Clinical implications of the intrinsic molecular subtypes in hormone receptor-positive and HER2-negative metastatic breast cancer

Traditionally, the classification of breast cancer relies on the expression of immunohistochemical (IHC) bio-markers readily available in clinical practice. Using highly standardized and reproducible assays across patient cohorts, intrinsic molecular subtypes of breast cancer -also called "intrinsic subtypes" (IS) -have been identified based on the expression of 50 genes. Although IHC-based subgroups and IS moderately correlate to each other, they are not superimposable. In fact, non-luminal biology has been detected in a substantial proportion (5-20%) of hormone receptor-positive (HoR+) tumors, has prognostic value, and identifies reduced and increased sensitivity to endocrine therapy and chemotherapy, respectively. During tumor progression, a shift toward a non-luminal estrogen-independent and more aggressive phenotype has been demonstrated. Intrinsic genomic insta-bility and cell plasticity, alone or combined with external constraints deriving from treatment selective pressure or interplay with the tumor microenvironment, may represent the determinants of such biological diversity between primary and metastatic disease, and during metastatic tumor evolution. In this review, we describe the distribution and the clinical behavior of IS as the disease progresses, focusing on HoR+/HER2-negative advanced breast cancer. In addition, we provide an overview of the ongoing clinical trials aiming to validate the predictive and prognostic value of IS towards their incorporation into routine care.