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01-01-2013 | Preclinical Study

Prognostic evaluation of the B cell/IL-8 metagene in different intrinsic breast cancer subtypes

Authors: Lars C. Hanker, Achim Rody, Uwe Holtrich, Lajos Pusztai, Eugen Ruckhaeberle, Cornelia Liedtke, Andre Ahr, Tomas M. Heinrich, Nicole Sänger, Sven Becker, Thomas Karn

Published in: Breast Cancer Research and Treatment | Issue 2/2013

Abstract

We recently reported that a ratio of high B cell and low IL-8 metagene expression identified 32 % of triple negative breast cancers (TNBC) with good prognosis and was the only significant predictor in multivariate analysis including routine clinicopathological variables. However, the clinical relevance of this signature in other breast cancer subtypes remains unclear. We compiled Affymetrix gene expression datasets from 4,467 primary breast cancer samples and excluded 329 triple negative samples which were used as discovery cohort in our previous study. Molecular classification of the remaining 4,138 samples was performed by two methods, including single genes (ER, PgR, HER2, and Ki67) and a centroid-based method using the intrinsic gene list. The prognostic value within the respective subtypes was assessed by analyzing the event-free survival of patients as a function of the B cell/IL-8 metagene ratio using previously published cutoff. ER-negative subtypes had the highest expression of the B cell and the IL-8 metagenes. The IL-8/B cell signature assigned a considerable fraction of samples (range 20.7–42.0 %) into the “good prognosis” group. However, a significant prognostic value was only observed in the subgroup of triple negative breast cancer (P = 0.035). The prognostic value of the B cell/IL-8 ratio is mainly confined to the basal-like and TNBC subtypes of breast cancer. This result underlines the importance of subtype-specific analyses and suggests a sequential multistep approach to developing and applying outcome predictors in the clinic.

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Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, Sougnez C, Zou L, Cortes ML, Fernandez-Lopez JC, Peng S, Ardlie KG, Auclair D, Bautista-Piña V, Duke F, Francis J, Jung J, Maffuz-Aziz A, Onofrio RC, Parkin M, Pho NH, Quintanar-Jurado V, Ramos AH, Rebollar-Vega R, Rodriguez-Cuevas S, Romero-Cordoba SL, Schumacher SE, Stransky N, Thompson KM, Uribe-Figueroa L, Baselga J, Beroukhim R, Polyak K, Sgroi DC, Richardson AL, Jimenez-Sanchez G, Lander ES, Gabriel SB, Garraway LA, Golub TR, Melendez-Zajgla J, Toker A, Getz G, Hidalgo-Miranda A, Meyerson M (2012) Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486(7403):405–409PubMedCrossRef

Bianchini G, Iwamoto T, Qi Y, Coutant C, Shiang CY, Wang B, Santarpia L, Valero V, Hortobagyi GN, Symmans WF, Gianni L, Pusztai L (2010) Prognostic and therapeutic implications of distinct kinase expression patterns in different subtypes of breast cancer. Cancer Res 70(21):8852–8862PubMedCrossRef

Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK, Valero V, Cristofanilli M, Green MC, Radvanyi L, Hatzis C, Hortobagyi GN, Andre F, Gianni L, Symmans WF, Pusztai L (2010) Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol 28(28):4316–4323PubMedCrossRef

Carey L, Winer E, Viale G, Cameron D, Gianni L (2010) Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol 7(12):683–692PubMedCrossRef

Curtis C, Shah SP, Chin S, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Gräf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Caldas C, Aparicio S, Brenton JD, Ellis I, Huntsman D, Pinder S, Purushotham A, Murphy L, Bardwell H, Ding Z, Jones L, Liu B, Papatheodorou I, Sammut SJ, Wishart G, Chia S, Gelmon K, Speers C, Watson P, Blamey R, Green A, Macmillan D, Rakha E, Gillett C, Grigoriadis A, Di Rinaldis E, Tutt A, Parisien M, Troup S, Chan D, Fielding C, Maia A, McGuire S, Osborne M, Sayalero SM, Spiteri I, Hadfield J, Bell L, Chow K, Gale N, Kovalik M, Ng Y, Prentice L, Tavaré S, Markowetz F, Langerød A, Provenzano E, Børresen-Dale A (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352PubMed

Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105–113PubMedCrossRef

Dupuy A, Simon RM (2007) Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting. J Natl Cancer Inst 99:147–157PubMedCrossRef

Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363(20):1938–1948PubMedCrossRef

Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) Affy-analysis of affymetrix genechip data at the probe level. Bioinformatics 20(3):307–315PubMedCrossRef

10.

Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JYH, Zhang J (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5(10):R80PubMedCrossRef

11.

Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, Wicinski J, Cabaud O, Charafe-Jauffret E, Birnbaum D, Guan JL, Dontu G, Wicha MS (2010) CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 120:485–497PubMedCrossRef

12.

Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn H (2011) Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer. Ann Oncol 22(8):1736–1747PubMedCrossRef

13.

Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, La Carey, Reynolds E, Dressler L, Nobel A, Parker J, Ewend MG, Sawyer LR, Wu J, Liu Y, Nanda R, Tretiakova M, Ruiz Orrico A, Dreher D, Palazzo JP, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush JF, Ellis MJ, Olopade OI, Bernard PS (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7:96PubMedCrossRef

14.

Hugh J, Hanson J, Cheang MCU, Nielsen TO, Perou CM, Dumontet C, Reed J, Krajewska M, Treilleux I, Rupin M, Magherini E, Mackey J, Martin M, Vogel C (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27(8):1168–1176PubMedCrossRef

15.

Iwamoto T, Bianchini G, Booser D, Qi Y, Coutant C, Shiang CY, Santarpia L, Matsuoka J, Hortobagyi GN, Symmans WF, Holmes FA, O’Shaughnessy J, Hellerstedt B, Pippen J, Andre F, Simon R, Pusztai L (2011) Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer. J Natl Cancer Inst 103(3):264–272PubMedCrossRef

16.

Karn T, Metzler D, Ruckhäberle E, Hanker L, Gätje R, Solbach C, Ahr A, Schmidt M, Holtrich U, Kaufmann M, Rody A (2010) Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer. Breast Cancer Res Treat 120(3):567–579PubMedCrossRef

17.

Karn T, Pusztai L, Holtrich U, Iwamoto T, Shiang CY, Schmidt M, Müller V, Solbach C, Gaetje R, Hanker L, Ahr A, Liedtke C, Ruckhäberle E, Kaufmann M, Rody A, Ranganathan S (2011) Homogeneous datasets of triple negative breast cancers enable the identification of novel prognostic and predictive signatures. PLoS ONE 6(12):e28403PubMedCrossRef

18.

Karn T, Pusztai L, Ruckhäberle E, Liedtke C, Müller V, Schmidt M, Metzler D, Wang J, Coombes KR, Gätje R, Hanker L, Solbach C, Ahr A, Holtrich U, Rody A, Kaufmann M (2012) Melanoma antigen family A identified by the bimodality index defines a subset of triple negative breast cancers as candidates for immune response augmentation. Eur J Cancer 48(1):12–23PubMedCrossRef

19.

Kaufmann M, Pusztai L (2011) Use of standard markers and incorporation of molecular markers into breast cancer therapy: consensus recommendations from an international expert panel. Cancer 117(8):1575–1582PubMedCrossRef

20.

Korkaya H, Liu S, Wicha MS (2011) Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest 121(10):3804–3809PubMedCrossRef

21.

Korkaya H, Liu S, Wicha MS (2011) Regulation of cancer stem cells by cytokine networks: attacking cancer’s inflammatory roots. Clin Cancer Res 17(19):6125–6129PubMedCrossRef

22.

Liu S, Wicha MS (2010) Targeting breast cancer stem cells. J Clin Oncol 28:4006–4012PubMedCrossRef

23.

Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A, Ellis P, Tutt ANJ, Gillett CE, Hennessy BT, Mills GB, Phillips WA, Piccart MJ, Speed TP, McArthur GA, Sotiriou C (2010) PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA 107(22):10208–10213PubMedCrossRef

24.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23:9067–9072PubMedCrossRef

25.

Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480(7378):480–489PubMedCrossRef

26.

Ogino S, Galon J, Fuchs CS, Dranoff G (2011) Cancer immunology—analysis of host and tumor factors for personalized medicine. Nat Rev Clin Oncol 8(12):711–719PubMedCrossRef

27.

Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen La, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRef

28.

Prat A, Ellis MJ, Perou CM (2011) Practical implications of gene-expression-based assays for breast oncologists. Nat Rev Clin Oncol 9(1):48–57PubMedCrossRef

29.

Reis-Filho JS, Pusztai L (2011) Gene expression profiling in breast cancer: classification, prognostication, and prediction. Lancet 378(9805):1812–1823PubMedCrossRef

30.

Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, Solbach C, Hanker L, Ahr A, Metzler D, Engels K, Karn T, Kaufmann M (2009) T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res 11(2):R15PubMedCrossRef

31.

Rody A, Karn T, Liedtke C, Pusztai L, Ruckhaeberle E, Hanker L, Gaetje R, Solbach C, Ahr A, Metzler D, Schmidt M, Müller V, Holtrich U, Kaufmann M (2011) A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res 13(5):R97PubMedCrossRef

32.

Schmidt M, Hellwig B, Hammad S, Othman A, Lohr M, Chen Z, Boehm D, Gebhard S, Petry I, Lebrecht A, Cadenas C, Marchan R, Stewart JD, Solbach C, Holmberg L, Edlund K, Kultima HG, Rody A, Berglund A, Lambe M, Isaksson A, Botling J, Karn T, Müller V, Gerhold-Ay A, Cotarelo C, Sebastian M, Kronenwett R, Bojar H, Lehr H, Sahin U, Koelbl H, Gehrmann M, Micke P, Rahnenführer J, Hengstler JG (2012) A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin κ C as a compatible prognostic marker in human solid tumors. Clin Cancer Res 18(9):2695–2703PubMedCrossRef

33.

Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570PubMedCrossRef

34.

Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, Bashashati A, Prentice LM, Khattra J, Burleigh A, Yap D, Bernard V, McPherson A, Shumansky K, Crisan A, Giuliany R, Heravi-Moussavi A, Rosner J, Lai D, Birol I, Varhol R, Tam A, Dhalla N, Zeng T, Ma K, Chan SK, Griffith M, Moradian A, Cheng SG, Morin GB, Watson P, Gelmon K, Chia S, Chin S, Curtis C, Rueda OM, Pharoah PD, Damaraju S, Mackey J, Hoon K, Harkins T, Tadigotla V, Sigaroudinia M, Gascard P, Tlsty T, Costello JF, Meyer IM, Eaves CJ, Wasserman WW, Jones S, Huntsman D, Hirst M, Caldas C, Marra MA, Aparicio S (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399PubMed

35.

Simon RM, Paik S, Hayes DF (2009) Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 101(21):1446–1452PubMedCrossRef

36.

Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360(8):790–800PubMedCrossRef

37.

Stephens PJ, Tarpey PS, Davies H, van Loo P, Greenman C, Wedge DC, Zainal SN, Martin S, Varela I, Bignell GR, Yates LR, Papaemmanuil E, Beare D, Butler A, Cheverton A, Gamble J, Hinton J, Jia M, Jayakumar A, Jones D, Latimer C, Lau KW, McLaren S, McBride DJ, Menzies A, Mudie L, Raine K, Rad R, Spencer Chapman M, Teague J, Easton D, Langerød A, OSBREAC, Lee MTM, Shen C, Tee BTK, Huimin BW, Broeks A, Vargas AC, Turashvili G, Martens J, Fatima A, Miron P, Chin S, Thomas G, Boyault S, Mariani O, Lakhani SR, van de Vijver M, van ‘t Veer L, Foekens J, Desmedt C, Sotiriou C, Tutt A, Caldas C, Reis-Filho JS, Aparicio SAJR, Salomon AV, Børresen-Dale A, Richardson A, Campbell PJ, Futreal PA, Stratton MR, Karesen R, Schlichting E, Naume B, Sauer T, Ottestad L (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486(7403):400–404PubMed

38.

Weigelt B, Mackay A, A’Hern R, Natrajan R, Tan DSP, Dowsett M, Ashworth A, Reis-Filho JS (2010) Breast cancer molecular profiling with single sample predictors: a retrospective analysis. Lancet Oncol 11(4):339–349PubMedCrossRef

39.

Weigelt B, Pusztai L, Ashworth A, Reis-Filho JS (2011) Challenges translating breast cancer gene signatures into the clinic. Nat Rev Clin Oncol 9(1):58–64PubMedCrossRef

40.

Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8(3):151–160PubMedCrossRef

Title: Prognostic evaluation of the B cell/IL-8 metagene in different intrinsic breast cancer subtypes
Authors: Lars C. Hanker
Achim Rody
Uwe Holtrich
Lajos Pusztai
Eugen Ruckhaeberle
Cornelia Liedtke
Andre Ahr
Tomas M. Heinrich
Nicole Sänger
Sven Becker
Thomas Karn
Publication date: 01-01-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-2356-2

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