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, a breast medical oncologist at the Winship Cancer Institute of Emory University. Joining me today are Drs. Bill Gradishar and Sara Tolaney. I'd like to invite them to introduce themselves for us. I'll start with Dr. Tolaney, please.
Dr. Tolaney:
Oh, thanks, Neil. So I'm Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute in Boston. Thanks for having me.
Dr. Gradishar:
And I'm Dr. Bill Gradishar, breast medical oncologist at Northwestern University in Chicago. Glad to be here.
Dr. Iyengar:
Wonderful. So our final case in the series will focus on the management of a patient with metastatic hormone receptor–positive/HER2-negative breast cancer with PTEN loss and emergent ESR1 mutation. So let's dive right in here.
This is a 61-year-old post-menopausal female with a history of primary hormone receptor–positive/HER2-negative breast cancer that was diagnosed in 2015. There you can see her initial treatment, which I'll briefly summarize here. She underwent breast conservation surgery with a lumpectomy, and this yielded a PT1BN0 invasive lobular carcinoma. Estrogen receptor was positive at 99%, PR positive at 80%, and HER2 negative or null. Germline testing showed that she was BRCA1 and 2 wild type. It did reveal a CDH1 pathogenic mutation, which is consistent with her presentation of lobular carcinoma. Genomic testing with the Oncotype DX platform showed a recurrent score of 14. So she went on to get adjuvant therapy, which included radiation and tamoxifen for 5 years. Her comorbidities include hypertension and a body mass index of 27.
So after completing the five years of treatment, in 2022, she presented with intermittent diarrhea, which was initially presumed to be irritable bowel syndrome. So she underwent a bit of a workup there and some treatments and dietary modifications and so forth for presumed IBS, but ultimately the diarrhea persisted and she went on to get a colonoscopy with random mucosal sampling. And this is what showed invasive lobular carcinoma in the colon now. This was, again, ER-positive, PR-positive, and HER2 non-amplified, this time classified as 0+ or less than 10% membranous staining. Next-generation sequencing showed no actionable alterations. And given that this was lobular carcinoma, she underwent an FES PET scan, which showed multiple osseous lesions and non-specific colonic uptake.
So let me just pause there. And Dr. Gradishar, I'll turn to you. Could you comment on the workup she's received so far? Do you agree, disagree? Are there other things that you would've done and how do you put this case together so far?
Dr. Gradishar:
So this is an interesting patient because I think it highlights a couple of things. One is with both the comorbidity of an IBS diagnosis as well as a diagnosis of metastatic cancer that's lobular, we don't use FES PET that often, but this is one of the situations where it may be useful to really understand the extent of her disease as opposed to using it in patients with ductal carcinoma. So FES PET looks to be more effective as a staging tool in this particular setting.
The other thing is in the absence of any actionable mutation, we would still think that she's probably gotten sufficient workup at this time. I would certainly think about, again, endocrine therapy as a first-line choice, and I would combine it with the CD4/6 inhibitor. We don't have anything else that's actionable where we might think about a PI3 kinase mutation as allowing us to consider a triplet. And with the irritable bowel syndrome, it might be problematic anyway. So I would start with a CD4/6 inhibitor and endocrine therapy.
Dr. Iyengar:
Great. And that is indeed what she received as her first line therapy. She was started on first line letrozole plus ribociclib. She did well initially on this treatment. And by the time she got to one year at 12 months, she had another FES PET scan. And this showed a bit of a mixed response. There were two osseous lesions with increased uptake. There were three osseous lesions with reduced uptake, but there were no new lesions. So she continued on therapy and three months later, now at 15 months into first line therapy, she undergoes FES PET again. And this time it's showing increased uptake in three osseous lesions and two of those lesions are stable.
So I think we often kind of get this mixed picture, particularly with bone only disease and particularly with lobular carcinomas here.
Dr. Tolaney, what do you make of this course for this patient? And would you order additional testing at this point?
Dr. Tolaney:
It's always really difficult to assess these patients, particularly when the disease is in the bone and then in the colon where it's obviously hard to get an assessment for how the disease is really doing. Obviously, it's nice to have FES PET these days to be able to do a little bit better with our lobular patients than we traditionally have done, but still challenging. I find these cases are tough when it's just subtle changes in the bone. And I would've done what was done previously too, is continue through in the setting of mixed response. Here, it does seem like now this is the second scan where there's continuing to be an increase in uptake, at least in a few of the lesions. And so that does make you concerned that something is changing.
This is where I try to corroborate it with other things. How are their symptoms doing? What's the trend with the tumor markers? Those kinds of things are always helpful to get in addition and to put it into context. But if things look like she was progressing, tumor markers are rising, she's starting to have more bone symptoms, that's when I think about changing therapy. And then I would want to get a ctDNA assay to understand if she's developed any targetable mutations.
I do wonder in the future though, if we'll be able to look at tumor fraction changes with ctDNA to help us in these situations where I think it is challenging sometimes to understand how much has the disease really changed. So I think we'll get there, but for now, we kind of integrate clinical data with the imaging.
Dr. Iyengar:
Yeah. Thank you for walking us through that. I agree with the lobulars particularly, it can be challenging. And so I like that kind of comprehensive approach here. And this patient in particular did get ctDNA testing at this point, which now revealed an ESR1 alteration, specifically a Y537S mutation. You'll recall that when she underwent colonic biopsy initially, there were no actionable mutations. So this is a new ESR1 mutation that's now popping up. And we've seen some recent data about emergent ESR1 mutations.
Dr. Gradishar, what do you do now in this situation?
Dr. Gradishar:
So with the emergence of an ESR1 mutation, I think it does open up options. And over the last year, year and a half, we've heard numerous either preliminary data sets suggesting that we can target ESR mutations. We have drugs like elacestrant and imlunestrant now available in that setting, and these might be attractive options to consider in a patient like this. And there are several others, of course, that are being evaluated.
So I think that talking about one of those drugs in this setting and somebody who has an ESR mutation that popped up, it also highlights the fact that I think most people are aware of that these are not necessarily truncal mutations and that you have to keep it at the top of your head thinking about these things 'cause if you test it once before they're absent and they show up later, you have another option that you can exploit.
Whereas things like PI3 kinase mutations, although they rarely emerge over time, they're often more truncal. So I think just as a sort of teaching point, I think that's always good to reemphasize.
Dr. Iyengar:
Really important to remember. Thank you.
And so Dr. Tolaney, you had mentioned putting together various data pieces. You now have this ctDNA finding of the emergent ESR1 mutation. So how does that impact your selection or treatment choice for the next line of therapy?
Dr. Tolaney:
That does make you think she's now developed resistance to HER aromatase inhibitor. We also have intriguing data that we had seen from SERENA-6 where a slightly different situation than this because that was at the time of developing molecular resistance. So meaning your scans were stable, but you had emergent ESR1 detected while on AI CDK that they found that switching the backbone from AI to SERD, but continuing CDK did much better than just sticking on your AI CDK.
Obviously that brings a lot of questions about whether or not you really need to change at time of molecular resistance or not. This case is a little different though because now we're saying this patient does seem to have progressive disease on FES PET and has an ESR1 mutation. And so as someone who would be a candidate for, as Dr. Gradishar mentioned, either elacestrant or imlunestrant at this time.
That being said, I will say that I think most of us are really interested in trying to give combination strategies to patients while technically we only have monotherapy approval right now for oral SERDs. I think we're all hopeful that in the future we will start to see combinations approved either based on what we've seen recently from evERA or potentially even from EMBER-3. So right now, technically elacestrant's what's available, but hopefully in the future we'll have combination strategies.
Dr. Iyengar:
So you both mentioned moving to a novel oral SERD given that ESR1 mutation. And that's indeed what happened here. So her treatment was changed now to elacestrant. Her ribociclib was actually continued. And I think we have data from ELEVATE and other smaller trials showing safety of these combinations here. So that kind of got snuck in there, if you will. And so she continued on ribociclib and elacestrant was started, and at nine months now, so she's well for nine months, her imaging, her FES PET shows a new sacral lesion. The other lesions are stable to slightly increased uptake.
So given the emergence of this new metastatic site, she has a biopsy of the sacral tumor. This is invasive lobular carcinoma, ERPR positive, HER2-negative or zero plus. And now we're seeing PTEN loss. So this is a new alteration here that we're seeing in the tissue PTEN loss.
So Dr. Gradishar, now given this molecular evolution, what would be your treatment approach?
Dr. Gradishar:
Well, again, I think the decision has to be, is she still endocrine sensitive? And she did get some distance out of elacestrant, maybe not as much as we would've liked, but not bad. And if she does not have anything threatening, immediately threatening viscerally, then I would think about another endocrine agent. And because she has an AKT abnormality, I would think of capivasertib with fulvestrant in all likelihood.
Dr. Iyengar:
Great. And that is indeed what happened next. This patient's treatment was changed to fulvestrant plus capivasertib. At three months on this therapy, her imaging showed stable to slightly increased uptake in the osseous metastases. She was continued on therapy. At six months, her FES PET showed increased uptake and new osseous metastasis with new hepatic metastasis at this point. So now at this point, her treatment was changed to trastuzumab deruxtecan, remembering that her HER2 expression was zero plus.
Dr. Tolaney, do you agree with this treatment choice? What do you make of this treatment course?
Dr. Tolaney:
Yeah, here I think you have choice. So certainly we know from DESTINY-Breast06 that T-DXd is approved as the first chemotherapy that patients can get with metastatic ER-positive disease if they have HER2-low or HER2 ultra low expression. It sounds like given the zero plus read that she's ultra-low. And so certainly is a candidate for T-DXd and she now has visceral involvement with new hepatic lesions, so it's not unreasonable.
That being said, sometimes I will use oral capecitabine for patients like this. I do find that it's a reasonable option. Technically, T-DXd is superior to capecitabine in this setting, but they could always get T-DXd next and allows them to continue on an oral drug. And so if this patient was, her GI symptoms were okay, I think that's the issue here. Obviously capecitabine will cause diarrhea. We need to make sure she's absorbing oral drugs well given her lobular cancer involvement, but if her gut symptoms are okay, then capecitabine, I think would have been a nice alternative to consider too.
Dr. Iyengar:
Great. Dr. Gradishar, any other comments about how you would manage this patient?
Dr. Gradishar:
No, I agree completely with how Sara outlined her thinking. I would echo that completely.
Dr. Iyengar:
Great. So we'll end with some key clinical takeaways here. As we've discussed in a patient like this with pure lobular carcinoma, FES PET can be superior to FDG PET for detecting and characterizing ER-positive invasive lobular carcinoma and combining it with other diagnostic tools or monitoring tools like ctDNA may further improve our ability to monitor treatment response.
Novel SERDs are superior to fulvestrant monotherapy for ESR1 mutant tumors. We've now seen that data for multiple novel SERDs, and there are emerging data to support the safety of combinations of these novel SERDs with molecular therapies, primarily early phase or phase two data, and we await the results of ongoing larger phase three trials to confirm the efficacy of these combinations.
And then finally, PTEN loss, which this particular patient had, is a mechanism of acquired resistance to CDK4/6 inhibitors and AKT inhibition therapy such as with capivasertib is active in patients who have tumors with PTEN loss. We certainly think about patients with PIK3CA alterations and AKT alterations, but patients with PTEN loss are also candidates for capivasertib.
So this brings us to the end of this case. Please see the other segments for further discussion about the latest research in breast cancer or visit ascopost.com. Thank you, Dr. Gradishar, and thank you, Dr. Tolaney, and thank you to you all for viewing.
