Timing of ESR1 Mutation Testing Is Critical to Overcome Adaptive Endocrine Resistance in HR+ Breast Cancer

Kevin Kalinsky, MD, MS

Switching from an aromatase inhibitor (AI) to camizestrant in patients with hormone receptor–positive breast cancer who develop ESR1 mutations on a first-line AI plus CDK4/6 inhibition appears to overcome the adaptive endocrine resistance conferred by emerging ESR1 mutations, which underscores the importance of timing in testing for these alterations, according to Kevin Kalinsky, MD, MS.

“It is nice right now because we have different options available [after treatment with an] AI plus CDK4/6 inhibitor,” Kalinsky stated in an interview with OncLive®. “However, the goal is to develop more precise [strategies] with new endocrine therapies.”

At the 2025 ASCO Annual Meeting, data from the phase 3 SERENA-6 trial (NCT04576455) showed that switching from an AI to camizestrant with continued CDK4/6 inhibition produced a superior progression-free survival (PFS) benefit in patients with an ESR1 mutation detected prior to radiographic progression on frontline therapy (n = 157) vs those who continued on an AI and CDK4/6 inhibition after the detection of an ESR1 mutation (n = 158; HR, 0.44; 95% CI, 0.31-0.60; P < .00001).

Analyses of additional efficacy end points from SERENA-6, such as time to second progression (PFS2) and overall survival (OS) will be essential to refine potential switching strategies and maximize clinical benefit, Kalinsky added.

In the interview, Kalinsky discussed the PFS benefit with camizestrant in the SERENA-6 trial; the field’s current understanding of ESR1 mutations as an adaptive resistance mechanism to AIs; the optimal timing for ESR1 mutation testing; and the need to refine testing strategies and develop targeted therapies for patients with hormone receptor–positive breast cancer whose progression is not driven by ESR1 mutations.

Kalinsky is a professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as director of the Glenn Family Breast Center at Winship Cancer Institute in Atlanta, Georgia.

OncLive: How do the data from SERENA-6 add to the field’s current understanding of how emergent ESR1 mutations drive endocrine resistance?

Kalinsky: We know that the development of ESR1 mutations is a way that the estrogen receptor [ER] can be constitutively activated. What we've also seen is that AIs don't benefit patients with tumors that are ESR1 mutated. In other studies, for patients who have ESR1 mutations, we’ve also seen that oral selective ER degraders [SERDs] can be better than we see with physician’s choice of endocrine therapy, including fulvestrant [Faslodex].

We know that ESR1 mutations are an adaptive resistance mechanism that occur after [exposure to] an AI. We have seen some data from other studies [on therapy change after the emergence of an ESR1 mutation], including PADA-1 [NCT03079011], which was a phase 3, open-label study, that randomly assigned patients to fulvestrant [and palbociclib (Ibrance) vs continuing on an AI and palbociclib].

In patients from SERENA-6 who had not experienced radiographic progression, early switching improved PFS. There are a few things to point out. First, the median time from starting the AI to random assignment was 22 months. Another thing to keep in mind is that we are waiting for maturity of some data, [including] PFS2, OS, and other secondary end points. [This will help elucidate] whether a switching strategy makes sense for patients.

What were the key findings from SERENA-6 presented at this year’s ASCO Annual Meeting?

This was a randomized phase 3 trial that evaluated patients receiving an AI and a CDK4/6 inhibitor. [These patients] started serial testing for ESR1 mutations using circulating tumor DNA [ctDNA] starting at 6 months; patients had to have been on therapy for at least 6 months.

We saw data primarily for PFS [in this readout]. In this randomized, placebo-controlled trial, patients were taking 3 pills. They were continuing on the CDK4/6 inhibitor and either maintained [treatment with] the same AI that they had been taking before or switched to camizestrant, an oral SERD. In patients who developed an ESR1 mutation, we saw an improvement in PFS among those randomly assigned to camizestrant, which was the primary end point.

What factors should be considered when determining the optimal timing of ESR1 mutation testing in routine practice?

It is important to think about [the timing of] when ESR1 mutations are detected. For instance, if we treat a patient with de novo disease and are checking tumor tissue, we are not going to see ESR1 mutations, because they would not have had a chance to develop any. The ASCO guidelines [recommend we should] check [for ESR1 mutations] after patients have been on endocrine-based therapy.

The preference for testing is to start with ctDNA because this is an adaptive mechanism. One could send tumor-based tissue, but that would have to be after progression on, for instance, an AI; otherwise, we are not going to see an ESR1 mutation.

What unmet needs still exist for patients with hormone receptor–positive disease whose first-line progression is not driven by an emergent ESR1 mutation?

In our current circumstances, we are seeing benefit with these novel oral SERDs. [We also] saw data [presented at ASCO] for vepdegestrant, which is an oral proteolysis-targeting chimera [involved in] the ubiquitination of the ER.

When we are comparing these agents with standard-of-care endocrine therapies like fulvestrant, we are seeing that the benefit is [primarily in] those with ESR1 mutations. The question is [whether] we will have other novel endocrine therapies that we can utilize for our patients even if they do not have ESR1 mutations. As a field, we are also looking into more specific inhibitors, such as CDK4 inhibitors, CDK2 inhibitors, and PI3K mutation–specific inhibitors.

Reference

Turner N, Mayer E, Park YH, et al. Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. J Clin Oncol. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4