Editor’s Note: Endocrine resistance is one of the major challenges in the treatment of HR+/HER2- breast cancer. At the 8th Conference on Oncology Precision Medicine and the 11th Conference on Individualized Therapy in Breast Cancer (COMB 2025), Professor Ping Zhang from the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, delivered a presentation titled “Therapeutic Options After Endocrine Failure in HR+ Advanced Breast Cancer.” Following the meeting, Oncology Frontier invited Professor Zhang to discuss the current status of endocrine resistance, patient stratification, and the evolving role of ADC therapies.01
Oncology Frontier: To begin, could you outline the current situation regarding endocrine resistance in HR+/HER2- breast cancer?
Professor Ping Zhang:Endocrine resistance in HR+/HER2- breast cancer can be divided into primary resistance and secondary (acquired) resistance. Primary resistance refers to recurrence within less than two years during adjuvant endocrine therapy, or disease progression within six months of first-line endocrine therapy in advanced disease. Secondary resistance refers to recurrence after more than two years of adjuvant endocrine therapy and within one year after discontinuation, or disease progression after at least six months of first-line endocrine therapy in the advanced setting.
Patients with secondary resistance initially retain some sensitivity to endocrine therapy, with resistance emerging later in the disease course. Primary resistance, by contrast, is often closely linked to intrinsic tumor biology. Multiple mechanisms are involved. While pathology and genomic testing can provide preliminary insight, current knowledge is still limited. ESR1 mutations, for instance, are a common mechanism, especially in patients developing secondary resistance following aromatase inhibitor therapy.
Alterations in the PI3K, AKT, or mTOR pathways may also explain primary or secondary resistance when detected early in treatment. Identifying these biomarkers has significant clinical value in shaping treatment strategies.
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Oncology Frontier: After progression on CDK4/6 inhibitor plus endocrine therapy, guidelines provide little clarity on optimal subsequent treatment. How should patients be stratified by characteristics such as PIK3CA or ESR1 mutations and prior treatment history?
Professor Ping Zhang:Endocrine therapy remains the cornerstone of treatment for HR+/HER2- advanced breast cancer. In both the first- and second-line settings, endocrine therapy combined with a CDK4/6 inhibitor is guideline-recommended, and these drugs are now reimbursed in China, making them widely accessible. However, when patients progress after one or two such regimens, treatment selection becomes challenging. The decision—whether to continue endocrine therapy with a new backbone and targeted agent, or to transition to chemotherapy or ADCs—must be individualized based on disease trajectory and biomarker status.
For patients who had a good response to prior endocrine + CDK4/6 therapy, with prolonged PFS and relatively slow progression, further endocrine-based therapy may still provide benefit. Trials such as MAINTAIN and postMONARCH demonstrated that switching to a different CDK4/6 inhibitor plus endocrine therapy can extend PFS, though the benefit is limited and does not fully meet clinical needs. For CDK4/6-experienced patients, identifying the resistance pathway is critical. Activation of the PI3K–AKT–mTOR pathway and ESR1 mutations are strongly linked to resistance. Blood or tissue testing should therefore be performed. In cases with ESR1 mutations, agents such as elacestrant are appropriate. In cases with PAM pathway alterations, such as PIK3CA or AKT mutations or PTEN loss, therapies combining PI3Kα inhibitors like inavolisib or AKT inhibitors like capivasertib with endocrine therapy are effective. Studies confirm that these combinations are superior to endocrine therapy alone, and both drugs have been approved in China with good accessibility.
For patients without such mutations but still suitable for endocrine therapy, mTOR inhibitors such as everolimus or HDAC inhibitors such as chidamide can be combined with endocrine therapy, which also improves outcomes compared to monotherapy.
In summary, early precision testing, especially for PAM pathway alterations and ESR1 mutations, is essential to guide treatment throughout the disease course.
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Oncology Frontier: Novel ADCs are steadily changing the treatment paradigm for HR+ advanced breast cancer. How should biomarkers such as HER2 or TROP2 expression be used to identify patients most likely to benefit?
Professor Ping Zhang:For patients no longer suitable for endocrine therapy—those with rapid progression, low hormone receptor expression, or aggressive disease—chemotherapy or ADC therapy can be considered. Current evidence shows ADCs offer better efficacy than single-agent chemotherapy.
ADC therapies fall into two main categories. The first targets HER2 expression. Studies such as DESTINY-Breast04 and DESTINY-Breast06 have demonstrated that trastuzumab deruxtecan (T-DXd) significantly prolongs PFS compared with chemotherapy in patients with HER2-low or even HER2-ultralow HR+ breast cancer. The second targets TROP2. TROP2 is highly expressed in breast cancer, observed in about 93% of triple-negative breast cancers and in a substantial proportion of HR+ tumors, making it an important therapeutic target beyond HER2. Importantly, clinical application of TROP2 ADCs does not require testing for TROP2 expression. Based on results from TROPiCS-02 and EVER-132-002, sacituzumab govitecan (SG) has been approved in China for HR+/HER2- breast cancer. Datopotamab deruxtecan (Dato-DXd) was approved in multiple countries following TROPION-Breast01 and is expected to be available in China soon.
Both HER2-targeted and TROP2-targeted ADCs have shown superior efficacy compared with chemotherapy in patients progressing after endocrine therapy and chemotherapy, providing important new treatment options. Regarding sequencing, clinical trials are ongoing. For HER2-low HR+ patients, T-DXd is currently recommended first. SG is effective in both HER2-low and HER2-zero patients but is supported by evidence mainly in the post–second-line setting. Whether its earlier use offers comparable benefit to T-DXd remains an open question that requires future head-to-head studies.
Professor Ping Zhang
Department of Medical Oncology National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences Chief Physician, Professor, Doctoral Supervisor
