Triple Receptor-Negative Breast Cancer: Current and Future Treatments | Page 2

Erika N. Brown, BS, MS, PharmD, and Ana M. Gonzalez-Angulo, MD
Published Online: Friday, March 4, 2011
Data show that a high proportion of patients with TNBC (~34%) experience distant recurrence, with a mean of 2.6 years to distant recurrence.11 This compares with a distant recurrence rate of 20% and a mean of 5 years to distant recurrence in other breast cancer subtypes.11 The 5-year OS rate is also inferior for patients with TNBC compared with the rate of 5-year OS observed with other types of breast cancer. In TNBC, the risk of recurrence peaks 1 to 3 years after diagnosis then decreases.11,14 Patients with TNBC are most likely to experience recurrence in the visceral organs. A study by Liedtke and colleagues found that 74% of patients with TNBC developed recurrences in visceral organs; for 13% of patients, recurrences developed in the soft tissue, and another 13% had recurrences in bone.14

A retrospective study by Dawood and colleagues of 679 patients with TNBC found that 6.2% had developed brain metastases at a median follow-up of 26.9 months, with a 2-year and 5-year cumulative incidence of 5.6% and 9.6%, respectively.15 When looking at breast cancer overall, including all subtypes, patients have a 10% to 16% risk of developing brain metastases at any point during the metastatic setting.16 The risk of developing brain metastasis is greater in patients who are younger, and in patients with ≥4 positive lymph nodes, high tumor grade, or HER2 overexpression.15,16

Pathological Characteristics of TNBC

TNBC tumors tend to be grade III and large (>2.0 cm) at diagnosis.11 They have been associated with a higher rate of lymph node positivity than other breast cancer subtypes, but there does not appear to be any correlation between tumor size and nodal status.14

TNBC is closely associated with expression of basal cytokeratins (CKs) 5/6, 14, and 17 and epidermal growth factor receptor (EGFR). Gene expression analysis of the basal-like subtype is similar to that of basal/myoepithelial cells found in normal breast tissue.2-4,8 In a panel of 21 basal-like tumors, Nielsen and colleagues observed IHC positivity for basal CKs, EGFR, and c-KIT overexpression.17 Overexpression of basal CKs and EGFR appear to be associated with poor survival in breast cancer patients.

Livasy and colleagues reported that basal-like tumors were commonly ER-negative and HER2-negative; other features of this subtype included an elevated mitotic rate, geographic necrosis, a pushing border of invasion, stromal lymphocytic infiltrate, and atypical medullary features.18 IHC assays for the basal-like subtype show high expression of EGFR, CK 5/6, CK 8/18, and vimentin.18 Cattoretti and colleagues reported a significant association between expression of p53, vimentin, and EGFR in ER-negative breast cancers based on positive IHC staining for the 3 proteins.19 Cumulatively, these studies suggest that CK 5/6, EGFR, vimentin, c-KIT, and p53 are potential targets for therapy in TNBC.

Current Treatments for TNBC

TNBC is a complicated disease because no dominant oncogenic factor has been identified as driving proliferation. It demonstrates high sensitivity to standard taxane/anthracycline systemic chemotherapy, but responses are often short-lived and early relapses are common (Table 2).

Preoperative Neoadjuvant Chemotherapy In a study by Rouzier and colleagues, the response to preoperative chemotherapy with 12 weeks of paclitaxel followed by 4 cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide was evaluated in different molecular subtypes of breast cancer, including luminal, basal-like, normal-like, and HER2-positive.5 The highest rates of pCR were seen in the basal-like subtype (45%; 95% confidence interval [CI], 24%-68%) and the HER2 subtype (45%; 95% CI, 23%-68%) groups. In comparison, the pCR rate in the group of patients with luminal subtype was 6% (95% CI, 1%-21%). While the study identified 61 genes associated with pCR in the basal-like subtype, expression of these genes did not appear to correlate with the rate of pCR in the HER2 subtype.5

While these data are not specific to TNBC, they suggest that different genetic profiles are associated with pCR in different molecular subtypes of breast cancer. Continued exploration with other chemotherapy regimens and/or targeted agents might reveal additional associations.

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