Are There Any Clinically Relevant Subgroups of Triple-Negative Breast Cancer in 2018? Jack J

Clinical Review

Are There Any Clinically Relevant Subgroups of Triple-Negative Breast Cancer in 2018? Jack J. Chan, Tira J.Y. Tan, and Rebecca A. Dent

National Cancer Centre Singapore and Abstract Duke-National University of Singapore Medical School, Singapore The working immunohistochemical definition of triple-negative breast cancer (TNBC) is ASSOCIATED CONTENT admittedly reductionist and has only limited usefulness for informing oncologists about therapeutic decisions beyond chemotherapy. Early molecular taxonomies of TNBC based See accompanying commentary heavily on gene expression profiling, which is not readily available in the clinic today, do not on page 290 necessarily encompass other molecular targets already incorporated into rationally designed clinical trials. We state that it is possible to delineate five subgroups of TNBC relevant to present-day clinical practice and cover the evidence that lends credence to emerging biomarker-directed treatment strategies for each subgroup.

INTRODUCTION version with distinct gene ontologies and Triple-negative breast cancers (TNBCs) therapeutic sensitivities. Perou5 led a col- lack expression of estrogen, progesterone, laboration to simplify the classification: and human epidermal growth factor receptor TNBCs are stratified as either luminal/ 2 (HER2)/c-erbB2 receptors but otherwise androgen receptor (AR; 20% to 30%) differ in histomolecular phenotypes. They or basal (70% to 80%). The luminal/ have greater and earlier risk of relapse1,2 and androgen receptor type is subdivided shorter survival2 than non-TNBCs. Although into luminal A plus B or HER2-enriched, patients with TNBC have greater sensitivity and the basal type is subdivided into to chemotherapy, those who have early claudin-low/mesenchymal or basal-like. TNBC have unfavorable prognosis com- These models enhance our understanding paredwiththeirhormonereceptor–positive of the molecular underpinning of TNBCs andHER2-positivecounterparts.2 The term and engender clinical research. However, “triple-negative paradox” epitomizes such they leverage sophisticated genomic expres- observations and represents an unmet clin- sion measurement techniques not readily ical need for precision medicine in TNBC. accessible for most oncology practices, and Sadly, a dearth of druggable oncogenic drivers they do not include tractable molecular andapprovednoncytotoxictreatmentsstill targets among those already elucidated plague clinical management of TNBC. within TNBCs.6,7 TNBCs are heterogeneous in their mo- In this review, we propose five clinically lecular drivers and immune traits. Various relevant subgroups of TNBC: defective groups have sought to categorize TNBCs, DNA repair, inflamed phenotype, andro- often with overlap (Fig 1). One such tax- gen receptor–positive, PI3K/AKT/PTEN onomy by Lehmann et al3,4 uses gene ex- altered, and unique antigen expressing. DOI: https://doi.org/10.1200/JOP. pression profiling that encompasses four Here,wesummarizetheevidencethat 18.00034 intrinsic molecular subtypes in a revised supports refining therapy selection by

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TNBC

20% to 30% 70% to 80%

Luminal/androgen Basal receptor

Claudin-low/ Luminal A + B HER2-enriched Basal-like mesenchymal

Basal-like 1, basal-like 2, mesenchymal

Fig 1. Overlaps in the stratification schemas of triple-negative breast cancer (TNBC) from Lehmann et al4 and the collaboration led by Perou.5 Lehmann’s revised intrinsic molecular subtypes are in italics. HER2, human epidermal growth factor receptor 2. using these subsets and suggest an algorithm to test for these Tumors resulting from a deleterious germline mutation in subsets (Fig 2). BRCA1/2 or one of the homologous recombination repair pathway genes have homologous recombination deficiency DEFECTIVE DNA REPAIR SUBGROUP (HRD) and are characterized by genomic instability, increased This subgroup is marked by defective DNA repair, focusing frequency of copy number gains and losses, and heightened on homologous recombination repair of single-strand breaks, sensitivity to damage by DNA crosslinking.9 A subset of a process that requires functional BRCA1 and BRCA2 genes TNBCs has been postulated to be phenotypically and mo- among others. Most breast cancers that occur in BRCA1 lecularly similar to hereditary BRCA1-associated breast mutation carriers are triple-negative and/or basal-like.8 cancers, a concept known as BRCAness.10 Acquired HRD can

TNBC

Germline BRCA1/2 Histologic and HR pathway examination for IHC for androgen gene mutation testing tumor-infiltrating receptor (?) IHC for lymphocytes (?) (Sequencing for targetable cancer (Somatic BRCA (Androgen-related PIK3CA/AKT1/ epithelial mutation testing) (Immune signature gene signature by PTEN alterations) antigens by gene expression genomic diagnostic (HRD score, HRD microarray) assay) scar biomarkers) Tested negative

Defective DNA Unique antigen- Unclassified Androgen receptor– PI3K/AKT/PTEN repair: Inflamed phenotype: expressing: TNBCs: positive: altered: platinums and PARP immunotherapy antibody-drug chemotherapy and androgen blockade AKT inhibitors inhibitors conjugates clinical trials

Fig 2. Proposed algorithm to define five clinically relevant subgroups of triple-negative breast cancer (TNBC) that are matched to their therapeutic sensitivities. Diagnostic tests with less well-established roles are shown in parentheses. TNBCs that tested negative are unclassified and can be treated with cytotoxic chemotherapy or in clinical trials. HR, homologous recombination; HRD, homologous recombination deficiency; IHC, immunohistochemistry; PARP, poly (ADP-ribose) polymerase.

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occur in sporadic breast cancers through epigenetic mecha- Data concerning the predictive value of HRD scar biomarkers nisms such as methylation of BRCA1/2 or somatic mutations to neoadjuvant platinum sensitivity are discordant. In the single- as part of the BRCAness spectrum.10,11 arm phase II PrECOG 0105 study of carboplatin, gemcitabine, and DNA-based companion diagnostic assays have been de- iniparib, high HRD score and HRD identified TNBC tumors, signed on the basis of whole genome tumor loss-of-heterozygosity including BRCA1/2 nonmutated tumors, more likely to respond score,12 telomeric allelic imbalance score,13 and large-scale to platinum-containing therapy.20 In contrast, HRD tumors state transitions score.14 Hypothesizing that BRCAness in responded better than non-HRD tumors in the GepartoSixto trial, sporadic TNBC predicts for sensitivity to DNA-damaging regardless of carboplatin exposure (test of interaction P 5 .77).21 agents, Isakoff et al15 reported that a BRCA-like genomic Shifting to the metastatic setting, the phase II TBCRC009 instability signature, including HRD score, heterozygosity trialthatevaluatedfirst-orsecond-lineplatinummonotherapy score, and large-scale state transitions, in 32 (48%) of 66 demonstrated that individuals with BRCA1/2 mutations were patients with sporadic TNBCs could discriminate responders more likely to respond than wild-type individuals (55% v 20%; from nonresponders. More recently, the use of mutational sig- P 5 .02) but without durability of response or improvement in natures derived from whole genome sequencing (HRDetect) progression-free survival (PFS) or overall survival. Platinum- identified BRCA1/2-deficient tumors with 98.7% sensitivity.16 responsive tumors exhibited higher values for large-scale state Two drug classes adopted in the DNA repair defect–targeted transitions and heterozygosity score assays.15 In the ran- approach are platinums and poly (ADP-ribose) polymerase domized phase III TNT trial (N 5 376), carboplatin was (PARP) inhibitors. compared with docetaxel as first-line treatment. Correlative analyses according to BRCA1/2 mutation status showed that Role of Platinums patients with mutations fared better with carboplatin than with Enthusiasm for using platinums against BRCA-related TNBCs docetaxel treatment, with greater overall response rate (ORR; was founded on their mechanism of inflicting DNA damage 68% v 33%; P 5 .03; test of interaction P 5 .01) and PFS (6.8 v via adducts and DNA crosslinking. A proof-of-principle study 3.1 months; P 5 .03; test of interaction P 5 .03).22 In contrast, reported a striking pathologic complete response (pCR) of HRD score,22 BRCA1 methylation, and BRCA1 silencing23 did 61% to neoadjuvant cisplatin in 107 Polish patients with stage not select for sensitivity to carboplatin over docetaxel (test of I to III germline BRCA1-associated breast cancers, most of interaction P 5 .91, .35, and .07, respectively). which were triple negative.17 The phase II GepartoSixto trial Mounting evidence contributes to the belief that plati- evaluated an investigational neoadjuvant chemotherapy nums are highly active in germline BRCA-mutant TNBC. In backbone (once-per-week paclitaxel with nonpegylated li- the neoadjuvant setting, preoperative platinum-based chemo- posomal doxorubicin for 18 weeks) in patients with either therapy is likely a reasonable choice for patients with locally TNBC or HER2-positive breast cancer. Bevacizumab was advanced disease who are young and fit. However the issue of administered to patients with TNBC, with or without once-per- whether germline BRCA mutation status predicts for better week carboplatin at area under the curve of 1.5 to 2.18 In the response from neoadjuvant platinum therapy remains con- TNBC subgroup, carboplatin improved pCR rate and disease- troversial. Data are lacking on adjuvant platinum; the phase III free survival.18a A hypothesis-generating secondary analysis of NRG-B003 trial(NCT02488967),stratifiedforBRCAmutation the TNBC subpopulation suggested that patients with BRCA1/2 status, is in progress. In the metastatic TNBC setting, platinum wild-type disease benefited from the addition of carboplatin but monotherapy is included in our armamentarium, with data not those with mutations.19 Conversely, CALBG 40603 is another most convincing for first-line platinum for patients with randomized phase II trial in TNBC which showed that pCR rate, germline BRCA mutation. although not event-free survival or overall survival, was increased by incorporating once-every-3-week carboplatin to a standard Role of PARP Inhibitors alkylator-containing chemotherapy backbone.19a The most re- Defining BRCAness led to development of PARP inhibition cent BrighTNess phase III study confirmed that the inclusion of as a therapeutic strategy exploiting synthetic lethality.24 PARP carboplatin to standard neoadjuvant chemotherapy for TNBC enzymes are required for the efficient repair of DNA single- enhanced pCR rate, but no incremental benefit was gained from strand breaks through base excision repair. When BRCA1/2- adding veliparib, a PARP inhibitor, plus carboplatin.19b dependent homologous recombination repair is disabled,

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PARP inhibition leads to the formation of double-stranded INFLAMED PHENOTYPE SUBGROUP breaks that cannot be accurately repaired, chromosomal in- Several lines of evidence support investigation of immuno- stability, cell cycle arrest, and apoptotic cell death.25 therapy in TNBC. We know from microarray signatures that In a proof-of-concept phase II trial, two sequential cohorts immune activation is observed within TNBC.4 Extensive with BRCA-mutated advanced breast cancer were treated analyses have also characterized the immune infiltrate in breast with olaparib at different doses, yielding ORRs of 25% to cancers at a histologic level not restricted to the medullary 54%.26 Results of two phase III registration trials that eval- histotype.29 Early TNBCs are enriched with high levels of uated PARP inhibitors versus chemotherapy of physician’s tumor-infiltrating lymphocytes; increasing levels of tumor- choice in pretreated patients with BRCA-mutant, HER2- infiltrating lymphocytes portend better prognosis.30,31 Stromal negative metastatic breast cancer were reported in 2017. tumor-infiltrating lymphocyte levels may also act as a surrogate Both OlympiAD (olaparib) and EMBRACA (talazoparib) for pre-existing antitumor immunity and may identify meta- reached their primary end point of PFS.27,28 Notably, for the static TNBCs more likely to respond to the anti-programmed prespecified TNBC subgroup in both trials, the PARP inhibitor celldeath-1 (PD-1) monoclonal antibody pembrolizumab.32 was favored over the chemotherapy comparator arm (that Checkpoint inhibitors relieve the immunosuppressive excluded a platinum) in terms of PFS prolongation (hazard ratio tumor microenvironment and promote antitumor immune [HR], 0.43; 95% CI, 0.29 to 0.63 and HR, 0.60; 95% CI, 0.41 to 0.87, responses. In phase I trials, pembrolizumab as well as anti- respectively). The US Food and Drug Administration approved programmed death-ligand 1 (PD-L1) antibodies atezolizumab olaparib for this indication in January 2018. Regulatory ap- and avelumab were well-tolerated and showed efficacy signals proval for talazoparib is likely to follow. These expand our ar- in TNBCs.33-35 PD-L1 expression within stroma and/or tu- mamentarium for treating germline BRCA-mutant metastatic mors had been applied in these trials as either a selection or breast cancer and potentially offer alternative options to spare or stratification criterion with variable impacts. delay the use of cytotoxic drugs. A third trial (BRAVO, The phase II KEYNOTE-086 assesses pembrolizumab in NCT01905592) is underway that is examining niraparib in a advanced TNBC through three cohorts: cohort A, previously similar patient population. treated irrespective of PD-L1 expression; cohort B, treatment- Ongoing efforts focus on molecular diagnostics beyond na¨ıve and PD-L1 positive; and cohort C, pretreated PD-L1 BRCA testing to predict benefit from PARP inhibition and positive. Preliminary results for cohorts A and B were reported extend the reach of PARP inhibitors to a broader population in 2017. Activity may be greater in patients with less heavily through combination strategies. Talazoparib Beyond BRCA pretreated disease: the ORR was 23% in cohort B versus 5% in (TBB) trial (NCT02401347) is a phase II study of talazoparib cohort A (on multivariate analysis; odds ratio, 4.19; 95% CI, in BRCA1/2-negative patients with advanced TNBC and HRD 1.41 to 13.00).32 ORR in cohort A was independent of PD-L1 as assessed by the HRD assay, or advanced HER2-negative expression. Median PFS was numerically similar in both breast cancer with germline or somatic mutation in homol- cohorts: 2.0 and 2.1 months, respectively.36,37 We await the ogous recombination pathway genes. Premised on platinum results of KEYNOTE-119 (NCT02555657), a randomized responsiveness as being enriched for defective DNA repair in phase III study comparing pembrolizumab monotherapy with tumors, DORA (NCT03167619) is a planned randomized investigator’s choice of chemotherapy for second- or third- phase II trial of maintenance olaparib versus olaparib plus line treatment of metastatic TNBC. durvalumab after response to first- or second-line platinum Chemotherapy has been postulated to enhance cancer therapy. This trial will be hypothesis-generating on two immunogenicity and thus be synergistic with immunother- fronts: whether there is a subset of TNBC to which PARP apy.38 In a phase IB trial of atezolizumab co-administered with inhibition is efficacious in lieu of germline BRCA testing and nab-paclitaxel in metastatic TNBC, confirmed ORR in all whether PARP inhibition is synergistic with immune check- patients was 42%. Importantly, the regimen had a tolerable point inhibition. safety profile, and responses were seen regardless of PD-L1 PARP inhibitors are also being investigated in neoadju- expression level.39 The combination of pembrolizumab with vant and adjuvant settings. OlympiA (NCT02032823) is an on- eribulin was also active in patients with metastatic TNBC going randomized placebo-controlled trial examining 12 months irrespective of PD-L1 status in the ENHANCE 1 phase IB/II of olaparib as adjuvant treatment of BRCA-mutant TNBC. trial: ORR was 26%, and median PFS was 4.2 months.40 Such

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promising efficacy signals coupled with manageable safety 19% was observed; median PFS was 12 weeks.44 This trial was have fostered placebo-controlled phase III trials of first-line followed by other single-arm phase II trials. The UCBG 12-1 checkpoint inhibitor plus chemotherapy combinations in trial of abiraterone acetate (a CYP17 inhibitor) in a cohort of advanced or metastatic TNBCs such as KEYNOTE-355 heavily pretreated AR-positive ($ 10%byIHC)TNBCs (NCT02819518) and the IMpassion series (IMpassion130, demonstrated a 6-month CBR of 20% and PFS of 2.8 months.45 NCT02425891; IMpassion131, NCT03125902; IMpassion132, In the MDV3100-11 trial of enzalutamide (a potent AR in- NCT03371017). hibitor), the 24-week CBR was 28%, and the median PFS was PD-L1 blockade plus chemotherapy is also actively stud- 3.3 months in 78 evaluable patients.46 In MDV3100-11, AR ied in the operable TNBC setting. I-SPY2 is an adaptively positivity was defined as . 0% by IHC. Exploratory analysis randomized phase II trial that aims to match experimental demonstrated that an androgen-related gene signature obtained regimens with responding subtypes. Regimens graduate from from the genomic diagnostic assay PREDICT AR was associ- phase II if they have a high Bayesian predictive probability of ated with greater clinical benefit.47 The phase III ENDEAR trial success in a subsequent phase III neoadjuvant trial within the (NCT02929576) of paclitaxel plus enzalutamide versus placebo biomarker signature in which they performed well. Notably, or enzalutamide monotherapy followed by paclitaxel for di- pembrolizumab plus standard neoadjuvant chemotherapy agnostic signature-positive TNBC has been withdrawn. graduated from the I-SPY2 platform, with the Bayesian-estimated New agents in development for AR-positive metastatic pCR rate in TNBC three times that of chemotherapy alone (60% v breastcancer(eitherTNBCorhormonereceptor–positive) are 20%).41 The ongoing KEYNOTE-522 (NCT03036488) trial orteronel (TAK-700), a CYP17 inhibitor (NCT01990209), and randomly assigns patients with locally advanced TNBCs to re- seviteronel (VT-464), a dual CYP17 inhibitor-cum-AR an- ceive neoadjuvant chemotherapy (pembrolizumab followed by tagonist (CLARITY-01, NCT02580448). adjuvant pembrolizumab) or neoadjuvant chemotherapy (placebo followed by adjuvant placebo). PI3K/AKT/PTEN-ALTERED SUBGROUP The field of immunotherapy for TNBCs is nascent. Only a Comprehensive pan-omic analyses of TNBCs found high small proportion of patients with TNBCs benefit from PD-L1 rates of PI3K/AKT/mTOR pathway aberrations.6,7 Activation checkpoint inhibition, with ORR in unselected cohorts on the of the PI3K pathway is mainly mediated at the protein level, order of 5%to 25% and seemingly better whenused as first-line less reliant on PI3KCA mutations (7%) but more commonly therapyratherthanlater-linetherapy.33-37 Furthermore, innate through the loss of negative regulators PTEN (mutation or resistance of pretreated TNBC to immunotherapy may po- loss, 35%) and/or INPP4B (loss, 30%).6 tentially be overcome by combination treatment with AKTinhibitorsseemmorepromisingthanmTORandPI3K chemotherapy.39,40 More research is needed to define a sen- inhibitors in TNBC. In I-SPY2, the AKT inhibitor MK-2206 sitive subset of TNBCs and develop biomarker-driven strat- combinedwithstandardneoadjuvantchemotherapyshowedan egies to render the tumor and its microenvironment more estimatedpCRrateof40%versus22%forchemotherapyalonefor amenable to immunotherapy-based strategies. the hormone receptor–negative, HER2-negative signature.48 Ipatasertib is an oral ATP-competitive AKT inhibitor. AR-POSITIVE SUBGROUP Preclinical studies provided the rationale for its combination The luminal AR subtype of TNBCs expresses AR messenger with paclitaxel. Sensitivity to ipatasertib was associated with RNA in addition to downstream AR targets and coactivators.3,42 high levels of phosphorylated AKT, PTEN protein loss, and There is significant variability in the reported frequency (7% mutations in PTEN or PIK3CA.49 LOTUS is a randomized, to 75%) and prognostic significance of AR expression in double-blind phase II study that investigated the efficacy of TNBCs.43 Preclinical work and early trials suggest that tar- ipatasertib versus placebo plus paclitaxel in treatment-na¨ıve geting AR has a clinical benefit in appropriately selected pa- advanced TNBC (N 5 124). LOTUS met one of its co-primary tients with TNBC. end points, wherein PFS in the intention-to-treat population The first of such trials, TBCRC011, assessed bicalutamide, was modestly but significantly longer with ipatasertib versus an AR inhibitor, in 51 hormone receptor–negative patients placebo (6.2 v 4.9 months; HR, 0.60; P 5 .037). Of note, in a who screened positive for AR (. 10% by immunohisto- prespecified subgroup of patients with PIK3CA/AKT1/PTEN- chemistry [IHC]). A 24-week clinical benefit rate (CBR) of altered tumors defined through next-generation sequencing;

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n 5 42), median PFS was 9.0 months with ipatasertib, longer conjugates (ADCs). ADCs amalgamate the targeted nature than 4.9 months with placebo (HR, 0.44; P 5 .04).50 of monoclonal antibody with a cytotoxic payload for an im- Further research regarding AKT inhibitors for TNBC in- proved therapeutic index. Candidate surface antigens and cludes another randomized placebo-controlled phase II ADCs along with the status of their clinical development are trial (NCT02423603) of first-line paclitaxel with or without presented in Table 1. Encouraging results have been reported AZD5363 and the completed randomized phase II FAIRLANE for ADCs in advanced TNBC. The following paragraphs trial (NCT02301988) assessing the addition of ipatasertib to describe two surface marker-ADC pairings. paclitaxel in the neoadjuvant setting. A phase III trial of Trop-2 is expressed in more than 80% of TNBCs and is ipatasertib in PIK3CA/AKT1/PTEN-altered locally advanced associated with poor prognosis and aggressive disease.53 or metastatic TNBC or hormone receptor–positive, HER2- Sacituzumab govitecan (IMMU-132) consists of humanized negative breast cancer is underway (IPATunity130, NCT03337724). immunoglobulin G antibody against Trop-2 linked to SN-38, an active metabolite of irinotecan. In a first-in-human phase UNIQUE ANTIGEN-EXPRESSING SUBGROUP I/II trial, sacituzumab govitecan had an acceptable safety The characterization of antigens that can be expressed by profile. Promising durable responses (ORR, 30%; median TNBCwithinthecytoplasmicmembraneandserveaspotential duration of response, 8.9 months) and PFS of 6.0 months were therapeutic targets has galvanized interest in antibody-drug seen in a heavily pretreated population of patients with

Table 1. Targetable Cancer Epithelial Antigens in TNBC, Candidate Antibody-Drug Conjugates, and the Status of Drug Development

Status of Drug Development

Antibody-Drug Trial Surface Antigen Conjugate Status Acronym Trial No.

Trop-2 Sacituzumab govitecan Phase I/II trial reported51 NCT01631552 (IMMU-132)

Phase III trial recruiting; FDA breakthrough therapy ASCENT NCT02574455 and fast-track designation

Glycoprotein nonmetastatic B Glembatumumab Phase I/II trial reported51a NCT00704158 (gpNMB) vedotin (CDX-011)

Phase II trial reported52 EMERGE NCT01156753

Phase IIb trial active, not recruiting METRIC NCT01997333

LIV-1 Ladiratuzumab vedotin Interim results of phase I trial reported NCT01969643 (SGN-LIV1A)

Phase Ib/2 trial in combination with pembrolizumab NCT03310957 planned

Mesothelin Anetumab ravtansine Phase I trial (MTD) reported NCT01439152 (BAY94-9343)

Phase Ib multi-indication trial including TNBC recruiting NCT03102320

Carbonic anhydrase 6 (CA6) SAR566658 Phase I trial (MTD) reported NCT01156870

Phase II trial recruiting NCT02984683

Protein tyrosine kinase 7 (PTK7) PF-06647020 Interim results of phase I trial reported NCT02222922

Phase I trial in combination with gedatolisib planned NCT03243331

Abbreviations: FDA, US Food and Drug Administration; MTD, maximum tolerated dose; TNBC, triple-negative breast cancer.

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TNBC.51 The US Food and Drug Administration has accorded setting for enrollment in targeted therapy trials (ARTEMIS, sacituzumab govitecan breakthrough therapy and fast-track NCT02276443). Prospective validation of circulating tumor DNA designation. A confirmatory phase III randomized trial versus may potentially revolutionize treatment planning, disease moni- physician’s choice of treatment in refractory/relapsed meta- toring, and prognostic evaluation of breast cancer. static TNBC is recruiting (ASCENT, NCT02574455). The treatment landscape will transform substantially in Glycoprotein nonmetastatic B (gpNMB) is highly ex- the coming years. Our five TNBC subsets in 2018 may be pressed in TNBC compared with normal tissue and is also an refined or become obsolete in the face of evolving evidence. As adverseprognosticmarker.54 Glembatumumab vedotin (CDX- emerging agents fulfill their potential, we look forward to more 011) is composed of a fully human immunoglobulin G2 robust discovery and validation of predictive biomarkers to monoclonal antibody with high affinity for the extracellular help better select, individualize, and sequence treatments for domain of gpNMB conjugated to the microtubule inhibitor TNBC. monomethyl auristatin E. Activity was noted in metastatic $ Authors’ Disclosures of Potential Conflicts of Interest gpNMB-overexpressing ( 25% by IHC) TNBCs in the phase Disclosures provided by the authors are available with this article at II EMERGE study that compared glembatumumab vedotin jop.ascopubs.org. with the investigator’s choice of chemotherapy. Post hoc anal- Author Contributions ysis showed that the ORR was 18% versus 0% in patients with Conception and design: All authors TNBC and 40% versus 0% in gpNMB-overexpressing TNBC.52 Manuscript writing: All authors Final approval of manuscript: All authors The METRIC trial (NCT01997333), a randomized phase IIb Accountable for all aspects of the work: All authors study that evaluated glembatumumab vedotin versus capeci- Corresponding author: Rebecca A. Dent, MD, National Cancer Centre tabine in gpNMB-overexpressing metastatic TNBC, is underway. Singapore, Division of Medical Oncology, 11 Hospital Dr, Singapore 169610; ORRs in the previously mentioned phase II studies com- e-mail: [email protected]. pare favorably against historical values for late-line cytotoxic References monotherapy in the refractory setting. It is conceivable that 1. Dent R, Trudeau M, Pritchard KI, et al: Triple-negative breast cancer: Clinical more compounds will be efficacious against TNBCs as new features and patterns of recurrence. Clin Cancer Res 13:4429-4434, 2007 cancer epithelial antigens are discovered. Immunostaining to 2. Liedtke C, Mazouni C, Hess KR, et al: Response to neoadjuvant therapy and long- term survival in patients with triple-negative breast cancer. J Clin Oncol 26: screen for targetable tumor antigens may become de rigeur in 1275-1281, 2008 the coming era of personalized medicine for TNBC. 3. Lehmann BD, Bauer JA, Chen X, et al: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750-2767, 2011 DISCUSSION 4. Lehmann BD, Jovanovic´ B, Chen X, et al: Refinement of triple-negative breast In this review, we discussed five clinically applicable sub- cancer molecular subtypes: Implications for neoadjuvant chemotherapy selection. PLoS One 11:e0157368, 2016 populations of TNBC. Our schema is motivated primarily by 5. Perou CM: Triple negative breast cancer: Biology and heterogeneity. Presented at the practicability for the everyday clinic. It is not intended to be a 2016 San Antonio Breast Cancer Symposium, San Antonio, TX, December 6-10, 2016 substitute for holistic, methodologically rigorous approaches 6. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 490:61-70, 2012 to classify this heterogeneous disease. Apart from platinums 7. Shah SP, Roth A, Goya R, et al: The clonal and mutational evolution spectrum of and PARP inhibitors against the defective DNA repair sub- primary triple-negative breast cancers. Nature 486:395-399, 2012 group, novel agents matched to the other four subgroups are 8. Sørlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100: still investigational, and we would not use them at this time to 8418-8423, 2003 treat TNBC outside of clinical trials. 9. Roy R, Chun J, Powell SN: BRCA1 and BRCA2: Different roles in a common Combinatorial strategies involving cytotoxics, targeted pathway of genome protection. Nat Rev Cancer 12:68-78, 2011 10. Turner N, Tutt A, Ashworth A: Hallmarks of ‘BRCAness’ in sporadic cancers. Nat drugs, and/or immunotherapy are now available. Molecular Rev Cancer 4:814-819, 2004 diagnostics are being evaluated as therapeutic decision-making 11. Stefansson OA, Jonasson JG, Johannsson OT, et al: Genomic profiling of breast tu- tools in TNBC. Examples include using high-throughput mours in relation to BRCA abnormalities and phenotypes. Breast Cancer Res 11:R47, 2009 12. Abkevich V, Timms KM, Hennessy BT, et al: Patterns of genomic loss of het- genome analysis to direct maintenance therapy after cyto- erozygosity predict homologous recombination repair defects in epithelial ovarian toxic induction in the metastatic setting (SAFIR02_Breast, cancer. Br J Cancer 107:1776-1782, 2012 NCT02299999) and using gene expression signature with im- 13. Birkbak NJ, Wang ZC, Kim JY, et al: Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2: aging to select chemotherapy nonresponders in the neoadjuvant 366-375, 2012

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Are There Any Clinically Relevant Subgroups of Triple-Negative Breast Cancer in 2018?

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conﬂict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jop/site/ifc/journal-policies.html.

Jack J. Chan Rebecca A. Dent Consulting or Advisory Role: Eisai Honoraria: Genentech, AstraZeneca, Pfizer Research Funding: OncoQuest (I) Consulting or Advisory Role: Roche, Pfizer, Merck, Eisai, AstraZeneca Travel, Accommodations, Expenses: Synthon, Novartis Travel, Accommodations, Expenses: Roche, Pfizer Tira J.Y. Tan Consulting or Advisory Role: Novartis, Pfizer Research Funding: Bayer HealthCare Pharmaceuticals, Novartis Travel, Accommodations, Expenses: Merck Sharp & Dohme, AstraZeneca, Eisai, Pfizer

Volume 14 / Issue 5 / May 2018 n Journal of Oncology Practice Copyright © 2018 by American Society of Clinical Oncology Downloaded from ascopubs.org by Journals Press Access on May 14, 2018 from 162.234.150.177 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.