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

Triple Receptor-Negative Breast Cancer: Current and Future Treatments

March 4, 2011

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.


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

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.

To further identify the clinical significance of potential predictive and prognostic factors associated with standard anthracycline/taxane neoadjuvant chemotherapy, Keam and colleagues conducted a prospective study of 145 breast cancer patients with stage II and stage III disease who received docetaxel (75 mg/m2 or 60 mg/m2) and doxorubicin (60 mg/m2 or 50 mg/m2) every 3 weeks for 3 cycles, combined with growth factor support.20 TNBC patients had a higher response rate than the non-TNBC patients (83% vs 62%, respectively; P = .012). TNBC patients also had a higher rate of pCR than non-TNBC patients (17% vs 3.1%, respectively; P = .005). As observed in other studies, RFS (hazard ratio [HR], 3.148; 95% CI, 1.539-6.441; P = .002) and OS (HR, 3.430; 95% CI, 1.133-10.378; P = .021) were significantly shorter by univariate analysis in TNBC patients.20 The authors said that the lower than expected pCR rate observed in this study’s non-TNBC group might be attributable to the abbreviated duration of chemotherapy (3 vs ≥4 cycles).

In a subsequent retrospective study, Liedtke and associates conducted a prospective analysis of 1118 patients with stage I-III breast cancer who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center Hospital from 1985 to 2004. Of the 15% of patients that achieved a pCR, more than half received a taxane followed by an anthracycline-based regimen. Of the 255 patients with TNBC who received neoadjuvant chemotherapy, 22% experienced pCR compared with 11% of the 863 non-TNBC patients (P = .034).14 Despite the higher response rate observed in the TNBC arm, these patients had significantly decreased OS compared with non-TNBC patients; 3-year OS rates were 74% versus 89%, respectively (HR, 2.53; 95% CI, 1.77-3.57; P <.0001). OS was similar, however, for those TNBC and non-TNBC patients who experienced pCR (HR 1.7; 95% CI, 0.7-4.2; P = .24). This is in contrast to TNBC patients with residual disease who had worse OS compared with non-TNBC patients with residual cancer (P <.0001).

Due to the poor survival outcomes for TNBC patients observed in these trials, which incorporated patients treated with what have traditionally been the most active classes of chemotherapy, investigators have explored the efficacy of unconventional chemotherapy regimens, particularly platinum analogues. Frasci and colleagues enrolled 74 consecutive patients with TNBC to receive preoperative 30 mg/m2 of cisplatin, 50 mg/m2 of epirubicin, and 120 mg/m2 of paclitaxel (PET) weekly for 8 cycles followed by growth factor support on days 3 to 5 each week.21

This study showed that 62% (95% CI, 50%-73%) of participants experienced a pCR in both the breast and axilla. After a median follow-up of 41 months, 13 outcome events were observed, 9 of which were distant metastases. The overall projected 5-year disease-free survival (DFS) rate was 76%. The 5-year DFS rate for patients who achieved a pCR with the PET regimen was 90%.21 Using World Health Organization criteria, grade 3/4 toxicities reported with this regimen consisted of hematological events such as neutropenia (31%, despite growth factor support) and anemia (11%); and nonhematological events, including emesis (13%), diarrhea (11%), and mucositis (12%).21 This nontraditional chemotherapy regimen yielded a high pCR rate, with moderate nonhematological toxicity, but despite the use of myeloid growth factors, it was associated with a relatively high percentage of hematologic toxicities in this small population of TNBC patients. A larger, randomized, controlled trial is needed to compare the PET regimen to traditional anthracycline/taxane-based chemotherapy in TNBC patients before it can be implemented as a standard of care.

In another attempt to incorporate platinum compounds into a neoadjuvant chemotherapy regimen for TNBC, Silver and colleagues recently reported preoperative response rates with single-agent cisplatin in 28 TNBC patients with stage II-III disease.22 The treatment for these patients consisted of 75 mg/m2 of cisplatin administered intravenously every 21 days for 4 cycles, followed by surgery, standard adjuvant chemotherapy, and radiation therapy. Based on the Miller-Payne score (ie, a score of 1-5 measuring response to chemotherapy), 14 patients (50%) achieved good pathologic responses, and 6 of these patients (20%) achieved a pCR, including the 2 patients with BRCA1 germline mutations. While this pCR rate is lower than that observed with more traditional chemotherapy regimens, investigators in this trial attempted to correlate BRCA1 status with response. Young age, low BRCA1 mRNA expression, BRCA1 promoter methylation, p53 nonsense or frameshift mutations, and E2F3 oncogenic pathway signature activation were associated with good response to cisplatin. Approximately 35% of patients receiving cisplatin therapy developed grade 3/4 toxicities, including elevated levels of alanine aminotransferase and aspartate aminotransferase, tinnitus, neutropenia, fatigue, hyperkalemia, nausea, myalgia, skin toxicity, and gastrointestinal toxicity. The relatively low pCR rate observed in this small study demonstrates that single-agent cisplatin is not beneficial for TNBC patients. Additional investigation is needed to determine whether combining other agents with cisplatin would have any beneficial effect in TNBC.

High pCR rates in clinical studies show that TNBC is sensitive to traditional preoperative, neoadjuvant, anthracycline/taxane-based chemotherapy regimens. Because of the short time to relapse observed in this population with platinum agents, the role of these compounds in combination with traditional agents remains unresolved. Single-agent platinum therapies would not be adequate in treating TNBC.

Sensitivity to Adjuvant Chemotherapy

As in the neoadjuvant setting, published trials have shown that TNBC patients benefit from adjuvant chemotherapy. One difficulty with investigating adjuvant regimens is the long time frame required to determine efficacy in a setting where disease is not clinically apparent. To compare clinical outcomes, it is necessary to use the endpoints of DFS and OS. In the prospective BCIRG 001 study, a chemotherapy regimen comprising docetaxel/doxorubicin/cyclophosphamide (TAC) was compared with fluorouracil/doxorubicin/cyclophosphamide (FAC) in patients with lymph node—positive breast cancer.23 In a retrospective subset analysis, Hugh and colleagues demonstrated that TNBC patients had a better response to the TAC regimen than to the FAC regimen; 3-year DFS rates were 73.5% versus 60% (HR, 0.50; 95% CI, 0.29-1.00; P = .051). The TAC regimen may be beneficial as a treatment for TNBC patients, but this regimen is quite toxic and is not tolerated by all patients. Also, studies have not yet explored how these results compare with other anthracycline/taxane sequential chemotherapy regimens.

Sensitivity in the Metastatic Setting

In the Eastern Cooperative Oncology Group (ECOG) E-2100 study, Miller and colleagues compared the efficacy and safety of paclitaxel alone versus paclitaxel plus bevacizumab (Avastin), a monoclonal antibody targeting vascular endothelial growth factor (VEGF)-A as an initial treatment of HER2-negative, metastatic breast cancer.24 Compared with paclitaxel alone, the bevacizumab/paclitaxel combination demonstrated significantly prolonged PFS (5.9 mo vs 11.8 mo, respectively; P <.001) and an increased objective response rate (ORR; 21.2% vs 36.9%, respectively; P <.001). Patients whose tumors were ER- and PR-negative had significantly improved PFS with the combination regimen than with paclitaxel monotherapy (8.8 mo vs 4.6 mo, respectively; HR, 0.53; 95% CI, 0.40-0.70).

Other studies have compared outcomes using different chemotherapy agents in patients with metastatic TNBC. A phase III trial by Thomas and colleagues randomly assigned 752 patients with advanced or metastatic breast cancer who were pretreated or resistant to anthracycline- and taxane-based regimens to 40 mg/m2 of intravenous (IV) ixabepilone every 21 days plus 2000 mg/m2 of oral capecitabine (Xeloda) daily for the first 14 days of a 21-day cycle or capecitabine alone at the same dosing regimen.25 Overall, the ixabepilone/capecitabine combination was more effective than capecitabine alone in prolonging median PFS (5.8 mo vs 4.2 mo, respectively; P = .0003) and was associated with a 25% reduction in the estimated risk of disease progression (HR, 0.75; 95% CI, 0.64-0.88; P = .0003). The ORR was also superior in the combination group versus the capecitabine-only arm (35% vs 14%, respectively; P <.0001). Based on a predefined subset analyses, the PFS remained significantly improved, with an HR <1, favoring the combination of ixabepilone plus capecitabine.25 This further emphasizes the overall sensitivity of TNBC to standard chemotherapy regimens.

Future of Targeted Treatments in TNBC

TNBC is a complex disease, lacking an obvious mechanism that drives proliferation. Studies have identified multiple pathways responsible for tumor progression in breast cancer—specifically, several in TNBC—that are all potential therapeutic targets. Numerous ongoing clinical trials are studying agents that target specific proteins in combination with traditional chemotherapy regimens (Table 3).

Poly(ADP-ribose) Polymerase (PARP) Inhibitors

The PARP family of enzymes is involved in DNA repair. Currently, there are 7 PARP homologues—PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), PARP-5 (tankyrases), PARP-7, and PARP-10—that have been characterized and shown to catalyze ADP ribosylation of DNA-binding proteins.26 PARP-1 was the first of this enzyme family found to facilitate DNA repair by catalyzing the addition of ADP-ribose units to DNA, histones, and other DNA-repair enzymes; this affects many cellular processes.26,27 Based on knockout mouse models, the deletion of PARP-1 results in impaired DNA repair, which only becomes lethal with additional PARP-2 deletion. This indicates that the relationship between different PARP enzymes is integral for normal cellular functioning.27 PARP inhibitors have demonstrated an ability to inhibit DNA repair enzymes in BRCA-deficient tumor cells, which share molecular and pathologic characteristics with TNBC.28,30 Because of these similar features, PARP inhibitor-based therapy is a reasonable approach to treating TNBC.

A number of novel PARP inhibitors are under investigation alone or in combination with traditional chemotherapy. These include olaparib (AZD2281), a PARP-1 and PARP-2 inhibitor; BSI-201, a PARP-1 inhibitor; linifanib (ABT-869), a multikinase inhibitor of Flt3, platelet-derived growth factor receptor (PDGFR), VEGFR, and PARP; veliparib (ABT-888), which inhibits PARP-1 and PARP-2; AGO14699, an inhibitor of PARP-1; and INO-1001, GPI-21016, and CEP-9722.29

BSI-201 has been tested in combination with gemcitabine (Gemzar) and carboplatin in a randomized phase II study of 86 metastatic TNBC patients.30 Preliminary data showed that the triplet combination was superior to the chemotherapy doublet alone on several endpoints, including the clinical benefit rate (CBR; 52% vs 12%, respectively; P =.0012;), PFS (211 d vs 87 d, respectively; P = .0003), and OS (254 d vs 169 d, respectively; P = .0012).30 The results of this study prompted initiation of a phase III randomized controlled trial (RCT) in metastatic TNBC patients, which has completed accrual. Results of this study are eagerly anticipated.

PARP inhibitors constitute an important class of targeted agents, with the potential to improve PFS and OS when added to chemotherapy regimens. The role of PARP inhibitors in the treatment of TNBC has yet to be determined; ongoing clinical studies are evaluating their effectiveness in combination with chemotherapy for TNBC in different treatment settings (Table 3).

Endothelial Growth Factor Receptor (EGFR) Inhibitors

Overexpression of EGFR has been associated with several cancers and is evident in ~30% of breast cancer cases.31 According to published data, breast cancers that are basal-like subtype and metaplastic subtype, which is usually triple-negative, have been found to overexpress EGFR.32 EGFR tyrosine kinase inhibitors (eg, erlotinib [Tarceva] and gefitinib) and monoclonal antibodies directed against EGFR (eg, cetuximab [Erbitux]) might benefit patients with TNBC, specifically those with metaplastic carcinomas.

A multicenter, phase II study by Carey and colleagues randomized 102 patients with metastatic TNBC to receive cetuximab alone (400 mg/m2 induction, followed by 250 mg/m2 weekly), with carboplatin (AUC 2 for 3 of 4 weeks) initiated at progression; or to receive a combination of cetuximab and carboplatin at the same dosages used in the other arm.33 Patients who received the combination regimen at the outset had a higher ORR than patients initiated on cetuximab alone (8% vs 6%, respectively) and a higher CBR (27% vs 10%, respectively).

In an exploratory trial by Hobday and colleagues, a small population of 19 metastatic breast cancer patients with prior anthracycline and/or taxane exposure received irinotecan plus cetuximab. The majority of the patients (58) had TNBC; 32% were ER- and/or PR-positive, and 11% were HER2-positive. Although the regimen was not efficacious for the population as a whole, TNBC patients appeared to benefit when compared with non-TNBC patients, with an ORR of 18% versus 0%, respectively; and a CBR of 27% versus 0%, respectively.34 Additional trials are required to corroborate these results prior to adopting any of these regimens as a standard of care, but the results are promising and suggest that EGFR inhibitors, in combination with chemotherapy, might be beneficial for patients with TNBC. Ongoing studies are further evaluating the role of these agents in this complex disease.

Src Inhibitors

c-Src is a proto-oncogene that has a role in cell signaling pathways via tyrosine kinase receptor activity.35 Dasatinib (Sprycel), an orally active inhibitor of Src and Abl, has been used in human breast cancer cell lines. The basal-like subtype demonstrated sensitivity to dasatinib, which resulted in growth inhibition.36 In a phase II clinical study investigating dasatinib in patients with locally advanced or metastatic TNBC who received prior anthracycline and/or taxane therapy, preliminary results showed that 2 out of 43 response-evaluable patients had a partial response and 2 additional patients had stable disease, with an overall CBR of 9.3%.37 The preliminary results of using dasatinib in a population of resistant patients with TNBC are encouraging, but more clinical studies are needed that evaluate the effects of dasatinib in combination with chemotherapy and its role in treating TNBC.

Angiogenesis Inhibitors

Angiogenesis plays an essential role in breast cancer development, invasion, and metastasis and is tightly regulated by proangiogenic factors.38 VEGF, an essential factor for the differentiation and development of the vascular system, is required to sustain tumor growth.38 Researchers have identified 5 VEGF isoforms that act on specific tyrosine kinase receptors, namely VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/Kdr), and VEGFR-3 (Flt-4).38.39

The ECOG E-2100 trial describes bevacizumab as a monoclonal antibody that targets VEGF-A, and it has been approved by the FDA as a treatment for HER2-normal metastatic breast cancer.23 (The FDA is reconsidering this approval decision.) Because of the positive results that the E-2100 study observed in patients with TNBC, the ongoing phase III BEATRICE (Bevacizumab Adjuvant Therapy in TNBC) trial was initiated to evaluate the efficacy and safety of adding bevacizumab to standard adjuvant chemotherapy. Patients are randomized to receive standard chemotherapy alone, with an anthracycline and/or taxane, or standard chemotherapy given concurrently with 1 year of bevacizumab at a dose equivalent to 5 mg/kg per week.

Sunitinib (Sutent), an oral multitargeted tyrosine kinase inhibitor, targets multiple proteins, including VEGFR, PDGFR, c-KIT, and colony-stimulating factor-1 receptor. A phase II study administered 50 mg of sunitinib once daily for 4 weeks, followed by 2 weeks off, to 64 patients with previously treated metastatic breast cancer. Partial response was seen in 11% of patients, and an additional 5% of patients had stable disease for ≥6 months, for an overall CBR of 16%.40 Clinical activity was noticeable regardless of the patient’s ER, PR, or HER2 status. The ORR was 15% for patients with TNBC. Sunitinib merits further testing for TNBC, especially in combination with traditional chemotherapy.

Even though studies have demonstrated the activity of VEGF inhibition in metastatic TNBC, data have not demonstrated improved overall survival. Several intriguing clinical trials are evaluating the effects of VEGF inhibitors in TNBC in the neoadjuvant, adjuvant, and metastatic setting (Table 3).

MAPK/ERK/MEK Inhibitors

Basal-like breast cancers have been associated with high expression of EGFR, and stimulation of EGFR results in activation of cell signaling along the RAS/RAF/MEK/ERK pathway.41 Preclinical studies investigated PD0325901, a potent and selective MEK-1/2 inhibitor, in breast cancer cell lines to determine its therapeutic value and to define molecular mechanisms associated with MEK and phosphatidylinositol 3-kinase (PI3K) in basal-like breast cancer.41 The results demonstrated similarities between basal-like tumors and RAS-mutant tumors, suggesting a possible role for MEK inhibition therapy. Investigators also determined that phosphatase and tensin homolog (PTEN) loss was a negative predictor of response to MEK inhibition and that treatment with a selective MEK inhibitor resulted in up-regulation of PI3K pathway signaling. These data imply that dual blockade of PI3K and MEK are required to impair cell growth in basal-like breast cancer.41

This hypothesis was supported by another preclinical study using the MEK inhibitors CI1040 and UO126.42 Both MEK inhibitors prevented the growth of basal-type breast cancer cells but also activated the PI3K signaling pathway. Investigators have yet to elucidate how these mechanisms occur in humans. Additional clinical studies are needed to evaluate the role of MAPK/ERK/MEK inhibition in TNBC.


TNBC is characterized as an aggressive disease based not on the lack of response, but on the poor clinical outcomes in relation to relapse and death. The complexity of this disease is confounded by the inability to identify a dominant oncogenic factor—as have been identified in other breast cancer subtypes—that drives cancer cell proliferation. Studies show that TNBC is highly sensitive to chemotherapy, but relapses occur quickly and survival is often shorter for patients with this breast cancer phenotype. In the hope of improving survival for patients with TNBC, current clinical trials are investigating targeted agents in combination with traditional chemotherapy to assess safety and clinical benefit.

About the Authors


Erika N. Brown, BS, MS, PharmD, is a clinical pharmacy specialist with the Division of Pharmacy, and Ana M. Gonzalez-Angulo, MD, is an associate professor of medicine with the Department of Breast Medical Oncology and Systems Biology at the University of Texas M.D. Anderson Cancer Center in Houston, Texas.


The authors have nothing to disclose.

Address all correspondence to:

Ana M. Gonzalez-Angulo, MD, MSc, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, TX 77030.


  1. American Cancer Society. Cancer Facts & Figures 2009. Atlanta, GA: American Cancer Society; 2009.
  2. Perou CM, Sorlie T, Elsen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747-752.
  3. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869-10874.
  4. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100(14):8418-8423.
  5. Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678-5685.
  6. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329-2334.
  7. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California Cancer Registry. Cancer. 2007;109(9):1721-1728.
  8. Tan DS, Marchi%u03CC C, Jones RL, et al. Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat. 2008;111(1):27-44.
  9. Cleator S, Heller W, Coombes RC. Triple-negative breast cancer: therapeutic options. Lancet Oncol. 2007;8:235-244.
  10. Gonzalez-Angulo AM. Advances in triple receptor-negative breast cancer. Clin Adv Hematol Oncol. 2007;5(12):956-957.
  11. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15):4429-4434.
  12. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492-2502.
  13. Dawood S, Broglio K, Kau SW, et al. Triple receptor-negative breast cancer: the effect of race on response to primary systemic treatment and survival outcomes. J Clin Oncol. 2009;27(2):220-226.
  14. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275-1281.
  15. Dawood S, Broglio K, Esteva FJ, et al. Survival among women with triple receptor-negative breast cancer and brain metastases. Ann Oncol. 2009;20(4):621-627.
  16. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 2004;22(17):3608-3617.
  17. Nielsen TO, Hsu FD, Jensen K, et al. Immun-ohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367-5374.
  18. Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2006;19:264-271.
  19. Catoretti G, Andreola S, Clemente C, D’Amato L, Rilke F. Vimentin and p53 expression on epidermal growth factor receptor-positive, oestrogen receptor-negative breast carcinomas. Br J Cancer. 1988;57:353-357.
  20. Keam B, Im S, Kim H, et al. Prognostic impact of clinicopathologic parameters in stage II/III breast cancer treated with neoadjuvant docetaxel and doxorubicin chemotherapy: paradoxical features of the triple negative breast cancer. BMC Cancer. 2007;7:203.
  21. Frasci G, Comella P, Rinaldo M, et al. Preoperative weekly cisplatin-epirubicin-paclitaxel with G-CSF support in triple-negative large operable breast cancer. Ann Oncol. 2009;20(7):1185-1192.
  22. Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28(7):1145-1153.
  23. Hugh J, Hanson J, Cheang MCU, et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol. 2009;27(8):1168-1176.
  24. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666-2676.
  25. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007;25(33):5210-5217.
  26. de la Lastra CA, Villegas I, Sánchez-Fidalgo S. Poly (ADP-ribose) polymerase inhibitors: new pharmacological functions and potential clinical implications. Curr Pharm Des. 2007;13:933-962.
  27. Ratnam K, Low JA. Current development of clinical inhibitors of poly (ADP-ribose) polymerase in oncology. Clin Cancer Res. 2007;13:1383-1388.
  28. Schreiber V, Dantzer F, Ame JC, de Murcia G. Poly (ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol. 2006;7:517-528.
  29. Rodon J, Iniesta MD, Papadopoulos K. Development of PARP inhibitors in oncology. Expert Opin Investig Drugs. 2009;18(1):31-43.
  30. O’Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. [ASCO abstract 3]. J Clin Oncol. 2009;27(18S).
  31. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5(5):341-354.
  32. Leibl S, Moinfar F. Metaplastic breast carcinomas are negative for Her-2 but frequently express EGFR (Her-1): potential relevance to adjuvant treatment with EGFR tyrosine kinase inhibitors? J Clin Pathol. 2005;58:700-704.
  33. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer. [ASCO abstract 1009]. J Clin Oncol. 2008;26(15S).
  34. Hobday TJ, Stella PJ, Fitch TR, et al. A phase II trial of irinotecan plus cetuximab in patients with metastatic breast cancer and prior anthracycline and/or taxane-containing therapy. [ASCO abstract 1081]. J Clin Oncol. 2008;26(15S).
  35. Alvarez RH, Kantarjian HM, Cortes JE. The role of src in solid and hematologic malignancies. Cancer. 2006;107:1918-1929.
  36. Finn RS, Dering J, Ginther C, et al. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res Treat. 2007;105:319-326.
  37. Finn RS, Bengala C, Ibrahim N, et al. Phase II trial of dasatinib in triple-negative breast cancer: results of study CA180059. Cancer Res. 2009;69(2)237S.
  38. Gasparini G. Prognostic value of vascular endothelial growth factor in breast cancer. Oncologist. 2000;5(suppl 1):37-44.
  39. Rosen LS. VEGF-targeted therapy: Therapeutic potential and recent advances. Oncologist. 2005;10:382-391.
  40. Burstein HJ, Elias AD, Rugo HS, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2008;26(11):1810-1816.
  41. Hoeflich KP, O’Brien C, Boyd Z, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. 2009;15(14):4649-4664.
  42. Mirzoeva OK, Das D, Heiser LM, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res. 2009;69(2):565-572.