Treating Triple-Negative Breast Cancer: Where Are We?

e8 Review

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

Abstract and rare types, such as adenoid cystic, metaplastic, apo- Unlike estrogen receptor (ER)–positive and HER2-positive breast can- crine, and neuroendocrine carcinoma.3 Nevertheless, cer, triple-negative breast cancer (TNBC) lacks a repertoire of targeted therapies. Hence, chemotherapy is the only available systemic option the clinical utility of this categorization has been robust in current clinical practice. In general, survival of patients with TNBC as a prognostic and predictive biomarker. is worse than that for those with ER-positive and HER2-positive breast Patients with TNBC are more likely to have a cancer, especially for advanced-stage disease. Thus, a great unmet poor prognosis than those with estrogen receptor (ER)/ need exists. Conventional chemotherapeutic agents such as platinum- progesterone receptor (PR)–positive and/or HER2-pos- salts have been examined for specific benefit in TNBC; however, no itive breast cancer.4 This is likely partially attributable one agent has yet been shown to offer a differential incremental benefit in metastatic TNBC. The hope is that ongoing research in tar- to a dearth of novel therapeutic options for TNBC, in getable molecular pathways will lead to new therapeutic options for contrast to the recent expansion of endocrine and anti- TNBC. Because these patients are likely to be increasingly subcatego- HER2 therapies (eg, ado-trastuzumab-emtansine, per- rized using potentially targetable molecular alterations, investigators tuzumab, everolimus with exemestane).5–7 Therefore, will need to be mindful of the challenges in designing and conduct- great interest has been shown in exploring potential ing clinical trials in smaller subpopulations. The successful incorporation of targeted therapies in routine clinical practice for TNBC, which biomarkers (prognostic and predictive) and developing mirrors the success achieved by anti-HER2 and endocrine therapies, is new therapeutic options. This article reviews current awaited. (J Natl Compr Canc Netw 2015;13:(e8–e18) treatment options (“where are we now?”) and ongoing therapeutic research (“where are we going?”) for TNBC. Contemporary systemic therapy is commonly informed by the classification of breast cancer based solely on hor- Heterogeneity of TNBC monal receptor and HER2 status. Triple-negative is a Because the utilitarian definition of TNBC is simply category of exclusion defined by immunohistochemical based on the exclusion of ER/PR/HER2 expression, it is and/or fluorescence in situ hybridization–based criteria, not unexpected that this clinical subtype remains bio- which has undergone modification over time (ASCO/ logically heterogeneous. Studies examining tumor char- CAP guidelines).1,2 Histologically, triple-negative breast acteristics have found correlations between TNBC and cancer (TNBC) is a heterogeneous group of breast can- certain molecular genomic features, such as basal cyto- cers that includes common infiltrating ductal carcinoma keratin (eg, CK5/6) and epidermal growth factor receptor (EGFR) expression, checkpoint kinase (Chk1), p53 From Breast Medicine Service, Memorial Sloan Kettering Cancer alterations, and BRCA1 germline mutations.8–13 TNBC Center, New York, New York. Submitted April 20, 2014; accepted for publication August 6, 2014. has also been shown to have overlapping features with Dr. Morikawa has received research support from the Susan G. the basal-like subtype (intrinsic breast cancer classifi- Komen Foundation and the ASCO Conquer Cancer Foundation 14,15 Bonadonna Fellowship. Dr. Seidman has served as a consultant for cation), including a high frequency of poorly differ- Genentech/Roche and Pfizer and has received payment for lectures, entiated tumors, expression of cytokeratins and EGFR, including service on speaker bureaus from Genentech, Genomic Health, Eisai, and Celgene, and research support from the Susan G. and p53 mutations. Although the basal-like–subtypes Komen Foundation. Correspondence: Andrew D. Seidman, MD, Evelyn H. Lauder Breast are most often triple-negative, they are not equivalent Center, Memorial Sloan Kettering Cancer Center, 300 East 66th groups.16,17 In a gene expression study of 579 TNBCs, Street, New York, NY 10065. E-mail: [email protected] 73% of TNBCs showed basal-like characteristics.18

Treating Triple-Negative Breast Cancer

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

Morikawa and Seidman

homologous recombination repair mechanism and carboplatin showed differential benefit compared are thought to be particularly vulnerable to DNA- with docetaxel (response rate, 68.0% vs 33.3% for damaging agents.35 In addition to the association of patients with BRCA mutations and 28.1% vs 36.6% TNBC with germline and somatic BRCA pathway for those with wild-type BRCA status, respectively; defects,19 some TNBCs, even in the absence of known PFS, 6.8 vs 3.1 months, respectively, in patients with BRCA mutations, have demonstrated homologous BRCA mutations). An assay for homologous repair DNA-repair deficiency and potential vulnerability deficiency used in this study was not predictive of to DNA-damaging agents, such as platinum salts, a differential carboplatin benefit.43 Currently, a ran- similar to that observed in BRCA-mutated tumors.36 domized phase III trial is evaluating nab-paclitaxel In this context, cisplatin and carboplatin have been in combination with gemcitabine or carboplatin ver- evaluated in unselected TNBC. sus gemcitabine and carboplatin alone in metastatic Most recently, the TBCRC009 phase II study TNBC (tnAcity trial; ClinicalTrials.gov identifier: reported a response rate of 25.6% to platinum mono- NCT01881230). therapy (cisplatin or carboplatin) as first- or second- The neoadjuvant use of platinum salts has been line therapy of metastatic TNBC.37 Of the 87 pa- evaluated in BRCA-mutated and unselected TNBC. tients enrolled, 11 were known BRCA mutation car- A recent meta-analysis of 28 neoadjuvant studies riers. The response rate was higher in BRCA mutants showed a pooled pCR rate of 45% (95% CI, 40%– (54.5%) than wild-type BRCA (19.7%), but median 49%) for platinum-containing regimens.44 The in- PFS (3.3 months for BRCA mutants and 2.8 months clusion of a platinum seemed to be associated with for wild-type BRCA) and median OS (13.7 months a higher proportion of pCRs compared with non– for BRCA mutants and 10.9 months for wild-type platinum-containing regimens (response rate, 1.45; BRCA) were not statistically significantly different 95% CI, 1.25–1.68; P<.001).44 The GeparSixto study (P>.05). evaluated the addition of carboplatin to paclitaxel In the metastatic setting, the combination of and pegylated liposomal doxorubicin (plus bevaci- gemcitabine and carboplatin was evaluated in a zumab in TNBC) in the neoadjuvant setting.45 The prospective trial showing modest antitumor activ- addition of carboplatin was associated with a signifi- ity.38–40 Selected examples of platinum regimens in cant increase in pCR for TNBC (37.9% vs 58.7%; locally advanced/metastatic TNBC along with non- P<.05), although a high rate of discontinuation (39%) platinum regimens are shown in Table 1. Notably, was noted for the regimen that included carbopla- gemcitabine/carboplatin was the comparator arm in tin.45 In the CALGB 40603 trial in which carbopla- phase II and III trials in metastatic TNBC evaluat- tin and/or bevacizumab was added to anthracycline/ ing the addition of the investigational drug inipa- paclitaxel chemotherapy in 454 patients with TNBC, rib.41,42 In the gemcitabine/carboplatin control arm, the breast pCR rate improved with the addition of car- the objective response rate was 30% and median boplatin (from 46% to 60%; P=.018), with more mar- PFS and OS were 4.1 and 11.1 months, respectively. row suppression noted in the carboplatin group: grade Notably, no direct comparison of gemcitabine and 3/4 neutropenia (56% vs 20%) and thrombocytopenia platinum versus other chemotherapy combinations (22% vs 4%).46 Thus the available evidence suggests has ever been performed in a prospective randomized that platinum can improve the pCR rate. Patients trial for metastatic TNBC. Therefore, whether this with TNBC who experience a pCR have significantly combination has any particular or unique advantage better survival than those who do not.23 However, an over other nonplatinum standard chemotherapy association between platinum use and relapse-free sur- regimens in TNBC remains unclear. Notably, results vival and OS still needs to be elucidated (ie, does the of the phase III TNT trial comparing single-agent incremental improvement in pCR translate to fewer docetazel and carboplatin in patients with TNBC “downstream” events). The NeoALTTO and ALTTO were recently reported. In unselected patients with trials recently reported that the addition of lapatinib, TNBC, the efficacy of carboplatin monotherapy was which improves pCR from 29.5% to 51.0% in the neo- similar to that of docetaxel, which is regarded as one adjuvant setting, did not translate into a significant of the most active agents against MBC in general. benefit in disease-free survival or OS when used as ad- In the subset of patients with a BRCA mutation, juvant therapy.47,48 At the time of this writing, whether

Treating Triple-Negative Breast Cancer

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

Patients Total With Drugs Study Design Patients TNBC Study Population TNBC RR TNBC TTP/PFSa TNBC OSa Reference Docetaxel (doc) vs Phase III 376 376 No previous taxane 31% (carb) 3.1 (carb) vs 12.4 (carb) Tutt et al,43 carboplatin (carb) or platinum in vs 36% (doc) 4.5 mo (doc) vs 12.3 mo 2014 metastatic setting (doc) Gemcitabine and Phase III, 519 519 Prior 0–2 lines 30% 4.1 mo 11.1 mo O’Shaughnessy carboplatin arm gemcitabine et al,42 2011 (gemcitabine and and carboplatin +/– iniparib) carboplatin– only arm Gemcitabine and Phase II 144 144 Relapsed after 33% 5.1 mo 73% at 1 y Kohail et al,89 cisplatin 1 adjuvant/NAC 2012 regimen or first- line metastatic regimen with anthracycline Gemcitabine and Phase II 38 38 Second-line, 42% 5.4 mo 13.9 mo Wang et al,90 cisplatin anthracycline and 2012 taxane pretreated Gemcitabine and Retrospective 33 33 Prior anthracycline 27% 5 mo 14 mo Ozkan et al,91 cisplatin review and taxane 2012 Gemcitabine and Retrospective 36 17 Prior taxane 5.3 mo Koshy et al,92 cisplatin review 2010 Gemcitabine and Phase II 31 31 Prior anthracycline 32% 5.5 mo 11 mo Maisano et carboplatin and taxane al,38 2011 Gemcitabine and Phase II 47 15 First-line 20% Yardley et al,39 carboplatin 2008 Gemcitabine and Phase II 150 30 Prior taxane or no 30% Loesch et al,40 carboplatin prior taxane 2008 Gemcitabine and Phase II 56 14 First-line 35.7% 6 mo Aogi et al,93 paclitaxel 2011 Cisplatin (cis) arm Randomized 115 115 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 87 87 First- or second- 25.6% 2.9 mo 11 mo Isakoff et al,37 line 2014 Cisplatin (cis) and Randomized 154 72 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,42 2014 (cisplatin, irinotecan +/– cetuximab) Docetaxel/cisplatin vs Randomized 53 53 First-line 63% vs 10.9 vs 4.8 mo 32.8 vs Fan et al,94 docetaxel/capecitabine phase II 15.4%; HR, 0.29; 21.5 mo 2013 P=.002 P<.001 HR, 0.41; P=.027 Docetaxel Retrospective 162 28 First-line 0% at 2 y 37.8% at Gonçalves et review 2 y al,95 2009 Capecitabine Retrospective 75 15 Prior anthracycline 0% 3.6 mo Gilabert et al,96 review and taxane 2011 Ixabepilone Retrospective 11–42 Prior anthracycline, 6%–55% 1.6–4.6 mo Perez et al,27 subanalysis taxane, 2010 capecitabine Ixabepilone Phase II 52 16 Prior anthracycline 6.3% Aogi et al,97 and taxane 2013 Ixabepilone + Phase III 752 71 Prior anthracycline 27% 4.1 vs 2.1 mo Pivot et al,28 capecitabine vs subanalysis and taxane (iri + cis) HR, 0.68; P<.05 2009 capecitabine vs 9% (cis) Oral vinorelbine and Phase II 54 9 First-line 22.2% 4 mo Tubiana- capecitabine Mathieu et al,98 2009 Metronomic oral Phase II 51 10 No more than 44.4% 10.7 mo Yoshimoto et cyclophosphamide and 1 prior line and al,99 2012 capecitabine no prior 5-FU, capecitabine, or cyclophosphamide Oral cyclophosphamide Phase II 45 12 No more than 1 41.7% 220.5 d Tanaka et al,100 and capecitabine prior line 2010 Eribulin vs capecitabine Phase III 1102 284 Prior anthracycline 14.4 vs Kaufman et subanalysis and taxane 9.4 mo al,31 2012 HR, 0.7; P<.05 Eribulin Phase II 56 12 First-line 16.7% 3.4 mo McIntyre et al,101 2014 Anthracycline and Retrospective 110 25 First-line 56.5% 8.1 mo 25.4 mo Yi et al,102 2010 cyclophosphamide review Paclitaxel arm Phase III, 722 233 First-line 4.6 mo Miller et al,103 (from paclitaxel +/– paclitaxel-only 2007 bevacizumab) arm 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. aMedian, unless otherwise noted.

Morikawa and Seidman

platinum agents deserve routine inclusion in regimens initial data,41 a larger phase III trial did not show sig- for TNBC of any stage remains uncertain. nificant benefit for iniparib when added to chemo- Based on a mechanistic rationale and efficacy in therapy.42 Additional studies showed that the drug nonrandomized trials, platinum is perhaps a reason- demonstrated poor PARP inhibition. However, oth- able choice for a subset of patients with TNBC who er PARP inhibitors are being evaluated in patients are more likely to have a DNA-repair deficiency.44 with BRCA-mutated and sporadic TNBC. Olapa- Several studies have reported biomarkers that may rib as a monotherapy did not show any confirmed be helpful in selecting an appropriate population.49 objective response in a phase II study for TNBC,51 For example, a homologous recombination deficien- although modest efficacy was noted in patients with cy assay is currently being evaluated as a biomark- a BRCA mutation.52 It is currently being evaluated er in sporadic TNBC, with a primary end point of in combination with chemotherapy or other biologic correlation with pCR (ClinicalTrials.gov identifier: agents, such as cediranib (anti–vascular endothelial NCT01982448). growth factor [VEGF]).53,54 Veliparib in combination with carboplatin (V+C) was evaluated in the I-SPY-2 neoadjuvant Treating TNBC: Where Are We Going? trial. There was a 92% predictive probability (Bayes- As knowledge of TNBC molecular features expands, ian) that the addition of V+C would be statistically several potential therapeutic targets have emerged, superior to the standard anthracycline/taxane-based which include “the hallmarks of cancer”: DNA re- therapy alone based on the observed pCR rates: pair and damage checkpoint mechanism, prolifera- 52% (28%–67%) for V+C and 26% (9%–43%) in tion and growth, angiogenesis, and invasion/metas- the control arm.55 Finally, perturbation of the PI3K/ tases. Whether disease can successfully be controlled AKT and cell cycle pathways (eg, CDK1 inhibition) through targeting a single pathway in a subpopula- have been shown to sensitize cells to PARP inhibition of TNBC (as in the case of some HER2-driven tion even in BRCA-proficient tumors in preclinical tumors) is unclear. It is likely that a rational com- models, and clinical studies of combination therapy bination of systemic agents will need to be found, with PARP and PI3K inhibitors are underway (Clin- which may include conventional chemotherapy (eg, icalTrials.gov identifier: NCT01623349).56 platinum drug and poly(ADP-ribose) polymerase Other efforts to target DNA damage repair and [PARP] inhibitor). The following are selected ex- cell cycle checkpoint mechanisms include use of amples of biologic and immunologic agents currently histone deactylase (HDAC), heat-shock protein 90 under investigation. (Hsp90), and Chk1 inhibition. Although a phase II study of Chk1 inhibition in combination with iri- PARP Inhibition Molecular genomic analyses have identified poten- notecan demonstrated limited activity in TNBC tially targetable pathways and areas of drug develop- (response rate, 4%), preclinical studies have suggest- ment for TNBC (Table 2). In addition to the plati- ed that these strategies may be particularly relevant in TNBC associated with p53 mutation and BRCA num drugs, PARP inhibitors have been evaluated in 57,58 TNBC to target their BRCA-ness. PARP1 is a DNA mutation and await further clinical evaluation. repair enzyme involved in single-strand break (SSB). Anti-VEGF Therapy When used in a setting of BRCA-related repair defi- VEGF is frequently expressed in TNBC and is a po- ciency, it is thought to facilitate “synthetic lethality,” tential therapeutic target.21 Anti-VEGF therapy, par- wherein SSB repair deficiency leads to double-strand ticularly bevacizumab, has been studied with modest breaks that cannot be repaired by homologous re- and inconsistent improvements in response rate and combination.50 Preclinical and clinical studies have PFS but not for OS in the metastatic setting.59 Re- shown a particular sensitivity to PARP inhibition in cently the phase III BEATRICE trial examined the BRCA-mutated tumors.50 addition of bevacizumab to standard adjuvant che- Initially, the investigational drug iniparib was motherapy in TNBC and failed to show a benefit thought to be a PARP inhibitor and was initially in DFS or OS.60 In CALGB 40603, the addition of evaluated in a randomized phase II study with gem- neoadjuvant bevacizumab was associated with a sig- citabine and carboplatin.41 Despite the promising nificant improvement in breast-only pCR but not for

Treating Triple-Negative Breast Cancer

Table 2 Potentially Targetable Pathways and Selected Examples of Drugs Being Preferentially Evaluated in TNBCa Pathway Drugs Mechanism ClinicalTrials.gov Identifier DNA repair Veliparib PARP inhibitor NCT01251874 NCT01351909 Olaparib PARP inhibitor 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 NCT01151449 inhibitor 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 Adoptive T-cell therapy NCT01837602 T cells

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. aActive on ClinicalTrials.gov as of June 1, 2014. breast and axillary nodes (36% increase with P=.06 in phase II studies, although results of the phase III for breast and axilla).46 On the other hand, the TNBC trial are currently awaited.65–68 subset analysis of GeparQuinto showed improvement Growth Factor Signaling Pathway in pCR (breast and lymph nodes): 27.9% to 39.3% EGFR is another receptor frequently expressed in with addition of bevacizumab (P=.003).61 Again, as TNBC and associated with the BL2 subtype. The with platinums, it is unclear (perhaps unlikely) that EGFR-targeting antibody cetuximab has been evalu- this incremental improvement is clinically meaningful and will translate to an improvement in DFS or OS. ated in otherwise unspecified TNBC, with a sug- 69,70 In addition, biomarker studies (eg, MERIDIAN trial) gestion of either modest benefit or improved re- 71 are being conducted to better select patients who may sponse rate but not PFS or OS. Ongoing studies for derive greater benefit from bevacizumab therapy.62 EGFR targets include panitumumab with platinum- Small molecule anti-VEGF drugs, such as suni- containing chemotherapy (ClinicalTrials.gov iden- tinib and sorafenib, have been also evaluated and tifiers: NCT00894504 and NCT01009983). Other have shown unclear benefit. Sunitinib failed to show growth factor pathways identified as potential targets benefit as a monotherapy or in combination with include the fibroblast growth factor receptor (FGFR) chemotherapy in HER2-negative MBC,63,64 whereas pathway. Preclinical studies have shown antitumor sorafenib in combination with chemotherapy has activity with anti-FGFR treatment, but a clinical tri- shown a modest association with PFS improvement al examining the FGFR inhibitor dovitinib in breast

Morikawa and Seidman

cancer did not report any responses, although the antitumor activity in a basal-like breast cancer xe- difference in the proportion of patients experienc- nograft model.77 In the TNBC preclinical study, cell ing stable disease and a minor reduction in tumor lines with PIK3CA mutations and PTEN deficiency size suggested that patients with FGFR amplification were highly sensitivity to dual PI3K/mTOR inhibi- may benefit from this strategy.72 tion.21 An intact PI3K/AKT/mTOR pathway has Recently, DUSP4 loss, a negative regulator been shown to also contribute to DNA damage re- of the Ras-ERK pathway, was reported as a poten- pair preclinically, and pathway inhibition sensitizes tial prognostic biomarker for basal-like breast can- cells to PARP inhibition.78 PI3K/AKT pathway in- cer after neoadjuvant chemotherapy and MEK as a hibition is currently being evaluated as monotherapy potential target in this setting.73 Phase I and phar- (ClinicalTrials.gov identifiers: NCT01629615 and macodynamics studies with MEK inhibitors are on- NCT01790932) or in combination with other agents going in patients with TNBC (ClinicalTrials.gov (ClinicalTrials.gov identifiers: NCT01918306, identifiers: NCT01467310, NCT01155453, and NCT01623349, and NCT01939418). NCT01363232). Immunotherapy Cell Motility and EMT Features TNBC has been associated with various characteristics Characteristics of the M-like subtype include cell in which immunotherapy would be a rational and at- motility and EMT features. Steroid receptor coacti- tractive mode of therapy. Tumor-infiltrating lympho- vator (SRC) is thought to play a role in migration cytes (TILs) have been associated with a better progno- and invasion.21 Dasatinib, an oral SRC inhibitor, has sis among patients with TNBC.77 An analysis of stromal shown antitumor activity in preclinical TNBC stud- TILs in TNBC from the ECOG 2197 and 1199 adju- ies. In a phase II trial of dasatinib monotherapy con- vant therapy trials reported that for every 10% incre- ducted among 44 patients with metastatic TNBC, mental increase in stromal TILs there was an associated dasatinib showed modest antitumor activity (overall 18% reduction in the risk for distant recurrence (P=.04) response rate, 4.7% with median PFS of 8.3 weeks; and 19% reduction in risk of death (P=.01).80 A higher 95% CI, 7.3–15.3).74 Dasatinib is currently being programmed death-ligand 1 (PD-L1) expression has studied in combination with chemotherapy (weekly been reported for TNBC compared with other breast paclitaxel) for MBC (ClinicalTrials.gov identifier: cancer subtypes, and immune checkpoint therapy with NCT00820170). a PD-L1 inhibitor is now being evaluated in breast can- cer81 (ClinicalTrials.gov identifiers: NCT01714739 and The LAR Subtype NCT01375842). Pembrolizumab, an anti–PD-1 anti- Although its prevalence is higher in ER-positive body, was reported to have single-agent activity in the breast cancer, androgen receptor (AR) is expressed phase I Keynote-012 trial.82 MUC1 is a tumor antigen in approximately 30% of TNBC and thought to be highly expressed in early-stage basal-like breast cancer,83 another potential target, especially for the LAR sub- and an MUC1 peptide vaccine trial is ongoing (Clini- type.21,75,76 AR-targeted drugs, such as bicalutamide calTrials.gov identifier:NCT00986609). With success and enzalutamide, approved for prostate cancer, reported in hematologic malignancies, adoptive T-cell are currently being evaluated in breast cancer, in- therapy is also being evaluated in breast cancer (Clini- cluding TNBC (ClinicalTrials.gov identifier: NCT calTrials.gov identifier: NCT01837602). 011889238).76 In the study evaluating bicalutamide, Ideally, molecularly directed studies would be 150 mg/d orally in ER/PR-negative breast cancer, conducted among specific subgroups of TNBC with 14% were AR-positive with no confirmed complete targetable pathways. Because TNBC represent ap- response or partial response, but with 19% stable dis- 76 proximately 20% of all breast cancer, further subset- ease. In the TNBC subtype analysis, it is interesting ting leads to smaller source populations for clinical to note that LAR subtype cell lines had a PI3K mu- 21 trials. Examples of TNBC and subtype prevalence tation and were sensitive to PI3K inhibition. are shown in Figure 1. In a recent sobering report, PI3K/AKT Pathway a molecular genomic alteration screening process PTEN loss is commonly noted in basal-like breast was used for patient accrual into targeted therapeu- cancer and is a negative regulator of the PI3K/AKT tic trials for breast cancer. Of 423 patients, rational pathway.17 mTOR inhibition with everolimus has targeted therapy was identified and offered in only

Treating Triple-Negative Breast Cancer

A B

Missing 1% Unclassied 4% LACE + Pathways 7% 11% Atlanta Carolina 7% Pathways 5% Basal-like 10% HR–/HER2+ 16% 4% LACE

30% TN 13% HER2+/ER- 13% 11% 8%

7% HR+/HER2+ 9% Luminal B 21% 11% 9%

56% HR+/HER2– 73% Luminal A 53% 68% 56%

0% 10% 20% 30% 40% 50% 60% 70% 80% 0% 10% 20% 30% 40% 50% 60% Prevalence Prevalence C

UNS 19%

LAR 9%

MSL 6%

M 24%

IM 18%

BL2 7%

BL1 17%

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 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. 13% of patients.84 If appropriate biomarkers are used associated treatment options have not been incorpo- to select the study population (ie, subset of TNBC), rated into clinical practice to improve the outcomes the hope is that the strength of the therapeutic ef- in TNBC. Conventional cytotoxic chemotherapy is fect would be strong enough to detect significant and still standard treatment for TNBC. An incremental clinically meaningful antitumor activity, even with benefit of platinum therapy for TNBC is demon- a modest number of patients. Therefore, the concur- strated by neoadjuvant studies, but the impact of rent development of reliable and validated biomark- platinums on outcomes other than pCR is uncertain, ers with novel targeted therapeutics is critical. limiting their incorporation into standard clinical practice. Whether the gain from the incremental improvement in pCR rates will translate to improved Conclusions relapse-free survival or OS is unclear. The discovery Although the amount of molecular genomic infor- of many candidate targetable pathways may provide mation informing potentially targetable pathways more rational treatment options and approaches for is expanding, additional predictive biomarkers and TNBC. The efficiency of clinical trial design for tar-

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geted therapy evaluation will be enhanced by the 21. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple- negative breast cancer subtypes and preclinical models for selection of use of appropriate biomarkers; however, validation targeted therapies. J Clin Invest 2011;121:2750–2767. of new biomarkers and their clinical utility remain 22. Chen X, Li J, Gray WH, et al. TNBCtype: a subtyping tool for triple- negative breast cancer. Cancer Inform 2012;11:147–156. to be established. Ongoing research in TNBC will 23. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and hopefully lead to practice-changing findings similar long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164–172. to or greater than those witnessed for ER-positive 24. Berry W, Friedland D, Fleagle J, et al. A phase II study of weekly paclitaxel/ and HER2-positive breast cancer, and ultimately estramustine/carboplatin in hormone-refractory prostate cancer. Clin Genitourin Cancer 2006;5:131–137. contribute to improved survival for TNBC; to this 25. Martin M, Rodriguez-Lescure A, Ruiz A, et al. Molecular predictors of end, enrollment of such patients into clinical trials efficacy of adjuvant weekly paclitaxel in early breast cancer. Breast Cancer Res Treat 2010;123:149–157. remains a high priority. 26. De Laurentiis M, Cancello G, D’Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta- analysis of randomized trials. J Clin Oncol 2008;26:44–53. 27. Perez EA, Patel T, Moreno-Aspitia A. Efficacy of ixabepilone in ER/PR/ References HER2-negative (triple-negative) breast cancer. Breast Cancer Res Treat 1. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical 2010;121:261–271. Oncology/College of American Pathologists guideline recommendations 28. Pivot XB, Li RK, Thomas ES, et al. Activity of ixabepilone in oestrogen for immunohistochemical testing of estrogen and progesterone receptors in receptor-negative and oestrogen receptor-progesterone receptor-human breast cancer. J Clin Oncol 2010;28:2784–2795. epidermal growth factor receptor 2-negative metastatic breast cancer. Eur J 2. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human Cancer 2009;45:2940–2946. epidermal growth factor receptor 2 testing in breast cancer: American 29. Hortobagyi GN, Gomez HL, Li RK, et al. Analysis of overall survival from Society of Clinical Oncology/College of American Pathologists clinical a phase III study of ixabepilone plus capecitabine versus capecitabine in practice guideline update. J Clin Oncol 2013;31:3997–4013. patients with MBC resistant to anthracyclines and taxanes. Breast Cancer 3. Dreyer G, Vandorpe T, Smeets A, et al. Triple negative breast cancer: Res Treat 2010;122:409–418. clinical characteristics in the different histological subtypes. Breast 30. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy 2013;22:761–766. versus treatment of physician’s choice in patients with metastatic breast 4. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: cancer (EMBRACE): a phase 3 open-label randomised study. Lancet clinical features and patterns of recurrence. Clin Cancer Res 2007;13(15 2011;377:914–923. Pt 1):4429–4434. 31. Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, 5. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus randomized, multicenter study of eribulin mesylate versus capecitabine docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-119. in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes [abstract]. Cancer Res 2012;72(24 6. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal Suppl):Abstract S6-6. hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520–529. 32. Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally 7. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2- advanced or metastatic breast cancer previously treated with an positive advanced breast cancer. N Engl J Med 2012;367:1783-1791. anthracycline and a taxane [published online ahead of print January 20, 8. Siziopikou KP, Cobleigh M. The basal subtype of breast carcinomas may 2015]. J Clin Oncol. pii: JCO.2013.52.4892. represent the group of breast tumors that could benefit from EGFR- Giordano SB, Jeruss JS, Bethke KP, et al. Neoadjuvant phase II trial with targeted therapies. Breast 2007;16:104–107. 33. carboplatin and eribulin in triple negative breast cancer patients [abstract]. 9. Rakha EA, El-Sayed ME, Green AR, et al. Prognostic markers in triple- Cancer Res 2013;73(24 Suppl):Abstract P3-14-14. negative breast cancer. Cancer 2007;109:25–32. 34. Luu T, Blanchard S, Yi MJ. Phase I/IB trial of eribulin and everolimus in 10. Rakha EA, Tan DS, Foulkes WD, et al. Are triple-negative tumours and patients with triple-negative metastatic breast cancer [abstract]. J Clin basal-like breast cancer synonymous? Breast Cancer Res 2007;9:404; Oncol 2014;32(Suppl):Abstract TPS 2637. author reply, 405. 35. Byrski T, Dent R, Blecharz P, et al. Results of a phase II open-label, non- 11. Verlinden L, Vanden Bempt I, Eelen G, et al. The E2F-regulated gene randomized trial of cisplatin chemotherapy in patients with BRCA1- Chk1 is highly expressed in triple-negative estrogen receptor /progesterone positive metastatic breast cancer. Breast Cancer Res 2012;14:R110. receptor /HER-2 breast carcinomas. Cancer Res 2007;67:6574–6581. 36. Lips EH, Mulder L, Oonk A, et al. Triple-negative breast cancer: BRCAness 12. Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and concordance of clinical features with BRCA1-mutation carriers. Br J and molecular forecasting of breast cancer: ready for clinical application? J Cancer 2013;108:2172–2127. Clin Oncol 2005;23:7350–7360. 37. Isakoff S, He L, Mayer E, et al. Identification of biomarkers to predict 13. Tischkowitz M, Brunet JS, Begin LR, et al. Use of immunohistochemical response to single-agent platinum chemotherapy in metastatic triple- markers can refine prognosis in triple negative breast cancer. BMC Cancer negative breast cancer (mTNBC): correlative studies from TBCRC009 2007;7:134. [abstract]. J Clin Onc 2014;32(Suppl):Abstract1020. 14. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast 38. Maisano R, Zavettieri M, Azzarello D, et al. Carboplatin and gemcitabine tumours. Nature 2000;406:747–752. combination in metastatic triple-negative anthracycline- and taxane- 15. Carey L, Winer E, Viale G, et al. Triple-negative breast cancer: disease pretreated breast cancer patients: a phase II study. J Chemother entity or title of convenience? Nat Rev Clin Oncol 2010;7:683–692. 2011;23:40–43. 16. Rakha E, Ellis I, Reis-Filho J. Are triple-negative and basal-like breast 39. Yardley DA, Burris HA 3rd, Simons L, et al. A phase II trial of gemcitabine/ cancer synonymous? Clin Cancer Res 2008;14:618; author reply 619. carboplatin with or without trastuzumab in the first-line treatment of 17. Comprehensive molecular portraits of human breast tumours. Nature patients with metastatic breast cancer. Clin Breast Cancer 2008;8:425– 2012;490:61–70. 431. 18. Rody A, Karn T, Liedtke C, et al. A clinically relevant gene signature 40. Loesch D, Asmar L, McIntyre K, et al. Phase II trial of gemcitabine/ in triple negative and basal-like breast cancer. Breast Cancer Res carboplatin (plus trastuzumab in HER2-positive disease) in patients with 2011;13:R97. metastatic breast cancer. Clin Breast Cancer 2008;8:178–186. 19. Cancer Genome Atlas Network. Comprehensive molecular portraits of 41. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy human breast tumors. Nature 2012;490:61–70. in metastatic triple-negative breast cancer. N Engl J Med 2011;364:205– 20. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution 214. spectrum of primary triple-negative breast cancers. Nature 2012;486:395– 42. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized 399. phase III study of iniparib (BSI-201) in combination with gemcitabine/

Treating Triple-Negative Breast Cancer

carboplatin (G/C) in metastatic triple-negative breast cancer. J Clin Oncol 63. Crown JP, Dieras V, Staroslawska E, et al. Phase III trial of sunitinib in 2014;32:3840–3847. combination with capecitabine versus capecitabine monotherapy for the 43. Tutt A, Ellis P, Kilbum L, et al. TNT: a randomized phase III trial of treatment of patients with pretreated metastatic breast cancer. J Clin carboplatin compared with docetaxel for patients with metastatic or Oncol 2013;31:2870–2878. recurrent locally advanced triple negative or BRCA 1/2 breast cancer. 64. Barrios CH, Liu MC, Lee SC, et al. Phase III randomized trial of sunitinib Presented at the 2014 San Antonio Breast Cancer Symposium; December versus capecitabine in patients with previously treated HER2-negative 9–13, 2014; San Antonio, Texas. Abstract S3-01. advanced breast cancer. Breast Cancer Res Treat 2010;121:121–131. 44. Petrelli F, Coinu A, Borgonovo K, et al. The value of platinum agents as 65. Baselga J, Segalla JG, Roche H, et al. Sorafenib in combination with neoadjuvant chemotherapy in triple-negative breast cancers: a systematic capecitabine: an oral regimen for patients with HER2-negative locally review and meta-analysis. Breast Cancer Res Treat 2014;144:223–232. advanced or metastatic breast cancer. J Clin Oncol 2012;30:1484–1491. 45. Von Minckwitz G, Schneeweiss A, Salat C, et al. A randomized phase 66. Schwartzberg LS, Tauer KW, Hermann RC, et al. Sorafenib or placebo II trial investigating the addition of carboplatin to neoadjuvant therapy with either gemcitabine or capecitabine in patients with HER-2-negative for triple-negative and HER2-positive early breast cancer (GeparSixto) advanced breast cancer that progressed during or after bevacizumab. Clin [abstract]. J Clin Oncol 2013;31(Suppl):Abstract 1004. Cancer Res 2013;19:2745–2754. 46. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of 67. Gradishar WJ, Kaklamani V, Sahoo TP, et al. A double-blind, randomised, carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel placebo-controlled, phase 2b study evaluating sorafenib in combination followed by dose-dense AC on pathologic complete response (pCR) rates with paclitaxel as a first-line therapy in patients with HER2-negative in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). advanced breast cancer. Eur J Cancer 2013;49:312–322. Cancer Res 2013;73(24 Suppl):Abstract S5-01. 68. Baselga J, Costa F, Gomez H, et al. A phase 3 trial comparing capecitabine 47. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for in combination with sorafenIb or placebo for treatment of locally advanced HER2-positive early breast cancer (NeoALTTO): a randomised, open- or metastatIc HER2-negative breast cancer (the RESILIENCE study): label, multicentre, phase 3 trial. Lancet 2012;379:633–640. study protocol for a randomized controlled trial. Trials 2013;14:228. 48. Piccart-Gebhart M, Holmes A, Baselga J, et al. First results from the phase 69. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase III ALTTO trial (BIG2-06; NCCTG [Alliance] N063D) comparing one II study of cetuximab in combination with carboplatin in stage IV triple- year of anti-HER2 therapy with lapaitnib along (L), trastuzumab alone negative breast cancer. J Clin Oncol 2012;30:2615–2623. (T), their sequence 9T_>L), or their combination (T+L) in the adjuvant 70. Baselga J, Gomez P, Greil R, et al. Randomized phase II study of the anti- treatment of HER2-positive early breast cancer (EBC) [abstract]. J Clin epidermal growth factor receptor monoclonal antibody cetuximab with Oncol 2014;32(Suppl):Abstract LBA4. cisplatin versus cisplatin alone in patients with metastatic triple-negative 49. De Summa S, Pinto R, Sambiasi D, et al. BRCAness: a deeper insight into breast cancer. J Clin Oncol 2013;31:2586–2592. basal-like breast tumors. Ann Oncol 2013;24(Suppl 8):viii13–viii21. 71. O’Shaughnessy J, Weckstein D, Vukelja S, et al. Preliminary results of a 50. Plummer R. Poly(ADP-ribose) polymerase inhibition: a new direction for randomized phase II study of weekly irinotecan/carboplatin with or without BRCA and triple-negative breast cancer? Breast Cancer Res 2011;13:218. cetuximab in patients with metastatic breast cancer [abstract]. Breast Canc 51. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparinib in patients with Res Treat 2007;106:S32–33. Abstract 308. recurrent high-grade serous or poorly differentiated ovarian carcinoma 72. Andre F, Bachelot T, Campone M, et al. Targeting FGFR with dovitinib or triple-negative breast cancer: a phase 2, multicentre, open-label, non- (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res randomizsed study. Lancet Oncol 2011;12:852–861. 2013;19:3693–3702. 52. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase 73. Balko JM, Cook RS, Vaught DB, et al. Profiling of residual breast cancers inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and after neoadjuvant chemotherapy identifies DUSP4 deficiency as a advanced breast cancer: a proof-of-concept trial. Lancet 2010;376:235– mechanism of drug resistance. Nat Med 2012;18:1052–1059. 244. 74. Finn RS, Bengala C, Ibrahim N, et al. Dasatinib as a single agent in triple- 53. Dent RA, Lindeman GJ, Clemons M, et al. Phase I trial of the oral PARP negative breast cancer: results of an open-label phase 2 study. Clin Cancer inhibitor olaparib in combination with paclitaxel for first- or second-line Res 2011;17:6905–6913. treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res 2013;15:R88. 75. Cochrane DR, Bernales S, Jacobsen BM, et al. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Liu J, Fleming G, Tolaney M, et al. A phase I trial of the PARP inhibitor 54. Cancer Res 2014;16:R7. olaparib (AZD2281) in combination with the antiangiogenic cediranib (AZD2171) in recurrent ovarian or triple-negative breast cancer [abstract]. 76. Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in J Clin Oncol 2011;29(Suppl):Abstract 5028. patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 2013;19:5505–5512. 55. Rugo HS, Olopade O, DeMichele A, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: first efficacy 77. Yunokawa M, Koizumi F, Kitamura Y, et al. Efficacy of everolimus, a novel results from the I-SPY2 TRIAL [abstract]. Cancer Res 2013;73(24 mTOR inhibitor, against basal-like triple-negative breast cancer cells. Suppl):Abstract S5-02. Cancer Sci 2012;103:1665–1671. 56. Johnson N, Li YC, Walton ZE, et al. Compromised CDK1 activity sensitizes 78. Ibrahim YH, Garcia-Garcia C, Serra V, et al. PI3K inhibition impairs BRCA-proficient cancers to PARP inhibition. Nat Med 2011;17:875–882. BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov 2012;2:1036–1047. 57. 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 79. Denkert C. Diagnostic and therapeutic implications of tumor-infiltrating breast cancer. Breast Cancer Res Treat 2013;137:483–492. lymphocytes in breast cancer. J Clin Oncol 2013;31:836–837. 58. Bhalla K, Rao R, Sharma P, et al. Treatment with histone deacetylase 80. Adams S, Gray R, Demaria S, et al. Prognostic value of tumor-infiltrating inhibitors creates BRCAness and sensitizes human triple negative breast lymphocytes (TILs) in two phase III randomized adjuvant breast cancer cancer cells to PARP inhibitors and cisplatin. Cancer Res 2012;72(24 trials: ECOG 2197 and ECOG 1199 [abstract]. Cancer Res 2013;73(24 Suppl):Abstract S3-7. Suppl):Abstract S1-07. 59. Rossari JR, Metzger-Filho O, Paesmans M, et al. Bevacizumab and 81. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in breast cancer: a meta-analysis of first-line phase III studies and a critical triple-negative breast cancer. Cancer Immunol Res 2014;2:361–370. reappraisal of available evidence. J Oncol 2012;2012:417673. 82. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab 60. Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumab-containing (MK-3475) in patients with advanced triple-negative breast cancer. therapy in triple-negative breast cancer (BEATRICE): primary results of a Presented at the 2014 San Antonio Breast Cancer Symposium; December randomised, phase 3 trial. Lancet Oncol 2013;14:933–942. 9–13, 2014; San Antonio, Texas. Abstract S1-09 61. Gerber B, Loibl S, Eidtmann H, et al. Neoadjuvant bevacizumab and 83. Siroy A, Abdul-Karim FW, Miedler J, et al. MUC1 is expressed at high anthracycline-taxane-based chemotherapy in 678 triple-negative primary frequency in early-stage basal-like triple-negative breast cancer. Hum breast cancers; results from the geparquinto study (GBG 44). Ann Oncol Pathol 2013;44:2159–2166. 2013;24:2978–2984. 84. Andre F, Bachelot T, Commo F, et al. Comparative genomic hybridisation 62. Miles DW, de Haas SL, Dirix LY, et al. Biomarker results from the AVADO array and DNA sequencing to direct treatment of metastatic breast cancer: phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol metastatic breast cancer. Br J Cancer 2013;108:1052–1060. 2014;15:267–274.

Morikawa and Seidman

85. Lund MJ, Trivers KF, Porter PL, et al. Race and triple negative threats to 96. Gilabert M, Bertucci F, Esterni B, et al. Capecitabine after anthracycline breast cancer survival: a population-based study in Atlanta, GA. Breast and taxane exposure in HER2-negative metastatic breast cancer patients: Cancer Res Treat 2009;113:357–370. response, survival and prognostic factors. Anticancer Res 2011;31:1079– 86. Sweeney C, Bernard PS, Factor RE, et al. Intrinsic subtypes from PAM50 1086. gene expression assay in a population-based breast cancer cohort: 97. Aogi K, Rai Y, Ito Y, et al. Efficacy and safety of ixabepilone in taxane- differences by age, race, and tumor characteristics. Cancer Epidemiol resistant patients with metastatic breast cancer previously treated with Biomarkers Prev 2014;23:714–724. anthracyclines: results of a phase II study in Japan. Cancer Chemother 87. Millikan RC, Newman B, Tse CK, et al. Epidemiology of basal-like breast Pharmacol 2013;71:1427–1433. cancer. Breast Cancer Res Treat 2008;109:123–139. 98. Tubiana-Mathieu N, Bougnoux P, Becquart D, et al. All-oral combination 88. Mayer IA, Abramson VG, Lehmann BD, Pietenpol JA. New strategies for of oral vinorelbine and capecitabine as first-line chemotherapy in HER2- triple-negative breast cancer—deciphering the heterogeneity. Clin Cancer negative metastatic breast cancer: an international phase II trial. Br J Res 2014;20:782–790. Cancer 2009;101:232–237. 89. Kohail H, Shehata S, Mansour O, et al. A phase 2 study of the combination 99. Yoshimoto M, Takao S, Hirata M, et al. Metronomic oral combination of gemcitabine and cisplatin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines with/without taxanes. chemotherapy with capecitabine and cyclophosphamide: a phase II Hematol Oncol Stem Cell Ther 2012;5:42–48. study in patients with HER2-negative metastatic breast cancer. Cancer Chemother Pharmacol 2012;70:331–338. 90. Wang T, Zhang S, Zeng M, et al. Gemcitabine and cisplatin combination regimen in patients with anthracycline- and taxane-pretreated metastatic 100. Tanaka M, Takamatsu Y, Anan K, et al. Oral combination chemotherapy breast cancer. Med Oncol 2012;29:56–61. with capecitabine and cyclophosphamide in patients with metastatic 91. Ozkan M, Berk V, Kaplan MA, et al. Gemcitabine and cisplatin breast cancer: a phase II study. Anticancer Drugs 2010;21:453–458. combination chemotherapy in triple negative metastatic breast cancer 101. McIntyre K, O’Shaughnessy J, Schwartzberg L, et al. Phase 2 study of previously treated with a taxane/anthracycline chemotherapy; multicenter eribulin mesylate as first-line therapy for locally recurrent or metastatic experience. Neoplasma 2012;59:38–42. human epidermal growth factor receptor 2-negative breast cancer. Breast 92. Koshy N, Quispe D, Shi R, et al. Cisplatin-gemcitabine therapy in Cancer Res Treat 2014;146:321–328. metastatic breast cancer: Improved outcome in triple negative breast 102. Yi SY, Ahn JS, Uhm JE, et al. Favorable response to doxorubicin cancer patients compared to non-triple negative patients. Breast combination chemotherapy does not yield good clinical outcome in 2010;19:246–248. patients with metastatic breast cancer with triple-negative phenotype. 93. Aogi K, Yoshida M, Sagara Y, et al. The efficacy and safety of gemcitabine BMC Cancer 2010;10:527. plus paclitaxel combination first-line therapy for Japanese patients with 103. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus metastatic breast cancer including triple-negative phenotype. Cancer paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666– Chemother Pharmacol 2011;67:1007–1015. 2676. 94. Fan Y, Xu BH, Yuan P, et al. Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple- 104. Kwan ML, Ambrosone CB, Lee MM, et al. The Pathways Study: a negative breast cancer. Ann Oncol 2013;24:1219–1225. prospective study of breast cancer survivorship within Kaiser Permanente Northern California. Cancer Causes Control 2008;19:1065–1076. 95. Goncalves A, Deblock M, Esterni B, et al. Docetaxel first-line therapy in HER2-negative advanced breast cancer: a cohort study in patients with 105. Caan B, Sternfeld B, Gunderson E, et al. Life After Cancer Epidemiology prospectively determined HER2 status. Anticancer Drugs 2009;20:946– (LACE) study: a cohort of early stage breast cancer survivors (United 952. States). Cancer Causes Control 2005;16:545–556.