For patients diagnosed with advanced hormone receptor (HR)–positive breast cancer, emerging therapies and tailored treatment strategies are shifting the landscape towards prolonged disease control and an improved quality of life, Dr. Daphne Stewart explained during a December 2025 Educated Patient® Breast Cancer Summit, highlighting the evolving landscape of advanced HR-positive breast cancer management.
Stewart is a clinical professor of medicine and chief of the Women’s Cancer Section at University of Southern California, Norris Comprehensive Cancer Center and Keck School of Medicine.
“We have so many treatment options, which is a positive, but we need to be very supportive,” she emphasized in the presentation. “We also need to continue to make progress. We need to continue to participate in clinical trials so that we can optimize the interventions, minimize the toxicity and optimize the sequencing.”
Understanding Advanced HR+ Breast Cancer
HR-positive breast cancer, which expresses estrogen and progesterone receptors on cancer cells, accounts for approximately 70% of all breast cancer cases. In the advanced setting, either after recurrence or as de novo metastatic disease, HR-positive breast cancer is no longer considered curable, yet modern therapies can significantly prolong survival and maintain quality of life.
“The most common breast cancer is HR-positive, which means that you have estrogen receptor and progesterone receptor positivity on the surface of the cells. This makes up nearly 70% of breast cancer,” Stewart explained in the presentation.
Most advanced HR-positive cases in the United States arise after prior treatment for early-stage disease. Approximately 90% of patients develop advanced cancer following curative-intent therapy, often due to endocrine therapy resistance or incomplete adherence to prescribed hormonal treatments. About 10% of patients present with de novo metastatic cancer, diagnosed at the outset with disease already spread to lymph nodes or other organs.
The Diagnosis and Initial Assessment of HR+ Disease
In her presentation, Stewart emphasized that a thorough evaluation is essential at diagnosis. Physicians aim to identify the extent and location of disease through imaging and perform biopsies to confirm HR-positive status. Genetic testing is also critical to identify inherited mutations such as BRCA1, BRCA2 or PALB2, which can guide therapy and inform family members about cancer risks. Biomarker testing, including ESR1, PIK3CA, PTEN and AKT mutations, helps tailor treatments to individual tumor profiles.
Liquid biopsies, which detect circulating tumor DNA in the blood, are increasingly supplementing traditional tissue biopsies for real-time monitoring of tumor mutations.
First-Line Therapy: Targeting Estrogen-Driven Cancer Growth
The cornerstone of first-line treatment for advanced HR-positive breast cancer combines anti-estrogen therapy with cyclin-dependent kinase (CDK) 4/6 inhibitors.
“The treatment strategy for advanced disease is to stop cancer cell growth and proliferation by depleting estrogen, because hormone receptor positive breast cancer is driven and fed by this signaling pathway,” Stewart explained.
Anti-estrogen options include aromatase inhibitors, selective estrogen receptor degraders (SERDs) such as fulvestrant, and selective estrogen receptor modulators (SERMs) like tamoxifen. Premenopausal patients often receive ovarian suppression to reduce estrogen production, whereas postmenopausal patients benefit primarily from aromatase inhibitors that block estrogen synthesis from adrenal and peripheral sources.
CDK 4/6 inhibitors are added to anti-estrogen therapy to further halt cancer cell proliferation by targeting proteins that drive cell cycle progression. Clinical trial data involving more than 9,000 patients demonstrate that combination therapy can double response rates compared with anti-estrogen therapy alone, with long-term disease control often extending for years.
Side effects vary by drug and may include neutropenia, diarrhea, liver dysfunction or QT interval prolongation, but careful monitoring and dose adjustments help maintain efficacy while minimizing toxicity.
Protecting Your Health and Monitoring Treatment Response, Progression
Advanced HR-positive breast cancer frequently spreads to bone, causing pain, fractures and spinal cord compression. Bisphosphonates such as zoledronic acid (IV) or denosumab (subcutaneous) are administered to reduce these risks. Side effects are generally mild, including short-term bone pain, fatigue or fever, and treatment is coordinated with regular lab monitoring.
Response to therapy is assessed regularly using imaging, lab tests and symptom evaluation. Emerging tools like circulating tumor DNA can detect early signs of treatment resistance, allowing clinicians to adapt therapy before clinical progression occurs.
When disease progresses or side effects become intolerable, patients may move to second-line therapies. For those who remain sensitive to endocrine therapy, next-generation SERDs such as elacestrant or targeted agents addressing mutations like PIK3CA or AKT are available. In cases of ESR1 mutation–driven resistance, these therapies can restore sensitivity and control tumor growth.
For patients with anti-estrogen therapy resistance, options include PARP inhibitors for BRCA1/2 or PALB2 mutations, antibody–drug conjugates (ADCs) for HER2-low tumors, or conventional chemotherapy. ADCs combine targeted cancer cell binding with a potent chemotherapy payload, improving outcomes and minimizing systemic toxicity.
Supporting Survivorship and Quality of Life
Stewart highlighted that advanced HR-positive breast cancer requires long-term management. Survivorship care focuses on optimizing quality of life, managing treatment-related side effects, and addressing psychosocial stress. Collaborative care involving oncologists, primary care providers, nutritionists, physical therapists, and mental health professionals helps patients maintain health, resilience, and daily function throughout prolonged treatment.
Participation in clinical trials remains critical for advancing care and offering patients access to cutting-edge therapies, according to Stewart.
Advancements in understanding tumor biology, identifying predictive biomarkers, and developing targeted therapies have transformed the treatment landscape for advanced HR-positive breast cancer. While cure remains elusive for metastatic disease, tailored treatment strategies and comprehensive survivorship support can extend life for these patients.
“Survivorship needs to focus on optimizing quality of life, supporting stress, the toxicity associated with the diagnosis and the treatment interventions, and maintaining excellent general health by collaborating with primary care physicians, cognitive therapists, nutritional therapists and physical therapists,” Stewart emphasized in the conclusion of her presentation.
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