Komal Jhaveri, MD, FACP: I was just thinking as we are talking about what more can we give our patients with high-risk [disease], but in this era of dose optimization and giving the right therapy to the right patient, how can we avoid giving more? Who would that be for? Are there any approaches in that regarding the early-stage setting that maybe you can walk us through?

Timothy Pluard, MD: So on the other end of the spectrum we know that there are patients who are probably very low risk and utilizing MammaPrint. You can identify those patients who are ultra low. There’s now a trial looking at de-escalating for those ultra-low patients at the LESS single-arm trial [NCT05297617] where patients will get 2 years of adjuvant endocrine therapy as opposed to 5 to see if in that population that’s adequate. You can reduce some of the toxicity and the [adverse] effects that go along with adjuvant endocrine therapy.

Komal Jhaveri, MD, FACP: Right. So [for] your low clinical-stage patients along with the genomic profile that is really, really low, can we give even less? We’ve avoided chemotherapy, and now we’re trying to see if we can further optimize endocrine therapy. It’s going backward because we started with 2 is better than zero, and 5 is better than 2, and 10 is better than 5 for our higher-risk patients. But I think trying to limit it or optimize it for the right patient population is such a good initiative. What about radiation? There is an ongoing trial that is trying to see where we could avoid radiation and, potentially, the [adverse] effects we face for our patients with radiation.

Timothy Pluard, MD: Yes, that’s equally as important. The DEBRA trial [NCT04852887] is looking at patients utilizing Oncotype [Dx] to identify patients between the ages of 50 and 70 that could potentially forgo radiation therapy. They’re looking at a 4% risk of IPSS lateral breast recurrence at 10 years. We have data that’s already out there about forgoing it in older populations where we know that the risk is about 10% at 10 years if you forgo radiation. But it doesn’t impact survival. So if we can avoid radiation in a significant number of patients, I think that that’s going to be beneficial as well.

Komal Jhaveri, MD, FACP: Absolutely. That’s such an interesting trial. I think that we struggle with patients from the RxPONDER [trial; NCT01272037] as well, right? We have our postmenopausal patients with 1 to 3 positive nodes and Oncotype [Dx scores] of less than 25, where we’re very comfortably now avoiding chemotherapy from the RxPONDER trial. But our experience with our premenopausal patients is not that straightforward. Greg, maybe you can tell us what your thoughts are about treating a premenopausal woman? Are you getting Oncotypes if they have 1 to 3 positive nodes? How are you interpreting that data and how would you think about your management there?

Gregory Vidal, MD, PhD: Certainly, my management style has changed after RxPONDER. I would have previously done Oncotype in some of those patients. I remember, I think plan B, that was done before suggesting that there probably is [fewer than] 10% [of] [Oncotype-tested patients who] may not benefit from chemotherapy. Even if they were premenopausal in that study; there [were] some premenopausal [patients]. Then RxPONDER came and says, no, everybody, as long as you’re premenopausal, and they should benefit less than 14. It was a well-conducted study. So yes, it’s changed the way I manage and what I order, there are patients that come to me who definitely do not want chemotherapy. In those patients, when I’m trying to figure out a reason to say chemotherapy or no chemotherapy, I’ve ordered Oncotype [testing] in that patient. If it’s really, really low, maybe I can support you if it’s really, really high Oncotype [score] based on the data. But in that patient population, as long as you have N1 based on the current data, I’ve been offering chemotherapy.

Komal Jhaveri, MD, FACP: Tim, any efforts in that space to perhaps further [pare] down and address this question more definitively? Do we really think we need this chemotherapy for every premenopausal woman?

Timothy Pluard, MD: Well, as you know, there’s an ongoing debate [about] the benefit of the chemotherapy due to induction of menopause, and do we really need the chemotherapy or could we just use ovarian suppression and endocrine therapy alone? There’s a trial called the INTERSTELLAR trial [NCT05333328] that is a single-arm trial that’s taking those patients and [randomly assigning] them to endocrine therapy alone in hopes of replicating the benefit that was seen in the chemotherapy arm of RxPONDER. So it’s not a randomized controlled trial against chemotherapy, but at least it will give us some data for those patients who maybe want to avoid chemotherapy [so] that we can say yes, there’s similar benefit.

Gregory Vidal, MD, PhD: NRG-BR009, which should be open hopefully soon, in July, probably,…is a study that’s looking at that exact question in the premenopausal patient, [randomly assigning] them to maximization of your anti-hormonal therapy, ovarian suppression, and whatever you’re giving with the anti-estrogen therapy vs chemotherapy. To answer that very question, which one of those patients really need chemotherapy? Is it really just the anti-estrogen therapy? There’s some data with the early breast cancer trials group that tend to suggest the anti-estrogen is really the biggest bang in that population. So there’s lots of data out there, and there are studies looking at that exact question.

Komal Jhaveri, MD, FACP: I completely agree, and that was an interesting data set to support this notion. I’m glad that we have the interest in our trial from South Korea. We have the NRG trial, which will definitively address this question. It’s going to take a few years before we get there, but until then, I think we will have to have these discussions with our patients in clinic and, for the right patient, see what the risk-benefit ratio means to them. We currently do not have any level 1 evidence to omit chemotherapy, [which]is exactly what our ASCO [American Society of Clinical Oncology] biomarker guidelines are currently suggesting as well. The NCCN [National Comprehensive Cancer Network] guidelines are suggesting as well that for post-menopausal, we can do that; premenopausal, I think there’s more to go. I think we talked about lidERA; before we move on to the metastatic setting, maybe one last question. Aditya, maybe you can refer to that. I know Greg told us about the lidERA study [NCT04961996] for giredestrant vs standard of care endocrine therapy up front. There are other trials that are looking at switch strategies. What is your impression about this, and is there one approach that you think is more appealing than the others, or do we need information on both? How are you thinking about them?

Aditya Bardia, MD, MPH: On different strategies—in a few years, we'll know what the better strategy was. [The lidERA study] is looking at upfront [endocrine therapy] and there are 2 clinical trials looking at a switch strategy. EMBER-4 [NCT05514054], which you are leading, which is looking at imlunestrant, which is an oral SERD [selective estrogen receptor degraders] vs endocrine therapy in patients who’ve received at least 2 years of prior endocrine therapy. The other is CAMBRIA-1 [NCT05774951]. These trials are similar to what was done previously in the era of Ais [aromatase inhibitors], where patients had received 2 to 5 years [of therapy]. After that, there was a switch. It is just a bit early on that these trials require 2 years of endocrine and then you make a switch. I think from a patient perspective, if these drugs bring an additional option, that’ll be good.

Komal Jhaveri, MD, FACP: Thank you.

Transcript edited for clarity.

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