In this CancerNetwork® Around the Practice program, Neil M. Iyengar, MD, moderated a discussion with Rebecca A. Shatsky, MD, and Carol Tweed, MD, on the emergence of ESR1 mutations during first-line therapy for hormone receptor–positive, HER2-negative metastatic breast cancer. The panel walked through the biology of acquired endocrine resistance, the design and results of the phase 3 SERENA-6 trial (NCT04964934), and the case for switching to camizestrant (Etcamah), an investigational oral selective estrogen receptor degrader (SERD), at the point of molecular progression rather than waiting for a scan to change.¹ The conversation also weighed the strategy’s open questions on how to interpret dueling progression-free survival end points, camizestrant’s safety profile, testing costs, and whether early switching makes sense for every patient.

Iyengar is director of survivorship services at Winship Cancer Institute of Emory University, a clinical member of Winship’s Glenn Family Breast Center, an associate professor and co-director of the Breast Medical Oncology Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and co-editor in chief of the journal ONCOLOGY®. Shatsky is medical director of the Breast Cancer Clinical Trials Program and the Inflammatory and Triple-Negative Breast Cancer Program at the University of California San Diego. Tweed is a breast medical oncologist with Maryland Oncology Hematology.

Background: Biology of Resistance and ESR1 Emergence

Iyengar: Could you take a deep dive into what is happening during aromatase inhibition in terms of tumor biology and clonal evolution, and why these changes are important in terms of how we think about treatment selection during first line therapy, as well as how we think about subsequent treatment selection?

Shatsky: An aromatase inhibitor blocks the enzyme aromatase that converts natural testosterone into estrogen, depriving breast cancer cells that depend on estrogen for growth. In metastatic breast cancer, though, the cells eventually get smart and find ways around aromatase inhibition. Mutations can happen in the estrogen receptor, where it becomes constitutively active, meaning it no longer needs the estradiol ligand to translocate to the nucleus and drive transcription and translation. This can lead to rapid clonal expansion, where different resistant clones emerge in different metastatic sites. Certain mutations within ESR1, like Y537S and D538G, are associated with more aggressive cell growth and, in some cases, liver tropism.

Tweed: When a patient is first diagnosed, you have to explain that this is a chronic process and that, at some point, there’s going to be biologic pressure toward resistance to first-line treatment. Helping them understand that cells can acquire mutations that make the current therapy stop working means they’re not as frightened. They think, “Okay, this happened, and we have next steps.” A number of patients come in already asking about this mutation. That’s empowering.

Camizestrant and the Oral SERD Landscape

Iyengar: Let’s talk specifically, Dr. Shatsky, about camizestrant, which was the drug that was studied in the SERENA-6 trial. Do you have experience with patients who have developed an ESR1 mutation in the tumor that has emerged or that you’ve detected on ctDNA during their first-line therapy while they’re on that aromatase inhibitor and CDK4/6 inhibitor? If so, how have you discussed this with the patient, and what has been your sense in terms of how patients themselves are perceiving this information?

Shatsky: There are a number of oral SERDs in clinical development. They tag the estrogen receptor and signal the proteasome to degrade it, so we no longer care about estrogen binding. We can get rid of that constitutively active receptor before it drives more transcription and translation. We have 2 that are FDA approved right now: elacestrant [Orserdu] and imlunestrant [Inluriyo]. Camizestrant is not currently FDA approved, but it is approved in Europe, and the SERENA-6 strategy is available there now.² We had an ODAC [Oncologic Drug Advisory Committee] vote earlier this year, and we’re looking for additional data before US approval.³ Giredestrant is another oral SERD in development, and there are SERD-SERM combinations like palazestrant in trials. This armamentarium is increasing, giving us more options for patients beyond the aromatase inhibitor but before chemotherapy.

Co-Mutations and Treatment Complexity

Tweed: As enthusiastic as we are about new agents, whether a SERD or a proteolysis targeting chimera [PROTAC], targeting PI3K is effective, but the problem is it’s not durable. When I see co-mutations, it creates a conundrum about what to do next. There’s more potential toxicity with something like capivasertib [Truqap], but also potential for a robust, brisk symptomatic response. It doesn’t change how I discuss tumor biology with a patient, though, because we understand a co-mutation predicts a less favorable behavior.

Iyengar: It does complicate treatment selection. We’re seeing data suggesting there’s still treatment response in the setting of co-mutations when you use an oral SERD, so I don’t view this in a vacuum. That said, some alterations, particularly PIK3CA and AKT, portend a worse prognosis, which raises the question of combining molecular strategies [such as] an AKT inhibitor like capivasertib with a SERD, for example. That’s an attractive approach biologically, but there’s additional burden to the patient in terms of adverse effects [AEs]. Ultimately, I’m very transparent with patients about the durability of response and try to arrive at a decision with their input.

Shatsky: It depends on the co-mutation and the specific patient in front of me. What I don’t like about the oral SERD data, across the board, is that at the top of the curve, there’s a very steep drop-off, meaning a significant portion of patients just doesn’t respond. That fear drives me to use dual therapy a little more. I’m excited about combinations like the phase 1/2 ELEVATE trial [NCT05563220] looking at elacestrant plus capivasertib, and other trials pairing CDK4/6 inhibitors with less toxic PI3K inhibitors.⁴ I think combination therapy is likely to be the future.

SERENA-6 Trial Design and Primary Efficacy

Iyengar: The SERENA-6 trial tested a fundamentally different approach: detecting ESR1 mutation emergence on ctDNA and switching, at that point of molecular progression, to camizestrant plus a CDK4/6 inhibitor before clinical or radiographic progression. Dr. Shatsky, could you lay out the trial design and what the primary data showed?

Shatsky: SERENA-6 was a very interesting trial design. Over 3300 women were screened, [who were] patients on first-line aromatase inhibitor and CDK4/6 inhibitor therapy for at least 6 months with no radiographic progression. Women were tested every 2 to 3 months for ESR1 using the Guardant360 platform. Once an ESR1 mutation without radiographic progression was detected, patients were [randomly assigned] 1:1 to stay on their aromatase inhibitor plus CDK4/6 inhibitor, or switch to camizestrant plus their CDK4/6 inhibitor. About half were already positive on the first test. Patients who stayed on their aromatase inhibitor had about 9 months of progression-free survival, whereas patients who switched to camizestrant had almost 17 months. There’s been a lot of debate about that, [as] we’re now looking at 2 lines of therapy. Are we calling this PFS1 vs PFS2? That controversy aside, there was about a 7-month difference in time to radiographic progression favoring the camizestrant switch group.

Interpreting the Data: PFS1/PFS2 Debate and ODAC Concerns

Iyengar: Ultimately, we have to keep in mind that the trial did meet its primary end point. Now, you highlighted the issue of when exactly the clock starts for counting PFS, and this can be challenging to parse out. Dr. Tweed, I’ll get your thoughts on this. How do you interpret that PFS benefit?

Tweed: As long as we’re thinking about PFS as clinical or radiologic, not molecular, progression, it’s PFS1. There was a lot of question about whether PFS2, meaning time to progression on the next line of therapy after switching, still favors the camizestrant switch arm. What was discussed well at the 2026 American Society of Clinical Oncology [ASCO] Annual Meeting is that this second PFS still favors the camizestrant arm, and that’s meaningful because a good number of patients on the aromatase inhibitor arm went on to a subsequent SERD, mostly fulvestrant [Faslodex], and there was still nearly the same absolute difference in PFS2 as PFS1. The way I interpret that is there’s something more than just getting the drug at some point because you’d expect some muting of that difference, and it didn’t happen.

What matters more to me is that patients—and the average oncologist, honestly—don’t fully understand these statistics. What the patient cares about is time to first chemotherapy, time to losing your hair, getting a port, coming in every 3 weeks for infusions, symptoms, quality of life, and global health outcomes, all of which have favored the camizestrant switch arm. I understand ODAC had some concerns, and part of that is that the notion of using PFS2 alone was never fully accepted by the FDA. In reality, PFS1 is improved when you switch. PFS2 is improved despite some crossover. The patient’s quality of life is better. I’m not sure what else we want to see.

Shatsky: Agreed. I want to highlight that patient-reported outcomes matter enormously to us as breast oncologists. [Avoiding] hair loss and being tied to an IV are astronomically important to patients with breast cancer.

Iyengar: I was a huge skeptic when I first saw the SERENA-6 data. I had residual concerns about lead-time bias and wanted to see overall survival data. I’ve made an almost complete reversal, and I favor the SERENA-6 paradigm. I’m compelled by the time-to-chemotherapy prolongation, that’s the number 1 concern we hear from patients at metastatic diagnosis. The flip side is there’s additional work: ctDNA screening means doing the testing but also having that conversation with a patient who was feeling well, who has a clean scan, and now telling them we’ve detected molecular progression and need to change therapy.

Bringing It to Practice: Testing Frequency, Patient Conversations, and Cost

Shatsky: I haven’t fully adopted this approach in the clinic yet. Because of the trial design, it’s not entirely clear how frequently I would be testing. I don’t know that every 2 to 3 months is right for everyone. I’d probably take a more personalized approach, maybe watch a patient’s tumor markers before deciding to test. It’s important to tell patients up front what the testing is for, so it isn’t a surprise. When you frame it as preventing the next bone metastasis before it happens, that’s the useful approach.

Tweed: We don’t practice based on anecdotal experiences, but they impact us. When you have a patient tearful in front of you saying, “We saw the marker going up, and now I can’t walk. Why didn’t we change?” All we used to think about was that we don’t have a survival benefit, we never thought about tracking quality of life. It’s very hard for me to understand, if this is approved, how I wouldn’t do this for everyone. There is a global cost-of-care consideration; that’s another discussion, but I can’t think of when I wouldn’t do this.

Iyengar: For me, this would be a default approach for everyone. I can’t see a good reason not to do it, except if a patient themselves is reluctant or if they’re truly tolerating treatment well. By default, I agree this is an approach I would discuss with everyone.

Safety Profile and Community Practice Considerations

Shatsky: The most notable AE is photopsia; flashing lights for a second or two in peripheral vision. It isn’t associated with any damage to the eye, but it can be scary for patients, especially when driving at night. The other notable one, and ODAC did note this, is bradycardia. We don’t know that this is hurting the heart in any way, but I call this the “Apple Watch effect.” Patients get beeped awake at night because their heart rate is in the 40s, sometimes the 30s. Aside from that, camizestrant causes musculoskeletal pain, just like an aromatase inhibitor, as well as hot flashes and some vaginal dryness. The most notable effects are bradycardia and photopsia, different from what we see with aromatase inhibitors.

Tweed: My answer is that this is a non-issue. The ocular symptoms are interesting to patients but don’t impair function, and they tend to burn out with time. You don’t need an ophthalmologist involved. There’s no role for a cardio-oncologist here, either. This is asymptomatic bradycardia; it doesn’t impair function or tolerance. I don’t need a cardiologist or ophthalmologist involved to feel comfortable using this drug. Most of my patients who switched to camizestrant on trial had significant improvement in arthralgias if they had them at baseline.

Iyengar: What we saw with the musculoskeletal reporting is an artifact of the instruments used for both patient-reported outcomes and AE grading. When you press somebody enough about whether their joints hurt, everybody’s joints hurt after a certain age. We need better instruments to dive into arthralgia, specifically.

Closing Takeaway

Iyengar: This was an excellent discussion. We began with the biology of what an aromatase inhibitor does to a tumor, talked about the SERENA-6 data and what it means to act at the molecular moment rather than waiting for a scan, and examined the questions this raises: who is it right for, how do we talk to patients about it, and how do we weigh the safety data?

References

1. Bidard FC, Mayer E, Park YH, et al. First-line camizestrant for emergent ESR1 mutations in advanced breast cancer: final progression-free survival results 2 from the phase III SERENA-6 trial. J Clin Oncol. 2026;44(suppl 17):LBA1007. doi:10.1200/JCO.2026.44.17_suppl.LBA1007
2. Etcamah (camizestrant) in combination with a CDK4/6 inhibitor approved in the EU for 1st-line advanced ER-positive breast cancer. News release. AstraZeneca. July 23, 2026. Accessed August 26, 2026. https://tinyurl.com/55mn9h96
3. April 30, 2026 meeting of the Oncologic Drug Advisory Committee (ODAC). YouTube. Accessed August 26, 2026. https://tinyurl.com/5cry64pu
4. Rugo H, Tolaney S, Chan N, et al. Elacestrant in combination with everolimus or abemaciclib in patients with ER+/HER2- locally advanced or metastatic breast cancer (mBC): phase 2 results from ELEVATE, an open-label, umbrella study. Presented at: 2025 San Antonio Breast Conference Symposium; December 9-12, 2024; San Antonio, TX. Abstract RF7-01.