Update on Novel Drug Targets in Metastatic Breast Cancer

Massimo Cristofanilli, MD, FACP
Published: Friday, May 16, 2014


Metastatic breast cancer (MBC) is a fatal disease involving the expansion of cancerous cells from the breast to other areas of the body. Treatments for MBC are often limited to palliative care; as a result of MBC is usually fatal. As research continues, factors such as age at diagnosis, hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and site of metastases are currently used to stratify patients into groups with different prognoses and to predict response to systemic treatments. More recently, researchers seek to understand the mechanisms related to tumor dissemination in hopes of therapeutically targeting this process. HRs are expressed in about two-thirds of breast tumors and endocrine therapy is probably the most important systemic therapy for HR-positive breast cancer. Selective estrogen modulators (SERMs) and aromatase inhibitors (AIs) represent the standard options in patients with HR-positive MBC, with selection based on previous exposure and sensitivity in the adjuvant setting. Preclinical models have identified several molecular abnormalities (eg, EGFR and HER-2 overexpression, ESR1 mutations) associated with endocrine resistance, providing rationale for conducting prospective studies. Novel therapeutic agents targeting the PI3KCA/mTOR cyclin-dependent kinases (CDKs) demonstrated the most promising results, with significant impact on the management of patients with endocrine resistance. Future challenges are represented by the testing of sensitive diagnostic tools with the ability to identify predictive markers allowing more personalized therapeutic choice and possibly monitoring.


Massimo Cristofanilli, MD, FACP

Breast cancer is the most prevalent female malignancy and the second most common cause of death in developed countries. In 2013 in the United States, an estimated 234,580 women were diagnosed with invasive breast cancer and 40,030 died from it.1 During the last decades, breast cancer survival has increased considerably2 in Western countries due to earlier diagnosis and increasing use of adjuvant and neoadjuvant therapies, but recent statistics suggest that approximately 30% to 70% of patients with primary breast cancer worldwide eventually develop recurrence and die of metastasis every year with an estimated increased mortality of 14%.3 Recent years have produced remarkable changes both in the treatment philosophy of metastatic breast cancer (MBC) and in the available therapies, contributing to improvements in survival rates and quality of life in Western Europe and the United States, with the potential to extend some of these benefits to low and medium income countries worldwide.4

Estrogen receptors (ERs) are expressed in about two-thirds of breast tumors, and endocrine therapy is probably the most important systemic therapy for hormone receptor (HR-) positive breast cancer.5,6 Several prospective studies established the superiority of aromatase inhibitors (AIs) in the management of ER-positive MBC.7-10 Fulvestrant (Faslodex), a pure estrogen receptor antagonist, demonstrated efficacy comparable to anastrozole and subsequently defined a role and a treatment schedule/ dosage, providing another available therapeutic option.10

More recently, a prospective, open label, randomized phase III study evaluated the combination of fulvestrant and anastrozole (Arimidex) compared with single agent anastrozole in postmenopausal women with ER-positive locally advanced or MBC.11 A total of 695 patients were randomly assigned to the two treatment arms. Forty percent of patients were de novo stage IV disease. Moreover, approximately 40% of patients had previously been exposed to tamoxifen and only 30% had received adjuvant chemotherapy. The results demonstrated superiority of the combination arm with a median progression- free survival (PFS) of 15 months (95% confidence interval [CI], 13.2-18.4) compared with 13.5 months for the single agent (95% CI, 12.1-15.1; P = .007 stratified log-rank test), suggesting a role for such combination in the management of a selected subset of patients.

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Online CME Activities
TitleExpiration DateCME Credits
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
Community Practice Connections: Oncology Best Practice™ Targeting Cell Cycle Progression: The Latest Advances on CDK4/6 Inhibition in Metastatic Breast CancerOct 31, 20181.0
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