Treating Triple-Negative Breast Cancer: Where Are We?

Transcription

1 e8 Treating Triple-Negative Breast Cancer: Where Are We? Aki Morikawa, MD, PhD, and Andrew D. Seidman, MD Abstract Unlike estrogen receptor (ER) positive and HER2-positive breast cancer, triple-negative breast cancer (TNBC) lacks a repertoire of targeted therapies. Hence, chemotherapy is the only available systemic option in current clinical practice. In general, survival of patients with TNBC is worse than that for those with ER-positive and HER2-positive breast cancer, especially for advanced-stage disease. Thus, a great unmet need exists. Conventional chemotherapeutic agents such as platinumsalts have been examined for specific benefit in TNBC; however, no one agent has yet been shown to offer a differential incremental benefit in metastatic TNBC. The hope is that ongoing research in targetable molecular pathways will lead to new therapeutic options for TNBC. Because these patients are likely to be increasingly subcategorized using potentially targetable molecular alterations, investigators will need to be mindful of the challenges in designing and conducting clinical trials in smaller subpopulations. The successful incorporation of targeted therapies in routine clinical practice for TNBC, which mirrors the success achieved by anti-her2 and endocrine therapies, is awaited. (J Natl Compr Canc Netw 2015;13:(e8 e18) Contemporary systemic therapy is commonly informed by the classification of breast cancer based solely on hormonal receptor and HER2 status. Triple-negative is a category of exclusion defined by immunohistochemical and/or fluorescence in situ hybridization based criteria, which has undergone modification over time (ASCO/ CAP guidelines). 1,2 Histologically, triple-negative breast cancer (TNBC) is a heterogeneous group of breast cancers that includes common infiltrating ductal carcinoma From Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, New York. Submitted April 20, 2014; accepted for publication August 6, Dr. Morikawa has received research support from the Susan G. Komen Foundation and the ASCO Conquer Cancer Foundation Bonadonna Fellowship. Dr. Seidman has served as a consultant for Genentech/Roche and Pfizer and has received payment for lectures, including service on speaker bureaus from Genentech, Genomic Health, Eisai, and Celgene, and research support from the Susan G. Komen Foundation. Correspondence: Andrew D. Seidman, MD, Evelyn H. Lauder Breast Center, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY [email protected] and rare types, such as adenoid cystic, metaplastic, apocrine, and neuroendocrine carcinoma. 3 Nevertheless, the clinical utility of this categorization has been robust as a prognostic and predictive biomarker. Patients with TNBC are more likely to have a poor prognosis than those with estrogen receptor (ER)/ progesterone receptor (PR) positive and/or HER2-positive breast cancer. 4 This is likely partially attributable to a dearth of novel therapeutic options for TNBC, in contrast to the recent expansion of endocrine and anti- HER2 therapies (eg, ado-trastuzumab-emtansine, pertuzumab, everolimus with exemestane). 5 7 Therefore, great interest has been shown in exploring potential biomarkers (prognostic and predictive) and developing new therapeutic options. This article reviews current treatment options ( where are we now? ) and ongoing therapeutic research ( where are we going? ) for TNBC. Heterogeneity of TNBC Because the utilitarian definition of TNBC is simply based on the exclusion of ER/PR/HER2 expression, it is not unexpected that this clinical subtype remains biologically heterogeneous. Studies examining tumor characteristics have found correlations between TNBC and certain molecular genomic features, such as basal cytokeratin (eg, CK5/6) and epidermal growth factor receptor (EGFR) expression, checkpoint kinase (Chk1), p53 alterations, and BRCA1 germline mutations TNBC has also been shown to have overlapping features with the basal-like subtype (intrinsic breast cancer classification), 14,15 including a high frequency of poorly differentiated tumors, expression of cytokeratins and EGFR, and p53 mutations. Although the basal-like subtypes are most often triple-negative, they are not equivalent groups. 16,17 In a gene expression study of 579 TNBCs, 73% of TNBCs showed basal-like characteristics. 18

2 e9 Treating Triple-Negative Breast Cancer The Cancer Genome Atlas (TCGA) project reporting of breast cancer molecular analysis also showed significant overlap between TNBC and basal-like features and similarity to high-grade serous ovarian cancer. 19 The TCGA basal-like subanalysis and the primary TNBC analysis identified several involved pathways that included PTEN, PI3K/PTEN, cell cycle, and growth factors, and highlighted the heterogeneity of TNBC. 19,20 Recently a large metaanalysis of 587 TNBC gene expression profiles from 21 data sets described 7 TNBC subtypes with 6 potentially targetable pathways. 21 Those subtypes consist of 2 basal-like types (BL1 and BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), luminal androgen receptor (LAR), and unstable (UNS). The BL1 subtype was characterized by cell cycle/cell division and DNA damage response pathways (and association with the BRCA deficiency). The BL2 subtype was typified by growth factor signaling such as via the EGFR pathway. The IM subtype was named for a cluster that contained immune-related processes. The M and MSL types were both associated with motility and epithelial to mesenchymal transition (EMT), but the MSL had more stem cell like features. The LAR subtype contained the genes involved in androgen and steroid pathways. In addition, various cell lines were classified into these TNBC subtypes and evaluated for responses to therapy designed to match to the appropriate representative subtype. 21 A Web-based subtyping tool was also created that allowed normalized gene expression data to be analyzed for TNBC subtypes. 22 Treating TNBC: Where Are We Now? Currently, cytotoxic chemotherapy is the standard therapeutic approach for TNBC. TNBC is relatively chemosensitive, as evidenced by relatively higher pathologic complete response (pcr) rates compared with other subtypes, such as ER-positive/HER2-negative. 23 This may be explained partially by the fact that TNBC is often associated with a high grade and proliferative rate. However, despite higher response rates, they have an inferior outcome with respect to time to recurrence and overall survival (OS) after chemotherapy. 4 Preclinical studies and subgroup analyses within clinical trials have suggested that certain chemotherapeutic agents have differential antitumor activity in TNBC compared with non- TNBC. Thus, certain classes of chemotherapeutic agents have been preferentially evaluated in patients with TNBC. Microtubule-Targeting Agents Based on the TNBC subtypes, the basal-like types are postulated to respond well to taxanes because of their expression of proliferation genes. 21 Efficacy of paclitaxel specifically for TNBC (compared with non-tnbc) has been observed in subtype analyses within clinical trials. 24,25 However, these associations between TNBC s have not been consistent; a meta-analysis has shown benefit for taxane in the adjuvant setting independent of ER status. 26 Ixabepilone is an epothilone B analogue that stabilizes microtubules and has activity in patients with TNBC as a monotherapy. 27 In a phase III study of ixabepilone and capecitabine versus capecitabine, improvements in response rate and median progression-free survival (PFS) were noted for the combination regimen in the TNBC subset compared with the ER-positive subset (response rate, 27% vs 9%, and median PFS, 4.1 vs 2.1 months, respectively). 28 However, no significant benefit was noted in terms of median OS for patients with TNBC (hazard ratio [HR], 0.83; P<.05). 29 Eribulin is a halichondrin B analogue that perturbs microtubule dynamics. It demonstrated a survival benefit in heavily pretreated metastatic breast cancer (MBC) compared with the treatment of physician s choice in the EMBRACE trial. 30 The phase III 301 trial compared eribulin with capecitabine in 1102 pretreated patients with MBC, and reported a significant improvement in median OS associated with eribulin among the subset of patients with TNBC in an exploratory analysis (14.4 vs 9.4 mo; HR, 0.7; P=.01). 31 However, in the published version of this study, the authors did not report any significant difference in benefit among the subgroups. 32 Given that patients with metastatic TNBC often require multiple lines of chemotherapy, eribulin and capecitabine are both likely to remain useful. Eribulin is also being evaluated in combination with carboplatin (neoadjuvant) and everolimus (metastatic) for the treatment of for TNBC. 33,34 Platinum Salts TNBCs have been associated with BRCA mutation status. BRCA-mutated tumors have defects in their

3 e10 Morikawa and Seidman homologous recombination repair mechanism and are thought to be particularly vulnerable to DNAdamaging agents. 35 In addition to the association of TNBC with germline and somatic BRCA pathway defects, 19 some TNBCs, even in the absence of known BRCA mutations, have demonstrated homologous DNA-repair deficiency and potential vulnerability to DNA-damaging agents, such as platinum salts, similar to that observed in BRCA-mutated tumors. 36 In this context, cisplatin and carboplatin have been evaluated in unselected TNBC. Most recently, the TBCRC009 phase II study reported a response rate of 25.6% to platinum monotherapy (cisplatin or carboplatin) as first- or secondline therapy of metastatic TNBC. 37 Of the 87 patients enrolled, 11 were known BRCA mutation carriers. The response rate was higher in BRCA mutants (54.5%) than wild-type BRCA (19.7%), but median PFS (3.3 months for BRCA mutants and 2.8 months for wild-type BRCA) and median OS (13.7 months for BRCA mutants and 10.9 months for wild-type BRCA) were not statistically significantly different (P>.05). In the metastatic setting, the combination of gemcitabine and carboplatin was evaluated in a prospective trial showing modest antitumor activity Selected examples of platinum regimens in locally advanced/metastatic TNBC along with nonplatinum regimens are shown in Table 1. Notably, gemcitabine/carboplatin was the comparator arm in phase II and III trials in metastatic TNBC evaluating the addition of the investigational drug iniparib. 41,42 In the gemcitabine/carboplatin control arm, the objective response rate was 30% and median PFS and OS were 4.1 and 11.1 months, respectively. Notably, no direct comparison of gemcitabine and platinum versus other chemotherapy combinations has ever been performed in a prospective randomized trial for metastatic TNBC. Therefore, whether this combination has any particular or unique advantage over other nonplatinum standard chemotherapy regimens in TNBC remains unclear. Notably, results of the phase III TNT trial comparing single-agent docetazel and carboplatin in patients with TNBC were recently reported. In unselected patients with TNBC, the efficacy of carboplatin monotherapy was similar to that of docetaxel, which is regarded as one of the most active agents against MBC in general. In the subset of patients with a BRCA mutation, carboplatin showed differential benefit compared with docetaxel (response rate, 68.0% vs 33.3% for patients with BRCA mutations and 28.1% vs 36.6% for those with wild-type BRCA status, respectively; PFS, 6.8 vs 3.1 months, respectively, in patients with BRCA mutations). An assay for homologous repair deficiency used in this study was not predictive of a differential carboplatin benefit. 43 Currently, a randomized phase III trial is evaluating nab-paclitaxel in combination with gemcitabine or carboplatin versus gemcitabine and carboplatin alone in metastatic TNBC (tnacity trial; ClinicalTrials.gov identifier: NCT ). The neoadjuvant use of platinum salts has been evaluated in BRCA-mutated and unselected TNBC. A recent meta-analysis of 28 neoadjuvant studies showed a pooled pcr rate of 45% (95% CI, 40% 49%) for platinum-containing regimens. 44 The inclusion of a platinum seemed to be associated with a higher proportion of pcrs compared with non platinum-containing regimens (response rate, 1.45; 95% CI, ; P<.001). 44 The GeparSixto study evaluated the addition of carboplatin to paclitaxel and pegylated liposomal doxorubicin (plus bevacizumab in TNBC) in the neoadjuvant setting. 45 The addition of carboplatin was associated with a significant increase in pcr for TNBC (37.9% vs 58.7%; P<.05), although a high rate of discontinuation (39%) was noted for the regimen that included carboplatin. 45 In the CALGB trial in which carboplatin and/or bevacizumab was added to anthracycline/ paclitaxel chemotherapy in 454 patients with TNBC, the breast pcr rate improved with the addition of carboplatin (from 46% to 60%; P=.018), with more marrow suppression noted in the carboplatin group: grade 3/4 neutropenia (56% vs 20%) and thrombocytopenia (22% vs 4%). 46 Thus the available evidence suggests that platinum can improve the pcr rate. Patients with TNBC who experience a pcr have significantly better survival than those who do not. 23 However, an association between platinum use and relapse-free survival and OS still needs to be elucidated (ie, does the incremental improvement in pcr translate to fewer downstream events). The NeoALTTO and ALTTO trials recently reported that the addition of lapatinib, which improves pcr from 29.5% to 51.0% in the neoadjuvant setting, did not translate into a significant benefit in disease-free survival or OS when used as adjuvant therapy. 47,48 At the time of this writing, whether

4 e11 Treating Triple-Negative Breast Cancer Table 1 Selected Chemotherapy Regimens With TNBC-Specific Outcomes in the Metastatic Setting Drugs Docetaxel (doc) vs carboplatin (carb) carboplatin arm (gemcitabine and carboplatin +/ iniparib) cisplatin cisplatin Patients With TNBC Study Population TNBC RR TNBC TTP/PFS a TNBC OS a Reference Total Study Design Patients Phase III No previous taxane or platinum in metastatic setting Phase III, gemcitabine and carboplatin only arm 31% (carb) vs 36% (doc) 3.1 (carb) vs 4.5 mo (doc) 12.4 (carb) vs 12.3 mo (doc) Tutt et al, Prior 0 2 lines 30% 4.1 mo 11.1 mo O Shaughnessy et al, Phase II Relapsed after 1 adjuvant/nac regimen or firstline metastatic regimen with anthracycline Phase II Second-line, anthracycline and taxane pretreated Retrospective Prior anthracycline review Retrospective review Phase II Prior anthracycline 33% 5.1 mo 73% at 1 y Kohail et al, % 5.4 mo 13.9 mo Wang et al, cisplatin 27% 5 mo 14 mo Ozkan et al, Prior taxane 5.3 mo Koshy et al, 92 cisplatin % 5.5 mo 11 mo Maisano et carboplatin al, Phase II First-line 20% Yardley et al, 39 carboplatin 2008 Phase II Prior taxane or no 30% Loesch et al, 40 carboplatin prior taxane 2008 Phase II First-line 35.7% 6 mo Aogi et al, 93 paclitaxel 2011 Cisplatin (cis) arm Randomized No more than 1 10% (cis) 1.5 mo (cis) Baselga et al, 70 (cisplatin +/ cetuximab) phase II prior 2013 Cisplatin or carboplatin Phase II First- or secondline 25.6% 2.9 mo 11 mo Isakoff et al, Cisplatin (cis) and Randomized Prior 0 1 line 30% 5.1 mo 12.8 mo O Shaughnessy irinotecan (iri) arm phase II (cis/iri) (cis/iri) (cis/iri) et al, (cisplatin, irinotecan +/ cetuximab) Docetaxel/cisplatin vs docetaxel/capecitabine Docetaxel Capecitabine Ixabepilone Randomized phase II Retrospective review Retrospective review Retrospective subanalysis First-line 63% vs 15.4%; P= vs 4.8 mo HR, 0.29; P< vs 21.5 mo HR, 0.41; P=.027 Fan et al, First-line 0% at 2 y 37.8% at 2 y Gonçalves et al, Prior anthracycline 0% 3.6 mo Gilabert et al, Prior anthracycline, 6% 55% mo Perez et al, 27 taxane, 2010 capecitabine 6.3% Aogi et al, Ixabepilone Phase II Prior anthracycline Ixabepilone + capecitabine vs capecitabine Oral vinorelbine and capecitabine Metronomic oral cyclophosphamide and capecitabine Oral cyclophosphamide and capecitabine Eribulin vs capecitabine Phase III subanalysis Prior anthracycline 27% (iri + cis) vs 9% (cis) 4.1 vs 2.1 mo HR, 0.68; P<.05 Pivot et al, Phase II 54 9 First-line 22.2% 4 mo Tubiana- Mathieu et al, Phase II No more than 1 prior line and no prior 5-FU, capecitabine, or cyclophosphamide Phase II No more than 1 prior line Phase III subanalysis Prior anthracycline 44.4% 10.7 mo Yoshimoto et al, % d Tanaka et al, vs 9.4 mo HR, 0.7; P<.05 Kaufman et al, Eribulin Phase II First-line 16.7% 3.4 mo McIntyre et al, Anthracycline and cyclophosphamide Retrospective review First-line 56.5% 8.1 mo 25.4 mo Yi et al, Paclitaxel arm (from paclitaxel +/ bevacizumab) Phase III, paclitaxel-only arm First-line 4.6 mo Miller et al, Abbreviations: HR, hazard ratio; NAC, neoadjuvant chemotherapy; OS, overall survival; PFS, progression-free survival; RR, response rate; TNBC, triple-negative breast cancer; TTP, time to progression. a Median, unless otherwise noted.

5 e12 Morikawa and Seidman platinum agents deserve routine inclusion in regimens for TNBC of any stage remains uncertain. Based on a mechanistic rationale and efficacy in nonrandomized trials, platinum is perhaps a reasonable choice for a subset of patients with TNBC who are more likely to have a DNA-repair deficiency. 44 Several studies have reported biomarkers that may be helpful in selecting an appropriate population. 49 For example, a homologous recombination deficiency assay is currently being evaluated as a biomarker in sporadic TNBC, with a primary end point of correlation with pcr (ClinicalTrials.gov identifier: NCT ). Treating TNBC: Where Are We Going? As knowledge of TNBC molecular features expands, several potential therapeutic targets have emerged, which include the hallmarks of cancer : DNA repair and damage checkpoint mechanism, proliferation and growth, angiogenesis, and invasion/metastases. Whether disease can successfully be controlled through targeting a single pathway in a subpopulation of TNBC (as in the case of some HER2-driven tumors) is unclear. It is likely that a rational combination of systemic agents will need to be found, which may include conventional chemotherapy (eg, platinum drug and poly(adp-ribose) polymerase [PARP] inhibitor). The following are selected examples of biologic and immunologic agents currently under investigation. PARP Inhibition Molecular genomic analyses have identified potentially targetable pathways and areas of drug development for TNBC (Table 2). In addition to the platinum drugs, PARP inhibitors have been evaluated in TNBC to target their BRCA-ness. PARP1 is a DNA repair enzyme involved in single-strand break (SSB). When used in a setting of BRCA-related repair deficiency, it is thought to facilitate synthetic lethality, wherein SSB repair deficiency leads to double-strand breaks that cannot be repaired by homologous recombination. 50 Preclinical and clinical studies have shown a particular sensitivity to PARP inhibition in BRCA-mutated tumors. 50 Initially, the investigational drug iniparib was thought to be a PARP inhibitor and was initially evaluated in a randomized phase II study with gemcitabine and carboplatin. 41 Despite the promising initial data, 41 a larger phase III trial did not show significant benefit for iniparib when added to chemotherapy. 42 Additional studies showed that the drug demonstrated poor PARP inhibition. However, other PARP inhibitors are being evaluated in patients with BRCA-mutated and sporadic TNBC. Olaparib as a monotherapy did not show any confirmed objective response in a phase II study for TNBC, 51 although modest efficacy was noted in patients with a BRCA mutation. 52 It is currently being evaluated in combination with chemotherapy or other biologic agents, such as cediranib (anti vascular endothelial growth factor [VEGF]). 53,54 Veliparib in combination with carboplatin (V+C) was evaluated in the I-SPY-2 neoadjuvant trial. There was a 92% predictive probability (Bayesian) that the addition of V+C would be statistically superior to the standard anthracycline/taxane-based therapy alone based on the observed pcr rates: 52% (28% 67%) for V+C and 26% (9% 43%) in the control arm. 55 Finally, perturbation of the PI3K/ AKT and cell cycle pathways (eg, CDK1 inhibition) have been shown to sensitize cells to PARP inhibition even in BRCA-proficient tumors in preclinical models, and clinical studies of combination therapy with PARP and PI3K inhibitors are underway (ClinicalTrials.gov identifier: NCT ). 56 Other efforts to target DNA damage repair and cell cycle checkpoint mechanisms include use of histone deactylase (HDAC), heat-shock protein 90 (Hsp90), and Chk1 inhibition. Although a phase II study of Chk1 inhibition in combination with irinotecan demonstrated limited activity in TNBC (response rate, 4%), preclinical studies have suggested that these strategies may be particularly relevant in TNBC associated with p53 mutation and BRCA mutation and await further clinical evaluation. 57,58 Anti-VEGF Therapy VEGF is frequently expressed in TNBC and is a potential therapeutic target. 21 Anti-VEGF therapy, particularly bevacizumab, has been studied with modest and inconsistent improvements in response rate and PFS but not for OS in the metastatic setting. 59 Recently the phase III BEATRICE trial examined the addition of bevacizumab to standard adjuvant chemotherapy in TNBC and failed to show a benefit in DFS or OS. 60 In CALGB 40603, the addition of neoadjuvant bevacizumab was associated with a significant improvement in breast-only pcr but not for

6 e13 Treating Triple-Negative Breast Cancer Table 2 Potentially Targetable Pathways and Selected Examples of Drugs Being Preferentially Evaluated in TNBC a Pathway Drugs Mechanism ClinicalTrials.gov Identifier DNA repair Veliparib Olaparib PARP inhibitor PARP inhibitor NCT NCT NCT TP53 mutation/checkpoint UCN-01 Chk1 inhibitor NCT P CDK inhibitor NCT Ganetespib Hsp90 inhibitor NCT Dinaciclib CDK inhibitor NCT Growth factor pathway MM-121 Anti-HER3 NCT Panitumumab Anti-EGFR NCT Anti-VEGF Cabozantinib Anti-VEGF and anti-met NCT Sorafenib Multi-TKI NCT AR pathway Enzalutamide Anti-AR NCT Notch pathway RO Gamma-secretase NCT inhibitor LDE225 Smoothened antagonist NCT Apoptosis LCL161 Smac pathway NCT PI3K/Akt pathway GDC-0941 PI3K inhibitor NCT BKM120 PI3K inhibitor NCT Immunotherapy PD-1 antibody Immune checkpoint NCT MUC1 peptide vaccine Vaccination NCT Autologous cmet-redirected T cells Adoptive T-cell therapy NCT Abbreviations: AR, androgen receptor; CDK, cyclin-dependent kinase; EGFR, epidermal growth factor receptor; PARP, poly(adpribose) polymerase; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor. a Active on ClinicalTrials.gov as of June 1, breast and axillary nodes (36% increase with P=.06 for breast and axilla). 46 On the other hand, the TNBC subset analysis of GeparQuinto showed improvement in pcr (breast and lymph nodes): 27.9% to 39.3% with addition of bevacizumab (P=.003). 61 Again, as with platinums, it is unclear (perhaps unlikely) that this incremental improvement is clinically meaningful and will translate to an improvement in DFS or OS. In addition, biomarker studies (eg, MERIDIAN trial) are being conducted to better select patients who may derive greater benefit from bevacizumab therapy. 62 Small molecule anti-vegf drugs, such as sunitinib and sorafenib, have been also evaluated and have shown unclear benefit. Sunitinib failed to show benefit as a monotherapy or in combination with chemotherapy in HER2-negative MBC, 63,64 whereas sorafenib in combination with chemotherapy has shown a modest association with PFS improvement in phase II studies, although results of the phase III trial are currently awaited Growth Factor Signaling Pathway EGFR is another receptor frequently expressed in TNBC and associated with the BL2 subtype. The EGFR-targeting antibody cetuximab has been evaluated in otherwise unspecified TNBC, with a suggestion of either modest benefit 69,70 or improved response rate but not PFS or OS. 71 Ongoing studies for EGFR targets include panitumumab with platinumcontaining chemotherapy (ClinicalTrials.gov identifiers: NCT and NCT ). Other growth factor pathways identified as potential targets include the fibroblast growth factor receptor (FGFR) pathway. Preclinical studies have shown antitumor activity with anti-fgfr treatment, but a clinical trial examining the FGFR inhibitor dovitinib in breast

7 e14 Morikawa and Seidman cancer did not report any responses, although the difference in the proportion of patients experiencing stable disease and a minor reduction in tumor size suggested that patients with FGFR amplification may benefit from this strategy. 72 Recently, DUSP4 loss, a negative regulator of the Ras-ERK pathway, was reported as a potential prognostic biomarker for basal-like breast cancer after neoadjuvant chemotherapy and MEK as a potential target in this setting. 73 Phase I and pharmacodynamics studies with MEK inhibitors are ongoing in patients with TNBC (ClinicalTrials.gov identifiers: NCT , NCT , and NCT ). Cell Motility and EMT Features Characteristics of the M-like subtype include cell motility and EMT features. Steroid receptor coactivator (SRC) is thought to play a role in migration and invasion. 21 Dasatinib, an oral SRC inhibitor, has shown antitumor activity in preclinical TNBC studies. In a phase II trial of dasatinib monotherapy conducted among 44 patients with metastatic TNBC, dasatinib showed modest antitumor activity (overall response rate, 4.7% with median PFS of 8.3 weeks; 95% CI, ). 74 Dasatinib is currently being studied in combination with chemotherapy (weekly paclitaxel) for MBC (ClinicalTrials.gov identifier: NCT ). The LAR Subtype Although its prevalence is higher in ER-positive breast cancer, androgen receptor (AR) is expressed in approximately 30% of TNBC and thought to be another potential target, especially for the LAR subtype. 21,75,76 AR-targeted drugs, such as bicalutamide and enzalutamide, approved for prostate cancer, are currently being evaluated in breast cancer, including TNBC (ClinicalTrials.gov identifier: NCT ). 76 In the study evaluating bicalutamide, 150 mg/d orally in ER/PR-negative breast cancer, 14% were AR-positive with no confirmed complete response or partial response, but with 19% stable disease. 76 In the TNBC subtype analysis, it is interesting to note that LAR subtype cell lines had a PI3K mutation and were sensitive to PI3K inhibition. 21 PI3K/AKT Pathway PTEN loss is commonly noted in basal-like breast cancer and is a negative regulator of the PI3K/AKT pathway. 17 mtor inhibition with everolimus has antitumor activity in a basal-like breast cancer xenograft model. 77 In the TNBC preclinical study, cell lines with PIK3CA mutations and PTEN deficiency were highly sensitivity to dual PI3K/mTOR inhibition. 21 An intact PI3K/AKT/mTOR pathway has been shown to also contribute to DNA damage repair preclinically, and pathway inhibition sensitizes cells to PARP inhibition. 78 PI3K/AKT pathway inhibition is currently being evaluated as monotherapy (ClinicalTrials.gov identifiers: NCT and NCT ) or in combination with other agents (ClinicalTrials.gov identifiers: NCT , NCT , and NCT ). Immunotherapy TNBC has been associated with various characteristics in which immunotherapy would be a rational and attractive mode of therapy. Tumor-infiltrating lymphocytes (TILs) have been associated with a better prognosis among patients with TNBC. 77 An analysis of stromal TILs in TNBC from the ECOG 2197 and 1199 adjuvant therapy trials reported that for every 10% incremental increase in stromal TILs there was an associated 18% reduction in the risk for distant recurrence (P=.04) and 19% reduction in risk of death (P=.01). 80 A higher programmed death-ligand 1 (PD-L1) expression has been reported for TNBC compared with other breast cancer subtypes, and immune checkpoint therapy with a PD-L1 inhibitor is now being evaluated in breast cancer 81 (ClinicalTrials.gov identifiers: NCT and NCT ). Pembrolizumab, an anti PD-1 antibody, was reported to have single-agent activity in the phase I Keynote-012 trial. 82 MUC1 is a tumor antigen highly expressed in early-stage basal-like breast cancer, 83 and an MUC1 peptide vaccine trial is ongoing (ClinicalTrials.gov identifier: NCT ). With success reported in hematologic malignancies, adoptive T-cell therapy is also being evaluated in breast cancer (ClinicalTrials.gov identifier: NCT ). Ideally, molecularly directed studies would be conducted among specific subgroups of TNBC with targetable pathways. Because TNBC represent approximately 20% of all breast cancer, further subsetting leads to smaller source populations for clinical trials. Examples of TNBC and subtype prevalence are shown in Figure 1. In a recent sobering report, a molecular genomic alteration screening process was used for patient accrual into targeted therapeutic trials for breast cancer. Of 423 patients, rational targeted therapy was identified and offered in only

8 e15 Treating Triple-Negative Breast Cancer A B Missing HR /HER2+ 1% 7% 7% 5% 4% Atlanta Pathways LACE Unclassified Basal-like 4% 11% 10% 16% LACE + Pathways Carolina TN 13% 11% 30% HER2+/ER- 8% 13% HR+/HER2+ 7% 9% 11% Luminal B 9% 21% HR+/HER2 56% 68% 73% Luminal A 53% 56% 0% 10% 20% 30% 40% 50% 60% 70% Prevalence C 80% 0% 10% 20% 30% 40% 50% 60% Prevalence UNS 19% LAR 9% MSL 6% M 24% IM 18% BL2 7% BL1 17% 13% of patients. 84 If appropriate biomarkers are used to select the study population (ie, subset of TNBC), the hope is that the strength of the therapeutic effect would be strong enough to detect significant and clinically meaningful antitumor activity, even with a modest number of patients. Therefore, the concurrent development of reliable and validated biomarkers with novel targeted therapeutics is critical. Conclusions Although the amount of molecular genomic information informing potentially targetable pathways is expanding, additional predictive biomarkers and 0% 5% 10% 15% 20% 25% 30% TCGA Primary Breast Cancer (N=163) Figure 1 Subtypes of breast cancer. (A) Prevalence of breast cancer subtypes according to estrogen receptor (ER)/progesterone receptor (PR)/HER2 status from population-based studies. The Atlanta study includes young women (aged years) diagnosed with invasive breast cancer from 1990 through 1992 (N=476). 85 The Pathway study 104 includes women diagnosed with invasive breast cancer from 2005 through 2013 (N=2172) and The Life After Cancer Epidemiology (LACE) study 105 includes women diagnosed with early-stage breast cancer from 1996 through 2000 (N=2135), reported by Sweeney et al. 86 (B) Prevalence of breast cancer subtypes according to intrinsic breast cancer subtype from population-based studies. The Carolina Breast Cancer Study (N=1424) subtype analysis was reported by Millikan et al, 87 and the combined subtype analysis on a subset of patients from each cohort (N=1319) was reported by Sweeney et al. 86 (C) Triple-negative breast cancer (TNBC) subtyping conducted on primary breast cancers from The Cancer Genome Atlas (N=163). Data from Mayer IA, Abramson VG, Lehmann BD, Pietenpol JA. New strategies for triple-negative breast cancer deciphering the heterogeneity. Clin Cancer Res 2014;20: Abbreviations: BL1/2, basal-like type 1/2; ER, estrogen receptor; HR, hormone receptor; IM, immunomodulatory; LAR, luminal androgen receptor; M, mesenchymal; MSL, mesenchymal stem-like; TCGA, The Cancer Genome Atlas; TN, triple-negative; UNS, unstable. associated treatment options have not been incorporated into clinical practice to improve the outcomes in TNBC. Conventional cytotoxic chemotherapy is still standard treatment for TNBC. An incremental benefit of platinum therapy for TNBC is demonstrated by neoadjuvant studies, but the impact of platinums on outcomes other than pcr is uncertain, limiting their incorporation into standard clinical practice. Whether the gain from the incremental improvement in pcr rates will translate to improved relapse-free survival or OS is unclear. The discovery of many candidate targetable pathways may provide more rational treatment options and approaches for TNBC. The efficiency of clinical trial design for tar-

9 e16 Morikawa and Seidman geted therapy evaluation will be enhanced by the use of appropriate biomarkers; however, validation of new biomarkers and their clinical utility remain to be established. Ongoing research in TNBC will hopefully lead to practice-changing findings similar to or greater than those witnessed for ER-positive and HER2-positive breast cancer, and ultimately contribute to improved survival for TNBC; to this end, enrollment of such patients into clinical trials remains a high priority. References 1. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28: Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31: Dreyer G, Vandorpe T, Smeets A, et al. Triple negative breast cancer: clinical characteristics in the different histological subtypes. Breast 2013;22: Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007;13(15 Pt 1): Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366: Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366: Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2- positive advanced breast cancer. N Engl J Med 2012;367: Siziopikou KP, Cobleigh M. The basal subtype of breast carcinomas may represent the group of breast tumors that could benefit from EGFRtargeted therapies. Breast 2007;16: Rakha EA, El-Sayed ME, Green AR, et al. Prognostic markers in triplenegative breast cancer. Cancer 2007;109: Rakha EA, Tan DS, Foulkes WD, et al. Are triple-negative tumours and basal-like breast cancer synonymous? Breast Cancer Res 2007;9:404; author reply, Verlinden L, Vanden Bempt I, Eelen G, et al. The E2F-regulated gene Chk1 is highly expressed in triple-negative estrogen receptor /progesterone receptor /HER-2 breast carcinomas. Cancer Res 2007;67: Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol 2005;23: Tischkowitz M, Brunet JS, Begin LR, et al. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 2007;7: Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406: Carey L, Winer E, Viale G, et al. Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol 2010;7: Rakha E, Ellis I, Reis-Filho J. Are triple-negative and basal-like breast cancer synonymous? Clin Cancer Res 2008;14:618; author reply Comprehensive molecular portraits of human breast tumours. Nature 2012;490: Rody A, Karn T, Liedtke C, et al. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res 2011;13:R Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature 2012;490: Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012;486: Lehmann BD, Bauer JA, Chen X, et al. Identification of human triplenegative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121: Chen X, Li J, Gray WH, et al. TNBCtype: a subtyping tool for triplenegative breast cancer. Cancer Inform 2012;11: Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384: Berry W, Friedland D, Fleagle J, et al. A phase II study of weekly paclitaxel/ estramustine/carboplatin in hormone-refractory prostate cancer. Clin Genitourin Cancer 2006;5: Martin M, Rodriguez-Lescure A, Ruiz A, et al. Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer. Breast Cancer Res Treat 2010;123: De Laurentiis M, Cancello G, D Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a metaanalysis of randomized trials. J Clin Oncol 2008;26: Perez EA, Patel T, Moreno-Aspitia A. Efficacy of ixabepilone in ER/PR/ HER2-negative (triple-negative) breast cancer. Breast Cancer Res Treat 2010;121: Pivot XB, Li RK, Thomas ES, et al. Activity of ixabepilone in oestrogen receptor-negative and oestrogen receptor-progesterone receptor-human epidermal growth factor receptor 2-negative metastatic breast cancer. Eur J Cancer 2009;45: Hortobagyi GN, Gomez HL, Li RK, et al. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines s. Breast Cancer Res Treat 2010;122: Cortes J, O Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011;377: Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines s [abstract]. Cancer Res 2012;72(24 Suppl):Abstract S Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane [published online ahead of print January 20, 2015]. J Clin Oncol. pii: JCO Giordano SB, Jeruss JS, Bethke KP, et al. Neoadjuvant phase II trial with carboplatin and eribulin in triple negative breast cancer patients [abstract]. Cancer Res 2013;73(24 Suppl):Abstract P Luu T, Blanchard S, Yi MJ. Phase I/IB trial of eribulin and everolimus in patients with triple-negative metastatic breast cancer [abstract]. J Clin Oncol 2014;32(Suppl):Abstract TPS Byrski T, Dent R, Blecharz P, et al. Results of a phase II open-label, nonrandomized trial of cisplatin chemotherapy in patients with BRCA1- positive metastatic breast cancer. Breast Cancer Res 2012;14:R Lips EH, Mulder L, Oonk A, et al. Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer 2013;108: Isakoff S, He L, Mayer E, et al. Identification of biomarkers to predict response to single-agent platinum chemotherapy in metastatic triplenegative breast cancer (mtnbc): correlative studies from TBCRC009 [abstract]. J Clin Onc 2014;32(Suppl):Abstract Maisano R, Zavettieri M, Azzarello D, et al. Carboplatin and gemcitabine combination in metastatic triple-negative anthracycline- pretreated breast cancer patients: a phase II study. J Chemother 2011;23: Yardley DA, Burris HA 3rd, Simons L, et al. A phase II trial of gemcitabine/ carboplatin with or without trastuzumab in the first-line treatment of patients with metastatic breast cancer. Clin Breast Cancer 2008;8: Loesch D, Asmar L, McIntyre K, et al. Phase II trial of gemcitabine/ carboplatin (plus trastuzumab in HER2-positive disease) in patients with metastatic breast cancer. Clin Breast Cancer 2008;8: O Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011;364: O Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/

10 e17 Treating Triple-Negative Breast Cancer carboplatin (G/C) in metastatic triple-negative breast cancer. J Clin Oncol 2014;32: Tutt A, Ellis P, Kilbum L, et al. TNT: a randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA 1/2 breast cancer. Presented at the 2014 San Antonio Breast Cancer Symposium; December 9 13, 2014; San Antonio, Texas. Abstract S Petrelli F, Coinu A, Borgonovo K, et al. The value of platinum agents as neoadjuvant chemotherapy in triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res Treat 2014;144: Von Minckwitz G, Schneeweiss A, Salat C, et al. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto) [abstract]. J Clin Oncol 2013;31(Suppl):Abstract Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel followed by dose-dense AC on pathologic complete response (pcr) rates in triple-negative breast cancer (TNBC): CALGB (Alliance). Cancer Res 2013;73(24 Suppl):Abstract S Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, openlabel, multicentre, phase 3 trial. Lancet 2012;379: Piccart-Gebhart M, Holmes A, Baselga J, et al. First results from the phase III ALTTO trial (BIG2-06; NCCTG [Alliance] N063D) comparing one year of anti-her2 therapy with lapaitnib along (L), trastuzumab alone (T), their sequence 9T_>L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC) [abstract]. J Clin Oncol 2014;32(Suppl):Abstract LBA De Summa S, Pinto R, Sambiasi D, et al. BRCAness: a deeper insight into basal-like breast tumors. Ann Oncol 2013;24(Suppl 8):viii13 viii Plummer R. Poly(ADP-ribose) polymerase inhibition: a new direction for BRCA and triple-negative breast cancer? Breast Cancer Res 2011;13: Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparinib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, nonrandomizsed study. Lancet Oncol 2011;12: Tutt A, Robson M, Garber JE, et al. Oral poly(adp-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010;376: Dent RA, Lindeman GJ, Clemons M, et al. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res 2013;15:R Liu J, Fleming G, Tolaney M, et al. A phase I trial of the PARP inhibitor olaparib (AZD2281) in combination with the antiangiogenic cediranib (AZD2171) in recurrent ovarian or triple-negative breast cancer [abstract]. J Clin Oncol 2011;29(Suppl):Abstract Rugo HS, Olopade O, DeMichele A, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: first efficacy results from the I-SPY2 TRIAL [abstract]. Cancer Res 2013;73(24 Suppl):Abstract S Johnson N, Li YC, Walton ZE, et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med 2011;17: Ma CX, Ellis MJ, Petroni GR, et al. A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer. Breast Cancer Res Treat 2013;137: Bhalla K, Rao R, Sharma P, et al. Treatment with histone deacetylase inhibitors creates BRCAness and sensitizes human triple negative breast cancer cells to PARP inhibitors and cisplatin. Cancer Res 2012;72(24 Suppl):Abstract S Rossari JR, Metzger-Filho O, Paesmans M, et al. Bevacizumab and breast cancer: a meta-analysis of first-line phase III studies and a critical reappraisal of available evidence. J Oncol 2012;2012: Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 2013;14: Gerber B, Loibl S, Eidtmann H, et al. Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44). Ann Oncol 2013;24: Miles DW, de Haas SL, Dirix LY, et al. Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer 2013;108: Crown JP, Dieras V, Staroslawska E, et al. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol 2013;31: Barrios CH, Liu MC, Lee SC, et al. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat 2010;121: Baselga J, Segalla JG, Roche H, et al. Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol 2012;30: Schwartzberg LS, Tauer KW, Hermann RC, et al. Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab. Clin Cancer Res 2013;19: Gradishar WJ, Kaklamani V, Sahoo TP, et al. A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer 2013;49: Baselga J, Costa F, Gomez H, et al. A phase 3 trial comparing capecitabine in combination with sorafenib or placebo for treatment of locally advanced or metastatic HER2-negative breast cancer (the RESILIENCE study): study protocol for a randomized controlled trial. Trials 2013;14: Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triplenegative breast cancer. J Clin Oncol 2012;30: Baselga J, Gomez P, Greil R, et al. Randomized phase II study of the antiepidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol 2013;31: O Shaughnessy J, Weckstein D, Vukelja S, et al. Preliminary results of a randomized phase II study of weekly irinotecan/carboplatin with or without cetuximab in patients with metastatic breast cancer [abstract]. Breast Canc Res Treat 2007;106:S Abstract Andre F, Bachelot T, Campone M, et al. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res 2013;19: Balko JM, Cook RS, Vaught DB, et al. Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat Med 2012;18: Finn RS, Bengala C, Ibrahim N, et al. Dasatinib as a single agent in triplenegative breast cancer: results of an open-label phase 2 study. Clin Cancer Res 2011;17: Cochrane DR, Bernales S, Jacobsen BM, et al. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res 2014;16:R Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 2013;19: Yunokawa M, Koizumi F, Kitamura Y, et al. Efficacy of everolimus, a novel mtor inhibitor, against basal-like triple-negative breast cancer cells. Cancer Sci 2012;103: Ibrahim YH, Garcia-Garcia C, Serra V, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov 2012;2: Denkert C. Diagnostic and therapeutic implications of tumor-infiltrating lymphocytes in breast cancer. J Clin Oncol 2013;31: Adams S, Gray R, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes (TILs) in two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199 [abstract]. Cancer Res 2013;73(24 Suppl):Abstract S Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2014;2: Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Presented at the 2014 San Antonio Breast Cancer Symposium; December 9 13, 2014; San Antonio, Texas. Abstract S Siroy A, Abdul-Karim FW, Miedler J, et al. MUC1 is expressed at high frequency in early-stage basal-like triple-negative breast cancer. Hum Pathol 2013;44: Andre F, Bachelot T, Commo F, et al. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol 2014;15:

11 e18 Morikawa and Seidman 85. Lund MJ, Trivers KF, Porter PL, et al. Race and triple negative threats to breast cancer survival: a population-based study in Atlanta, GA. Breast Cancer Res Treat 2009;113: Sweeney C, Bernard PS, Factor RE, et al. Intrinsic subtypes from PAM50 gene expression assay in a population-based breast cancer cohort: differences by age, race, and tumor characteristics. Cancer Epidemiol Biomarkers Prev 2014;23: Millikan RC, Newman B, Tse CK, et al. Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 2008;109: Mayer IA, Abramson VG, Lehmann BD, Pietenpol JA. New strategies for triple-negative breast cancer deciphering the heterogeneity. Clin Cancer Res 2014;20: Kohail H, Shehata S, Mansour O, et al. A phase 2 study of the combination of gemcitabine and cisplatin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines with/without taxanes. Hematol Oncol Stem Cell Ther 2012;5: Wang T, Zhang S, Zeng M, et al. cisplatin combination regimen in patients with anthracycline- -pretreated metastatic breast cancer. Med Oncol 2012;29: Ozkan M, Berk V, Kaplan MA, et al. cisplatin combination chemotherapy in triple negative metastatic breast cancer previously treated with a taxane/anthracycline chemotherapy; multicenter experience. Neoplasma 2012;59: Koshy N, Quispe D, Shi R, et al. Cisplatin-gemcitabine therapy in metastatic breast cancer: Improved outcome in triple negative breast cancer patients compared to non-triple negative patients. Breast 2010;19: Aogi K, Yoshida M, Sagara Y, et al. The efficacy and safety of gemcitabine plus paclitaxel combination first-line therapy for Japanese patients with metastatic breast cancer including triple-negative phenotype. Cancer Chemother Pharmacol 2011;67: Fan Y, Xu BH, Yuan P, et al. Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triplenegative breast cancer. Ann Oncol 2013;24: Goncalves A, Deblock M, Esterni B, et al. Docetaxel first-line therapy in HER2-negative advanced breast cancer: a cohort study in patients with prospectively determined HER2 status. Anticancer Drugs 2009;20: Gilabert M, Bertucci F, Esterni B, et al. Capecitabine after anthracycline exposure in HER2-negative metastatic breast cancer patients: response, survival and prognostic factors. Anticancer Res 2011;31: Aogi K, Rai Y, Ito Y, et al. Efficacy and safety of ixabepilone in taxaneresistant patients with metastatic breast cancer previously treated with anthracyclines: results of a phase II study in Japan. Cancer Chemother Pharmacol 2013;71: Tubiana-Mathieu N, Bougnoux P, Becquart D, et al. All-oral combination of oral vinorelbine and capecitabine as first-line chemotherapy in HER2- negative metastatic breast cancer: an international phase II trial. Br J Cancer 2009;101: Yoshimoto M, Takao S, Hirata M, et al. Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer. Cancer Chemother Pharmacol 2012;70: Tanaka M, Takamatsu Y, Anan K, et al. Oral combination chemotherapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: a phase II study. Anticancer Drugs 2010;21: McIntyre K, O Shaughnessy J, Schwartzberg L, et al. Phase 2 study of eribulin mesylate as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2-negative breast cancer. Breast Cancer Res Treat 2014;146: Yi SY, Ahn JS, Uhm JE, et al. Favorable response to doxorubicin combination chemotherapy does not yield good clinical outcome in patients with metastatic breast cancer with triple-negative phenotype. BMC Cancer 2010;10: Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357: Kwan ML, Ambrosone CB, Lee MM, et al. The Pathways Study: a prospective study of breast cancer survivorship within Kaiser Permanente Northern California. Cancer Causes Control 2008;19: Caan B, Sternfeld B, Gunderson E, et al. Life After Cancer Epidemiology (LACE) study: a cohort of early stage breast cancer survivors (United States). Cancer Causes Control 2005;16: