Targeted Therapy for Breast Cancer

Targeted Therapy for Breast Cancer: Introduction

What is targeted therapy for breast cancer? It means blocking the growth of breast cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth. A greater understanding of the underlying biology of breast cancer has resulted in the identification of a number of molecular targets. Among them are tyrosine kinase inhibitors (TKIs) directed at a number of targets (HER1, HER2, HER3, IGF receptor [IGFR], C-MET, FGF receptor [FGFR]), inhibitors of intracellular signaling pathways (PI3K, AKT, mammalian target of rapamycin [mTOR], ERK), angiogenesis inhibitors, and agents that interfere with DNA repair. Some of these agents have shown remarkable activity and have already become part of the standard of care in patients with breast cancer (exemplified by the anti-HER2 agents trastuzumab and lapatinib). Others have shown clinical activity but are not yet approved for clinical practice. In this group are novel anti-HER2 agents as well as rapamycin analogs (“rapalogs,” or inhibitors of mTOR) and the poly(ADP-ribose) polymerase (PARP) inhibitors for BRCA-deficient tumors . The third (and clearly the largest) group of compounds are still in an early phase of development, but in some cases, indications of clinical responses have already been observed.

Hormone receptor positive breast cancers are largely driven by the estrogen/ER pathway, and endocrine therapy targeting this pathway has been most successful. However, resistance to endocrine therapy, either de novo or acquired, is a common phenomenon and a significant clinical challenge. The mechanisms of endocrine resistance are complex and not fully understood.
Experimental models indicate that endocrine resistance is accompanied by activation of estrogen-independent growth and survival signaling pathways as a result of genomic or epigenetic alterations; these pathways could be targeted for therapeutic interventions.

Overexpression of HER2 as a result of gene amplification occurs in 18% to 20% of human breast cancers and is associated with a more aggressive phenotype. Introduction of the monoclonal antibody trastuzumab has led to significant improvement in the outcome of this disease. In addition to trastuzumab, several HER2-targeted agents, including laptinib, pertuzumab, and trastuzumab emtansine have been approved for treatment of advanced HER2 positive disease.

Overexpression of HER2 as a result of gene amplification occurs in 18% to 20% of human breast cancers and is associated with a more aggressive phenotype. Introduction of the monoclonal antibody trastuzumab has led to significant improvement in the outcome of this disease. In addition to trastuzumab, several HER2-targeted agents, including laptinib, pertuzumab, and trastuzumab emtansine have been approved for treatment of advanced HER2 positive disease.

Targeted Therapy for Breast Cancer: Reference

Higgins M J et al. Targeted therapies for breast cancer[J]. The Journal of clinical investigation, 2011, 121(10): 3797-3803.
Mohamed A, Krajewski K, Cakar B, et al. Targeted therapy for breast cancer[J]. The American journal of pathology, 2013, 183(4): 1096-1112.