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.

Automated summary

Traditionally, breast cancer classification has relied on the expression of immunohistochemical bio-markers available in clinical practice. However, intrinsic molecular subtypes based on gene expression have been identified and show different characteristics compared to IHC-based subgroups. Hormone receptor-positive tumors can demonstrate non-luminal biology, which has prognostic value and impacts sensitivity to treatment. Genomic instability, cell plasticity, treatment selective pressure, and tumor microenvironment all contribute to the diversity observed between primary and metastatic breast cancer. This review focuses on hormone receptor-positive/HER2-negative advanced breast cancer and discusses the distribution and clinical behavior of intrinsic subtypes, as well as ongoing clinical trials investigating their predictive and prognostic value for routine care.