Targeting HER2 heterogeneity in early-stage breast cancer

Purpose of review HER2-positive (HER2+) breast cancer is clinically and biologically a heterogenous disease and not all patients benefit to the same extent from current anti-HER2 therapies. Recent findings Among HER2+ breast cancer, molecular intrinsic subtypes, PIK3CA mutation status, levels of HER2 gene/protein, immune infiltration, or intratumor heterogeneity modulate HER2-treatment sensitivity. HER2-enriched carcinomas, with high levels of HER2 and tumor-infiltrating lymphocytes (TILs) are highly sensitive to anti-HER2 therapies, regardless of chemotherapy. Luminal A/B tumors are more estrogen receptor-dependent than HER2-dependent, harbor higher rates of PIK3CA mutations, and are less responsive to anti-HER2 treatment. HER2 intratumoral heterogeneity that exists in approximately 10% of HER2+ disease may also cause treatment resistance. Early changes occur during neoadjuvant anti-HER2 therapy that can predict response. Importantly, HER2 expression is not a binary but rather a continuous variable. Overall, 34-63% of HER2-negative breast cancers express HER2, and HER2-low tumors have become a new entity, for which novel targeted therapies may be effective. Although much of what is discussed currently remains investigational, it is clear that HER2+ breast cancer is a complex disease comprising different entities. Future strategies to escalate or de-escalate treatment in early-stage HER2+ disease should consider other biomarkers beyond HER2 and estrogen receptor status, including intrinsic subtype, HER2 levels, and TILs; and evaluate different treatment strategies among patients with estrogen receptor-positive/HER2+ and estrogen receptor-negative/HER2+ diseases.