Joyce A. O’Shaughnessy, MD: Let’s go on to this second case now, which I’ll present here for us. It’s a 62-year-old female who presented with a 6-centimeter, right breast mass present for about a year, no family history, and CT scan shows 2 lung nodules, the largest 1.8 centimeters, bone scan normal, liver function test normal, biopsy of the breast shows grade 2 invasive ductal breast cancer, ER [estrogen receptor] 100%, PR [progesterone receptor] 0, and HER2 IHC [immunohistochemistry] 0. She does have a fine needle aspirate of a lung nodule that shows adenocarcinoma consistent with her breast primary, with similar markers. So she is presenting de novo metastatic T3N1M1 with [an ECOG] performance status of one with her disease in her lungs.... So she’s treated with an aromatase inhibitor [AI] plus a CDK4/6 inhibitor. She has a partial response, both in breast and lung, and then goes quite a long time—32 months after treatment initiation. She developed some pulmonary symptoms, cough, dyspnea on exertion, and she is found to have enlarging lung nodules and new lung nodules. Bone scan now shows progression of disease in thoracic spine and ribs, performance status of 1, liver function still normal, hemoglobin A1C is normal. So, she has ctDNA [circulating tumor DNA] sent [for testing], and she’s progressing on the CDK4/6 [inhibitor].… It’s negative for PIK3CA, ESR1, HER2 mutation, and some of the other things we look for that would be able to give her a very specific, targeted therapy. So I’m going to go ahead here because I’m going to go on and talk about other scenarios. This is one scenario. Here is a patient, she’s got mild pulmonary symptoms, she’s got bone and lung, and she’s done well. She’s done well for quite a long time, but she doesn’t have an actionable mutation. So I’m going to come back and see what you think about this. But she’s treated with exemestane [and] everolimus. So I’ll be curious to see if that would have been your choice. And she had 8 months of stable disease, and then she progressed … Eight months is not bad post CDK4/6, and now she’s got progression of disease, and it’s still in the lung and bone, and she’s treated with capecitabine. But she only gets about 5 months of treatment on capecitabine. And now she’s got 2 new liver metastases. So let me just ask here. In terms of evaluating her, we’re not told that she had another ctDNA [test] after progression on everolimus and exemestane before she went on capecitabine. Would that have been an opportunity to get another ctDNA [test]? Because you didn’t have any actionable mutations the first time. How often are we going to find a PIK3CA, how often are we going to find a ESR1 or HER2 mutation, something targetable where she didn’t have anything before? So now she’s got new liver [metastases].… She initially was HER2 0. Should we biopsy something else to see if she’s got HER2-low? So let me ask Komal. What do you think, and what would you have done for her second-line treatment as well?

Komal Jhaveri, MD, FACP: This is post capecitabine you are talking about, right?

Joyce A. O’Shaughnessy, MD: Yes. Now she’s [post capecitabine]. But let’s wait on that for a second because we want to talk about the ADCs [antibody-drug conjugates] in a second. Going back [to] post CDK, 32 months on her CDK4/6, but on ctDNA she didn’t have anything to go after. So she was given oral everolimus [and] exemestane. So would you have done that with that? And then she went on to [capecitabine] without more ctDNA [testing] in the meantime.

Komal Jhaveri, MD, FACP: You know, I have become a convert of fulvestrant [plus everolimus], and, of course...[that has] to get approved. You know, I would go with that, given the efficacy that we see with the everolimus in the world datasets compared to what we see here. Of course, the clinical trial would be best. We have so many clinical trials in the second-line space that are currently ongoing, and that one could apply too…we have [the phase 3] ELAINE III [trial; NCT05696626], [looking at] ESR1 [mutations]. This patient does not have an ESR1 mutation…but let’s assume there’s no clinical trial and there are no alterations found, and she [had] a durable first-line response…for 32 months. I would have chosen fulvestrant-everolimus as an option until…gets approved. I don’t recall the last time I used exemestane...[there’s] nothing wrong with it. There [are] no ESR1 alterations. If [an] oral drug is preferred and [an] injectable is not preferred, I think it’s very appropriate. I just feel like it’s probably a better partner to use fulvestrant, and that’s been my approach post-AI...and that’s what I would have done for this patient.

Joyce A. O’Shaughnessy, MD: Thank you.… I’m an exemestane-everolimus person without an ESR1 mutation because I have found that if patients get at least 6 months—this is just my anecdotal experience—that if they get 6 months and they get clinical benefit and then they progress, I often find that just going back and targeting the estrogen receptor is helpful because they seem to escape at least in part to the estrogenreceptor—it gives you another chance to do a ctDNA [test]. And now if you’ve got an ESR1 mutation, you haven’t chewed up the estrogen receptor with fulvestrant, so you can go after it with elacestrant. So sometimes I do that to try to keep the ER intact and get that baby to be the escape mechanism, as long as there’s not an ESR1 mutation there. So…, Pedram, what would you have done with this patient? She’s got no targets after she’s progressing on [a] CDK4/6 [inhibitor].

Pedram Razavi, MD, PhD: My practice pattern is similar to Komal’s as well. So I have been giving a lot of fulvestrant-everolimus also when I’m giving everolimus. But I can see your point, and I think that’s completely acceptable and appropriate for the patients who don’t have a ESR1 mutations to give them exemestane everolimus as well. So I think both approaches are appropriate. This patient obviously had a lot of shortness of breath. So I would have a very close eye on the everolimus-induced ILD [interstitial lung disease] in these types of patients and make sure that I have an eye on that. But overall, [it] seems like the patient did well. I would have given the patient fulvestrant-everolimus. That’s just the way I practice as well, but nothing wrong with everolimus-exemestane. The patients, in this type of setting, obviously at MSK [Memorial Sloan Kettering] and other academic centers and [in] some of the community settings, when there are clinical trials available, these are great patients for consideration [for] clinical trials. We have novel approaches for anti-estrogen therapies, downstream of ER, [and] other forms of anti-estrogens that can be used in this type of setting, other targeted therapies that can be used in this setting. So I think these are great settings for clinical trials if it is available. But standard of care, I would have probably done the same.

Joyce A. O’Shaughnessy, MD: And then upon progression on everolimus with fulvestrant, let’s say you found an ESR1 [mutation].…You got another ctDNA [test] before you went on to capecitabine, and now you found an ESR1 mutation. There were some patients in [the phase 3] EMERALD [trial; NCT03778931], weren’t there, who had prior fulvestrant and then got elacestrant, and there was benefit? There was benefit from the elacestrant, even in patients who had prior fulvestrant. There wasn’t a big number of those patients because mostly it was fulvestrant in the control arm. But just because you’ve had fulvestrant does not mean if you’ve developed a ESR1 mutation that you couldn’t get elacestrant. I think the main point is to keep looking. Don’t just look once for the ESR1 mutation. Look again. Now, this patient was HER2 0 on her primary breast cancer, but now she’s got liver [metastases], and she’s already progressing through [capecitabine], and she didn’t do that well and now she’s got lung, liver, and bone, she’s symptomatic. You’re looking for a cytotoxic agent. Would you biopsy [her]? Komal, would you biopsy the liver at this point? And why, if you would?

Komal Jhaveri, MD, FACP: I would biopsy for 2 reasons. One, to ensure I can defeat the ER, PR, HER2, she was IHC 0 before, and we don’t have any other metastatic biopsy where we might be able to possibly deem her to have HER2, know and apply…data, and offer a trastuzumab deruxtecan, which would really be a very attractive option for her in this right setting…so that would be the first reason. And, 2, to ensure there has been no change in the tumor biology, and if there’s something else we can uncover or identify from the liver as a metastatic site that has now become a part of the disease burden. So I think I would try and do genomics again, if it’s feasible, available, and amenable financially for the patient. So I would do that, and I would certainly, at the very minimum…to find if there is HER2 1+ or 2+ that’s not amplified to apply trastuzumab deruxtecan as an option. And if it’s not, it’s persistently IHC 0, I’ll be very comfortable offering sacituzumab govitecan based on the [phase 3] TROPiCS-02 trial [NCT03901339]. So regardless, I think that inflammation will help me with my immediate next choice of therapy, and so that’s why I would definitely choose [a biopsy].

Transcript is AI-generated and edited for clarity and readability.