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Developing a new generation of breast cancer clinical gene expression tests Kos, Zuzana; Nielsen, Torsten O Jul 7, 2014

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EDITORIALDeveloping a new generaem/When treatment is based solely on clinicopathological riskfactors, many women with estrogen receptor-positive/women who experienced no distant recurrences at 10 years.Kos and Nielsen Breast Cancer Research 2014, 16:103http://breast-cancer-research.com/content/16/4/103Vancouver, BC V6H 3Z6, CanadaFull list of author information is available at the end of the articletherapy-treated population may identify women notneeding extended endocrine therapy, consistent with the(ER /HER2 ) tumors are overtreated – subjected tomorbidity from cytotoxic chemotherapy for negligiblebenefit. Identifying patients safely treated by endocrine* Correspondence: torsten@mail.ubc.ca2Genetic Pathology Evaluation Centre, Department of Pathology andLaboratory Medicine, University of British Columbia, 2660 Oak Street,ficult to infer, although the 100% metastasis-free survivalin both the fluorouracil–epirubicin–cyclophosphamide andthe fluorouracil–epirubicin–cyclophosphamide–paclitaxelrandomized arms does imply no benefit from addingpaclitaxel.The authors speculate that the EPclin low-risk group(recurrence-free at 10 years) in this 5-year endocrinehuman epidermal growth factor receptor 2-negative+ −As the whole of this cohort received chemotherapy, theclinical utility of this finding (to avoid chemotherapy) is dif-When treatment decisions are based purely onclinicopathological factors, many women with estrogenreceptor-positive/human epidermal growth factorreceptor 2-negative cancers are overtreated. Geneexpression profiles are valuable clinical tools that stratifythe recurrence risk to identify patients most likely tobenefit from adjuvant systemic therapies. Buildingupon greater understanding of tumor biology andmore rigorous approaches to validation (includingindependent studies with a high level of evidence),several second-generation multigene tests have beendeveloped. In the previous issue, Martin and colleaguesreport the third clinical validation study for EndoPredict,a distributed assay to assess risk of distant recurrencesin estrogen receptor-positive/human epidermal growthfactor receptor 2-negative women. The authorsconfirm the assay’s independent prognostic value inpremenopausal and postmenopausal, node-positivewomen treated with contemporary chemotherapyfollowed by endocrine therapy. EndoPredict did not,however, predict benefit from adding paclitaxel.Predictive signatures for selecting among chemotherapyregimens remain an area needing further development.Abstracttherapy alone has driven the development of prognosticgene expression assays.clinical gene expression tZuzana Kos1 and Torsten O Nielsen2*See related research by Martin et al., http://breast-cancer-research.co© Kos and Nielsen; licensee BioMed CenCreative Commons Attribution License (http:/distribution, and reproduction in any mediumDomain Dedication waiver (http://creativecomarticle, unless otherwise stated.2014tion of breast cancerstscontent/16/2/R38In the previous issue, Martin and colleagues describethe third clinical validation of EndoPredict (EP; SividonDiagnostics GmbH, Cologne, Germany) [1], a second-generation multigene test trained to predict distant recur-rence in ER+/HER2− tumors, and by extension the needfor adjuvant chemotherapy. EP was previously validated inprospective–retrospective analyses of endocrine-treatedpostmenopausal ER+/HER2− breast cancer patients intwo clinical trials (ABCSG-6 and ABCSG-8) [2].Genomic-based assays developed from complex, high-dimensional data are susceptible to overfitting. Clinicalvalidation must be performed in entirely independentdatasets using predefined, locked-down classifier algo-rithms and analysis plans. Martin and colleagues’ studyexemplifies the rigor required by Simon and colleagues fora formal prospective–retrospective study to contributeto generating level IB evidence [3]. The authors presentEP validation results in ER+/HER2− patients from theGEICAM/9906 clinical trial of node-positive womentreated with contemporary chemotherapy. The prognosticability of EP remains robust in this higher risk group, iden-tifying a 10-year metastatic rate of 7% in the predefined EPlow-risk group (versus 30% in the high-risk group). Includ-ing tumor size and nodal status as the EPclin classifier iden-tifies a small (13%) but impressively low-risk cohort oftral Ltd. This is an Open Access article distributed under the terms of the/creativecommons.org/licenses/by/4.0), which permits unrestricted use,, provided the original work is properly credited. The Creative Commons Publicmons.org/publicdomain/zero/1.0/) applies to the data made available in thisTable 1 Overview of selected multigene signatures for breast cancerAssay;platform,clinicalmaterialTraining parameter Approval orendorsementAnalyticalvalidity:publishedassayvalidationClinicalvalidity:prognosisvalidationPredicting treatment benefit using randomized clinical trials RandomizedprospectivetrialsTamoxifen Herceptin Chemotherapyversus nochemotherapySpecificagent:anthracyclineSpecific agent:taxaneBreast CancerIndex; RT-PCR, FFPE(central)Outcome (ER+, pN0,endocrine-treated women)MGI component – biology(tumor grade related genes)H:I component – outcome(recurrence in tamoxifen-treated women)No No ATAC [13],Stockholm [17],multiplenonrandomizedtrial cohortsNoa No No No No NoEndoPredict;RT-PCR, FFPE(distributed)Outcome (distantrecurrence in endocrine-treated ER+/HER2− pN0/pN+women)CE Mark Yes [18,19] ABCSG6 [2],ABCSG8 [2],GEICAM/9906[1]No No No No GEICAM/9906 [1](failed to predictbenefit)NoIHC4; IHC,FFPE(distributed)Outcome (distantrecurrence in ER+endocrine-treated women)No No ATAC [14],TEAM [20]No No No No No NoMammaPrint;microarray,fresh andFFPE (central)Outcome (5-year metastasisrate in pN0 women)FDA (fresh): risk fordistant metastasis,<61 years, stage I andII, tumor ≤5 cm andnode-negativeNo Multiplenonrandomizedtrial cohortsincludingRASTERNo No No No No MINDACTprognosisvalidation (toreport 2015)Mammostrat;IHC, FFPE(central)Outcome (unselectedcohort of breast cancerpatients)No No NSABP-B14,NSABP-B20 [15]multiple non-randomized trialcohortsNo No NSABP-B20(±CMF) [15] (allwomen benefit– high riskbenefit themost)No No NoOncotype DX;RT-PCR, FFPE(central)Outcome (recurrence inmainly tamoxifen-treatedER+, pN0 women)NCCN, ASCO, St.Gallen (role foridentifying womenthat may benefit fromchemotherapy)Yes [21] NSABP-B14 [9],NSABP-B28 [22],SWOG8814 [23],multiple non-randomized trialcohortsNSABP-B14[24] (largestbenefit inquantitativeER high/recurrencerisk lowpatients)No NSABP-B20(±CMF) [25],SWOG8814(±CAF) [23](benefit fromchemotherapywith highrecurrence score)No NSABP-B28 [22](failed to predicta benefit)TAILORx(node-negative, toreport 2015)RxPONDER(one to threepositive nodes,recruiting)PAM50(researchbased assay);RT-PCR andmicroarray,FFPE andfresh(distributed)Biology (identification ofmajor molecular subtypes)N/A research assay No NCIC-MA5 [26],NCIC-MA12 [27],GEICAM/9906[28], multiplenonrandomizedtrial cohortsNCIC-MA12[27] (luminalsubtypepredictsbenefit)NOAH[29](HER2-enrichedbenefitsthe most)No NCIC-MA5[26] (CMF vs.CEF;epirubicinbenefit inHER2-enrichedsubtype only)GEICAM/9906,CALGB/9342 andCALGB/9840 [30](low proliferationscore predictsweekly paclitaxelbenefit)NoKosandNielsenBreastCancerResearchPage2of62014, 16:103http://breast-cancer-research.com/content/16/4/103Table 1 Overview of selected multigene signatures for breast cancer (Continued)Prosigna;nCounter,FFPE(distributed)Biology (subtype); outcome(ROR score)CE Mark, HealthCanada, FDA:prediction of 10-yearDRFS in ER+, node 0to 3, postmenopausalwomen treated withendocrine therapyYes [31] ATAC [32],ABCSG08 [33]No No No o No RxPONDER(one to threenodes,recruiting;embeddedadditionalanalysis)CAF, cyclophosphamide, doxorubicin, fluorouracil; CEF, cyclophosphamide, epirubicin, fluorouracil; CMF, cyclophosphamide, methotrexate and fluorouracil; DR , distant relapse-free survival; ER, estrogen receptor;FDA, US Food and Drug Administration; FFPE, formalin-fixed paraffin-embedded; HER2, human epidermal growth factor receptor 2; H:I, HOXB13:IL17BR; IHC, im unohistochemistry; MGI, molecular grade index; N/A,not applicable; pN0, pathological lymph node-negative; pN+, pathological lymph node-positive; ROR, risk of recurrence; RT-PCR, reverse transcription polymera chain reaction. Breast Cancer Index: bioTheranostics,San Diego, CA, USA; EndoPredict: Sividon Diagnostics GmbH, Cologne, Germany; IHC4: MammaPrint: Agendia, Amsterdam, The Netherlands; Mammostrat: Clarient, Inc. liso Viejo, CA, USA; Oncotype: Genomic Health, RedwoodCity, CA, USA; PAM50: NanoString Technologies Inc., Seatlle, WA, USA; Prosigna: NanoString Technologies Inc., Seattle, WA, USA. aNested cohort study using material fro NCIC CTG MA.17 – HOXB13/IL17BR predictive of benefitfrom extended letrozole.KosandNielsenBreastCancerResearchPage3of62014, 16:103http://breast-cancer-research.com/content/16/4/103NFSmse, AmKos and Nielsen Breast Cancer Research Page 4 of 62014, 16:103http://breast-cancer-research.com/content/16/4/103ABCSG-8 trial [4]. This promising idea must be inter-preted cautiously given that only 16 of the 74 EPclinlow-risk patients had 10-year follow-up data. Both theaTTom and ATLAS trials have shown that survival ben-efits of extended hormonal therapy become more appar-ent after year 10 [5,6].Several multigene prognostic assays have now been de-veloped for use in ER+/HER2− breast cancers. First-generation assays including MammaPrint (MammaPrint:Agendia, Amsterdam, The Netherlands) and OncotypeDX (Oncotype: Genomic Health, Redwood City, CA, USA)suffered from early methodological issues, most seriously afailure to maintain rigorous separation between trainingand validation sets, and inclusion of nonluminal and/orHER2+ tumors in their training sets, thereby allowing thesehigh-risk tumors to skew outcome-related gene selectionaway from the relevant patient group [7-9]. MammaPrintwas specifically trained around early relapse (within 5 years)in node-negative women, most having received no adjuvantsystemic therapy, and has not been shown to predict laterecurrence outside the original training-validation cohort.Oncotype DX heavily weighed the tamoxifen-only arm ofthe NSABP-B20 trial in its training set, where most recur-rences occurred within 5 years, and has diminished prog-nostic ability beyond year 5 [10].More recently, building upon biological and technicaladvances and more rigorous approaches to validation,second-generation multigene tests have been developed,including the Breast Cancer Index (BCI: bioTheranostics,San Diego, CA, USA), PAM50 (PAM50: NanoStringTechnologies Inc., Seattle, WA, USA) and EP. The BreastCancer Index combines a molecular grade index (quanti-fying tumor grade-associated genes) and a two-generatio,HOXB13:IL17BR, related to estrogen signaling [11].PAM50, unlike signatures trained around outcome, wasdeveloped as a biological classifier of the major intrinsicmolecular subtypes of breast cancer [12]. These threeassays predict both early and late recurrences [4,10,13].IHC4 and Mammostrat (Mammostrat: Clarient, Inc.,Aliso Viejo, CA, USA) immunohistochemical panels arealso prognostic in early breast cancer [14,15]. IHC4 usesstandard pathology markers (ER, progesterone receptor,HER2 and Ki67) to provide prognostic information com-parable with Oncotype DX [14]. Immunohistochemicalstaining and scoring does suffer from limited analyticalreproducibility, probably contributing to Martin and col-leagues’ identification of low Ki67 scores (<14%; a pub-lished cutoff point for good-prognosis luminal A tumors)in a surprisingly high fraction (almost three-quarters) ofthis node-positive cohort [16].Each of these gene expression and immunohistochemicalpanels identifies a good prognosis group that may notneed chemotherapy. Emerging evidence suggests that somepanels identify women at such low risk of late recurrencethat they may safely avoid extended endocrine therapy.For high-risk women, however, the question is not one ofchemotherapy versus no chemotherapy, but rather a ques-tion of which chemotherapy agent(s) will be most effectivefor which patients – a true predictive indication. In Martinand colleagues’ report, the EP score did not predict benefitfrom adding weekly paclitaxel to fluorouracil–epirubicin–cyclophosphamide chemotherapy. Outcome-trained sig-natures from nonchemotherapy populations are unlikelyto predict between chemotherapy regimens; Table 1 sum-marizes some relevant features of the referenced molecu-lar signatures, including predictive studies.What does the future hold for gene expression signa-tures? Cheaper and faster next-generation sequencinghas been touted as the pinnacle of personalized medi-cine, destined to render multigene expression assaysobsolete. However, the genetic complexity of tumors(copy number variations, chromosome-scale structuralchanges, thousands of mutations, epigenetic changesand intratumoral genetic heterogeneity) is proving evenmore complex than anticipated. Much as the increaseddetail from electron microscopy never did replace lightmicroscopy for cancer diagnosis, the broader signaturesdetected by representative gene expression profile as-says, reflecting clinically significant patterns commonacross many patients, are likely to remain relevant forimportant treatment decisions.AbbreviationsEP: EndoPredict; ER: Estrogen receptor; HER2: Human epidermal growthfactor receptor 2.Competing interestsTON reports a proprietary interest in the PAM50 assay, which has beenlicensed to Nanostring Technologies. ZK has no competing interests.Author details1Department of Laboratory Medicine and Pathobiology, University ofToronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. 2GeneticPathology Evaluation Centre, Department of Pathology and LaboratoryMedicine, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H3Z6, Canada.Published:References1. 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Filipits M, Nielsen TO, Rudas M, Greil R, Stöger H, Jakesz R, Bago-Horvath Z,Dietze O, Regitnig P, Gruber-Rossipal C, Müller-Holzner E, Singer CF,Mlineritsch B, Dubsky P, Bauernhofer T, Hubalek M, Knauer M, Trapl H,Fesl C, Schaper C, Ferree S, Liu S, Cowens JW, Gnant M, Austrian Breastand Colorectal Cancer Study Group: The PAM50 risk-of-recurrencescore predicts risk for late distant recurrence after endocrine therapyin postmenopausal women with endocrine-responsive early breastcancer. Clin Cancer Res 2014, 20:1298–1305.Cite this article as: Kos and Nielsen: Developing a new generation ofbreast cancer clinical gene expression tests.Breast Cancer ResearchKos and Nielsen Breast Cancer Research Page 6 of 610.1186/bcr36882014, 16:1032014, 16:103http://breast-cancer-research.com/content/16/4/103

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