Early ESR1 Mutation Detection via ctDNA Monitoring Could Enhance Treatment Adaptation in HR+ Breast Cancer

Sara M. Tolaney, MD, MPH

Primary resistance to CDK4/6 inhibitors in the frontline setting can lead to rapid disease progression and necessitate earlier transition to subsequent therapies in metastatic hormone receptor (HR)–positive breast cancer. Accordingly, the detection of ESR1 mutations through circulating tumor DNA (ctDNA) monitoring may facilitate real-time treatment adaptation in this setting, offering a strategy to identify emerging endocrine resistance and guide the use of oral selective estrogen receptor degraders (SERDs), according to Sara M. Tolaney, MD, MPH.

Topline data from a planned interim analysis of the ongoing phase 3 SERENA-6 trial (NCT04964934), reported in a press release, showed that the study met its primary end point of improved progression-free survival (PFS) with the addition of the oral SERD camizestrant to a standard-of-care (SOC) CDK4/6 inhibitor vs continuation of the frontline aromatase inhibitor (AI) plus CDK4/6 inhibitor in patients with HR-positive/HER2-negative advanced breast cancer harboring an emergent ESR1 mutation. Notably, all patients in SERENA-6 underwent serial liquid biopsies every few months to monitor for ESR1 mutations, Tolaney added.

“This represents a potential paradigm shift in the way that we’re thinking [about testing for ESR1 mutations],” Tolaney shared in an interview with OncLive®. “I’ve never used ctDNA monitoring [of ESR1 mutation status] to make therapeutic decisions; usually I wait until the time of disease progression. This could be a big step forward.”

In the interview, Tolaney discussed challenges in the frontline management of advanced HR-positive breast cancer, differences in survival outcomes between frontline CDK4/6 inhibitors, and emerging strategies within HR-positive breast cancer, such as triplet regimens or continuing CDK4/6 inhibition post-progression.

Tolaney is chief of the Division of Breast Oncology and the associate director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: What are some challenges in the frontline treatment of patients with advanced HR-positive breast cancer?

Tolaney: We’ve been fortunate to have CDK4/6 inhibitors to treat our patients with metastatic HR-positive breast cancer, and now even with early-stage HR-positive disease. Although some patients experience prolonged benefit from these therapies, there is a smaller subset of patients who may be refractory to these agents.

That is a challenge for us because what we find is that these patients don’t last on therapy for very long in the metastatic setting and are moving on very quickly to subsequent lines of treatment.

Understanding why that is occurring is still something that we don’t really have a good grasp on, and what the optimal way is to overcome that resistance is also not entirely clear.

What are some factors you consider when selecting between available CDK4/6 inhibitors?

We’re fortunate to have choices. Three CDK4/6 inhibitors are approved to treat [patients with] metastatic HR-positive breast cancer: ribociclib [Kisqali], abemaciclib [Verzenio], and palbociclib [Ibrance]. Each of these agents, when added to endocrine therapy, has been shown to essentially double PFS in the metastatic setting. They all offer significant improvements in outcomes.

The challenge is that we have seen some differing data with respect to overall survival [OS]. In the first-line setting, the only CDK4/6 inhibitor to have demonstrated a statistically significant improvement in OS has been ribociclib. For example, in [the phase 3] MONALEESA-2 [trial (NCT01958021)], there was a statistically significant survival benefit with ribociclib. Survival benefit has also been observed with abemaciclib in the second-line setting. Although it was not technically statistically significant in the first-line setting, there is about a 14-month [difference] in median OS between the 2 arms, which is a very clinically meaningful benefit.

In contrast, with palbociclib, no survival benefit has been seen in the metastatic setting—whether in the first-line or second-line setting—nor has there been benefit for palbociclib in the early-stage setting. Something about the data has felt different.

Given the clear survival benefit, the vast majority of us will consider ribociclib when selecting a drug in the first-line setting. That being said, treatment decisions need to be individualized by evaluating potential drug interactions, patient comorbidities, and determining the most appropriate option based on the adverse effect profiles of the drugs.

What is the rationale for testing for ESR1 mutations earlier in the disease course and how might this approach change the management of metastatic disease?

ESR1 has been an important biomarker for understanding resistance to AI therapy. We know that approximately 30% to 40% of patients receiving an AI in the metastatic setting will develop ESR1 mutations, and these patients are unlikely to benefit from subsequent AI therapy. Therefore, it is critical to determine whether this mutation is present, as it also helps identify patients who are particularly likely to benefit from oral SERDs.

For example, with elacestrant [Orserdu], we’ve seen that the benefits are far greater than standard endocrine therapy in patients whose tumors harbor ESR1 mutations. Understanding whether an ESR1 mutation is present is essential for guiding treatment decisions.

Generally, I will obtain a liquid biopsy, specifically, a ctDNA blood draw, at the time of progression on first-line therapy with endocrine treatment and a CDK4/6 inhibitor. I look for an ESR1 mutation, but I am also assessing for other biomarkers, such as alterations in the PI3K pathway, which may guide optimal therapeutic selection.

One might ask: why wait until progression to test? Why not assess ctDNA while the patient is still receiving an AI, as this could potentially detect early resistance? Even if imaging doesn’t yet show progression, the presence of an ESR1 mutation could indicate that resistance is developing and disease progression is imminent. This raises the question of whether we should begin monitoring patients with serial liquid biopsies during treatment.

The [phase 3] SERENA-6 study did exactly this in a clever way. Patients receiving an AI plus a CDK4/6 inhibitor received liquid assays every couple of months. If an ESR1 mutation [emerged], they were randomly assigned to receive either camizestrant while continuing CDK4/6 inhibition, or to continue their AI plus the CDK4/6 inhibitor. A recent press release reported that the study met its primary end point, showing that PFS was longer with camizestrant plus CDK4/6 inhibition compared with continued AI plus CDK4/6 inhibition. These data are expected to be presented at the 2025 ASCO Annual Meeting this year.

How do you approach treatment for patients harboring actionable mutations, and how do they compare with strategies for patients without these resistance mutations?

If a patient has another available target—such as a PIK3CA mutation, AKT mutation, or PTEN alteration—they may be a candidate for an oral AKT inhibitor like capivasertib [Truqap], which targets that pathway. For example, if a patient has an alteration in the PI3K/AKT/PTEN pathway, I would consider fulvestrant [Faslodex] in combination with capivasertib for that patient.

There are certainly other [options] if a patient does not have an ESR1 mutation or a PI3K pathway alteration. [In such cases], I may consider fulvestrant with everolimus [Afinitor]. We know that mTOR inhibition can enhance the efficacy of endocrine therapy, particularly in patients with visceral metastases or more aggressive disease.

Another alternative is the continuation of CDK4/6 inhibition beyond progression. For example, if a patient was on an AI plus a CDK4/6 inhibitor, one might consider switching them to fulvestrant combined with a different CDK4/6 inhibitor. Several trials have studied this [approach], although I would say the data are not yet conclusive.

Data from the phase 3 postMONARCH trial [NCT05169567] suggested that switching to abemaciclib improved PFS. Data from the [phase 2] MAINTAIN trial [NCT02632045] demonstrated that switching the endocrine backbone and continuing with ribociclib could also improve PFS. However, data from the [phase 2] PACE [NCT03147287] and PALMIRA studies [NCT03809988] showed that we could not continue palbociclib [beyond disease progression].

[Based on these data], it seems clear that palbociclib should not be continued after progression. It is probably okay to [consider] abemaciclib post–CDK4/6 inhibitor therapy, although most of the available data [in this setting] are from patients [previously treated with palbociclib]. This is the same for the MAINTAIN study; most of the data are from the post-palbociclib setting. As we start using ribociclib more up front, [the utility of] CDK4/6 switching post-ribociclib [remains uncertain].

Do outcomes with estrogen receptor (ER)–targeted agents differ across patient subsets and mutational profiles in the advanced setting?

There do appear to be fairly consistent data across most of the novel ER-targeting agents indicating greater activity in the ESR1-mutant subset compared with ESR1 wild-type disease. For example, in the [phase 3] EMERALD trial [NCT03778931], elacestrant demonstrated a much larger delta in PFS between treatment arms among patients with ESR1 mutations. Similarly, in the [phase 2] AMEERA-3 trial [NCT04059484], amcenestrant appeared to perform better than standard endocrine therapy in patients with ESR1-mutant tumors.

We have also seen a press release reporting that vepdegestrant, an oral proteolysis-targeting chimera, showed benefit compared with fulvestrant in patients with ESR1 mutations, but not in those with ESR1 wild-type disease. The trend does appear to be consistent across trials.

That said, there were interesting findings from AMEERA-3 evaluating combination therapy with amcenestrant and abemaciclib, which demonstrated improved outcomes over amcenestrant alone in an all-comer population. This suggests that when moving toward combination strategies, the predictive value of ESR1 mutation status may be less critical.

Overall, for most oral antiestrogen monotherapies, the presence of an ESR1 mutation appears to be associated with greater benefit compared with SOC therapies.

What’s next for the treatment of patients with metastatic ER-positive breast cancer, particularly in the first line and post–first-line progression?

It’s hard to keep up. The metastatic ER-positive breast cancer space is evolving [rapidly] and it feels like every few weeks [there’s something new]. Right now, the standard approach is to give endocrine therapy with a CDK4/6 inhibitor in the first line. However, for patients who have a PIK3CA mutation, we may be moving toward using a triplet regimen. As seen in SERENA-6, we may also begin monitoring with ctDNA in the frontline setting.

Post-progression, there are a plethora of options, which requires a thorough understanding of the genomic alterations present. There are going to be more and more therapies entering the post–CDK4/6 inhibitor space, and [we’ll likely see] more triplets move into the first-line [setting]. The field continues to change very quickly, which is great for our patients, but it can be challenging for us to keep up. It’s nice, though, to see this level of progress.

Reference

Camizestrant demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival in 1st-line advanced HR-positive breast cancer with an emergent ESR1 tumour mutation in SERENA-6 pPhase III trial. News release. AstraZeneca. February 26, 2025. Accessed April 21, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/camizestrant-improved-pfs-in-1l-hr-breast-cancer.html