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New Targets for Triple-Negative Breast CancerPublished on Cancer Network (http://www.cancernetwork.com)

New Targets for Triple-Negative Breast CancerReview Article [1] | September 15, 2013 | Oncology Journal [2], Breast Cancer [3], Ovarian Cancer[4], Triple-Negative Breast Cancer [5]By Christina I. Herold, MD [6] and Carey K. Anders, MD [7]

With regard to potential research strategies relevant to the treatment of triple-negative breastcancer/basal-like breast cancer, potential targets include PTEN, INPP4B, PIK3CA, KRAS, BRAF, EGFR,FGFR1, FGFR2, IGFR1, KIT, MET, PDGFRA, and the HIF1-α/ARNT pathway. Many of these will bediscussed further in this review article.

Introduction

Triple-negative breast cancer (TNBC) is a unique subset of breast cancer. It is characterized by thelack of the three most commonly targeted receptors in human breast cancer: the estrogen receptor(ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)/neu. Giventhe lack of traditional targets, the propensity of early-stage TNBC to metastasize to visceral sites,and the poor survival associated with advanced TNBC, this subset of breast cancer is appropriatelythe subject of tremendous preclinical and clinical study.[1,2] While TNBC has historically representeda unique group of breast cancer patients, recent studies have continued to dissect the molecularheterogeneity of TNBC into smaller, distinct subsets, including the basal-like and claudin-lowsubtypes, both of which have unique genetic characteristics and treatment responses.[3,4]Moreover, a second molecular classification system of TNBC, also based on gene expressionprofiling, has identified six TNBC subtypes, including two basal-like subtypes (BL1 and BL2), animmunomodulatory subtype, mesenchymal and mesenchymal stem cell–like subtypes, and a luminalandrogen receptor subtype, again with different responses to treatment.[5,6] Finally, The CancerGenome Atlas (TCGA) project, supervised by the National Cancer Institute and the National HumanGenome Research Institute, has also provided tremendous insight into the molecular heterogeneityand driver mutations specific to breast cancer, including TNBC.[7] As we unravel the biologiccomplexity of TNBC and develop rationally designed clinical trials rooted in strong preclinicalevidence, our ability to treat this disease should continue to improve (Table). TABLE

Agents in Clinical Development for Treatment of Triple-Negative Breast Cancer

Characterization of Breast Cancer According to The Cancer Genome Atlas(TCGA)

A recent report from TCGA Research Network has provided new insights into the molecularcharacteristics of TNBC.[7] Breast tumor and germline DNA samples were analyzed comprehensivelyby six technology platforms, including genomic DNA copy number arrays, DNA methylation, exomesequencing, messenger RNA arrays, microRNA sequencing, and reverse-phase protein arrays. To

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briefly summarize this complex body of work with respect to TNBC, TCGA revealed that molecularcharacterizations of TNBC, specifically the basal subtype, included loss of TP53, RB1, and BRCA1function, MYC amplification, and phosphatidylinositol 3-kinase (PIK3) pathway activation.A striking finding of this study was that basal-like breast cancers (BBCs) were found to bemolecularly distinct from the luminal A, luminal B, and HER2 subtypes of breast cancer, but to sharemany characteristics with high-grade serous ovarian cancers (HGSOC), including loss of TP53, RB1,and BRCA1, as well as MYC amplification. This suggests that shared treatment approaches could beconsidered for BBC and HGSOC. Specific to BRCA loss, approximately 20% of patients with BBC hadgermline variants of BRCA1 or BRCA2; a significant proportion of patients with BBC could potentiallybenefit from therapies that target DNA repair, such as poly (ADP-ribose) polymerase (PARP)inhibitors and platinum drugs. Finally, with regard to potential research strategies relevant to thetreatment of TNBC/BBC, potential targets include PTEN, INPP4B, PIK3CA, KRAS, BRAF, EGFR, FGFR1,FGFR2, IGFR1, KIT, MET, PDGFRA, and the HIF1-α/ARNT pathway. Many of these will be discussedfurther in this review article.

Targeting EGFR

Preclinical data have indicated that the epidermal growth factor receptor (EGFR) may be a potentialtarget in the treatment of advanced TNBC. In an attempt to identify molecular targets, Nielsen andcolleagues conducted DNA microarray analysis on a large series of BBC cases.[8] In this series, highexpression of EGFR was noted in approximately 60% of BBCs. Similarly, in a second series of BBCs,Livasy and colleagues showed that the most common immunophenotype for this subtype includedEGFR expression.[9]Despite these encouraging preclinical data, results from clinical trials utilizing cetuximab, amonoclonal antibody that targets EGFR, have shown somewhat limited benefit. A randomized, phaseII trial evaluated the combination of carboplatin and cetuximab in patients with previously treatedadvanced TNBC.[10] Patients (n = 120) were randomized to either cetuximab alone, with carboplatinadded at disease progression, or to the combination of cetuximab and carboplatin from treatmentinitiation. The rate of response (RR) to cetuximab monotherapy was low at 6%. The RR tocombination therapy with carboplatin at progression was 16%, while the RR to the combination atinitiation of treatment was 17%. Overall, combination therapy with carboplatin/cetuximab wasassociated with a short median time to progression (TTP) of 2.1 months and a median overallsurvival (OS) of 10.4 months. Combination therapy was well tolerated, with rash, fatigue, and nauseabeing the most common toxicities.The addition of cetuximab to chemotherapy was evaluated in a second, randomized phase II study inwhich 150 patients with advanced, HER2− breast cancer were randomly assigned to irinotecan andcarboplatin either with cetuximab (ICE) or without cextuximab (IC).[11] In the overall cohort, theobjective RRs (ORRs) for the ICE and IC groups were 33% and 28%, respectively; however, the groupwith TNBC experienced higher ORRs to both ICE and IC—49% and 33%, respectively. The mostsignificant grade 3/4 toxicities reported in the ICE arm were diarrhea (50%) and neutropenia (91%).Baselga and colleagues conducted a phase II trial of cisplatin with or without cetuximab (randomized2:1 to the combination arm) in 173 patients with metastatic TNBC.[12] Patients in the cisplatin armwho experienced disease progression were allowed to cross over to the combination arm. The ORRfor cisplatin/cetuximab therapy was superior to that with cisplatin alone, at 20.0% vs 10.3%. Medianprogression-free survival (PFS) was also higher in the combination arm, at 3.7 months vs 1.5 monthsin the cisplatin monotherapy arm. Grade 3 and 4 adverse events were higher in patients whoreceived combination therapy, and included rash, neutropenia, fatigue, and dyspnea.Finally, selected studies have evaluated the efficacy of small-molecule EGFR inhibitors, includingerlotinib and gefitinib, as single agents in the setting of advanced breast cancer, with disappointingresults; RRs were 3.0% and 0.0%, respectively.[13,14] While there is still a strong preclinicalrationale to treat advanced TNBC with EGFR inhibition with or without chemotherapy, the modestclinical activity observed has dampened the enthusiasm for this therapeutic strategy.

Inhibition of Angiogenesis and VEGF and Its Receptors

In breast cancer and other malignancies, the development of agents that inhibit tumor angiogenesishas been an active area of investigation. Strategies to inhibit tumor vessel growth include the use ofbevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), andtyrosine kinase inhibitors (ie, sunitinib, sorafenib). These targeted agents have been studied incombination both as monotherapies and in combination with cytotoxic chemotherapy. Initial studies

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in the treatment of metastatic breast cancer (MBC) formed the basis for later studies incorporatingbevacizumab into earlier lines of treatment, such as the neoadjuvant setting.

Use of bevacizumab in the metastatic setting

Bevacizumab was initially studied in MBC in a series of studies that ultimately proved to haveinconsistent results. The landmark E2100 study was a phase III randomized trial evaluatingincorporation of bevacizumab into a weekly paclitaxel regimen in the first-line treatment of MBC.[15]In the overall analysis of 722 HER2− patients, bevacizumab demonstrated an approximate doublingof PFS compared with placebo (11.8 months vs 5.9 months, P < .001). Despite these impressiveimprovements in PFS, there was no benefit in OS associated with the use of bevacizumab. Toxicitiesincluding hypertension, proteinuria, headaches, and cerebrovascular ischemia; also, infections weremore common in patients treated with bevacizumab. Based on the magnitude of improvement in PFSseen in E2100, in February 2008 the US Food and Drug Administration (FDA) initially grantedaccelerated approval for the use of bevacizumab as first-line therapy in the treatment of HER2−MBC.Following E2100, two other phase III studies in the first-line treatment of HER2− MBC were reported:the AVastin And DOcetaxel (AVADO) trial and the Regimens in Bevacizumab for Breast Oncology(RIBBON-1) trial.[16,17] AVADO randomized 736 patients to receive docetaxel every 3 weeks with orwithout bevacizumab.[16] In AVADO, bevacizumab was given at two different doses, either 7.5mg/kg or 15 mg/kg, both every 3 weeks. In the combination therapy group, PFS was approximately10 months, compared with 8 months with docetaxel alone; this benefit was restricted to the groupthat received bevacizumab at the higher dose of 15 mg/kg. Although this difference of 2 months wasstatistically significant, the clinical relevance of this benefit, especially in light of the cost associatedwith bevacizumab therapy, is controversial.RIBBON-1 randomized 1,237 patients in a 2:1 ratio to receive chemotherapy with bevacizumab orplacebo.[17] The study design allowed the investigator to choose the chemotherapy backbone fromone of three approved strategies: taxane-based chemotherapy, anthracycline-based chemotherapy,or capecitabine. For each of the bevacizumab-containing combinations, PFS was prolongedcompared with the PFS for placebo, and these improvements were statistically significant. Forexample, both the taxane-based and anthracycline-based bevacizumab combination arms resultedin PFS of 8.6 months vs 5.7 months for placebo (P < .001).In conclusion, the magnitudes of improvement in PFS in AVADO and RIBBON-1 were not comparableto the impressive doubling of PFS observed in E2100. Furthermore, none of the studiesdemonstrated improvement in OS with bevacizumab. For these reasons, as well as because of thecosts and toxicities associated with bevacizumab, the FDA ultimately revoked the initial approval ofbevacizumab for HER2− MBC in November 2011. The use of bevacizumab to treat advanced TNBCshould, therefore, be restricted to the clinical trial setting.

Use of bevacizumab in the adjuvant and neoadjuvant settings

Although the impact of bevacizumab did not appear to improve outcomes for patients withestablished metastatic TNBC, investigators sought to understand whether inhibition of angiogenesiswould prove fruitful in the prevention of metastases. Thus, a series of adjuvant and neoadjuvantstudies incorporating bevacizumab have been conducted. In the adjuvant setting, the BevacizumabAdjuvant Therapy in Triple-Negative Breast Cancer (BEATRICE) trial randomized over 2,500 patientswith TNBC to anthracycline- and/or taxane-based chemotherapy, with or without 1 year ofbevacizumab.[18] At a median follow-up of 32 months, there was no statistically significantimprovement in disease-free survival (DFS) associated with adjuvant bevacizumab; OS outcomeshave yet to be reported. We also await the results of E5103, a randomized, phase III trial evaluatingthe potential benefit of adding bevacizumab to standard anthracycline/taxane-based adjuvantchemotherapy in high-risk breast cancer patients (National Cancer Institute [NCI] ClinicalTrials.govIdentifier: NCT00433511).In the neoadjuvant setting, two randomized phase III trials investigated the addition of bevacizumabto chemotherapy with somewhat contradictory findings. The National Surgical Adjuvant Breast andBowel Project (NSABP) B-40 trial evaluated the addition of bevacizumab toanthracycline/taxane-based preoperative chemotherapy in 1,206 women with HER2− breastcancer.[19] The addition of bevacizumab was associated with an increased pathologic completeresponse (pCR) rate in the breast (34.5% vs 28.2%, P = .02). Improvements in the pCR rate byaddition of bevacizumab to chemotherapy were more pronounced in women with hormonereceptor–positive (HR+) breast cancer (23.2% vs 15.1%, P = .007) than in women with TNBC (51.5%

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vs 47.1%, P = .34). The GeparQuinto trial evaluated the addition of bevacizumab to preoperativeanthracycline/taxane-based chemotherapy in 1,948 women with HER2− breast cancer.[20] The rateof pCR was improved with the addition of bevacizumab to chemotherapy (18.4% vs 14.9% withoutbevacizumab, P = .04). In contrast to results of the NSABP B-40 trial, the benefit of bevacizumab wasmore pronounced in the TNBC group (39.3% vs 27.9%, P = .003) than in the HR+ group (7.7% vs7.8%, P = 1.00). Similar to the metastatic setting, incorporation of bevacizumab into neoadjuvantregimens should remain restricted to the clinical trial setting. Meanwhile, results of the Cancer andLeukemia Group B (CALGB) 40603 trial, which also seeks to determine the benefit of preoperativebevacizumab, are anticipated (NCI ClinicalTrials.gov Identifier: NCT00861705).

Tyrosine kinase inhibitors

Beyond bevacizumab, small-molecule tyrosine kinase inhibitors that target pathways integral toangiogenesis, including vascular endothelial growth factor receptor (VEGFR) and platelet-derivedgrowth factor receptor (PDGFR), have been evaluated as monotherapy in MBC. A phase II single-armstudy evaluated sunitinib in 64 patients previously treated with an anthracycline and a taxane, anddemonstrated a clinical benefit rate (CBR) of 16%.[21] Notable toxicities included fatigue, nausea,diarrhea, mucositis, and anorexia. A phase II single-arm study evaluated sorafenib as first- orsecond-line treatment for MBC in patients who had previously received an anthracycline and/or ataxane.[22] In the first cohort of 20 evaluable patients, sorafenib was well-tolerated, with no grade 4and minimal grade 3 toxicities; however, the trial was stopped early due to limited efficacy. Therewere no partial respones (PRs) or complete responses (CRs), and only two patients (10%) haddocumented stable disease (SD) lasting greater than 6 months.

Conclusions

While preclinical data supported development of angiogenesis-inhibiting agents to treat TNBC acrossall stages, the most noteworthy clinical results have been in the neoadjuvant setting. Continuedfollow-up will be required to help determine whether higher pCR rates seen in response to inhibitionof angiogenesis will translate into longer-term, durable responses.

The Relationship Between TNBC and DNA Repair

Over the past decade, there has been a tremendous amount of research, both in the laboratory andin the clinic, focusing on the relationship between TNBC and DNA repair capacity. Among womenwho develop TNBC, as compared with other subtypes of breast cancer, studies have identified notonly a higher incidence of BRCA1 and BRCA2 germline mutations, with an associated impairment inhomologous recombination, but also shared clinical-pathologic features between sporadic TNBC and BRCA-associated breast cancer. Specifically, among a cohort of 77 patients with TNBC, the incidenceof BRCA1 and BRCA2 mutations was 19.5%; 15.6% (12 patients) harbored a mutation in BRCA1, and3.9% (3 patients) had a mutation in BRCA2. Interestingly, clinical outcomes, including 5-yearrecurrence-free survival (RFS) and OS estimates, were superior for BRCA-mutation carriers comparedwith those with wild-type BRCA status (86.2% vs 51.7%, P = .031; and 73.3% vs 52.8%, P = .225;respectively) suggesting possible inherent sensitivity to chemotherapy among BRCA-mutated breastcancers.[23] Moreover, studies have identified shared clinicopathologic features between TNBC and BRCA-associated breast cancers, including high-grade and ER−/PR−/HER2− status, high rates of TP53 gene mutations, genome-wide aneuploidy, and BBC subtype classification, as well as sensitivityto DNA-damaging agents (ie, platinum salts).[9,24-28] Such observations have led to the expression“the ‘BRCAness’ of TNBC” and to subsequent analysis of DNA-damaging agents and inhibition of DNArepair, namely through PARP, in clinical trials focusing on this unique subset of breast cancer.

PARP inhibition

PARPs are a family of enzymes involved in cellular processes, such as genomic stability, DNA repair,cell cycle progression, and apoptosis.[29,30] PARP-1, the most abundant of the PARP family ofenzymes, is critical for the DNA repair process of base excision repair (BER). Investigatorshypothesized that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependentmechanisms, would result in “synthetic lethality” and augmented cell death—a hypothesis that hasbeen borne out in both the preclinical and clinical arenas.[31-34]Olaparib, an oral PARP inhibitor, has demonstrated efficacy and safety among patientswith BRCA-associated solid tumors, including breast cancer, in early-phase clinical trials.[33,34]Specific to breast cancer, a multicenter phase II sequential cohort study evaluated the safety and

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efficacy of olaparib in 54 patients with advanced BRCA-mutated breast cancer, of whomapproximately 50% had TNBC. The RR at the optimal dose of 400 mg orally twice daily was 44%,while the median PFS was 5.7 months (range, 4.6 to 7.4 months). Treatment was generally welltolerated, with common grade 3 adverse events of fatigue, nausea, and vomiting.[33] A secondinvestigation, Canadian Study 20, evaluated olaparib in patients within four distinct cohorts; (1)ovarian cancer, BRCA wild-type and/or unknown; (2) TNBC, BRCA wild-type and/or unknown; (3)ovarian cancer, BRCA-mutated; and (4) breast cancer, BRCA-mutated, ER− or ER+.[35] Interestingly,responses were seen in all cohorts except patients with sporadic TNBC, illustrating that additionalDNA damage via chemotherapy concurrent with PARP inhibition is likely necessary to yield responsesin sporadic TNBC.Veliparib (ABT-888) is an oral inhibitor of PARP 1 & 2, and it has been studied in early-phase clinicaltrials that included patients with advanced breast cancer.[36] Combination therapy with velipariband the oral alkylating agent temozolomide (TMZ) was studied in 41 patients with heavily pretreatedMBC, of whom 8 harbored a BRCA1/2 mutation and 23 had advanced TNBC.[37] Patients receivedveliparib at a dosage of 40 mg twice daily for 7 days in combination with temozolomide at 150mg/m2 orally daily for 5 days of a 28-day treatment cycle. Across the entire patient population, theCBR was 17% and PFS was 1.9 months. Among BRCA mutation carriers, the CBR was 62.5% andmedian PFS was 5.5 months, illustrating the impact of dysfunctional homologous recombination onpatients’ response to PARP inhibition. Based on these provocative data, an expansion cohort of 21additional BRCA mutation carriers, of whom 7 had TNBC, were treated with TMZ/veliparib, yielding aCBR of 42.9% and a median PFS of approximately 3.5 months, further supporting the assertion thatthe efficacy of this combination therapy is limited to patients with germline BRCA mutations.[38]Iniparib was initially developed as a PARP inhibitor and later found to exert its DNA-damaging effectsvia alterations in metabolism of reactive oxygen species in cancer cells.[39-41] In a randomizedphase II trial, iniparib yielded improvements in ORR, PFS, and OS when combined with gemcitabineand carboplatin chemotherapy in 123 patients with advanced TNBC.[42] Efficacy was not duplicatedin a subsequent and definitive randomized phase III trial in 519 patients with advanced TNBC;however, patients receiving second- and third-line treatment appeared to derive benefit from theaddition of iniparib, with an improvement in median PFS from 2.9 to 4.2 months (hazard ratio [HR] =0.67) and an improvement in median OS from 8.1 to 10.8 months (HR = 0.65).[43] A randomizedphase III study of carboplatin/gemcitabine with or without iniparib in patients with advanced TNBC inthe second- and third-line setting is in development.

Platinum salts

Given the BRCAness of TNBC and the putative sensitivity of these cancer cells to DNA damage, theplatinum salts (carboplatin and cisplatin)—which bind and crosslink DNA, ultimately triggeringapoptosis and programmed cell death—are a rational drug class to study in the treatment of thisdisease. The neoadjuvant setting has provided an interesting platform for studying the effects ofplatinum agents on BRCA-mutant and BRCA–wild-type TNBC. Byrski et al published comparativeeffects of chemotherapy among 102 patients with BRCA1-mutated breast cancer.[44] The overallpCR rate across the entire patient population was 24% (24 of 102 patients); the pCR rate in patientstreated with cisplatin was 83%, compared with a pCR rate of 22% (11 of 51 patients) in those treatedwith anthracycline-containing regimens. Silver et al reported a pCR rate of 21% (6 of 28 patients) inwomen with sporadic TNBC treated with 4 cycles of preoperative cisplatin.[45]More recently, the results of GeparSixto, a randomized phase II trial evaluating the efficacy of theaddition of carboplatin to neoadjuvant therapy in 595 patients with TNBC and HER2+ disease, werereported.[46] All patients received preoperative bevacizumab, and those with HER2+ breast canceralso received preoperative trastuzumab and lapatinib. The impact of adding carboplatin to standardanthracycline/taxane-based preoperative therapy was more profound in those with TNBC (the pCRrate with carboplatin was 58.7% vs 37.9% without carboplatin; P < .05) than in the HER2+ subset ofpatients. (The pCR rate was 33.1% with carboplatin vs 36.3% with no carboplatin; P > .05.) Results ofan ongoing large phase III randomized trial, CALGB 40603 (NCI ClinicalTrials.gov Identifier:NCT00861705), are also anticipated. This study will evaluate the additive effect of preoperativecarboplatin used with standard anthracycline/taxane-containing chemotherapy in patients withearly-stage TNBC. In non–BRCA mutation carriers with TNBC, investigators have also identifiedtissue-based biomarkers, specifically intratumoral quantification of telomeric allelic imbalances,which may prove capable of predicting response to preoperative platinum-based chemotherapy.[47]While platinum salts have often been combined with targeted agents in clinical trials, single-agentplatinum therapy is an accepted treatment for advanced TNBC and is associated with respectable

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RRs. (See, for example, data from the National Comprehensive Cancer Network [NCCN], at www.nccn.org.) Perhaps the most extensive experience with single-agent platinum therapy inadvanced TNBC was reported from the Translational Breast Cancer Research Consortium (TBCRC)009 study.[37] In this study, 86 platinum therapy–naive patients with advanced TNBC received eithercarboplatin to AUC (area under the curve) 6 or cisplatin at a dose of 75 mg/m2, per physician’schoice, in the first or second line of treatment. The overall RR was 30.2% (4 CRs and 22 PRs). Anexploratory subgroup analysis of response rate by platinum type showed an RR of 37% with cisplatintherapy and an RR of 23% with carboplatin. Treatment was well tolerated, with the most commongrade 3/4 toxicities being neutropenia, hypertension, fatigue, anemia, and hyponatremia. Biomarkeranalyses, including BRCA and p63/p73 status, are ongoing to identify responders vs nonresponders.

Targeting Epigenetics, Including Use of HDAC Inhibitors, in TNBC

While driver mutation events are commonly targeted in breast cancer, epigenetic alterations, whichmay include histone hypoacetylation and abnormal DNA methylation in promoter regions ofimportant oncogenes, are also known to promote cancer initiation and progression. Targeting suchepigenetic events via histone deacetylase (HDAC) inhibitors has been explored in the preclinical andclinical treatment of TNBC. In the in vitro setting, treatment of three different TNBC cell lines(MDA-MB-231, MDA-MB-435, and Hs578t) with the HDAC inhibitor Scriptaid not only resulted ingrowth inhibition and increased acetylation of histone tails, but also in a significant increase in levelsof ER mRNA transcript.[48] Moreover, the ability of the HDAC inhibitor vorinostat to overcomeendocrine-therapy resistance in 43 women with hormone therapy–refractory, ER+ breast cancer wasinvestigated in a phase II clinical trial.[49,50] The ORR in patients treated with vorinostat/tamoxifenwas 19% and the CBR was 40%, illustrating the ability of HDAC inhibition to possibly abrogateresistance to endocrine therapy. This strategy of pharmacologically manipulating ER expression viaHDAC inhibition, specifically with panobinostat plus letrozole, is currently being studied in the settingof advanced TNBC (NCI ClinicalTrials.gov Identifier: NCT01105312). Moreover, the addition ofvorinostat to carboplatin and nab-paclitaxel chemotherapy has also been evaluated in theneoadjuvant treatment of TNBC; in a phase II study of 62 women with early-stage TNBC, the pCRrates were similar in patients treated with carboplatin/nab-paclitaxel/vorinostat (27.6%) and in thosetreated with carboplatin/nab-paclitaxel/placebo (26.7%). Biomarker analyses from this study areongoing to help identify which patients with TNBC may derive benefit from addition of HDACinhibition to chemotherapy.[51]

The Role of the Androgen Receptor in TNBC

Given the paucity of effective and nontoxic treatment options for TNBC, the observation that theandrogen receptor (AR) may be expressed in 60% to 80% of human breast cancers has generatedenthusiasm.[52] Furthermore, recent work in gene expression profiling has identified a subset ofER−/PR− tumors with an active hormonally regulated transcriptional program.[53] Theseobservations have led to a phase II single-arm study of the nonsteroidal anti-androgen bicalutamidein patients with ER−/PR− and AR+ MBC as defined by immunohistochemistry (IHC). (See Traina et al,NCI ClinicalTrials.gov Identifier: NCT00468715.) Patient accrual is completed and efficacy results areanticipated.

Targeting the Folate Receptor in TNBC

Another promising new strategy in the treatment of TNBC may be targeting the folate receptor (FR)through the use of vintafolide (EC145), a conjugate of folate linked to the vinca alkaloiddesacetylvinblastine hydrazide. In a phase I study of 32 patients with advanced solid tumors,including breast and ovarian cancer, vintafolide was tolerated, with constipation as the dose-limitingtoxicity.[54] Other toxicities included fatigue, nausea, and vomiting. In this heavily pretreatedpopulation, 7 patients demonstrated SD ranging in duration from 42 to 211 days, and 1 patient withadvanced ovarian cancer demonstrated a PR to therapy.The phase I experience with vintafolide led to the Platinum Resistant Ovarian Cancer Evaluation ofDoxiland EC145 Combination Therapy (PRECEDENT) trial, a randomized phase II study evaluatingpegylated liposomal doxorubicin (PLD) alone or in combination with vintafolide.[55] Compared withpatients treated with PLD alone, patients who received the combination of PLD and vintafolideexperienced an improved PFS, 24 weeks vs 11.7 weeks with just PLD (P = .014). Expression of the FR

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as measured by the EC20 scan, a nuclear medicine scan utilizing technetium-labeled folate, mayprove to be predictive of benefit from vintafolide. Specifically, in PRECEDENT, patients with tumorsthat were 100% EC20+ demonstrated particular benefit in PFS with combination therapy comparedwith PLD alone, with PFS of 24.0 weeks vs 6.6 weeks, respectively (P = .018).These data have fueled enthusiasm for the Study for Women With Platinum Resistant Ovarian CancerEvaluating EC145 in Combination With Doxil (PROCEED; NCI ClinicalTrials.gov Identifier:NCT01170650). This ongoing phase III trial in advanced platinum-resistant ovarian cancer utilizes thesame study design as thePRECEDENT trial. Based on molecular and genomic commonalities between HGSOC and BBC,vintafolide is also being developed in combination with taxane therapy in advanced TNBC.

Promising Preclinical and Early-Phase Investigations in the Treatment ofTNBC

Meaningful improvement in the care of women with advanced TNBC will require a true partnershipbetween physicians, translational investigators, and basic scientists. The clinical care of our patientswith TNBC will continue to drive a wealth of critical questions in need of attention. In parallel,preclinical investigations of TNBC biology will continue to dissect this aggressive, heterogeneousdisease and elucidate novel targets to treat it more optimally. As described above, several studiesthat include the comprehensive analysis of TNBC/BBC per TCGA have identified several additionaltargets that are being investigated in both preclinical work and early-phase clinical trials.

p53 mutations and inhibitors of Chk1

As described in TCGA, BBC exhibits comparatively high rates of p53 mutations (~80%) comparedwith luminal A (12%) and luminal B (32%) breast cancers.[7] Mutations in p53 result in loss of the G1checkpoint in the cell cycle and shifts toward reliance on checkpoint kinase 1 (Chk1) to arrest cells inresponse to DNA damage. In an elegant series of preclinical experiments, Ma and colleagues showedthat Chk1 inhibition potentiated cytotoxity of the DNA-damaging agent irinotecan in two p53-mutantTNBC cell lines that were derived from human tumors and subsequently passaged in xenografttumor models.[56] Interestingly, cytotoxicity in response to combination Chk1 inhibitor/irinotecantherapy was not duplicated in a p53–wild-type TNBC cell line. In vitro results were confirmed in vivo,as Chk1 inhibition plus irinotecan inhibited tumor growth and prolonged survival in a p53-mutantxenograft model but not a p53–wild-type model. Based on these preclinical results, developmentstrategies for Chk1 inhibitors in TNBC will most certainly need to take p53 mutation status intoaccount in order to optimize response and clinical outcomes.

Inhibition of the PI3K/mTOR and MEK pathways

The PIK3CA gene is commonly mutated in TNBC/BBC, with a mutational frequency rate of 9% perTCGA; furthermore, activation of the PI3K pathway at the gene and/or protein level was highest inTNBC/BBC compared witih other subtypes.[7] In contrast to luminal breast cancer, in which PIK3CAgene mutation rates are 30% to 50%, alternate means of PI3K pathway activation in TNBC/BBC mayoccur through loss of either PTEN or INPP4B.[57] Inhibition of the PI3K pathway and of downstreammammalian target of rapamycin (mTOR) has been identified as a promising therapeutic strategy fortreating TNBC. Moreover, compensatory activation of the PI3K pathway has also been shown inresponse to mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibition inresults from in vitro studies of TNBC.[58] Synergy has also been observed with dual inhibition ofPI3K/mTOR and MEK in genetically engineered mouse models (GEMMs) of both basal-like TNBC(C3-Tag GEMM) and claudin-low TNBC (T-11), as evidenced by improved tumor response and relativeimprovement in survival compared with placebo and most single-agent treatments.[59]In addition to preclinical studies, clinical evaluation of inhibitors of PI3K, mTOR, and MEK areunderway, with varying results. In the preoperative setting, Gonzalez-Angulo et al treated 50 womenwith early-stage TNBC by coupling the mTOR inhibitor everolimus with weekly paclitaxel, followed by4 cycles of every-3-weeks preoperative FEC chemotherapy (5-fluorouracil [5-FU], epirubicin,cyclophosphamide).[60] Combination mTOR/taxane therapy yielded numerically higher rates of pCR,although this difference was not statistically significant (30.4% vs 25.9%, P = .76). Biomarker studiesusing tissue specimens obtained from this study are ongoing. More recently, a second studyevaluated the CBR of everolimus plus carboplatin chemotherapy in 25 women with advancedTNBC.[61] This study met its prespecified endpoint, as the CBR was 36% (95% confidence interval[CI], 23%–55%) and median PFS was 3.3 months (95% CI, 2.4 months to 7.7 months).

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Thrombocytopenia was the most common dose-limiting toxicity, requiring carboplatin dose reductionfrom AUC 6 to AUC 4 IV every 3 weeks, with everolimus administered at 5 mg orally daily. Similar tothe neoadjuvant study, real-time biopsies were collected at baseline and following 2 cycles oftherapy to help identify the subset of patients most likely to benefit from mTOR inhibition incombination with standard chemotherapy.To investigate the strategy of MEK inhibition, a preoperative “window of opportunity” studyevaluated reprogramming of the kinome among nine women with operative TNBC.[62] Eligiblepatients were treated with the MEK 1/2 inhibitor trametinib at 1.5 mg to 2.0 mg orally daily for 7days preceding definitive surgery. Fresh tumor was obtained at baseline and from the operativespecimen. Reported treatment toxicities were minimal and included grade 1 nausea, diarrhea, andrash.Results of correlative tissue analysis from this study showed kinome reprogramming in response toMEK 1/2 inhibition similar to that seen in preclinical models. This novel trial design showed that TNBCkinome response differs by subtype (claudin-low and basal-like) and provided evidence that MEKinhibition upregulates “druggable” targets (PDGFR-beta, VEGFR2, the receptor tyrosine kinase Axl).These observations may provide a rationale for combining MEK inhibitors with other relevanttargeted therapies in future studies.Finally, inhibition of the PI3K/mTOR pathway has shown activity in TNBC in preclinical studies,particularly the mesenchymal and mesenchymal stem–like subsets of TNBC.[5] Additional preclinicalstudies have illustrated synergy between PI3K inhibitors and PARP inhibitors in the treatment ofTNBC cell lines and animal models.[63,64] While clinical experience with PI3K inhibition is quitelimited to date, the results of several ongoing clinical studies (SOLTI, NCI ClinicalTrials.gov Identifier:NCT01629615; and LCCC1024, NCI ClinicalTrials.gov Identifier: NCT01300962) should yield valuableinformation regarding the treatment of patients with advanced TNBC.

Conclusions and Future Directions

The landscape of TNBC treatment is changing rapidly. At present and based on guidelines set forthby the National Comprehensive Cancer Network, the mainstay of treatment for TNBC, in both thecurative and metastatic settings, is traditional cytotoxic chemotherapy. Concurrent with unravelingthe biologic underpinnings of TNBC at the preclinical level to identify “druggable” targets, we arecharged as a medical community with continuing to develop novel clinical trials rooted in soundscience and to expand our armamentarium of targeted therapies to treat this aggressive diseasemore effectively. Perhaps our greatest hurdle is the amount of time necessary to carefully translatepromising preclinical findings to the bedside, with the ultimate goal being FDA approval of new drugsthat yield both superior survival and quality of life outcomes for patients with TNBC. In themeantime, we can only continue to stress the importance of clinical trial participation to move theentire field forward and provide patients with TNBC access to promising therapies.Acknowledgements: Research reported in this publication was supported by the National CancerInstitute of the National Institutes of Health, under award number K23CA157728. The content issolely the responsibility of the authors and does not necessarily represent the official views of theNational Institutes of Health. Carey K. Anders, MD, is a Damon Runyon Clinical Investigator,supported in part by the Damon Runyon Cancer Research Foundation (CI-64-12).Financial Disclosure: Dr. Anders receives research funding from BiPar Sanofi-Aventis, Novartis,Bristol Myers-Squibb, Geron, and to-BBB. Dr. Herold has no significant financial interest or otherrelationship with the manufacturers of any products or providers of any service mentioned in thisarticle. References:

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Links:[1] http://www.cancernetwork.com/review-article[2] http://www.cancernetwork.com/oncology-journal[3] http://www.cancernetwork.com/breast-cancer[4] http://www.cancernetwork.com/ovarian-cancer[5] http://www.cancernetwork.com/triple-negative-breast-cancer[6] http://www.cancernetwork.com/authors/christina-i-herold-md[7] http://www.cancernetwork.com/authors/carey-k-anders-md

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