Breaking Down the Impact of SERENA-6 for Some With Breast Cancer

Dr. Julia E. McGuinness and Dr. Joshua K. Sabari discuss the SERENA-6 trial and its outcomes for patients with ESR1-mutated HR+/HER2— breast cancer.

Dr. Joshua K. Sabari and Dr. Julia E. McGuinness sat down for an interview following the 2025 ASCO Annual Meeting to highlight key takeaways from the conference across the landscape of breast cancer treatment. During the interview, McGuinness highlighted the SERENA-6 trial.

The SERENA-6 trial evaluated patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer who had an ESR1 mutation. According to McGuinness, the trial aimed to answer the question of if ESR1 mutation detection prior to progression would help extend the efficacy of first-line treatment for those with this disease.

During the interview, they covered what circulating tumor DNA (ctDNA) is, how it works, and how it impacted the SERENA-6 trial, as well as highlighted trial outcomes and what is next for this clinical investigation.

Sabari is the editor in chief of CURE. He also serves as an assistant professor in the Department of Medicine at NYU Grossman School of Medicine and director of High Reliability Organization Initiatives at Perlmutter Cancer Center. McGuinness is a medical oncologist and serves as an assistant professor of medicine within the Division of Hematology/Oncology at Columbia University Irving Medical Center, Columbia University Herbert Irving Comprehensive Cancer Center, located in New York.

Read on to hear their insights on SERENA-6!

Sabari: Hello, I'm Dr. Joshua Sabari. I'm a thoracic medical oncologist at NYU Perlmutter Cancer Center, and I'm the editor in chief of CURE magazine. I want to introduce Dr. Julia E. McGuinness. Dr. McGuinness, please introduce yourself.

McGuinness: Hi everyone. I'm Dr. Julia E. McGuinness. I'm an assistant professor of medicine at Columbia and a breast medical oncologist.

Sabari: Julia, welcome. We're excited to have you. I know this is an exciting following ASCO 2025, so give us some breast cancer abstract takeaways from the meeting.

McGuinness: There was actually a lot of significant news this year in all areas of breast cancer, encompassing both metastatic and earlier-stage disease. I anticipate some controversy over several of the major abstracts that are already making headlines. I think the biggest one, which made the plenary session, was SERENA-6.

This is a really interesting trial design that builds upon prior research in metastatic breast cancer. Essentially, it enrolled patients with metastatic hormone receptor-positive, HER2-negative breast cancer who were receiving their first line of treatment for metastatic disease. Typically, that first-line treatment is a combination of an aromatase inhibitor (an anti-estrogen medication) and a targeted therapy called a CDK4/6 inhibitor. In this study, Kisqali [ribociclib] was used as the primary CDK4/6 inhibitor.

The question they aimed to answer was: Is there a way to prolong the benefit of that first-line therapy by looking for the emergence of mutations that might indicate resistance to the anti-estrogen component (the aromatase inhibitor)? Specifically, they focused on the ESR1 mutation.

What they did was try to identify women who developed this ESR1 mutation while on their first-line treatment. They utilized serial liquid biopsies — blood tests every three months — to look for changes in circulating tumor cells in the blood and to detect an ESR1 mutation. They actually had to screen about 30,000 women to find approximately 300 who developed this mutation to then proceed to the next part of the trial.

In this situation, when these women developed an ESR1 mutation on their initial therapy, the control arm (standard of care) was to continue their current therapy, continue getting scans, and then switch their treatment when the scans showed that the disease had progressed, meaning the cancer had grown through therapy.

However, the experimental arm they were testing involved, once these women developed the mutation even before the cancer had progressed on scans, prolonging the time patients remained on their anti-estrogen therapy by switching the anti-estrogen backbone to something called camizestrant, an oral SERD (selective estrogen receptor degrader). Camizestrant actually breaks down the estrogen receptor, thus potentially overcoming the ESR1 mutation.

What they found, at least in this initial readout (presented as a rapid abstract with late-breaking results), was that this switch did prolong what they call progression-free survival — the amount of time women were on their first treatment, whether that was the combination with the switch from the aromatase inhibitor to camizestrant, or in the control arm, just the continuation of the aromatase inhibitor until progression.

This is very controversial, and I think it's being touted in the news as something that's going to be practice-changing. However, there are some big caveats before we actually use this in practice, because this would be a significant shift from our standard approach. Typically, many of us, at least in academic centers, perform these liquid biopsies at the time of diagnosis to evaluate initial mutations for future therapy planning. Then, when a patient's cancer progresses (when their scans show it's growing), we repeat the testing to look for that ESR1 mutation.

This new strategy would impose a significant burden. Instead of just doing that testing twice (at the beginning and end), we would be doing it every two to three months on treatment, as per the trial. This adds a lot of cost, requires a lot of testing, and could add a lot of anxiety and burden to patients as they anxiously await not only scan results but also potentially results that could indicate their first-line treatment is no longer working effectively.

The discussion by Dr. Nadia Harbeck was actually very helpful in breaking down the limitations and what we truly need to see next. The biggest limitation was in the control arm: when women on their aromatase inhibitor and CDK4/6 inhibitor had disease progression on scans, the best or simplest, clearest design would have been to then switch them to the camizestrant with the CDK4/6 inhibitor. But they didn't; they allowed the treating physician to choose whatever treatment they deemed appropriate. Therefore, it's hard to truly compare that to the camizestrant combination. It's going to be statistically difficult to definitively show that people are getting more overall benefit from all of these treatments through this switch. And there's always the question of whether this is genuinely better than just waiting until someone has disease progression on their scans.

So, I think what we're going to really need before we make this huge change in our practice for so many women (because, again, this applied to only about 10% of women who, even after all this testing, could receive these therapies) is to see the long-term data. We're going to really have to look at the statistical analyses, and this will probably need to be carefully reviewed by the FDA before we can even make a switch.

As it stands now, camizestrant is not even approved for metastatic breast cancer, so we'd first need drug approval before we could even prescribe it, and then we'd have to assess whether this strategy is appropriate.

Ultimately, what we're trying to achieve with any of these treatments is to help women live longer, which is measured by overall survival. That outcome is going to take a while to read out, and it might be that we have to wait for some of these longer-term outcomes before we actually make such a significant change.

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