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Azka Ali, MD, discusses the need to refine predictive strategies for endocrine sensitivity in HER2-low metastatic breast cancer.
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"The most important piece of information that's needed is a good prediction of endocrine sensitivity in these [patients with HER2-low] metastatic breast cancer."
Azka Ali, MD, a medical oncologist in the Department of Hematology and Medical Oncology at Cleveland Clinic, emphasized the need to refine predictive strategies for endocrine sensitivity in patients with HER2-low metastatic breast cancer.
Accurately identifying patients who may derive sustained benefit from endocrine-based therapy remains a key clinical challenge, particularly given the heterogeneity of response within this biologically distinct subgroup, Ali said. She noted that a subset of patients either can either exhibit primary endocrine resistance where hormone therapy is ineffective from the outset, or secondary resistance that develops during treatment. For patients who develop endocrine resistance, alternative treatment strategies, including chemotherapy or antibody-drug conjugates (ADCs), could clinical outcomes.
Notably, data from the phase 3 DESTINY-Breast06 trial (NCT04494425) demonstrated a progression-free survival and overall survival advantage with fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-low metastatic breast cancer who had progressed on at least 1 prior line of endocrine therapy in the metastatic setting. This finding has reinforced the rationale for earlier incorporation of ADCs in the treatment paradigm, particularly for patients who are endocrine-refractory.
Ali emphasized that for patients predicted to remain endocrine-sensitive, there remains an opportunity to optimize the use of oral selective estrogen receptor degraders (SERDs), CDK4/6 inhibitors, and emerging PI3K pathway–targeting agents. Ongoing trials are exploring novel combinations aimed at overcoming acquired resistance, such as the addition of targeted agents to endocrine backbones following progression on standard CDK4/6 inhibitor regimens.
Ultimately, Ali highlighted the importance of developing validated biomarkers to guide the sequencing of therapies. This includes identifying patients who may benefit from extended endocrine therapy versus those who require an early switch to ADCs like trastuzumab deruxtecan or chemotherapy. A tailored approach based on predictive indicators of endocrine sensitivity would help maximize clinical benefit and avoid ineffective treatments.
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