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

Jason A. Mouabbi, MD

A growing body of evidence suggests that serial monitoring via circulating tumor DNA (ctDNA) could enable early detection of resistance mutations, including ESR1, 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 ESR1 mutations, emerging data from the phase 3 SERENA-6 trial (NCT04964934) suggest clinical benefit with this proactive intervention.1 According to topline results from a press release, SERENA-6 met its primary end point 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 ESR1 mutation.2

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 OncLive®. “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 ESR1 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.

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

Mouabbi: 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.

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 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.

The ESR1 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 ESR1 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 ESR1 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, ESR1 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 ESR1 mutation becomes.

What advantages does ctDNA offer over tissue biopsy for the detection of ESR1 mutations in breast cancer, and what considerations should be made when selecting the most appropriate method for mutation testing?

The best way to test for an ESR1 mutation is via liquid biopsy using ctDNA. This is because the ESR1 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 ESR1-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 ESR1 mutations.

This approach has already been validated in a JAMA publication, which demonstrated that liquid biopsy is the preferred method for ESR1 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 ESR1 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 ESR1 or other resistance mutations in breast cancer before radiographic progression is evident?

Regarding timing—the earlier ESR1 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 ESR1 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 ESR1-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 ESR1 or other mutations. [For example], the PIK3CA 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 PTEN or AKT mutation. Altogether, [PIK3CA/PTEN/AKT 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

References

1. 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/
2. 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