Dr McCann on the Biologic Heterogeneity Within HER2+ Breast Cancer

"We can see that there's a difference in how aggressive [hormone receptor (HR)–positive, HER2-positive vs HR-negative, HER2-positive breast] cancers are. There's a difference in prognosis. Some of those [HR-positive, HER2-positive] cancer actually more like a luminal A/B phenotype than the basal HER2-enriched phenotype [we may see] with HR-negative, HER2-positive disease]."

Kelly E. McCann, MD, PhD, a breast medical oncologist and an assistant clinical professor of medicine at the UCLA Health David Geffen School of Medicine, discussed the biologic heterogeneity within HER2-positive breast cancer and highlighted the clinical implications of hormone receptor (HR) status in this disease subset.

HER2-positive breast cancer encompasses biologically distinct subtypes, which can vary based on HR expression, McCann began. HER2-positive tumors that are also HR positive exhibit markedly different behavior and treatment considerations compared with HR-negative, HER2-positive counterparts. These differences are reflected in both clinical outcomes and underlying tumor biology, she explained.

HR-positive/HER2-negative tumors tend to share features with luminal A or B subtypes, including dependence on estrogen signaling pathways and relatively more indolent growth patterns. In contrast, HR-negative/HER2-positive tumors are typically more proliferative and exhibit characteristics consistent with a basal-like or HER2-enriched phenotype, McCann noted. These distinctions translate into differential prognoses, with HR-positive/HER2-positive tumors generally associated with more favorable outcomes than HR-negative/HER2-positive tumors.

This biologic divergence may also influence responsiveness to various treatment modalities, McCann continued. Although HER2-targeted therapies remain foundational across subtypes of HER2-positive breast cancer, the potential integration of hormone-directed therapies and pathway-specific inhibitors—such as PI3K or CDK4/6 inhibitors—into the HR-positive/HER2-positive treatment landscape is of growing interest, McCann said.