Switching from an aromatase inhibitor (AI) to camizestrant in patients with hormone receptor–positive breast cancer who develop 

 mutations on a first-line AI plus CDK4/6 inhibition appears to overcome the adaptive endocrine resistance conferred by emerging 

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 

. “However, the goal is to develop more precise [strategies] with new endocrine therapies.”

, 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 

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 

 mutation (n = 158; HR, 0.44; 95% CI, 0.31-0.60; 

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 

 mutations as an adaptive resistance mechanism to AIs; the optimal timing for 

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 

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.

: How do the data from SERENA-6 add to the field’s current understanding of how emergent 

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 

 mutated. In other studies, for patients who have 

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].

 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 

 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 

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 

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 

It is important to think about [the timing of] when 

 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 

mutations, because they would not have had a chance to develop any. The ASCO guidelines [recommend we should] check [for 

 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 

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

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

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

 mutations. As a field, we are also looking into more specific inhibitors, such as CDK4 inhibitors, CDK2 inhibitors, and 

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. 

. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4

Articles

Kevin Kalinsky, MD, MS, FASCO, discusses how findings from SERENA-6 reinforce the importance of timely ESR1 testing in HR-positive breast cancer.

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

Kevin Kalinsky, MD, MS, FASCO,  discussed efficacy data from the phase 3 SERENA-6 study (NCT04964934) of camizestrant in combination with a CDK4/6 inhibitor in patients with estrogen receptor–positive, HER2-negative advanced breast cancer. 

Dr Kalinsky on Efficacy Data From SERENA-6 in ER+/HER2– Advanced Breast Cancer

“We saw that early switching [to camizestrant from an aromatase inhibitor] improved PFS in patients who did not have radiographic disease progression.”

Kevin Kalinsky, MD, MS, FASCO, director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University and professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, discussed efficacy data from the phase 3 SERENA-6 study (NCT04964934) of camizestrant in combination with a CDK4/6 inhibitor in patients with estrogen receptor–positive, HER2-negative advanced breast cancer. 

 revealed that patients who switched from an aromatase inhibitor (AI) to camizestrant plus a CDK4/6 inhibitor following the detection of an 

 mutation (n = 157) experienced a median progression-free survival (PFS) of 16.0 months (95% CI, 12.7-18.2) per investigator assessment. Comparatively, patients who remained on an AI plus a CDK4/6 inhibitor (n = 158) achieved a median PFS of 9.2 months (95% CI, 7.2-9.5).

The adjusted HR for PFS was 0.44 (95% CI, 0.31-0.60; 

 < .00001) in favor of the camizestrant arm. The 12- and 24-month PFS rates in the camizestrant were 60.7% and 29.7%, respectively. These respective rates were 33.4% and 5.4% in the control arm.

In terms of second PFS (PFS2), which was a key secondary end point of SERENA-6, the adjusted HR was 0.52 (95% CI, 0.33-0.81; 

 = .0038). The study authors noted that the interim analysis threshold for PFS2 significance was 

 mutations are adaptive resistance mechanisms which happen following treatment with an AI, Kalinsky explained. In SERENA-6, it was notable that early switching to camizestrant improved the median PFS despite these patients not showing evidence of radiographic disease progression, he added. The median time from initiation of treatment with an AI plus a CDK4/6 inhibitor to random assignment in the investigational arm was 23 months (range, 7-96), which is important to consider when interpreting the data from SERENA-6, Kalinsky said. Investigators are looking forward to more mature data from the study, including overall survival and detailed PFS2 findings, Kalinsky concluded.

Education to be funded by AstraZeneca. All content to be independently created, produced, and owned by OncLive.

Videos

Kevin Kalinsky, MD, MS, FASCO, discusses data with camizestrant plus a CDK4/6 inhibitor in ER–positive, HER2-negative advanced breast cancer. 

Findings from the phase 3 SERENA-6 trial (NCT04964934) demonstrated the feasibility of guiding treatment decisions through early detection of 

 mutations through circulating tumor DNA (ctDNA) monitoring in patients with advanced hormone receptor–positive breast cancer, according to Erica L. Mayer, MD, MPH. She added that with the improved outcomes for patients who switched to a camizestrant-based regimen prior to radiographic progression, this may represent a new paradigm for identifying emerging treatment resistance to guide treatment decisions with the goal of delaying disease progression.

 and showed that adding camizestrant to continued therapy with CDK4/6 inhibition significantly improved progression-free survival (PFS) vs continued therapy with an aromatase inhibitor (AI) and CDK4/6 inhibition in patients with a detected 

mutation prior to radiographic progression on frontline therapy.

The median investigator-assessed progression-free survival (PFS) was 16.0 months (95% CI, 12.7-18.2) with camizestrant plus CDK4/6 inhibition (n = 157) vs 9.2 months (95% CI, 7.2-9.5) with continued AI plus CDK4/6 inhibition (n = 158; HR, 0.44; 95% CI, 0.31-0.60; 

 < .00001). The 12- and 24-month PFS rates in the camizestrant arm were 60.7% and 29.7%, respectively, vs respective rates of 33.4% and 5.4% in the continued AI plus CDK4/6 inhibition arm.

“These were exciting findings. [We] not only saw the efficacy of camizestrant, but also the greater new paradigm of using molecular progression as a moment when we can intervene with an effective therapy and make a difference for patients,” said Mayer, the director of clinical research at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

, Mayer expanded on how the SERENA-6 trial set out to address the development of endocrine resistance driven by 

mutations in hormone receptor–positive, HER2-negative metastatic breast cancer; primary results from the study; and how these data could enable earlier detection of endocrine resistance and earlier treatment modifications to optimize patient outcomes in this disease setting.

: What challenges in disease management did SERENA-6 seek to address, and how might its findings influence the timing of 

 testing and subsequent treatment decisions in metastatic hormone receptor–positive, HER2-negative breast cancer?

One of the most exciting abstracts we saw at ASCO 2025 this year is the SERENA-6 study. SERENA-6, which was presented in a plenary presentation, is a global phase 3 study that is looking at the oral selective estrogen receptor degrader camizestrant. SERENA-6 also explored a very novel paradigm in breast cancer. [We are starting to] think about what to do next when we define progressive disease. [Moreover], if we can define [when the] disease is becoming resistant, does early intervention help?

The concept behind SERENA-6 was that patients who have hormone receptor–positive, HER2-negative breast cancer develop resistance to endocrine therapy over time, which eventually leads to disease progression and the need to change treatments. One of the major drivers of resistance includes 

mutations are quite rare when patients initially begin therapy, but after they have been on first-line therapy in the metastatic setting, [which includes] an AI plus a CDK4/6 inhibitor, the rate of 

mutations tends to go up significantly. This is thought to be one of the main reasons that patients develop resistance to their regimen.

The [thought process] in SERENA-6 was that if one could detect this molecular progression prior to the eventual development of clinical progression, then early intervention with an effective therapy to target the 

mutation may help prevent or delay eventual progression and improve outcomes for patients.

What was the design and methodology of this study?

In SERENA-6, there were two steps. The first step was the screening step. Patients entered screening—there were several thousand patients who had serial ctDNA [testing] performed to look for the emergence of the 

 mutation. All of these patients had metastatic hormone receptor–positive, HER2-negative breast cancer and had already been on their first-line therapy with an AI and a CDK4/6 inhibitor for at least 6 months. Patients had ctDNA testing, usually timed with their restaging every 2 to 3 months.

mutation was detected but there was no evidence of clinical progression, patients then moved to step 2, where 315 patients were randomly assigned to either continue on an AI plus CDK4/6 inhibitor with a placebo, or switch to camizestrant plus a CDK4/6 inhibitor with a placebo for an AI.

What were the primary efficacy and safety results from SERENA-6? How do these data add to the knowledge regarding the emergence of 

The PFS results from the study were highly significant, favoring the switch to camizestrant. Patients receiving an AI had a PFS of 9.2 months, and this significantly improved to 16.0 months with the switch to camizestrant, with a highly significant HR of 0.44. The curves separated early and stayed separated, showing early benefit in making this switch.

Additionally, a very important finding from the study was related to quality of life. Patients who switched to camizestrant had a substantially longer time until they experienced deterioration in quality of life—an improvement from 6.4 months to 23.0 months. This means those patients had an extra year and a half of living without substantial symptoms related to their cancer, which is incredibly clinically meaningful.

Other important end points from SERENA-6 included time to second progression [PFS2] and overall survival [OS]. We did see some early PFS2 data; [they were] still immature but trending in a favorable way, and we are waiting for OS data.

Camizestrant is extremely well tolerated. Very few patients had serious toxicities, and very few patients had to discontinue therapy. There is a unique toxicity of camizestrant called photopsia, which is like [seeing] flashing lights in low-light conditions. Patients who experience this do not seem bothered by it, it does not interfere with activities of daily living, there is no change to visual acuity, and it is very rapidly reversible and generally very mild.

Erica L. Mayer, MD, MPH, discusses the implications of data from the SERENA-6 trial for ESR1 testing in hormone receptor–positive breast cancer.

SERENA-6 Introduces Potential New Paradigm of Early ESR1 Mutation Detection to Delay Progression in HR+ Breast Cancer

Erica L. Mayer, MD, MPH, director, breast cancer clinical research, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, discussed ESR1 mutation detection by circulating tumor DNA (ctDNA) liquid biopsy in the phase 3 SERENA-6 study (NCT04964934).

Dr Mayer on ESR1 Testing Methods in the SERENA-6 Study of Patients With ER+/HER2– Advanced Breast Cancer

“Patients prefer [mutation testing with ctDNA] as it is noninvasive…and we [saw] in the SERENA-6 study that it is feasible to do…in a serial manner.”

Erica L. Mayer, MD, MPH, director, breast cancer clinical research, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, discussed 

 mutation detection by circulating tumor DNA (ctDNA) liquid biopsy in the phase 3 SERENA-6 study (NCT04964934).

SERENA-6 examined camizestrant in combination with a CDK4/6 inhibitor vs continuing with aromatase inhibition (AI) plus a CDK4/6 inhibitor in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer who received an AI plus a CDK4/6 inhibitor as their initial endocrine-based therapy for advanced breast cancer for at least 6 months. The study authors hypothesized that using camizestrant to treat emerging 

 mutations prior to disease progression could extend the benefit of frontline therapy.

 showed that patients who received camizestrant (n = 157) achieved a median progression-free survival (PFS) of 16.0 months (95% CI, 12.7-18.2) compared with 9.2 months (95% CI, 7.2-9.5) in the control arm (n = 158; adjusted HR, 0.44; 95% CI, 0.31-0.60; 

 < .00001). The 24-month PFS rates were 29.7% and 5.4%, respectively. The study authors noted that SERENA-6 was the first global registrational study to demonstrate the clinical utility of ctDNA monitoring to detect and treat emerging resistance in breast cancer.

ctDNA testing in SERENA-6 was performed using the Guardant360 CDx assay, Mayer began. ctDNA testing is often used in clinical practice to identify resistance mutations such as those in 

 and this practice is a part of the American Society of Clinical Oncology guidelines, she noted. Any patient with ER-positive breast cancer with evidence of disease progression should undergo ctDNA testing to look for actionable mutations, she added.

Mayer noted that tissue and ctDNA mutation testing can produce discordant results, partially due to tissue testing only examining a certain area and ctDNA encompassing all aspects of tumor heterogeneity. Patients often prefer ctDNA testing as it is noninvasive, she added. In SERENA-6, study authors demonstrated that 

 mutation testing by ctDNA can be feasibly performed in a serial manner, she concluded.

Erica L. Mayer, MD, MPH, discusses ESR1 mutation detection by ctDNA liquid biopsy in the phase 3 SERENA-6 study.

A growing body of evidence suggests that serial monitoring via circulating tumor DNA (ctDNA) could enable early detection of resistance mutations, including 

, prior to radiographic progression, which may allow for earlier intervention to help improve outcomes for patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, according to Jason A. Mouabbi, MD.

Building on prior findings from the phase 3 PADA-1 trial (NCT03079011), which demonstrated improvements in time to progression after switching patients to fulvestrant (Faslodex) plus palbociclib (Ibrance) vs continuing on an aromatase inhibitor (AI) and palbociclib based on early ctDNA detection of 

 mutations, emerging data from the phase 3 SERENA-6 trial (NCT04964934) suggest clinical benefit with this proactive intervention.

 According to topline results from a press release, 

 of improved progression-free survival (PFS) with the addition of the oral selective estrogen receptor degrader (SERD) camizestrant to a standard-of-care CDK4/6 inhibitor vs an AI plus CDK4/6 inhibitor in patients with HR-positive/HER2-negative advanced breast cancer harboring an emergent 

Full data from this trial are expected to inform future treatment algorithms by emphasizing the value of real-time molecular monitoring to guide therapeutic decisions, Mouabbi asserted.

“SERENA-6 is the first step into the future of oncology,” Mouabbi explained in an interview with 

. “The future of oncology is going to be proactive—not reactive—meaning that as soon as we identify the mutation before overt progression, we're going to be acting so we can be in charge of the situation.”

In the interview, Mouabbi highlighted emerging therapeutic classes that could help close the treatment gap for patients in the frontline setting; discussed the importance of early 

 mutation testing; and emphasized the need for continued innovation to expand treatment options for patients with endocrine-refractory disease lacking targetable mutations.

Mouabbi is an assistant professor in the Departments of Breast Medical Oncology and General Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

: What are some key treatment challenges for patients with HR-positive breast cancer in the frontline setting?

We've come a long way over the past decade in the treatment of [patients with] first-line HR-positive metastatic breast cancer, but there is still room to innovate and do better, especially when it comes to the endocrine therapy backbone. Because those cancers are driven by hormones, effective blockade of the estrogen receptor [ER] pathway is key. There has been a lot of innovation in terms of the partner of endocrine therapy; however, the last innovation for endocrine therapy itself happened in the 1990s, so it has been a long time.

There are a few drugs with different mechanisms of action coming to the market, [such as] oral SERDs, which are [gaining] headway right now. There are also other drugs, such as complete estrogen receptor antagonists [CERANs], that are showing very exciting data and are going to [be evaluated] in [the] first line.

There are [agents with] other mechanisms of action, such as proteolysis-targeting chimeras [PROTACs]. This is another exciting mechanism of action to block the ER pathway. These are a few of the agents coming soon. Press releases have already reported optimistic results, and hopefully we will see those data in the first-line therapy setting. That is what is needed at this point in time.

 mutations earlier in the disease course, and how might this approach change the management of metastatic disease?

 mutations are very important in HR-positive, HER2-negative breast cancer. They are what we call therapy-selected mutations, meaning that they arise due to treatment pressure. Endocrine therapy, particularly AIs, which are typically used in the first-line setting, can select for a specific cancer clone harboring this mutation.

 mutation causes the ER to remain in its active configuration without requiring estrogen. Under normal circumstances, the ER remains in an off configuration until estrogen enters the cell, binds to the receptor, and activates it—at which point it becomes a master regulator of cell division. However, with the 

 mutation, the receptor remains in an on configuration regardless of estrogen presence. As a result, AIs—which block estrogen formation—become ineffective, and the cancer continues to progress.

Detecting this mutation early is critical. If patients are kept on AIs without switching therapies, the resistant clone can expand, potentially leading to disease progression and metastasis that becomes more difficult to control. The mutation can emerge at any time, making it important to assess for

 mutations early and perform serial testing over the course of treatment.

Data show that among patients who received endocrine therapies in the early-stage setting and later develop metastatic disease, 

mutations are present in approximately 5% of cases at the time of metastatic diagnosis. However, with ongoing treatment and progression in the first-line setting, the frequency increases to [approximately] 20% to 30%. By the second- or third-line setting, the prevalence approaches 40%. The longer a patient is exposed to endocrine or anti-estrogen therapies, the more common the 

What advantages does ctDNA offer over tissue biopsy for the detection of

mutations in breast cancer, and what considerations should be made when selecting the most appropriate method for mutation testing?

 mutation is via liquid biopsy using ctDNA. This is because the 

 mutation arises from a clone that may be underrepresented early on and only becomes dominant over time. Tissue biopsy provides only a small piece of the puzzle, [as it is] typically sampled from a single tumor site. That specific area may not contain the 

-mutated clone, but this does not mean it is absent elsewhere in the body. In contrast, a liquid biopsy captures DNA shed by tumors from multiple sites, offering a more comprehensive representation of tumor heterogeneity. For this reason, liquid biopsy is a much more reliable method for detecting 

This approach has already been validated in a 

publication, which demonstrated that liquid biopsy is the preferred method for 

mutation testing, not tissue biopsy. If liquid biopsy is not feasible, a fresh tissue biopsy is important. Testing archived tissue samples is not recommended, as 

 mutations increase in prevalence over time, and historical biopsies are likely to miss the mutation.

How might serial monitoring using ctDNA enhance early detection of 

 or other resistance mutations in breast cancer before radiographic progression is evident?

 mutations are detected, the better. The PADA-1 trial showed that early intervention prior to radiographic progression led to improved patient outcomes.

That study was small and received some criticism because it was not a registration-enabling trial. However, a larger study is on the horizon that may address these concerns: SERENA-6. SERENA-6 is a well-designed study, and in February, a press release reported that the trial met its primary end point [of PFS]. The language used in the release is [noteworthy]—terms like ‘highly significant’ and ‘clinically meaningful’ suggest the findings may be practice-changing.

Although the full data have not yet been presented, the results are highly anticipated. Based on this study, early detection of 

mutations before radiologic progression is associated with improved patient outcomes. This is logical, as patients may remain on ineffective endocrine therapy once the mutation emerges. Promptly switching to a therapy capable of targeting the 

-mutant clone is therefore essential to improve treatment efficacy.

This study is going to open the way for future studies to be designed in a similar fashion. When a targetable mutation emerges, we start targeting it early. We already know from multiple studies that the best way to make cancer history is to start as early as possible. We have targeted therapies that are very good; the problem is that, unfortunately, we lose the opportunity [to achieve maximum benefit] by using them too late. The sooner we can use them, the better the outcome will be for our patients.

How do you approach treatment for patients harboring actionable mutations, and how does your treatment approach differ for patients without these resistance mutations?

A lot of patients will have mutations, either in 

mutation is also a very common mutation in breast cancer; it is observed in patients approximately 40% of the time. This is a targetable mutation. We already have agents that can target that, and we have emerging new, novel agents that target the same pathway. Patients can also have other mutations, like a 

 mutations are] they're found in approximately 50% of [these] cancers. [Approximately] 70% of HR-positive breast cancers will eventually develop a mutation, which means that [just under] one-third of patients would not have any targetable mutation at this point in time.

For those patients, it's first important to know [whether they] are still endocrine-sensitive vs endocrine-refractory. If they're endocrine-sensitive, it makes sense to still target the ER pathway with targeted therapies that are approved, irrespective of a targetable mutation. However—and this is the area of need—these are the patients who become endocrine-refractory, meaning they're not reliant on the ER pathway anymore. Those cancers, although they're not triple-negative breast cancer on paper, behave similarly and are aggressive.

Historically, we used to manage these tumors with chemotherapy. Recently, we started using antibody-drug conjugates, such as fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd], with the [phase 3] DESTINY-Breast04 [NCT03734029] and DESTINY-Breast06 [NCT04494425] trials showing that T-DXd is highly effective in those patients who have HER2-low [disease], which was practice-changing.

However, we need more innovation. There are another 2 drugs that target TROP2: sacituzumab govitecan-hziy [Trodelvy] and datopotamab deruxtecan [Dato-DXd]. [Dato-DXd was evaluated in] the [phase 3] TROPION-Breast01 trial [NCT05104866], which showed that ADCs [like Dato-DXd] are very promising. We need more innovation. We need more ADCs and effective therapies for endocrine-refractory patients.

Education to be funded by AstraZeneca. All content to be independently created, produced, and owned by OncLive

Breast cancer patients with estrogen receptor mutations may benefit from early switch to fulvestrant/palbociclib. News release. AACR. December 7, 2021. Accessed April 25, 2025. 

https://www.aacr.org/about-the-aacr/newsroom/news-releases/breast-cancer-patients-with-estrogen-receptor-mutations-may-benefit-from-early-switch-to-fulvestrant-palbociclib/

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 Phase III trial. News release. AstraZeneca. February 26, 2025. Accessed April 25, 2025. 

https://www.astrazeneca.com/media-centre/press-releases/2025/camizestrant-improved-pfs-in-1l-hr-breast-cancer.html

Jason A. Mouabbi, MD, discusses the use of ctDNA to enhance early detection of ESR1 or other resistance mutations in HR-positive breast cancer. 

Proactive ctDNA Monitoring May Guide Earlier Intervention in Endocrine-Resistant HR+/HER2– Breast Cancer

Dr Mouabbi on the Rationale for Early, Serial ESR1 Mutation Testing in HR+ Breast Cancer  

] mutation early is critical. If patients are kept on AIs without switching therapies, the resistant clone can expand, potentially leading to disease progression… The mutation can emerge at any time, making it important to assess for 

mutations early and perform serial testing over the course of treatment."

Jason A. Mouabbi, MD, an assistant professor in the Departments of Breast Medical Oncology and General Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the importance of testing for 

 mutations prior to radiographic progression in patients with hormone receptor (HR)–positive, HER2-negative breast cancer.

 mutations represent a clinically significant mechanism of resistance in HR-positive, HER2-negative breast cancer, Mouabbi began. These mutations are classified as therapy-selected alterations, commonly arising in response to prolonged exposure to endocrine therapies, particularly aromatase inhibitors (AIs), which are widely used in the first-line metastatic setting, he stated.

 mutations result in a constitutively active estrogen receptor (ER), which no longer requires ligand binding for activation, he continued. Under healthy physiologic conditions, the ER remains inactive until bound by estrogen, at which point it promotes transcriptional activity leading to cell proliferation, Mouabbi detailed. However, in the presence of 

 mutations, the receptor remains in an active conformation independent of estrogen, according to Mouabbi. Consequently, AIs—which work by depleting estrogen—lose efficacy, allowing tumor proliferation to continue despite estrogen suppression, Mouabbi explained.

 mutations is critical for optimizing treatment sequencing, Mouabbi reiterated. Continued use of AIs in patients harboring 

 mutations may enable clonal expansion of resistant subpopulations, resulting in more aggressive disease that is less responsive to subsequent therapies, he said. Because 

 mutations can arise dynamically throughout treatment, serial testing, such as with circulating tumor DNA, is essential to identify the emergence of resistance and guide timely therapeutic adjustments, Mouabbi added.

 mutations are uncommon at the time of initial metastatic diagnosis among patients previously treated with endocrine therapy in the early-stage setting, he reported. However, this frequency increases with continued exposure to anti-estrogen therapies, reaching approximately 20% to 30% in the first-line metastatic setting and approximately 40% in later-line settings, Mouabbi noted. These data underscore the cumulative selection pressure imposed by endocrine agents and highlight the importance of molecular monitoring to inform precision treatment strategies in advanced HR-positive, HER2-negative breast cancer, Mouabbi concluded.

Jason A. Mouabbi, MD, discusses how ESR1 mutations can cause patients with HR-positive, HER2-negative breast cancer to develop endocrine resistance.