Triple-negative breast cancer (TNBC), a subtype distinguished by negative immunohistochemical assays for expression of the estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2(HER2) represents 15% of all breast cancers. Patients with TNBC generally experience a more aggressive clinical course with increased risk of disease progression and poorer overall survival. Furthermore, this subtype accounts for a disproportionate number of disease-related mortality in part due to its aggressive natural history and our lack of effective targeted agents beyond conventional cytotoxic chemotherapy. In this paper, we will review the epidemiology, risk factors, prognosis, and the molecular and clinicopathologic features that distinguish TNBC from other subtypes of breast cancer. In addition, we will examine the available data for the use of cytotoxic chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents.
Each year more than 1.3 million new cases of breast cancer are diagnosed worldwide. In spite of numerous advances in prevention, surgical resection, and adjuvant radiotherapy and chemotherapy, it is estimated that approximately 450,000 women will die of this disease globally each year [
Human breast cancers represent a heterogenous disease group characterized by varied clinical presentations and responses to therapy. In the past decade, the use of complementary DNA (cDNA) microarrays has furthered our understanding of the underlying biologic diversity of these tumors well beyond the identification of hormone receptor and HER2 status, to include distinct gene expression profiles which correlate with disease progression and clinical outcomes.
Perou, Sørlie, and colleagues have identified 5 molecularly distinct gene expression profiles that may one day allow for clinically relevant classification of breast cancer [
Epidemiologic studies demonstrate that women diagnosed with TNBC manifest a significantly different set of clinicopathologic features and risk factors when compared to women with other subtypes of breast cancer. TNBC comprises approximately 15% of all breast cancers diagnosed; however, in certain select populations, the prevalence may be higher, for example, among premenopausal African American and Hispanic patients [
Population-based studies have confirmed the increased rate of breast cancer-related deaths among patients with TNBC and have identified distinct patterns of recurrence for this subgroup [
Women with TNBC more often develop visceral versus osseous metastases when compared to their hormone receptor-positive counterparts [
To date, many studies have examined the utility of traditional chemotherapy for the treatment of patients with TNBC and have confirmed the benefits of these agents in both the adjuvant and neoadjuvant settings. A meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) was one of the first reviews to determine the efficacy of polychemotherapy in the treatment of ER-poor individuals. Over 6000 women with ER-poor breast cancer, treated in 46 separate randomized trials of adjuvant polychemotherapy (CMF X6 45%; FAC or FEC X6 31%, other 24%) in the prepaclitaxel era were examined. At ten-years followup, the women treated with polychemotherapy demonstrated a significantly reduced risk of recurrence (age <50 hazard ratio (HR) 0.73, age 50–69 HR 0.82) as well as both breast cancer-related (age < 50 HR 0.73, age 50–69 HR 0.86) and all-cause mortality (age < 50 HR 0.75, age 50–69 HR 0.87) [
Similarly, Berry and colleagues completed a retrospective analysis regarding the efficacy of adjuvant chemotherapy in relation to ER status among women enrolled in three adjuvant chemotherapy trials coordinated by the Cancer And Leukemia Group B (CALGB) and the US Breast Intergroup (CALGB 8541, 9344/INT 1048, 9741/INT C9741). In comparison to the women with ER-positive disease, the women with ER-negative tumors treated with regimens which included higher doses, taxanes, and dose-dense (dd) scheduling fared better in terms of risk of recurrence and overall survival. When examined in total, ER-negative women who received dd doxorubicin, cyclophosphamide followed by paclitaxel (AC→T) compared to low-dose cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) experienced a 55% (Confidence Interval (CI) 37–68%) relative risk reduction in recurrence. In comparison, women with ER-positive disease experienced a 26% risk reduction, (CI −4–48%). Furthermore, the absolute improvement in disease-free survival (DFS) (22.8% versus 7%
When analyzed individually, CALGB 9344 and 9741 not only highlighted the therapeutic benefit of taxanes in the adjuvant setting but also contributed to the observation that ER-negative individuals specifically may experience preferentially improved outcomes from use of taxane-inclusive regimens. Unplanned subset analyses in both of the aforementioned studies demonstrated a trend towards improved risk reduction in terms of recurrence for women with ER-negative disease (9344: 28% versus 9%; 9741: 32% versus 19%) [
Several studies have substantiated the positive impact of chemotherapy in the treatment of patients with TNBC in the neoadjuvant setting as well. Among 1,118 patients treated with neoadjuvant chemotherapy, (>80% treated with anthracycline-based regimen; 53% treated with an additional taxane), patients with TNBC had a significantly higher rate of pathologic complete response (pCR) in comparison to patients with non-TNBC (22% versus 11%;
Many trials support the use of cytotoxic agents for the treatment of patients with TNBC; however, the superiority of one regimen over another has not been clearly established. For example, a retrospective review of the MA5 trial, (adjuvant cyclophosphamide/epirubicin/ fluorouracil (CEF) versus CMF), delineated overall survival in relation to molecular phenotype. Patients with BLBC who received CMF were shown to have a superior 5-year overall survival rate in comparison to those who received the anthracycline-based regimen (71% versus 51%) [
More recently, a number of preclinical studies examining the activity of platinum agents in the treatment of TN and BRCA1-associated breast cancers have demonstrated increased sensitivity to these agents. BRCA1-associated tumors are deficient in the genes that encode for proteins critical in DNA integrity, genomic stability, and DNA repair. In preclinical models of BRCA1-deficient breast cancers, there is an increased susceptibility to DNA-damaging agents, particularly those able to induce double-strand breaks such as cisplatin or carboplatin [
TNBC share numerous clinical, molecular, and pathologic features with BRCA mutation-related breast cancers including altered BRCA function and a high degree of genomic instability as well as impaired DNA damage repair. Consequently, many studies have been initiated to study the efficacy of platinum salts in this subgroup. Silver and colleagues tested the efficacy of neoadjuvant cisplatin in a TNBC population not enriched for BRCA-mutation carriers. Eighteen of the 28 patients experienced a clinical response to therapy demonstrating either a partial or complete response with 6 achieving complete pathologic remission. Two of the 6 patients who attained pCR were germline BRCA1-mutation carriers. As a correlate, levels of BRCA1 mRNA expression and BRCA1 promoter methylation were measured in relation to response to therapy. Both lower levels of BRCA expression as well as BRCA promoter methylation, which is inversely proportional to BRCA expression, were correlated with response to cisplatin therapy suggesting that a subgroup of TNBC patients may demonstrate a “BRCA-like” phenotype which predisposes them to cisplatin-sensitivity [
Most recently, the BALI-1 trial randomized 173 patients with metastatic TNBC to receive either cisplatin alone versus cisplatin in combination with cetuximab. Final analysis of the trial demonstrated a modest yet statistically significant improvement in PFS among patients who received combination therapy, 1.5 versus 3.7 months (HR 0.675 CI 0.470–0.969,
Numerous trials are currently underway in the adjuvant and neoadjuvant setting to prospectively study the efficacy of polychemotherapy, including combinations with newer chemotherapeutic agents and novel targeted therapies. CALGB 40603 is a randomized Phase II trial where patients are enrolled in 1 of 4 arms which include: Arm 1: weekly paclitaxel x12 followed by dd AC x4, Arm 2: Arm 1 + bevacizumab every 2 weeks, Arm 3: Arm 1 + carboplatin, and Arm 4: Arm I + bevacizumab as in arm II + carboplatin as in arm III (NCT00861705). A Phase III trial enrolling patients into either docetaxel/anthracycline (epirubicin versus doxorubicin)/cyclophosphamide versus docetaxel and cyclophosphamide is set to assess the added benefit of anthracycline-containing preoperative regimens in TNBC (NCT00912444). A randomized Phase III study of standard adjuvant chemotherapy alone or followed by 1 year of metronomic capecitabine (650 mg/m2 BID) is underway with the primary endpoint of DFS. (NCT01112826) Thus far, capecitabine has not been studied specifically in the triple-negative population. Additionally, the data which currently exist are based on retrospective subgroup analyses which demonstrated that treatment with capecitabine resulted in limited activity in comparison to standard chemotherapy in the adjuvant setting as well as poorer survival outcomes in comparison to non-TNBC patients in the metastatic setting [ A Phase II study of ixabepilone in the neoadjuvant setting demonstrated promising results; in subgroup analysis, patients with TNBC demonstrated a pCR rate of 19% (CI 9–34%) [
Agents that target angiogenesis are appealing for the treatment of TNBC because higher levels of vascular endothelial growth factor (VEGF) and VEGF-2 have been shown in women with TNBC suggesting its potential as a prognostic tool as well as a putative target for therapeutic intervention [
Bevacizumab has been studied in three randomized Phase III trials in combination with chemotherapy for the first-line treatment of metastatic breast cancer. E2100 randomized >700 women to receive weekly paclitaxel with or without bevacizumab. Women who received bevacizumab experienced a significantly higher objective response rate (36.9% versus 21.2%,
The benefit of bevacizumab for patients with triple-negative MBC was replicated in AVADO, a placebo-controlled study evaluating the addition of bevacizumab (at 2 doses: 7.5 mg/kg or 15 mg/kg) to docetaxel. PFS was significantly improved for those patients who received docetaxel in combination with bevacizumab when compared to women who received docetaxel monotherapy. Median PFS for docetaxel monotherapy in comparison to the bevacizumab7.5 and bevacizumab15 groups was 8.0 versus 8.7 (HR 0.79
The third Phase III trial of bevacizumab in the first-line setting randomized patients to receive bevacizumab or placebo in combination with several different chemotherapy options (anthracyclines, taxanes, and capecitabine). Based on investigator assessment, the addition of bevacizumab to capecitabine or an anthracycline/taxane resulted in statistically significant prolongation in PFS as compared to placebo (8.6 versus 5.7 months HR 0.69
Although all three trials failed to demonstrate an OS benefit with the addition of bevacizumab in the metastatic setting, improvements in response rate and PFS were achieved across all subtypes suggesting activity in breast cancer. Furthermore, despite the inherent limitations associated with unplanned retrospective subgroup analyses all three trials demonstrated at least a trend towards improved RR and PFS with the addition of bevacizumab in patients with TNBC.
Currently, there are multiple Phase II/III trials designed to test the efficacy of bevacizumab in the neoadjuvant/adjuvant setting. Three Phase II studies are currently accruing patients to assess the benefits of including bevacizumab in conjunction with platinum agents in the neoadjuvant setting for patients with TNBC. As previously discussed, CALGB 40603 is a multiarm trial comparing weekly T followed by dd AC with the addition of either bevacizumab or carboplatin alone or in combination. (NCT00861705) The NEAT trial is a single-arm, open-label study of docetaxel/carboplatin in combination with bevacizumab given every 3 weeks for 6 cycles preoperatively. (NCT01208480) In a similar study based at the University of Tennessee Cancer Institute, patients will receive neoadjuvant nanoparticle albumin bound (nab-) paclitaxel (day 1, 8, 15), carboplatin (day 1), and bevacizumab (day 1, 15) over the course of a 28-day cycle × 4 cycles followed by ddAC × 4 in addition to bevacizumab for the first two cycles. In this trial to assess the utility of maintenance bevacizumab, postoperatively patients will receive 8 cycles of bevacizumab given every 2 weeks for a total of 16 doses (NCT00777673).
In the adjuvant setting, the BEATRICE study randomizes patients with TNBC to either standard adjuvant chemotherapy (anthracycline ± taxane or taxane only) or adjuvant chemotherapy in combination with bevacizumab x1 year to assess the primary endpoint of disease-free survival (NCT00528567).
Additionally multitargeted small molecule tyrosine kinase inhibitors (TKIs), such as sunitinib and sorafenib, which inhibit numerous targets in the antiangiogenesis pathway, have been evaluated for the treatment of MBC. Unfortunately, these agents have thus far demonstrated modest single-agent activity [
PARP is an essential nuclear enzyme that is involved in the recognition of DNA damage and facilitation of single-strand DNA repair through the base excision repair (BER) pathway. Following detection of a DNA strand break, PARP1, the predominant cellular PARP catalyzes the synthesis and transfer of ADP-ribose polymers to target proteins using NAD+ as substrate. As a result, PARP recruits other repair enzymes and facilitates DNA repair and cell survival. BRCA1 and BRCA2 genes encode for proteins critical for DNA integrity and genomic stability. BRCA1 and BRCA2 proteins are essential for cell division, DNA error control, DNA repair, and apoptosis. In patients with BRCA loss (hereditary mutation), inhibition of PARP induces synthetic lethality which means that DNA damage is irreparable and leads to cell death in homozygote tumor cells, but not in normal tissue heterozygote cells which have one functional BRCA allele [
In 2005, Farmer and colleagues showed that BRCAdeficient breast cell lines were extremely sensitive to PARP inhibition [
As discussed previously, preclinical tumor models of BRCA-associated breast cancers have demonstrated increased sensitivity to therapies which induce DNA damage such as alkylators and radiation (Table
Clinicopathological Features of TNBC versus BLBC versus BRCA-associated Breast Cancer.
Characteristics | Triple-negative breast cancer | Basal-like breast cancer | BRCA-associated breast cancer |
---|---|---|---|
Receptor status | Negative | Negative | Often negative |
HER2 Status | Negative | Negative | Negative |
Cytokeratin 5/6, 17 | Often positive | Positive | Often positive |
EGFR expression | Often positive | Often positive | Often positive |
p53 | Often mutated | Often mutated | Often mutated |
BRCA status | May be dysfunctional secondary to diminished expression or increased expression of negative regulators of the BRCA pathway | May be dysfunctional secondary to diminished expression or increased expression of negative regulators of the BRCA pathway | Inactivated secondary to a hereditary mutation |
Molecular gene expression profile | Often basal-like | Basal-like | Often basal-like |
Histology | Ductal/poorly differentiated/high grade | Ductal/poorly differentiated/high grade | Ductal/poorly differentiated/high grade |
Neoadjuvant/Adjuvant clinical trials for patients with triple-negative breast cancer*.
NCI ID | Status | Primary location | Study type | Setting adjuvant | Stage | Regimen |
---|---|---|---|---|---|---|
NCT00861705 | Recruiting | Miriam Hospital (Providence, RI) | Phase II | Neoadjuvant | II-III | Arm A: Paclitaxel D1 weekly × 12 weekly → ddAC D1 × 4 cycles |
Arm B: Arm A + Bevacizumab q2wks (weeks 1, 3, 5, 7, 9, 10, 11, 13, 15, 17) | ||||||
Arm C: Arm A + Carboplatin q3wks (wks 1, 4, 7, 10 | ||||||
Arm D: Arm A + Bevacizumab as in Arm B + Carboplatin as in Arm C. | ||||||
NCT00912444 | Recruiting | Shanghai Jiao Tong University School of Medicine (Shanghai, China) | Phase III | Neoadjuvant | T2N1 OR T3-4/N0-3 OR T0-4/N2-3 | Arm A: Docetaxel 75 mg/m2 & Doxorubicin 50 mg/m2 OR Epirubicin 60 mg/m2 & Cyclophosphamide 500 mg/m2 D1 × 6 cycles (cycle = 21 days) |
Arm B: Docetaxel 75 mg/m2 & Cyclophosphamide 500 mg/m2 D1 × 6 cycles (cycle = 21 days) | ||||||
NCT01112826 | Recruiting | Sun Yat-sen University Cancer Center (Guangzhou, China) | Phase III | Adjuvant | T1c-T3, pN0-2 | Arm A: Standard adjuvant chemotherapy followed by capecitabine 650 mg/m2 BID × 1 yr |
Arm B: standard adjuvant chemotherapy | ||||||
NCT00789581 | Active/Not recruiting | Sarah Cannon Research Institute (Nashville, TN) | Phase III | Adjuvant | Node negative T1c-T3 OR Node positive pN1mi -N2b) | Arm A: Doxorubicin 60 mg/m2 & Cyclophosphamide 600 mg/m2 D1 × 4 cycles (cycle = 21 days) → Ixabepilone at 40 mg/m2 D1 × 4 cycles (cycle = 21 days) |
Arm B: Doxorubicin 60 mg/m2 & Cyclophosphamide 600 mg/m2 D1 × 4 cycles (cycle = 21 days) → Paclitaxel at 80 mg/m2 D1 weekly × 12 weeks | ||||||
NCT00630032 | Active/Not recruiting | Centre Regional Rene Gauducheau (Nantes-Saint Herblain, France) | Phase III | Adjuvant | Node-positive disease OR node-negative disease: II-III OR pT1-4 | Arm A: Epirubicin & 5-Fluorouracil & Cyclophosphamide D1 × 3 cycles (cycle = 21 days) → Docetaxel D1 × 3 cycles (cycles = 21 days) |
Arm B: Epirubicin & 5-Fluorouracil & Cyclophosphamide D1 × 3 cycles (cycle = 21 days) → Ixabepilone D1 × 3 cycles (cycles = 21 days) | ||||||
NCT01216111 | Available | Fudan University (Shanghai, China) | Expanded Access | Adjuvant | I-IIIA | Paclitaxel 100 mg/m2 & Cisplatin AUC = 2 D1, 8, 15 × 6 cycles (cycle = 28 days) |
NCT01276769 | Recruiting | Cancer Institute Hospital/Chinese Academy of Medical Sciences (Beijing, China) | Phase II | Neoadjuvant | IIa-IIIc (no T4 disease) | Arm A: Paclitaxel 175 mg/m2 D3 & Epirubicin 75 mg/m2 D 1, 2 × 2–6 cycles (cycle = 21 days) |
Arm B: Paclitaxel 175 mg/m2 D1 & Carboplatin AUC = 5 D2 × 2–6 cycles (cycle = 21 days) | ||||||
NCT01216124 | Available | Fudan University (Shanghai, China) | Expanded Access | Neoadjuvant | I-IIIA | Docetaxel 75 mg/m2 D1 & Oxaliplatin 130 mg/m2 D2 × 6 cycles (cycle = 21 days) |
NCT01238133 | Recruiting | Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center (Columbus, OH) | Phase I | Neoadjuvant | II-III | RO4929097 D1-3, 8-10, 15-17 & Paclitaxel D1, 8, 15 & Carboplatin D1 × 6 cycles (cycle = 21 days) |
NCT01167192 | Recruiting | Washington University School of Medicine (St. Louis, MO) | Phase II | Neoadjuvant | T2-T4, any N | Cisplatin 75 mg/m2 IV or Carboplatin AUC = 6 IV, at physician discretion) + XRT × 6 weeks (50–60 Gy to breast/CW; 45–50 Gy to internal mammary nodes, supraclavicular fossa nodes and axillary nodal basins) |
NCT00861705 | Recruiting | Miriam Hospital (Providence, RI) | Phase II | Neoadjuvant | II-III | Arm A: Paclitaxel D1 weekly × 12 weekly → dd AC D1 × 4 cycles |
Arm B: Arm A + Bevacizumab q2wks (weeks 1, 3, 5, 7, 9, 10, 11, 13, 15, 17) | ||||||
Arm C: Arm A + Carboplatin q3wks (wks 1, 4, 7, 10 | ||||||
Arm D: Arm A + Bevacizumab as in Arm B + Carboplatin as in Arm C. | ||||||
NCT01208480 | Recruiting | Severance Hospital (Seoul, Korea) | Phase II | Neoadjuvant | II-III | Bevacizumab & Docetaxel & Carboplatin D1 × 5 cycles (cycle = 21 days → Docetaxel & Carboplatin C6D1 |
NCT00777673 | Recruiting | University of Tennessee Cancer Institute (Memphis, TN) | Phase II | Neoadjuvant | T2-T3, cN1-cN2a | Nab-paclitaxel D1, 8, 15 & Carboplatin D1 & Bevacizumab D1,15 × 4 cycles (cycle = 28 days) → ddAC × 4 cycles (cycle = 14 days) & Bevacizumab D1 × 2 cycles (cycle = 14 days) |
NCT00528567 | Recruiting | Hoffmann-La Roche; International | Phase III | Adjuvant | Operable primary invasive breast cancer | Arm A: Standard adjuvant chemotherapy (anthracycline ± taxane or taxane only) & 1 yr of Bevacizumab 5 mg/kg/week dosing equivalent |
Arm B: Standard adjuvant chemotherapy (anthracycline ± taxane or taxane only) | ||||||
NCT00887575 | Recruiting | Tennessee Oncology, PLLC (Nashville, TN) | Phase I/II | Neoadjuvant | T1-3, any N (excluding T1N0) | Paclitaxel D1, 8, 15 & Carboplatin D1 & Sunitinib D1-21 × 6 cycles (cycle = 28 days) |
NCT01194869 | Recruiting | Emory University (Atlanta, GA) | Phase II | Neoadjuvant | I-IIIA | Sorafenib 400 mg BID throughout the study: single agent for weeks 1–4, then in combination with cisplatin followed by dose dense paclitaxel |
NCT00813956 | Recruiting | Stanford Comprehensive Cancer Center (Stanford, CA) | Phase II | Neoadjuvant | I-IIIA | Gemcitabine & Carboplatin & BSI-201 q3wks |
NCT01204125 | Recruiting | Grupo Espanol de Estudio Tratamiento y Otras Estrategias Experimentales en Tumores Solidos (France/Spain) | Phase II | Neoadjuvant | II-IIIA | Arm A: Iniparib 5.6 mg/kg D1, 4 &Paclitaxel 80 mg/m2 D1 weekly × 12 weeks |
Arm B: Iniparib 11.2 mg/kg D1 &Paclitaxel 80 mg/m2 D1 weekly × 12 weeks | ||||||
Arm C: Paclitaxel 80 mg/2 D1 weekly × 12 weeks | ||||||
NCT01074970 | Recruiting | Indiana University Melvin and Bren Simon Cancer Center (Indianapolis, IN) | Phase II | Adjuvant | Residual disease post neoadjuvant chemotherapy (I-III) | Arm A: PF-01367338 D1-3 C1: 30mg C2-4: 24 mg & Cisplatin 75 mg/m2 D1 × 4 cycles (cycle = 21 days) |
Arm B: Cisplatin 75 mg/m2 D1 × 4 cycles (cycle = 21 days) | ||||||
NCT01097642 | Recruiting | The Methodist Hospital Research Institute (Houston, TX) | Phase II | Neoadjuvant | T1N1-3M0 or T2-4 N0-3M0 | Arm A: Cetuximab 400 mg/m2 D1 then weekly 250 mg/m2 & Ixabepilone 40 mg/m2 D1 1 × 4 cycles (cycle = 21 days) |
Arm B: Ixabepilone 40 mg/m2 D1 1 × 4 cycles (cycle = 21 days) | ||||||
NCT00600249 | Recruiting | Centre Jean Perrin (Clermont-Ferrand, France) | Phase II | Neoadjuvant | II-IIIa | Cetuximab Wk1D1 400 mg/m2 → 250 mg/m2 D1 weeks 2–18. |
NCT00491816 | Active/Not recruiting | University of Kansas Medical Center (Kansas City, KS) | Phase II | Neoadjuvant | II-III (T2-4, N1-2) | Erlotinib150 mg orally D3-14 with cycles 1 to 6 or 3 to 6 of neoadjuvant chemotherapy. Adjuvant chemotherapy given at the discretion of treating physician followed by 1 yr of maintenance erlotinib 150 mg daily |
NCT00930930 | Recruiting | Vanderbilt-Ingram Cancer Center (Nashville, TN) | Phase II | Neoadjuvant | II-III | Arm A: Cisplatin & Everolimus D1 weekly × 12 weeks & Paclitaxel D1 weekly in weeks 4–12 |
Arm B: Cisplatin & Placebo D1 weekly × 12 weeks & Paclitaxel D1 weekly in weeks 4–12 | ||||||
NCT00499603 | Active/Not recruiting | M.D. Anderson Cancer Center (Houston, TX) | Phase II | Neoadjuvant | IIa-IIIc | Arm A: Drug: Paclitaxel 80 mg/m2 D1 weekly & RAD001 30 mg D1, 8, 15 × 12 cycles (cycle = 21 days) → 5-Fluorouracil 500 mg/m2 & Epirubicin100 mg/m2 & Cyclophosphamide 500 mg/m2 D1 × 4 cycles (cycle = 21 days) |
Arm B: Paclitaxel 80 mg/m2 D1 weekly × 12 cycles (cycle = 21 days) → 5-Fluorouracil 500 mg/m2 & Epirubicin100 mg/m2 & Cyclophosphamide 500 mg/m2 D1 × 4 cycles (cycle = 21 days) |
*Details outlined above as per
Given the clinical, histologic, and molecular overlap between BRCA-1-associated tumors and TNBC, multiple investigators have theorized that PARP inhibitors may prove efficacious in this subgroup as well. In a Phase II study O’Shaughnessy and colleagues randomly assigned patients to receive carboplatin and gemcitabine alone or in combination with iniparib, an intravenous PARP inhibitor. The data from this trial showed significant improvement in clinical benefit rate (CBR = CR + partial response + stable disease (SD) ≥6 months; 56 versus 34%,
Trials incorporating PARP inhibitors, alone or with concomitant cytotoxic agents, are currently being developed in the neoadjuvant/adjuvant BRCA-associated and TNBC populations. Two Phase II trials are currently accruing patients in the neoadjuvant setting either in combination with platinum agents or taxanes. (NCT00813956; NCT01204125) An adjuvant Phase II trial is underway which randomizes patients with residual disease after nonplatinum-based neoadjuvant chemotherapy and definitive surgery to receive either cisplatin alone or in combination with PF-01367338. (NCT01074970).
EGFR is expressed in approximately 60% of TNBC [
Two Phase II studies are currently open to test the efficacy of cetuximab in combination with preoperative chemotherapy, ixabepilone (NCT01097642) and docetaxel (NCT00600249). A neoadjuvant study is accruing patients to assess the pCR rate of erlotinib in combination with chemotherapy. A second component of this trial involves the addition of maintenance erlotinib X1 year after the completion of the patient’s adjuvant regimen. (NCT00491816).
Currently, standard chemotherapy remains the cornerstone of treatment for patients with TNBC in the preoperative and adjuvant settings. The development of newer biologic and targeted therapies, such as antiangiogenic agents, EGFR inhibitors, and PARP inhibitors, continues to be a promising area of research. Trials are ongoing to assess the efficacy of specific chemotherapeutic regimens alone or in combination with newer targeted agents in both the neoadjuvant and adjuvant setting and will potentially provide the basis for practice-altering changes in our management of this high-risk population. Ideally, clinically appropriate patients with TNBC should be counseled about the availability of ongoing clinical trials and whenever possible be treated within the context of a research study.