Targeted therapy for breast cancer and molecular mechanisms of resistance to treatment
Introduction
Invasive breast cancer is classified into three therapeutic clinical subtypes: HR-positive, HER2-positive or TNBC lacking Estrogen Receptor (ER), progesterone receptor, and HER2 expression. None of these subtypes is a single disease but each is heterogeneous. High-throughput technology using next-generation or massive parallel sequencing has expanded our knowledge on the genomic complexity of breast cancer and intra-tumoral heterogeneity [1]. In addition to this heterogeneity, breast cancer can also evolve and acquire new mutations during metastatic evolution which reveal additional longitudinal heterogeneity or clonal evolution [2•]. Molecularly targeted agents in breast cancer have been successfully used, but resistance to these agents still occurs. Predictive markers are urgently needed to predict which patients are likely to develop resistance and consequently need alternative therapies.
Section snippets
ER-positive breast cancer
ER-positive breast cancer is characterized by expression of estrogen and progesterone receptors in which ER activation and function drives tumor cell growth and proliferation. Due to ER-dependent mechanisms of cell proliferation, endocrine therapies targeting ER using tamoxifen or aromatase inhibitors (AI) are the first-line adjuvant therapies offered to patients with early stage ER-positive breast cancer [3••]. Ten-year breast cancer mortality rates are reduced by a third with hormone therapy,
HER2 positive breast cancer
The epidermal growth factor receptor 2 (ErbB2, HER2), a member of the growth factor receptor family (HER1/2/3/4), has been one of the most successful targets discovered in breast cancer. HER2-targeted therapy using the humanized monoclonal antibody trastuzumab has significantly improved disease-free and overall survival (DFS and OS) in early stage HER2-positive breast cancer [20]. With longer follow-up of these large adjuvant studies, adjuvant trastuzumab treatment continues to make
Triple-negative breast cancer
Triple-negative breast cancer (TNBC) is the most heterogeneous subtype of breast cancer with a high risk of relapse and shorter OS compared with subtypes discussed above. Currently, anthracyclines, taxanes and anti-metabolites are FDA-approved chemotherapy regimens recommended in the adjuvant and neoadjuvant settings for TNBC [3••]. There is an urgent need for predictive markers for specific chemotherapy treatment. We clustered TNBC using 41 nuclear receptor gene expression, and found that
Conclusions
Remarkable progress has been made in breast cancer treatment in last decade, especially for targeted therapies in ER positive or HER2 positive MBC. However, resistance still develops and patients suffer from recurrence and metastasis. TNBC still remained un-targetable due to its extremely heterogeneous phenotype. Personalized therapy according to TNBC classification should be applied to guide targeted therapy in combination with chemotherapy in TNBC. Optimization of patient selection and
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by NIH/NCI R01-CA72038, CPRIT RP120732, and the Breast Cancer Research Foundation to SAWF.
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