Treating Triple-Negative Breast Cancer: Where Are We?

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Abstract

Unlike estrogen receptor (ER)–positive and HER2-positive breast can-cer, 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 platinum-salts 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 tar-getable molecular pathways will lead to new therapeutic options for TNBC. Because these patients are likely to be increasingly subcatego-rized using potentially targetable molecular alterations, investigators will need to be mindful of the challenges in designing and conduct-ing clinical trials in smaller subpopulations. The successful incorpora-tion 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)

and rare types, such as adenoid cystic, metaplastic, apo-crine, 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-pos-itive 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, per-tuzumab, 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 bio-logically heterogeneous. Studies examining tumor char-acteristics have found correlations between TNBC and certain molecular genomic features, such as basal cyto-keratin (eg, CK5/6) and epidermal growth factor recep-tor (EGFR) expression, checkpoint kinase (Chk1), p53

alterations, and BRCA1 germline mutations.8–13 TNBC has also been shown to have overlapping features with the basal-like subtype (intrinsic breast cancer classifi-cation),14,15 including a high frequency of poorly differ-entiated 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 From Breast Medicine Service, Memorial Sloan Kettering Cancer

Center, New York, New York.

Submitted April 20, 2014; accepted for publication August 6, 2014. 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 10065. E-mail: seidmana@mskcc.org

Treating Triple-Negative Breast Cancer:

Where Are We?

Aki Morikawa, MD, PhD, and Andrew D. Seidman, MD

C

ontemporary systemic therapy is commonly informed by the classification of breast cancer based solely on hor-monal 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 can-cers that includes common infiltrating ductal carcinoma

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The Cancer Genome Atlas (TCGA) project reporting of breast cancer molecular analysis also showed significant overlap between TNBC and bas-al-like features and similarity to high-grade serous ovarian cancer.19 The TCGA basal-like subanalysis and the primary TNBC analysis identified several in-volved pathways that included PTEN, PI3K/PTEN, cell cycle, and growth factors, and highlighted the heterogeneity of TNBC.19,20 Recently a large meta-analysis of 587 TNBC gene expression profiles from 21 data sets described 7 TNBC subtypes with 6 po-tentially targetable pathways.21 Those subtypes con-sist of 2 basal-like types (BL1 and BL2), immuno-modulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), luminal androgen receptor (LAR), and unstable (UNS). The BL1 subtype was charac-terized 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 con-tained the genes involved in androgen and steroid pathways. In addition, various cell lines were clas-sified into these TNBC subtypes and evaluated for responses to therapy designed to match to the ap-propriate representative subtype.21 A Web-based subtyping tool was also created that allowed normal-ized 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-neg-ative.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 and taxanes have not been consis-tent; 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 progres-sion-free survival (PFS) were noted for the combi-nation 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 per-turbs microtubule dynamics. It demonstrated a sur-vival benefit in heavily pretreated metastatic breast cancer (MBC) compared with the treatment of phy-sician’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 associ-ated 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 ver-sion of this study, the authors did not report any sig-nificant 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. Eribu-lin is also being evaluated in combination with car-boplatin (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

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homologous recombination repair mechanism and are thought to be particularly vulnerable to DNA-damaging 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 mono-therapy (cisplatin or carboplatin) as first- or second- line therapy of metastatic TNBC.37 Of the 87 pa-tients enrolled, 11 were known BRCA mutation car-riers. 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

activ-ity.38–40 Selected examples of platinum regimens in

locally advanced/metastatic TNBC along with non-platinum regimens are shown in Table 1. Notably, gemcitabine/carboplatin was the comparator arm in phase II and III trials in metastatic TNBC evaluat-ing the addition of the investigational drug inipa-rib.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 ran-domized phase III trial is evaluating nab-paclitaxel in combination with gemcitabine or carboplatin ver-sus gemcitabine and carboplatin alone in metastatic TNBC (tnAcity trial; ClinicalTrials.gov identifier: NCT01881230).

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 in-clusion 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, 1.25–1.68; P<.001).44 The GeparSixto study evaluated the addition of carboplatin to paclitaxel and pegylated liposomal doxorubicin (plus bevaci-zumab in TNBC) in the neoadjuvant setting.45 The addition of carboplatin was associated with a signifi-cant 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 carbopla-tin.45 In the CALGB 40603 trial in which carbopla-tin and/or bevacizumab was added to anthracycline/ paclitaxel chemotherapy in 454 patients with TNBC, the breast pCR rate improved with the addition of car-boplatin (from 46% to 60%; P=.018), with more mar-row 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 sur-vival 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 neo-adjuvant setting, did not translate into a significant benefit in disease-free survival or OS when used as ad-juvant therapy.47,48 At the time of this writing, whether

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Table 1 Selected Chemotherapy Regimens With TNBC-Specific Outcomes in the Metastatic Setting

Drugs Study Design Total Patients

Patients With

TNBC Study Population TNBC RR TNBC TTP/PFSa TNBC OSa Reference Docetaxel (doc) vs

carboplatin (carb) Phase III 376 376 No previous taxane or platinum in metastatic setting

31% (carb)

vs 36% (doc) 3.1 (carb) vs 4.5 mo (doc) 12.4 (carb) vs 12.3 mo (doc) Tutt et al,43 2014 Gemcitabine and carboplatin arm (gemcitabine and carboplatin +/– iniparib) Phase III, gemcitabine and carboplatin– only arm

519 519 Prior 0–2 lines 30% 4.1 mo 11.1 mo O’Shaughnessy

et al,42 2011

Gemcitabine and

cisplatin Phase II 144 144 Relapsed after 1 adjuvant/NAC regimen or first-line metastatic regimen with anthracycline 33% 5.1 mo 73% at 1 y Kohail et al,89 2012 Gemcitabine and

cisplatin Phase II 38 38 Second-line, anthracycline and

taxane pretreated

42% 5.4 mo 13.9 mo Wang et al,90

2012 Gemcitabine and

cisplatin Retrospective review 33 33 Prior anthracycline and taxane 27% 5 mo 14 mo Ozkan et al,

91

2012 Gemcitabine and

cisplatin Retrospective review 36 17 Prior taxane 5.3 mo Koshy et al,

92

2010 Gemcitabine and

carboplatin Phase II 31 31 Prior anthracycline and taxane 32% 5.5 mo 11 mo Maisano et al,38 2011

Gemcitabine and

carboplatin Phase II 47 15 First-line 20% Yardley et al,

39

2008 Gemcitabine and

carboplatin Phase II 150 30 Prior taxane or no prior taxane 30% Loesch et al,

40

2008 Gemcitabine and

paclitaxel Phase II 56 14 First-line 35.7% 6 mo Aogi et al,

93

2011 Cisplatin (cis) arm

(cisplatin +/– cetuximab) Randomized phase II 115 115 No more than 1 prior 10% (cis) 1.5 mo (cis) Baselga et al,

70

2013 Cisplatin or carboplatin Phase II 87 87 First- or

second-line 25.6% 2.9 mo 11 mo Isakoff et al,

37

2014 Cisplatin (cis) and

irinotecan (iri) arm (cisplatin, irinotecan +/– cetuximab)

Randomized

phase II 154 72 Prior 0–1 line 30% (cis/iri) 5.1 mo (cis/iri) 12.8 mo (cis/iri) O’Shaughnessy et al,42 2014

Docetaxel/cisplatin vs

docetaxel/capecitabine Randomized phase II 53 53 First-line 63% vs 15.4%;

P=.002 10.9 vs 4.8 mo HR, 0.29; P<.001 32.8 vs 21.5 mo HR, 0.41; P=.027 Fan et al,94 2013 Docetaxel Retrospective

review 162 28 First-line 0% at 2 y 37.8% at 2 y Gonçalves et al,95 2009

Capecitabine Retrospective

review 75 15 Prior anthracycline and taxane 0% 3.6 mo Gilabert et al,

96

2011 Ixabepilone Retrospective

subanalysis 11–42 Prior anthracycline, taxane, capecitabine

6%–55% 1.6–4.6 mo Perez et al,27

2010

Ixabepilone Phase II 52 16 Prior anthracycline

and taxane 6.3% Aogi et al,

97 2013 Ixabepilone + capecitabine vs capecitabine Phase III

subanalysis 752 71 Prior anthracycline and taxane 27% (iri + cis) vs 9% (cis)

4.1 vs 2.1 mo

HR, 0.68; P<.05 Pivot et al,

28

2009 Oral vinorelbine and

capecitabine Phase II 54 9 First-line 22.2% 4 mo Tubiana-Mathieu et

al,98 2009

Metronomic oral cyclophosphamide and capecitabine

Phase II 51 10 No more than

1 prior line and no prior 5-FU, capecitabine, or cyclophosphamide 44.4% 10.7 mo Yoshimoto et al,99 2012 Oral cyclophosphamide

and capecitabine Phase II 45 12 No more than 1 prior line 41.7% 220.5 d Tanaka et al,

100

2010 Eribulin vs capecitabine Phase III

subanalysis 1102 284 Prior anthracycline and taxane 14.4 vs 9.4 mo HR, 0.7;

P<.05

Kaufman et al,31 2012

Eribulin Phase II 56 12 First-line 16.7% 3.4 mo McIntyre et

al,101 2014

Anthracycline and

cyclophosphamide Retrospective review 110 25 First-line 56.5% 8.1 mo 25.4 mo Yi et al,

102 2010 Paclitaxel arm (from paclitaxel +/– bevacizumab) Phase III, paclitaxel-only arm

722 233 First-line 4.6 mo Miller et al,103

2007 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.

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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 reason-able 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 deficien-cy assay is currently being evaluated as a biomark-er in sporadic TNBC, with a primary end point of correlation with pCR (ClinicalTrials.gov identifier: NCT01982448).

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 re-pair and damage checkpoint mechanism, prolifera-tion and growth, angiogenesis, and invasion/metas-tases. Whether disease can successfully be controlled through targeting a single pathway in a subpopula-tion of TNBC (as in the case of some HER2-driven tumors) is unclear. It is likely that a rational com-bination 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 ex-amples of biologic and immunologic agents currently under investigation.

PARP Inhibition

Molecular genomic analyses have identified poten-tially targetable pathways and areas of drug develop-ment for TNBC (Table 2). In addition to the plati-num 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 defi-ciency, it is thought to facilitate “synthetic lethality,” wherein SSB repair deficiency leads to double-strand breaks that cannot be repaired by homologous re-combination.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 gem-citabine and carboplatin.41 Despite the promising

initial data,41 a larger phase III trial did not show sig-nificant benefit for iniparib when added to chemo-therapy.42 Additional studies showed that the drug demonstrated poor PARP inhibition. However, oth-er PARP inhibitors are being evaluated in patients with BRCA-mutated and sporadic TNBC. Olapa-rib 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 (Bayes-ian) 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 inhibi-tion even in BRCA-proficient tumors in preclinical models, and clinical studies of combination therapy with PARP and PI3K inhibitors are underway (Clin-icalTrials.gov identifier: NCT01623349).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 iri-notecan demonstrated limited activity in TNBC (response rate, 4%), preclinical studies have suggest-ed 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 po-tential therapeutic target.21 Anti-VEGF therapy, par-ticularly bevacizumab, has been studied with modest and inconsistent improvements in response rate and PFS but not for OS in the metastatic setting.59 Re-cently the phase III BEATRICE trial examined the addition of bevacizumab to standard adjuvant che-motherapy 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 sig-nificant improvement in breast-only pCR but not for

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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 suni-tinib 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.65–68

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 evalu-ated in otherwise unspecified TNBC, with a sug-gestion of either modest benefit69,70 or improved re-sponse rate but not PFS or OS.71 Ongoing studies for EGFR targets include panitumumab with platinum-containing chemotherapy (ClinicalTrials.gov iden-tifiers: NCT00894504 and NCT01009983). 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 tri-al examining the FGFR inhibitor dovitinib in breast

Table 2 Potentially Targetable Pathways and Selected Examples of Drugs Being

Preferentially Evaluated in TNBCa

Pathway Drugs Mechanism ClinicalTrials.gov

Identifier

DNA repair Veliparib

Olaparib PARP inhibitor PARP inhibitor NCT01251874 NCT01351909 NCT01167192

TP53 mutation/checkpoint UCN-01 Chk1 inhibitor NCT00031681

P276-00 CDK inhibitor NCT01333137

Ganetespib Hsp90 inhibitor NCT01677455

Dinaciclib CDK inhibitor NCT01676753

Growth factor pathway MM-121 Anti-HER3 NCT01451632

Panitumumab Anti-EGFR NCT00894504

Anti-VEGF Cabozantinib Anti-VEGF and anti-met NCT01738438

Sorafenib Multi-TKI NCT01194869

AR pathway Enzalutamide Anti-AR NCT01889238

Notch pathway RO4929097 Gamma-secretase

inhibitor NCT01151449

LDE225 Smoothened antagonist NCT02027376

Apoptosis LCL161 Smac pathway NCT01617668

PI3K/Akt pathway GDC-0941 PI3K inhibitor NCT01918306

BKM120 PI3K inhibitor NCT01629615

Immunotherapy PD-1 antibody Immune checkpoint NCT01928394

MUC1 peptide vaccine Vaccination NCT00986609

Autologous cMet-redirected T cells

Adoptive T-cell therapy NCT01837602

Abbreviations: AR, androgen receptor; CDK, cyclin-dependent kinase; EGFR, epidermal growth factor receptor; PARP, poly(ADP-ribose) polymerase; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

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cancer did not report any responses, although the difference in the proportion of patients experienc-ing 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 poten-tial prognostic biomarker for basal-like breast can-cer after neoadjuvant chemotherapy and MEK as a potential target in this setting.73 Phase I and phar-macodynamics studies with MEK inhibitors are on-going in patients with TNBC (ClinicalTrials.gov identifiers: NCT01467310, NCT01155453, and NCT01363232).

Cell Motility and EMT Features

Characteristics of the M-like subtype include cell motility and EMT features. Steroid receptor coacti-vator (SRC) is thought to play a role in migration and invasion.21 Dasatinib, an oral SRC inhibitor, has shown antitumor activity in preclinical TNBC stud-ies. In a phase II trial of dasatinib monotherapy con-ducted 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, 7.3–15.3).74 Dasatinib is currently being studied in combination with chemotherapy (weekly paclitaxel) for MBC (ClinicalTrials.gov identifier: NCT00820170).

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 sub-type.21,75,76 AR-targeted drugs, such as bicalutamide and enzalutamide, approved for prostate cancer, are currently being evaluated in breast cancer, in-cluding TNBC (ClinicalTrials.gov identifier: NCT 011889238).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 dis-ease.76 In the TNBC subtype analysis, it is interesting to note that LAR subtype cell lines had a PI3K mu-tation 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 xe-nograft model.77 In the TNBC preclinical study, cell lines with PIK3CA mutations and PTEN deficiency were highly sensitivity to dual PI3K/mTOR inhibi-tion.21 An intact PI3K/AKT/mTOR pathway has been shown to also contribute to DNA damage re-pair preclinically, and pathway inhibition sensitizes cells to PARP inhibition.78 PI3K/AKT pathway in-hibition is currently being evaluated as monotherapy (ClinicalTrials.gov identifiers: NCT01629615 and NCT01790932) or in combination with other agents (ClinicalTrials.gov identifiers: NCT01918306, NCT01623349, and NCT01939418).

Immunotherapy

TNBC has been associated with various characteristics in which immunotherapy would be a rational and at-tractive mode of therapy. Tumor-infiltrating lympho-cytes (TILs) have been associated with a better progno-sis among patients with TNBC.77 An analysis of stromal TILs in TNBC from the ECOG 2197 and 1199 adju-vant therapy trials reported that for every 10% incre-mental 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 can-cer81 (ClinicalTrials.gov identifiers: NCT01714739 and NCT01375842). Pembrolizumab, an anti–PD-1 anti-body, 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 (Clini-calTrials.gov identifier: NCT00986609). With success reported in hematologic malignancies, adoptive T-cell therapy is also being evaluated in breast cancer (Clini-calTrials.gov identifier: NCT01837602).

Ideally, molecularly directed studies would be conducted among specific subgroups of TNBC with targetable pathways. Because TNBC represent ap-proximately 20% of all breast cancer, further subset-ting 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 therapeu-tic trials for breast cancer. Of 423 patients, rational targeted therapy was identified and offered in only

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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 ef-fect would be strong enough to detect significant and clinically meaningful antitumor activity, even with a modest number of patients. Therefore, the concur-rent development of reliable and validated biomark-ers with novel targeted therapeutics is critical.

Conclusions

Although the amount of molecular genomic infor-mation informing potentially targetable pathways is expanding, additional predictive biomarkers and

associated treatment options have not been incorpo-rated 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 demon-strated 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 im-provement 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-0% 10% 20% 30% 40% 50% 60% 70% HR+/HER2– TN HR+/HER2+ HR–/HER2+ A Missing 80% 1% 7% 7% 5% 4% 7% 30% 13% 11% 9% 11% 56% 73% 68% Atlanta Pathways LACE 0% 10% 20% 30% IM MSL M LAR C UNS 19% 9% 6% 17% 24% 18% 7% BL1 BL2 5% 15% 25% 0% 10% 20% 30% 40% 50% 60% Luminal A HER2+/ER-Luminal B Basal-like B

Unclassified LACE + Pathways

Carolina 4% 11% 10% 16% 21% 53% 13% 8% 9% 56%

TCGA Primary Breast Cancer (N=163)

Prevalence Prevalence

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 20–54 years) diagnosed with invasive breast cancer from 1990 through 1992 (N=476).85 The Pathway study104 includes women diagnosed with invasive breast cancer from 2005 through 2013 (N=2172) and The Life

After Cancer Epidemiology (LACE) study105 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;20:782–790.

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.

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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.

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References

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