this, and the list of medications we're talking about here, metformin, SGLT2 inhibitors, even insulin...
I think we're fairly comfortable starting metformin, personally. Once we're getting into insulin territory and other things, I'm working really closely with some of my colleagues in endocrinology, and those of us who are at bigger academic centers are lucky to be able to put these folks on speed dial and help us manage some of these medical comorbidities and toxicities. But this is a challenging area. So for this patient, probably we would pause, work with pharmacy, think about adding metformin, keep an eye on the blood sugar, and hopefully be able to restart.
Dr. Adam Brufsky:
Got it. So her capivasertib is held, and she's given metformin, 500 mg PO BID, and within a week her fasting glucose goes down to 100. So capivasertib is restarted, at 320 mg by mouth, twice daily. Now it's 3 weeks later, and she has a grade 2 rash over her upper torso. Heather, what do you do?
Dr. Heather McArthur:
In response to the hyperglycemia, we would have restarted her capivasertib at a lower dose. She originally started at full dose, so we would have reduced to 320 mg twice daily. And then with the rash, typically we start with... and it depends on the grade of the rash, but we would typically apply topical steroids, et cetera. And we have dermatology. We're very spoiled, as Seth pointed out. We have endocrinology, we have dermatology at our disposal. But typically we would start with topicals, unless it were grade three and higher, in which case we would consider something oral, like steroids.
Dr. Adam Brufsky:
Great. All right, so basically after the grade 2 rash, the patient applies steroid cream to her rash, and she's given cetirizine, 10 mg a day, and within a week her rash goes down to grade 1. Hold on a second. So what would you do then? Okay? So now she still has the rash, it's grade 1. Do you keep going at the same dose? Seth.
Dr. Seth Wander:
Again, working closely with our colleagues in pharmacy and dermatology, I think it wouldn't be unreasonable to consider another dose reduction with careful monitoring. Where people land with these dose reductions, I think depends on the constellation of their toxicity experience and what some of their medical comorbidities were going in. I also think we need some data like we have for both adjuvant and metastatic CDK4/6 use, where we know at different dose levels how effective the drug is and what the benefit is, right? That's been very helpful for us with CDK4/6 inhibitors and making brisk dose reductions. But I think I would re-challenge, keep watching closely, consider maybe one more dose reduction if feasible, and keep watching.
Dr. Adam Brufsky:
Got it. So they reduced her capivasertib to 200 mg by mouth twice daily, the same thing. She continues her fulvestrant, metformin, and cetirizine. She gets serial CTs, but after 9 months her liver lesions start to progress, and now the largest one is 8 cm. Her LFTs remain roughly the same. A bit of a transaminitis for the bilirubin still is normal. What would you guys do at that point? Is it time for an ADC, do you think?
Dr. Heather McArthur:
I think so. She had only 9 months on her first-line therapy. I think she was lucky to get 9 months, rather, on her second-line therapy. It's longer than I might have expected, given the limited durability of response to first-line therapy. With progression in her liver, with an 8-cm lesion, I would be tempted, especially in HER2-low disease, to switch to an ADC.
Dr. Adam Brufsky:
Seth?
Dr. Seth Wander:
I agree. I do think we are coming to a place where we're developing better doublet therapies. I would love to be able to give this patient with the ESR1 mutation a next-generation antiestrogen. For all the reasons that Heather was just alluding to and that we discussed previously, I'm not sure I love the idea of single-agent antiestrogen right now. We can see a future where we might be able to re-challenge with either next-generation PI3K AKT pathway inhibitor, or perhaps a next-generation CDK4, CDK2 inhibitor for patients that have progressed on currently available therapies. And we're coming to a place, I think, where we're going to have those options. We already have them in clinical trials right now. But standard of care right now for this patient, I agree, and I think I would probably go for the ADC.
Dr. Adam Brufsky:
Got it. All right, so let me give some key clinical takeaways. I think first of all, the choice of therapy at first-line progression really depends on the pace of disease, the bulk of disease, and what mutations we find in next-generation sequencing. I think in a dual mutation of ESR1 and PI3K is a difficult clinical decision, but I think it's really, I think at the end of the day, based on patient tolerability and the pace of the disease.
I think the treatment options at that point would include either an IM SERD and a different CDK, an IM SERD and PI3K inhibitor, an ADC or an oral SERD. I think the side effects of PI3K inhibitors are common, but they are manageable, and usually are treated with symptom control and dose reduction. At progression of disease with a second-line SERD and PI3K, again, I think the choice is likely determined by patient tolerability and the pace of their disease.
So again, I want to thank you all for listening to this case. Please see us for other segments and for further discussion about the latest research in metastatic hormone receptor–positive, HER2-negative breast cancer, or visit the ascopost.com.
