Sara Tolaney, MD, MPH: One of the things I thought was really interesting at the San Antonio [Breast Cancer Symposium] is what to do when someone progresses on a CDK4/6 inhibitor. Let’s say this patient did start with endocrine therapy and a CDK4/6 inhibitor. We would guess [they would] hopefully have a very long duration of response, especially a de novo patient. But if they were to progress, what do you do? Are you getting genomic data, for example, up front? In this patient, let’s say you had a breast biopsy and did a liver biopsy. Would you have sent genomic information then? Would you also send it at the time of progression? And how do you think about utilizing that information to help you make a decision about what to do next?

Massimo Cristofanilli, MD: For de novo patients, the genomic test probably will not add much because treatment is pretty much set. There’s no developing resistance to treatment yet. But certainly, when a patient has progressed with short-term—and more importantly, long-term—exposure to CDK4/6, you want to know, because we now know the resistance to endocrine therapy is much more complex than we believed. Of course, there is a possibility that you can use a targeted agent if you were to find a PI3K mutation, for example, in cell-free DNA or a biopsy of recurrent disease. But that’s probably a truncal mutation, not really a resistance mutation. But we have a drug, so we can act on that.

The second is what has been extensively discussed in the last 2 San Antonio [annual meetings], certainly more in the current San Antonio [symposium], the ESR1 mutations. Not only the detection of the mutation but the specific variants. Do we have agents we can use in that setting? And are we going to use a single agent, or are we going to use a combination? In a future study, we’ll obviously see if one of these agents is effective, particularly on the ESR1 mutation, and maybe even more effective when it’s combined with a CDK4/6 earlier.

One of the studies that was presented was the PACE study. They asked a specific question regarding potential immunotherapy, and of course the single agent, the combination with Faslodex [fulvestrant] and CDK4/6—in that case, palbociclib—and then avelumab, Faslodex, and palbociclib. There’s an indication that a group of patients may benefit, but it was not statistically significant. The follow-up is relatively short.

This brings back what has been reported in the past in preclinical models, and maybe regulation of the immune microenvironment and T cells may have an impact on the long-term benefit of a patient receiving CDK4/6. This is probably the group of patients for whom we may take the opportunity to use a checkpoint inhibitor. There’s more to come. That study was rich in biomarkers, but we haven’t seen much data except for the cell-free DNA and ESR1 mutation and PI3K. But it would be interesting to follow that lead.

Now we have the new SERDs [selective estrogen receptor degraders]. Elacestrant showed an update on the EMERALD study. Camizestrant, from AstraZeneca, is becoming an important additional option. So we have at least 2 SERDS. We also have the possibility to look into the question of the checkpoint. Lasofoxifene also was presented in terms of biomarker, decreasing the allele frequency of some ESR1 mutations. The space is expanding, and what you do after CDK4/6 will depend on what the molecular test may be able to do.

At some point, maybe we will have patients who will continue on a CDK4/6, or change to a different one, like the MAINTAIN study, but would change the endocrine agent to combine in order to affect the molecular feature, maybe affecting response. We’re becoming more precise in terms of directing therapy after a CDK4/6, and that probably will extend the survival of these patients and delay the chemotherapy. This is exciting for us as oncologists, discussing with our patients and explaining how we can approach their disease step by step. This is also an introduction to the liquid biopsy, cell-free DNA monitoring of patients at multiple levels. The estrogen-positive disease is very heterogeneous and tends to change, so we need to have that information.

Sara Tolaney, MD, MPH: You’ve been a big proponent of liquid biopsies and leading the field here. It’s exactly the point where we need to use it: at the point of progression on a CDK4/6. Because as you point out, we’re going to get more sophisticated in making these decisions. Right now, we do have this important information for understanding ESR1 mutations. If elacestrant gets approval, maybe we’d think about elacestrant monotherapy in someone who had an ESR1 mutation and had a very prolonged benefit to upfront CDK4/6, as they showed. Because it was maybe that group of patients that achieved benefit with PFS [progression-free survival] almost in the 8-month range, which was impressive. But if they have a PI3K/PTEN/AKT alteration, maybe we’re going to have capivasertib move into this space, which also would help us. The question will be, will that agent also be truly beneficial in the biomarker-negative group?

I don’t know what you thought, but at San Antonio, it wasn’t 100% clear to me that if you looked at the people without a biomarker alteration to get capivasertib if it was really having benefit, because there are a bunch of unknowns. Once they get the ctDNA [circulating tumor DNA] data, we’ll understand that a little better. It may be for all comers, but as of now, to me, it looked very strong in the biomarker-enriched population. And then this idea of continuing a CDK4/6 is also an open question. While MAINTAIN was positive, PACE was negative. We have other large studies that are pending, particularly those looking at abemaciclib post-progression, which I think will be very important, like post-MONARCH, and also the EMBER study,looking at it even in combination with a SERD. This space is very much evolving, but it’s going to be complicated to make decisions, and we will need that genomic information.

Massimo Cristofanilli, MD: Yes, we need to have an algorithm to try to identify which pathway is more active at a specific point and then act on that. But having the availability of this drug, and of course, a large multicenter study that can address these questions in a timely fashion [is important].

Transcript edited for clarity.