<p>Stage III breast cancer often demands the deployment of a broader treatment regimen due to the risk of recurrence with greater tumor burden and lymph node involvement. At the recent<strong> 2025 San Antonio Breast Cancer Symposium (SABCS 2025)</strong>, 2 data sets stood out for HR+ stage III disease. Together, they spotlight both better endocrine therapy options and a clearer path to identifying relapse earlier.</p> <p><br></p> <p><em>Following these presentations, featured expert Seth A. Wander, MD, PhD, was interviewed by </em>Conference Reporter<em> Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Wander on these findings are presented here.</em></p>

Stage III, or locally advanced breast cancer, typically refers to higher-grade tumors and multinode involvement, in contrast to lower-stage disease. This, unfortunately, portends a higher risk of local and distant recurrence, as well as the need for more aggressive treatments. Many of these patients receive combination chemotherapy and 7 to 10 years of optimal antiestrogen treatment, and the vast majority are now offered a CDK4/6 inhibitor.

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Despite many recent advances, new therapeutic tools continue to be developed in this higher-risk setting and remain of great interest. Important advances were presented at SABCS 2025 that have the capacity to reshape the treatment landscape for HR+/HER2- stage III breast cancer. For example, the phase 3 lidERA study, which was presented by Aditya Bardia, MD, MPH, evaluated the use of adjuvant giredestrant, a next-generation oral SERD, vs standard-of-care (SOC) endocrine therapy for patients with ER+/HER2- early-stage breast cancer (abstract GS1-10).

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We have a variety of new antiestrogen drugs that are emerging as new SOCs for stage IV disease, but the data from lidERA were the first that we have seen for these next-generation oral SERDs in the early-stage setting. The results suggest that 5 years of giredestrant provide a statistically and clinically significant improvement in the risk of disease recurrence compared with conventional antiestrogen therapy. This is very exciting and suggests that these newer antiestrogens may convey important clinical benefit compared with traditional drugs such as tamoxifen or aromatase inhibitors.

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One important limitation of the lidERA study is that many of the patients would have been eligible for a CDK4/6 inhibitor in the current treatment paradigm. (The study design and initiation of lidERA preceded subsequent US Food and Drug Administration [FDA] approvals of both ribociclib and abemaciclib in this population.) As a result, the control arm in lidERA may not completely reflect the current SOC. We will have to wait for some additional data to understand how the use of giredestrant might add to the standard use of CDK4/6 inhibitors in this large patient population.

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The lidERA study takes its place in the treatment landscape in the context of positive phase 3 data for giredestrant in combination with everolimus in the metastatic setting, which was presented last year at the European Society for Medical Oncology (ESMO) Congress 2025. Based on these large phase 3 trials, pending regulatory evaluation and approval, there may be future opportunities to deploy giredestrant alone as endocrine therapy in the early-stage setting or in combination with everolimus in the metastatic setting.

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Also presented at this year’s SABCS meeting was a study by Ranjan Upadhyay, MD, et al exploring ultrasensitive circulating tumor DNA (ctDNA)–based minimal residual disease monitoring to predict relapse in postoperative, HR+, inflammatory, stage III breast cancer (poster PS4-02-02). In this small, prospective, single-arm, phase 2 trial, patients received pembrolizumab plus physician-chosen endocrine therapy during or after radiation treatment. The investigators noted that all patients who had disease progression within 24 months had persistent and rising ctDNA levels ahead of these clinical changes on imaging. Lead times were up to 1.5 years, suggesting that investigators could detect increasing ctDNA levels well before the patient had any imaging findings that may have been concerning for disease progression. Interestingly, all patients who were ctDNA minimal residual disease–negative after surgery remained disease free after 2 years.

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These data suggest that ctDNA monitoring for minimal residual disease is feasible and, in the rare and difficult-to-treat high-risk subset of HR+, inflammatory, stage III breast cancer, we may be able to differentiate patients who are more or less likely to experience disease recurrence. Further validation of these results may indicate that minimal residual disease can be used to risk stratify patients in the postoperative setting.

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Still, questions remain. For example, how can we continue to personalize and optimize treatment for patients with HR+ stage III breast cancer? How should we deploy ctDNA and minimal residual disease testing to escalate or deescalate therapy selection in this diverse patient population? In the coming years, we will continue to build on these promising results to help us further personalize treatment selection across the spectrum of breast cancer subtypes and stages.