Triple Receptor-Negative Breast Cancer: Current and Future Treatments

Erika N. Brown, BS, MS, PharmD, and Ana M. Gonzalez-Angulo, MD
Published: Friday, Mar 04, 2011


Breast cancer is the most frequently diagnosed malignancy in women in the United States. Triple receptor-negative breast cancer (TNBC) represents a small percentage of all breast cancers, but it constitutes the majority of breast cancers of the basal-like subtype. TNBC is characterized by the lack of expression of estrogen and progesterone receptors and by the lack of overexpression of human epidermal growth factor receptor-2 (HER2). Published studies have shown that TNBC is highly sensitive to chemotherapy in the neoadjuvant, adjuvant, and metastatic settings. Even with TNBC’s high sensitivity to chemotherapy, patients with TNBC have high recurrence and relapse rates. Many of the ongoing clinical trials available for patients with TNBC focus on the safety and/or efficacy of new, targeted agents given alone or in combination with standard or alternative chemotherapy.
Breast cancer is the number one malignancy diagnosed  in women in the United States. In 2009, it was estimated that more than 190,000 individuals would be diagnosed with breast cancer and approximately 40,000 would die from the disease.1 The incidence of invasive breast cancer has decreased over the years, largely because screening rates have increased, facilitating earlier diagnosis. Even when diagnosed early, however, triple receptor–negative breast cancer (TNBC) has a poor prognosis and represents a major unmet need.

Molecular Subtypes of Breast Cancer

Breast cancer consists of a group of diseases with many clinical, pathologic, and molecular characteristics that affect prognosis and treatment. There are 4 intrinsic breast cancer subtypes by gene expression: basal-like, HER2, luminal A, and luminal B.2 These 4 subtypes have been shown to have different prognoses and different responses to therapy.2-5

The majority of cases of breast cancer of the basal-like subtype lack expression of estrogen and progesterone receptors and exhibit normal expression of HER2 receptors. Like the basal-like subtype, the HER2 subtype does not express estrogen receptors (ER) and progesterone receptors (PR), but it is associated with overexpression and/or gene amplification of HER2. The basal-like and HER2 subtypes have high rates of pathologic complete response (pCR) to preoperative chemotherapy. pCR is typically defined as no microscopic evidence of residual invasive cancer in the breast and axillary lymph nodes. Studies show that after preoperative chemotherapy, rates of pCR range from 27% to 45% for the basal-like subtype and from 36% to 45% for the HER2 subtype.3-6 These subtypes have also been associated with short durations of relapse-free survival (RFS) and overall survival (OS).3-6

The advent of trastuzumab (Herceptin) for HER2-positive breast cancer, however, has significantly improved outcomes for patients with this subtype.

The luminal subtypes (luminal A and luminal B), which express ER and PR, have low rates of pCR to preoperative chemotherapy (6%-7%), but they seem to have more favorable clinical outcomes with the use of endocrine therapy.3-6

Clinical Characteristics of Triple Receptor–Negative Breast Cancer (TNBC)

TNBC represents about 10% to 15% of all breast cancers and constitutes more than 80% of all basal-like diagnoses.7-9 TNBC’s classification is established by the lack of ER and PR expression by immunohistochemical (IHC) assay and by the normal expression of HER2 by IHC or fluorescence in situ hybridization.

TNBC is characterized as an aggressive disease with poor clinical outcomes, including short durations of RFS and OS.4 Today’s patients with TNBC have a worse clinical outcome than patients whose tumors are HER2-positive.4,10 A TNBC diagnosis is associated with an earlier age of onset compared with other breast cancer subtypes (Table 1).11 A descriptive analysis by Bauer and colleagues found that TNBC was significantly associated with younger age, non-Hispanic black race, and lower socioeconomic status.7 In a study by Carey and colleagues, African-American women had a higher incidence of TNBC compared with other subtypes.12 Data from this study also showed a higher incidence of TNBC among premenopausal women compared with postmenopausal women.12 In a recent study by Dawood and colleagues, designed to analyze the effect of race on pCR rates and OS in women with TNBC treated with systemic chemotherapy, data showed that 17% of black patients achieved pCR compared with 25.1% of white/other patients (P = .091).13 The researchers found that after controlling for patient and tumor characteristics, race did not significantly affect pCR, RFS, or OS.13

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