<p>Advances in circulating tumor DNA (ctDNA) testing are transforming how clinicians identify and manage treatment resistance in HR+/HER2- metastatic breast cancer. Data from the <strong>2025 San Antonio Breast Cancer Symposium (SABCS 2025)</strong> reveal the complex and heterogeneous resistance pathways that emerge across lines of therapy and the potential role of ctDNA-guided strategies in personalizing treatment, optimizing sequencing, and improving long-term disease control.</p> <p><br></p> <p><em>Following these presentations, featured expert Angela M. DeMichele, MD, MSCE, FASCO, was interviewed by </em>Conference Reporter<em> Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr DeMichele on these findings are presented here.</em></p>

The ctDNA assay is a sensitive test that monitors measurable residual disease by looking for microscopic levels of tumor-specific “fingerprints” (ie, genetic mutations) that are still present in patients posttreatment. So, from a blood sample, we can determine whether actionable mutations are present and whether a patient is a candidate for targeted therapy. The ctDNA assay has really been a game changer in revolutionizing how we manage metastatic breast cancer.

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In the advanced cancer setting, the hope is that ctDNA testing will evolve to the point where we can look at a patient’s risk for treatment resistance, allowing us to detect emerging resistant mutations before we even see a change on a scan. The phase 3 SERENA-6 trial by François-Clément Bidard, MD, PhD, and colleagues evaluated this strategy in patients with HR+/HER2- advanced breast cancer who received an aromatase inhibitor during first-line treatment. All patients underwent ctDNA testing every few months to look for the presence of the aromatase inhibitor–resistant mutation, ESR1. When mutations were detected, patients were randomized 1:1 to switch to the SERD camizestrant with a continued CDK4/6 inhibitor plus placebo or to remain on aromatase inhibitor treatment plus a CDK4/6 inhibitor plus placebo.

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Interim results showed that patients who switched to camizestrant at the time of ESR1 mutation detection had a longer median progression-free survival (PFS) than patients who did not switch to camizestrant (16 months vs 9.2 months, respectively). The final PFS results from SERENA-6, which were presented at SABCS 2025 by Dr Bidard, seem about the same (abstract RF7-03). The median PFS at the time of the next progression also looked to be longer among patients who made an early switch compared with those who did not switch (25.7 vs 19.4 months, respectively).

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One shortcoming of this trial is that patients who waited until they had a scan that showed progression did not cross over to camizestrant. So, there was no way to determine the activity of camizestrant treatment at the time of ESR1 mutation detection vs at the time of a change detected on a scan. This is a limitation because it makes it impossible for us to know whether switching treatment early on makes a difference.

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For a clinical trial, it is important to look at not only the current treatment(s) patients are receiving but also the treatment(s) they receive after that because this could really impact overall survival. We will not know the overall survival outcomes from the SERENA-6 trial for several years, but it does appear that switching to camizestrant at the time an ESR1 mutation is detected in the blood allows for disease control. I think that switching treatment early is a very reasonable thing to do, but whether that is better than waiting until the scan changes to give camizestrant, we just will not know.

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We are starting to see data from large studies characterizing the mutation profiles we see as patients move from first- to second- to third-line therapy. This is important because it can help us understand the evolution of metastatic breast cancer resistance, which therapies will continue to work, and which ones will not work. This can be very helpful for optimizing the sequence of therapies.

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Another study presented at SABCS 2025 was by a consortium of investigators who used the Guardant360 test (Guardant Health, Inc), one of the panel-type tests for ctDNA, to look at time-to-progression patterns during first- and second-line endocrine therapy in patients with HR+/HER2- metastatic breast cancer (poster PS2-07-04). The study showed that if a patient had certain mutations, including TP53, their time to progression on subsequent therapies was much shorter than it would have been if they had other kinds of mutations.

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This is helpful information, both for helping patients understand their prognosis and for developing new therapeutic strategies. We are starting to see which mutations predict response to some of our newer PI3K inhibitors (eg, inavolisib and capivasertib), which mutations are emerging as those therapies stop working, and what the resistance mechanisms to those therapies are.

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I think the take-home message from these studies, however, is that the panel of the different mutations we see is quite broad. In fact, there is a lot of variability. This tells us that not all cancers that are treated with the same PI3K inhibitor are the same. They can take different paths to mutations and resistance, and we will need to understand all those different resistance pathways as we continue to search for effective therapies for these patients.