Komal Jhaveri, MD, FACP: The whole idea of treatment optimization is so important, and we’ve definitely made leaps. We figured out where we could avoid chemotherapy with genomic profiling, with the TAILORx [NCT00310180] and RxPONDER [NCT01272037] trials where we might need more, and we’re adding a CDK4/6 inhibitor. But now I think it might be a good idea to see where CDK4/6 inhibitors [can] replace the need for adjuvant chemotherapy in this high-risk patient population who’s getting extended endocrine therapy, who’s also getting CDK4/6 inhibitor therapy, and maybe even a PARP inhibitor if they have a germline [BRCA] mutation.

Continuing the thought process about ctDNA [circulating tumor DNA], I know you mentioned the role for ctDNA. There was data presented at the annual meeting about utilizing ctDNA in the high-risk patients. The example that they chose was from the PENELOPE-B [trial; NCT01864746] where we utilized the CDK4/6 inhibitor. That was after patients have residual disease after neoadjuvant therapy. Do you have thoughts about that, Aditya? Maybe you can tell us about what your impression was.

Aditya Bardia, MD, MPH: I think these are early data, but very provocative. The PENELOPE-B trial looked at patients who had residual disease despite neoadjuvant therapy, [randomly assigned] to endocrine plus endocrine with a CDK4/6 inhibitor. The overall sample size was more than 1000, but in the ctDNA analyses, it was about 10% of that population. Because they wanted to look at patients who had baseline samples before a patient started endocrine therapy, which is critical, and then cycle 7, day 1, and at the time of progression if a patient had progression. You could see a small subset. They had about 70 patients who had ctDNA data available. Seven of them had detectable ctDNA, and these were the patients who were really at high risk of recurrence. So ctDNA appears to be a very strong prognostic marker, even more than grade and other clinical pathological features that we use, and probably in future studies it will be something that we consider either as a stratification factor or as a high-risk factor. I think the bigger question then is that it’s a prognostic factor, but how can we convert that to a predictive factor in terms of something that’s actionable? I think that would be the next step.

Komal Jhaveri, MD, FACP: I think here they showed us baseline information, right? As you mentioned, they pointed out before patients started any therapy. When we looked at ctDNA and what that prognostic implication looked like. What do you think the impact is? If we were to do that more frequently, do you think that would provide us more information, or do you think getting this information at baseline will [help] to accurately predict what’s happening at distant relapse even later down the line in the disease course?

Aditya Bardia, MD, MPH: I think both. So ctDNA at baseline, that is without any therapy. There’s a subset of patients who will have ctDNA clearance with additional therapy, be it endocrine or endocrine plus CDK4/6 inhibitor vs patients who have persistent ctDNA. I think the prognosis is going to be different. So [ctDNA] monitoring would help.

Komal Jhaveri, MD, FACP: Thank you. Have you had patients who have asked you about ctDNA in your practice?

VK Gadi, MD, PhD: Certainly. People are very curious about this. They’re reading about it on Dr Google and I’m sure ChatGPT will be informing them very soon about it as well. The challenge really is operationalizing that in general practice in the general population. As you know, the data around biomarker testing, even in the metastatic setting where we have indications, things like getting ESR1 testing and PIK3 mutation testing, is hard. We just need a lot more education of everybody, the payers, the colleagues, etc, on how we would order these tests in a regular fashion, track them, and then make decisions of ultimately once the data comes in, on what we do when we see persistence of ctDNA. So that’s where my anxieties are about being able to get the test for people. This is another instance where innovation can inadvertently worsen disparity because the haves will be at centers that can continue to do this type of testing. Where we’re going to see problems, as Greg mentioned, is in communities of color and others where [getting] access to these tests is even [harder].

Komal Jhaveri, MD, FACP: I think access is one issue, and then actionability of the test result is another, right?

VK Gadi, MD, PhD: Right.

Komal Jhaveri, MD, FACP: Because if we have a result, what do we do with that? Especially if we do a reflex imaging test. Say somebody has a ctDNA positive and then you end up doing an image with the CT scan. If that did not show, what do you do with that result? How do you intervene?

VK Gadi, MD, PhD: It’s like our old days with CEA and CA 27.29 biomarkers—we’re revisiting those challenges.

Komal Jhaveri, MD, FACP: We are revisiting them with novel technologies and newer technologies, which hopefully will turn out to be something that we might act upon better.

VK Gadi, MD, PhD: I’m more optimistic about the concept of a deep molecular remission because that’s what we’re talking about. We’re accustomed to that in the HE malignancies. We’re embarking on that in the solid tumor. So it’s exciting, but we want to roll this out in a way that is meaningful for as many people as possible.

Timothy Pluard, MD: I think the neoadjuvant setting is ideal for combining utilization of ctDNA and novel agents and using that as a biomarker in addition to cell cycle arrest and pathologic CR [complete response]. At least at that point, if patients don’t clear their ctDNA, that’s probably an adverse prognostic indicator, but you [can] act upon that in the adjuvant setting as opposed to when you’re monitoring serial ctDNA in the adjuvant setting. What do we do with it, right, as we’ve talked about it.

Komal Jhaveri, MD, FACP: So [there is] more to learn from the ctDNA experience, something that we really want to act upon moving forward.

Transcript edited for clarity.

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