Understanding And Treating Triple-Negative Breast Cancer
Triple-negative breast cancer is a subtype of breast cancer that is clinically negative for expression of estrogen and progesterone receptors (ER/PR) and HER2 protein. It is characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis, and lack of targeted therapies.
Although not synonymous, the majority of triple-negative breast cancers carry the “basal-like” molecular profile on gene expression arrays. The majority of BRCA1-associated breast cancers are triple-negative and basal-like; the extent to which the BRCA1 pathway contributes to the behavior of sporadic basal-like breast cancers is an area of active research.
Epidemiologic studies illustrate a high prevalence of triple-negative breast cancers among younger women and those of African descent. Increasing evidence suggests that the risk factor profile differs between this subtype and the more common luminal subtypes.
Although sensitive to chemotherapy, early relapse is common and a predilection for visceral metastasis, including brain metastasis, is seen. Targeted agents, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly (ADP-ribose) polymerase (PARP) inhibitors, are currently in clinical trials and hold promise in the treatment of this aggressive disease.
In 2008, it is estimated that over 1 million women worldwide will be diagnosed with breast cancer, of which 172,695 will be classified as “triple-negative.” The triple-negative phenotype encompasses a breast tumor subtype that is clinically negative for expression of the estrogen and progesterone receptors (ER and PR) and lacks overexpression of the HER2 protein, with unique prognostic and therapeutic implications.
Over the past decade, our understanding and treatment of breast cancer has undergone a metamorphosis, shifting from a generally homogeneous approach to a more sophisticated view as guided by gene expression analysis.
Putting the brakes on an abundant growth-promoting protein causes breast tumors to regress, according to a study published on March 19th in the Journal of Experimental Medicine.
Triple-negative breast tumors lack all of the known growth receptors that serve as treatment targets in other types of breast cancer, making this the most clinically challenging subtype of the disease. Patients with these tumors tend to relapse earlier and have shorter disease-free survival.
Andrei Goga and colleagues now show that triple-negative breast tumors express elevated levels of the growth-driving protein called MYC. MYC activity was required for the growth of these aggressive tumors, and blocking a MYC-cooperating protein, CDK, caused triple-negative tumors to shrink in mice.
Together, these results identify a potential new target for triple-negative tumor treatment.
Multiple studies have reproducibly identified the intrinsic breast cancer subtypes, which include several luminal subtypes characterized by expression of hormone receptor-related genes, and two hormone receptor-negative subtypes - the HER2-positive/ER-negative subtype and the “basal-like” subtype. Contrary to the luminal subtypes, the basal-like subtype is characterized by low expression of ER- and HER2-related genes and clinically is usually, but not always, ER/PR-negative and lack HER2 overexpression, thereby constituting the “triple-negative” phenotype.
Multiple studies have demonstrated that the intrinsic subtypes vary by prognosis, with inferior outcomes illustrated among the two hormone receptor-negative subgroups as compared to the luminal subtypes.[3,4] They may also differ in other important ways. Recent studies suggest that patients with triple-negative breast cancer have a high incidence of visceral metastasis, including brain metastasis. This clinically challenging scenario is an area of fertile research.
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Carey Anders, MD, Lisa A. Carey, MD