Dr. Virginia Kaklamani:
Hello, welcome to The ASCO Post Roundtable Series on Next-Generation Therapies for Metastatic Hormone Receptor–Positive Breast Cancer. I'm Dr. Virginia Kaklamani from UT Health, San Antonio. Joining me today, I have Dr. William Gradishar and Dr. Komal Jhaveri. Bill, would you like to intro-duce yourself?
Dr. William Gradishar:
Sure. Bill Gradishar, Professor of Medicine at the Lurie Cancer Center, Northwestern, in Chicago. Happy to be here.
Dr. Kaklamani:
And Komal?
Dr. Komal Jhaveri:
Hi. I am Komal Jhaveri, breast medical oncologist at Memorial Sloan Kettering Cancer Center. Thrilled to be here with you, Virginia and Bill.
Dr. Kaklamani:
Thank you both for being here today. So today we'll be discussing the treatment and management of metastatic breast cancer with three patient cases. Our first installment will focus on a patient with ESR1-mutated metastatic breast cancer. Let's look at the case. This is HB, a 54-year-old post-menopausal woman, who is diagnosed with a left ER 90%, PR 30%, HER2 1+ breast cancer. She un-dergoes partial mastectomy, showing a 2.3-cm tumor that is lymph node negative.
She has a genomic score done, showing a score of 21, and receives radiation therapy, started on an aromatase inhibitor, and then completes five years of the AI. Then two years after completion, she presents with back pain. Imaging shows three lesions in the lumbar spine, and a biopsy of one of the lesions confirms that this is metastatic HR-positive breast cancer. Now ER is 80%, PR 40%, and the HER2 remains as 1+. A couple of things that come out of this. First of all, what do we do next, as far as other testing? Bill, what would you do in clinic?
Dr. Gradishar:
Well, today—literally today—our first-line approach is still to use a CDK4/6 inhibitor with endo-crine therapy. There may be a role for a newer drug if it gets approved. If we find, for example, that the patient had a PI3 kinase mutation, where you could add yet another targeted agent, inavolisib, but that's not today. I'm sure we'll discuss that data, suggesting a triplet in those that harbor a PI3 kinase mutation, could have an advantage over simply using a CD4/6 inhibitor and en-docrine therapy. But today, I would use the doublet. I think you could make a case for doing NGS testing now, even though you wouldn't act on it today. But that's how I would proceed.
Dr. Kaklamani:
Komal, would you do NGS testing in that first-line setting, and if you would, what kind of testing would you do?
Dr. Jhaveri:
Yeah. No, I think it's a fantastic point to discuss. As Bill was pointing out, I think the data that we now have with the triplet regimen, with the PI3K inhibitor, I would do that for that patient that was enrolled on that clinical trial, which is so-called your endocrine-resistant tumor that has either recurred on or within 12 months of their endocrine therapy. I think we still need to figure out if strategies like this need to be studied, evaluated, and proven to be effective in endocrine-sensitive settings as well. But PIK3CA mutations at truncal and clonal mutations.
Unlike ESR1 mutations, which we'll talk about a whole lot today, PIK3CA mutations, whether tested from the primary tumor or metastatic tumor, they should be seen consistently throughout the course of the disease. If we were to get an NGS, I think it could be done from the tissue that has already been taken to prove metastatic disease. We already have that available.
That information might be coming in handy, even if we did not use it in the first-line metastatic setting, because we could certainly offer targeted therapies for PIK3CA mutation, if and when there is progression on the first-line CDK4/6 inhibitor therapy. I would think that, right now, if I were to choose, it would not to be change my treatment for the first line, but to potentially offer a PI3K-targeted therapy in the second line, which might be available from the NGS testing that we would do today.
Dr. Kaklamani:
Yeah. I do something very similar, mostly so that I don't forget, and so that I can plan my second-line therapy as well. When you get that NGS testing, you potentially find other things. You might find a TP53 mutation, you might find other things that help you understand what the potential PFS would be for this patient. We know that with CDK4/6 inhibitors, the PFS around a couple of years. But maybe that changes if this is a P53 mutation the tumor has as well.
We already saw that the ER and PR just decreased a little bit from the initial presentation to meta-static disease, so I feel that that would be beneficial.
She receives denosumab, letrozole, and ribociclib as first-line therapy. I know this is not our focus for today, but how about the fact that she received ribociclib? Would that be something that the two of you would do? Would you be agnostic as far as which CDK4/6 inhibitor to use?
Dr. Gradishar:
I think the data that's been emerging, they're all effective drugs. That's the baseline thing. I would-n't feel bad if one fell off the face of the earth. We still have three good drugs, but the most com-pelling data right now, I think, is with ribociclib, followed by abemaciclib. Then, palbociclib—real-world surveys, et cetera, suggest it may be equal, but from the clinical trials, it isn't equal in terms of efficacy and in terms of overall survival advantage. I would tend to use ribociclib.
Dr. Jhaveri:
I agree with Bill. Yeah, I do something similar to Bill, as well, that my practice has now started fa-voring ribociclib over palbociclib, which was my go-to choice, I think, up until we got the overall survival data consistently from the MONALEESA program. Unless there is a QTC issue that are multi-ple medications that are really coming in the way, that might make me worried about this baseline QTC value is really high, my choice is ribociclib. That doesn't happen very often. I haven't seen that happen very often in my practice, so I've been fortunate with that.
Dr. Kaklamani:
She receives that triplet therapy and has a tumor response that last 26 months, which is pretty much standard. But that's what we've seen with most of these clinical trials, anywhere between what 24 and 28 month median PFS. At that point, she's now found to have two new liver lesions and progression of her bone disease. The question is, "What do we do next?"
Dr. Jhaveri:
I think, at this point, when I have progression on a CDK4/6 inhibitor, I would tend to do a liquid biopsy. This is particularly helpful to guide therapies, not only because, again, you could confirm mutation such as PIK3CA mutations, but very importantly, you can also uncover ESR1 mutations, which we know get acquired with endocrine therapy under the selective pressure of aromatase inhibitors, which she's on. She had it for a decent amount of time, for 26 months. I think we have therapies that have now become approved for ESR1 mutations as well. She has this disease which responded how we would have hoped she would have on a triplet regimen. I would check for a liquid biopsy to see if she has ESR1 mutations, or any other mutations that might help me guide my treatment choices.
Dr. Gradishar:
Yeah, and I agree. The duration suggests she's endocrine sensitive—the PFS on the CD4/6 inhibitor. I just wanted to throw in, even though this patient doesn't fit the criteria perfectly for RIGHT Choice, or Young-PEARL, or PEARL, there's often the notion that you have to give chemotherapy because there's liver lesions. We know that endocrine therapy can be as effective, so I think that that's still an important point to make.
Dr. Kaklamani:
That's a great point to make, Bill. How do you decide, in that second-line setting, who to switch to chemotherapy and who to continue endocrine therapy?
Dr. Gradishar:
I think somebody who's got disease blowing up in front of your face, and that sounds rather de-scriptive in a way, but it's not. It's somebody who's got rapidly progressing—you have a narrow win-dow for those kind of patients, because they're getting to a point where you may not be able to give them chemotherapy. But it's somebody who's got bulky, rapidly progressing disease, may be the one where I'd be inclined, obviously, to take the course of chemotherapy.
Dr. Jhaveri:
I would agree. I think I would say that the duration of therapy that we had, fortunately, in this pa-tient was 26 months. But sometimes, we see patients who really blow through their first-line ther-apy very, very quickly. If somebody has had a response on their first-line CDK4/6 inhibitor for 6 months or shorter, or less than 12 months, that's a tumor I'm worried about.
That's a tumor that's trying to tell us that they're not necessarily behaving the same way endocrine therapy combinations are supposed to derive benefit from. There I might be tempted to think, "Okay, should I be doing something differently to slow down the pace of this disease?" Certainly, a disease burden, and duration of first-line therapy does help guide as to what approach should be taken in the second-line setting.
Dr. Kaklamani:
She has a liquid biopsy performed, then that shows an ESR1 mutation. And so now, Komal, what would you do as your next step of therapy?
Dr. Jhaveri:
Okay, so here in this case, this patient doesn't seem like, from the liquid biopsy, has other muta-tions, perhaps, that I need to worry about a little bit at this point. Hopefully, there are no other concurring mutations that make me wonder what complex decisions I will need to make. But be-cause she's responded really well on their first-line therapy, or durably to their first-line therapy, in this case 26 months, and ESR1 mutation is serving as a surrogate for endocrine sensitive, in addition to that duration of therapy, I think I would apply the data from the EMERALD trial that led to the approve of elacestrant, an oral SERD, and offer this patient elacestrant, which gives good quality of life as it's very well tolerated.
Dr. Kaklamani:
Bill, would you do anything different?
Dr. Gradishar:
No, I agree. I think, again, data you presented, the duration on the prior CD4/6 inhibitor would make you think that this patient is likely to benefit from elacestrant, to a greater degree than counterparts who had a shorter duration. Yeah, that's exactly what I would do. Again, today it's monotherapy, tomorrow or in the near future it may be combo with elacestrant, but today I would use monotherapy.
Dr. Kaklamani:
I would do the same thing as well. I think it's important to try to keep this patient on endocrine therapy for as long as we possibly can. We have other options. We have everolimus that we can combine with endocrine therapy. But when we look at toxicity profile between single-agent endo-crine therapy and combination, obviously the single agent is going to be more favorable, and I'd rather do this for the patients than move on to combination. Then I can move to combination in that third-line setting, hopefully getting a nice response from elacestrant as well.
To summarize the first case, I think the key clinical takeaways are going to be that molecular profile of tumors is important, and can provide therapeutic options for our patients. Liquid ctDNA testing is more accurate in identifying these ESR1 mutations, because those are subclonal events. By look-ing at the primary tumor, you may not be able to capture all of these ESR1 mutations that the met-astatic sites may have developed during endocrine resistance.
The frequency of these ESR1 mutations increases, and so looking at ESR1 mutations in that first-line setting may not be as accurate as looking at it in the second, third line, because they do build up over time. Elacestrant, as well as other novel oral SERDs are coming out very soon. Komal is going to be sharing some of those clinical trials, that hopefully we'll be seeing in the next few years. They've really transformed the field in patients with ESR1-mutated tumors.
This brings us to the end of the first case. Please see the other segments for further discussion about the latest research in metastatic breast cancer, or visit ascopost.com.
