Volume 13 Supplement 2
Molecular heterogeneity of luminal breast cancer
- S Loi1
© Loi. 2011
Published: 16 November 2011
Luminal (or clinically defined as estrogen receptor (ER)-positive and Her2-negative) breast cancer has long been successfully treated with anti-estrogen therapy, the first targeted anti-cancer agent in breast cancer. Recently, molecular profiling approaches have allowed better identification of a poor prognostic subgroup; however, the biological mechanisms which contribute this phenotype are currently unclear.
With regards to defining prognosis, it is clear that proliferation markers can clearly separate ER+/HER2- breast cancer into at least two prognostic groups. Immunohistochemistry using Ki67 at the protein level and prognostic gene signatures such as Mammaprint™, the 21-gene Recurrence Score, the two-gene ratio and genomic grade all provide quantitative measurements of proliferation activity. However, a biologically relevant cut-off does not exist. Molecular subtype definitions using PAM50 or other gene expression-based classifiers do not provide a more concordant or reproducible luminal A or B definition. Improved definition and clinical management of luminal subtypes will come from an increased understanding of the molecular drivers of the phenotype.
Lately, PIK3CA and AKT1 mutations have been shown to be associated with the good prognosis luminal A phenotype whilst FGFR1 and ZNF703 amplifications are responsible for about 25% of the luminal B phenotype. It is hoped that new genomic technologies such as next-generation sequencing will offer new insights into the biology of ER-positive breast cancer. Recent next-generation sequencing studies have identified MAP3K1, ATR and MYST3 mutations in around 10% of ER+ breast cancer which may be associated with de novo endocrine therapy resistance. These, if shown to be driver oncogenes, may shed new light on the biology of endocrine nonresponsive breast cancer and inspire new treatment strategies. Finally, recent results from the BOLERO-2 trial suggest that metastatic ER+ disease may be effectively treated with the addition of a mTORC1 inhibitor, which suggests for many patients with acquired endocrine therapy resistance, mTOR pathway activation plays a significant part in their tumor biology.