Understanding and Treating Triple-Negative Breast Cancer
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. 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.[5,6]
Unlike the other subtypes, targeted agents specifically aimed at triple-negative breast tumors are not yet available, intensifying the need and interest in advancing novel therapeutic strategies beyond chemotherapy for this subset of high-risk patients. This review will focus on the molecular and clinicopathologic features, epidemiology and risk factors, prognosis, and current and future therapeutic strategies for patients diagnosed with triple-negative breast cancer, including a brief discussion of intracranial disease.
Definitions and Molecular Features
It is important to clarify the relationship between triple-negative breast cancer and the basal-like phenotype. Triple-negative is a term based on clinical assays for ER, PR, and HER2, whereas basal-like is a molecular phenotype initially defined using cDNA microarrays.[2,3] Although most triple-negative breast tumors do cluster within the basal-like subgroup, these terms are not synonymous; there is up to 30% discordance between the two groups.[7-10] In this review we will use the term “basal-like” when microarray or more comprehensive immunohistochemical profiling methodology was used, and “triple-negative” when the salient studies relied on clinical assays for definition.
In order to fully understand the molecular and pathologic features classically associated with the triple-negative phenotype, a review of the normal mammary gland parenchymal cells, including their immunophenotype, is essential. The more central luminal cells classically express low-molecular-weight cytokeratins including CK7, CK8, CK18, and CK19, along with MUC1 alpha-6 integrin, BCL1, ER, PR, and GATA3. Moving outward toward the basement membrane, myoepithelial cells comprising the basal cell layer express high-molecular-weight cytokeratins including CK5, CK14, and CK17 in addition to smooth muscle–specific markers, calponin, caldesmon, p63, beta-4 integrin, laminin, maspin, CD10, P-cadherin, caveolin-1, and nerve growth factor receptor (NGFR) and S100 (see Table 1).[11-16] Classically, basal-like breast cancers have been characterized by low expression of ER, PR, and HER2 and high expression of CK5, CK14, caveolin-1, CAIX, p63, and epidermal growth factor receptor (EGFR, HER1), which reflects the mammary gland basal/myoepithelial cell component.[1,17]
Among this list of markers characteristic of triple-negative breast tumors, several are potentially targetable, notably HER1/EGFR. A member of the “basal cluster” intrinsic gene list, HER1/EGFR is expressed in approximately 60% of basal-like breast tumors.[10,18] It has also been observed that c-Kit expression is higher in basal-like tumors. In one study, 31% of tumors expressing basal cytokeratins had c-Kit staining compared to 11% in basal cytokeratin–negative tumors (P < .001).
Finally, several molecules integrally involved in DNA repair are aberrantly expressed in triple-negative breast cancer, which may have implications for chemotherapy sensitivity. High p53 IHC expression or p53 gene mutations are common in basal-like breast cancer.[3,19] Furthermore, one series illustrates that 82% of basal-like breast cancers expressed a p53 mutation compared with only 13% in the luminal A subtype (P < .001). Several additional and targetable molecular pathways implicated in the pathogenesis of basal-like breast cancer include the mitogen-activated protein (MAP) kinase pathway, the Akt pathway, and the poly ADP-ribose polymerase 1 (PARP1) pathway, which will be addressed in more detail in the context of BRCA1 and therapeutics below.
Association With BRCA1 Mutation Status
It has been observed that the majority of BRCA1-associated breast cancers are triple-negative and express a high proportion of basal-like cytokeratins (CK5, 14, 17), as well as P-cadherin and HER1/EGFR.[20-24] The BRCA1 tumor-suppressor gene, originally identified in 1994 by positional cloning on chromosome 17q21, is a multifocal protein in many normal cellular functions including DNA repair, transcriptional regulation, cell cycle checkpoint control, and ubiquitination.[22,25]
Several studies have shown that breast tumors arising in women carrying germline mutations of the BRCA1 tumor-suppressor gene are triple-negative.[24,26] Gene expression studies support this association; among patients with BRCA1 mutations, breast tumors tend to cluster within the basal-like category. As BRCA1 is in part responsible for DNA repair, exploitation of this essential pathway holds therapeutic implications in the context of the triple-negative phenotype and will be discussed further below.
Clinical Characteristics, Epidemiology, and Risk Factors
Triple-negative breast tumors have been characterized by several aggressive clinicopathologic features including onset at a younger age, higher mean tumor size, higher-grade tumors, and, in some cases, a higher rate of node positivity.[27,28] A histologic study of basal-like tumors, of which all were ER/HER2–negative, illustrated marked increases in mitotic count, geographic necrosis, pushing borders of invasion, and stromal lymphocytic response. The majority of triple-negative breast carcinomas are ductal in origin; however, several other aggressive phenotypes appear to be overrepresented, including metaplastic, atypical or typical medullary, and adenoid cystic.[8,27,30]
In parallel with our understanding of the molecular basis of triple-negative breast cancer, our awareness of the epidemiology and risk factors associated with this disease process has matured, specifically related to age and race. Among approximately 500 women evaluated in the Carolina Breast Cancer Study, those with basal-like tumors (defined as ER-negative, PR-negative, HER2-negative, CK 5/6-positive, and/or HER1-positive) were more likely to be African-American (prevalence of 26% vs 16% in non–African-Americans) and premenopausal (24% vs 15% postmenopausal). These investigators observed a particularly high prevalence of basal-like tumors among premenopausal, African-American women compared to postmenopausal African-American women and non–African-American women of any age (39% vs 14% and 16%, respectively; P < .001). These findings are consistent with several large-scale, population-based studies indicating that triple-negative breast cancers are more likely to occur among premenopausal women of African-American descent.[31,32]
Several epidemiologic studies have provided insight into risk factors associated with triple-negative breast cancers. Further examination of approximately 1,400 breast cancer cases in the Carolina Breast Cancer Study illustrated that compared to luminal A tumors (ER-positive and/or PR-positive and HER2-negative), basal-like breast tumors were more likely to arise among women with a younger age at menarche, higher parity, younger age at full-term pregnancy, shorter duration of breast-feeding, and higher body mass index (BMI) and waist-to-hip ratio (WHR), especially among premenopausal patients. Additionally, those who used methods to suppress lactation were also at higher risk for basal-like breast cancers compared to luminal A breast cancers. Although not definitive, these findings suggest that among younger African-American women, close to two-thirds of aggressive, basal-like breast cancers might be prevented by promoting breast-feeding and decreasing abdominal obesity.
Similarly, the Polish Breast Cancer Study demonstrated a stronger reduction in risk associated with increasing age at menarche for basal-like tumors compared to luminal A–type breast cancer. Among premenopausal women, increasing BMI was associated with a reduced risk of luminal but not basal-like breast cancers. These findings illustrate that breast cancer risk factors vary by molecular subtype (ie, luminal A, basal-like, etc), supporting subtype-specific approaches when examining risk factors and prevention.