<p>Advances in endocrine and targeted therapies have transformed outcomes for patients with HR+/HER2- metastatic breast cancer, but they have also introduced new toxicities that require a heightened clinical awareness. Related real-world data presented at the recent <strong>2025 San Antonio Breast Cancer Symposium (SABCS 2025)</strong> highlight the need for proactive monitoring and the early management of treatment-related adverse events.</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>

Over the past decade, the treatment of HR+/HER2- metastatic breast cancer has really evolved. Endocrine therapy remains the backbone for initial treatment in patients who are not in a visceral crisis. Most patients can start with endocrine therapy along with a targeted agent, typically a CDK4/6 inhibitor and/or a PI3K inhibitor if they have a PIK3CA mutation.

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Now, these targeted agents have varying side effects. For example, the main side effects of CDK4/6 inhibitors have to do with suppressing the cell cycle and stopping cellular division, which leads to not only myelosuppression (primarily neutropenia) but also, potentially, anemia or thrombocytopenia. These are dose related, and they are rapidly reversible when the drugs are stopped. In addition, we can see mucositis, oral ulcers, diarrhea, and fatigue with CDK4/6 inhibitor use.

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If a patient has a PIK3CA mutation, they are often treated with a PI3K inhibitor, as previously noted. Several second-generation PI3K inhibitors are now approved by the US Food and Drug Administration (FDA). They are better tolerated than first-generation PI3K inhibitors; however, they do have several key toxicities that we need to be aware of and manage aggressively. This is why the first month of therapy is so critical. Treatment-related toxicities usually occur almost immediately, and we often need to institute supportive care and/or dose modifications to ensure that patients can tolerate these agents.

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The most serious of the toxicities seen with PI3K inhibitor use is hyperglycemia. Patients can develop diabetic ketoacidosis, which can be fatal if it is not treated immediately. As medical oncologists, many of us have not managed hyperglycemia for many years—maybe even decades—perhaps not since we were doing our internal medicine training. And so, we often work with endocrinologists and diabetologists to treat these patients.

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Rash is another commonly seen toxicity with PI3K inhibitor use, as is diarrhea. We often collaborate with dermatologists to manage rash if it becomes extensive over a large portion of the body or if it evolves to include ulceration or superinfection. Further, we work with gastroenterologists to help us manage severe cases of diarrhea that present with liver function test abnormalities or even as bloody diarrhea. This type of multidisciplinary approach has been shown to enable patients to remain on treatment longer and to improve treatment outcomes and quality of life.

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Real-world studies help us better understand the prevalence of these treatment-related toxicities and how best to manage them. There was a fair amount of real-world data presented at SABCS 2025 for some of the newer agents for metastatic breast cancer. One study presented at the meeting by Jasmin Hundal, MD, DipABLM, MS, MPH, from Cleveland Clinic, reported on the real-world incidence and management of trastuzumab deruxtecan–associated interstitial lung disease in patients with metastatic breast cancer (poster PS5-04-11). This study showed that all-grade trastuzumab deruxtecan–associated interstitial lung disease was less common in the community than in all the DESTINY-BREAST trials, that it can be managed with steroids when initiated promptly, and that these patients can have good outcomes.

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Another interesting study presented at SABCS 2025 by Victoria Barghout focused on the implementation of a patient guide to aid in the management of symptoms and treatment-related side effects in patients with metastatic breast cancer (poster PS1-03-29). These patient guides can help us provide much-needed patient education within the clinic, and they help support patient-provider communication and shared decision making. It is wonderful having new agents to manage metastatic breast cancer, but this requires ongoing self-education for clinicians and the education of patients about the toxicities, including how to recognize the toxicities that can become life-threatening (eg, hyperglycemia, neutropenia, and diarrhea), and really supplementing our work with educational materials.

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I would love to see more tools become available for both patients and clinicians that allow us to understand a patient’s risk for some of these more severe toxicities based on their comorbidities and other factors. Tools like this will really help us tailor our supportive care to the individual patient. Additionally, I hope to see more integration of patient-reported outcomes into our clinical care so that we can not only have a more complete picture of the patient’s experience but also amass more data on the true patient experience associated with these drugs.