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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

An 8-gene mRNA expression profile in circulating tumor cells predicts response to aromatase inhibitors in metastatic breast cancer patients

Authors: Esther A. Reijm, Anieta M. Sieuwerts, Marcel Smid, Joan Bolt-de Vries, Bianca Mostert, Wendy Onstenk, Dieter Peeters, Luc Y. Dirix, Caroline M. Seynaeve, Agnes Jager, Felix E. de Jongh, Paul Hamberg, Anne van Galen, Jaco Kraan, Maurice P. H. M. Jansen, Jan W. Gratama, John A. Foekens, John W. M. Martens, Els M. J. J. Berns, Stefan Sleijfer

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Molecular characterization of circulating tumor cells (CTC) is promising for personalized medicine. We aimed to identify a CTC gene expression profile predicting outcome to first-line aromatase inhibitors in metastatic breast cancer (MBC) patients. Methods: CTCs were isolated from 78 MBC patients before treatment start. mRNA expression levels of 96 genes were measured by quantitative reverse transcriptase polymerase chain reaction. After applying predefined exclusion criteria based on lack of sufficient RNA quality and/or quantity, the data from 45 patients were used to construct a gene expression profile to predict poor responding patients, defined as disease progression or death <9 months, by a leave-one-out cross validation.

Results

Of the 45 patients, 19 were clinically classified as poor responders. To identify them, the 75 % most variable genes were used to select genes differentially expressed between good and poor responders. An 8-gene CTC predictor was significantly associated with outcome (Hazard Ratio [HR] 4.40, 95 % Confidence Interval [CI]: 2.17–8.92, P < 0.001). This predictor identified poor responding patients with a sensitivity of 63 % and a positive predictive value of 75 %, while good responding patients were correctly predicted in 85 % of the cases. In multivariate Cox regression analysis, including CTC count at baseline, the 8-gene CTC predictor was the only factor independently associated with outcome (HR 4.59 [95 % CI: 2.11–9.56], P < 0.001). This 8-gene signature was not associated with outcome in a group of 71 MBC patients treated with systemic treatments other than AI.

Conclusions

An 8-gene CTC predictor was identified which discriminates good and poor outcome to first-line aromatase inhibitors in MBC patients. Although results need to be validated, this study underscores the potential of molecular characterization of CTCs.
Appendix
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Literature
1.
Thompson AM, Jordan LB, Quinlan P, Anderson E, Skene A, Dewar JA, et al. Prospective comparison of switches in biomarker status between primary and recurrent breast cancer: the Breast Recurrence In Tissues Study (BRITS). Breast Cancer Res. 2010;12(6):R92.PubMedCentralCrossRefPubMed
2.
Gong Y, Han EY, Guo M, Pusztai L, Sneige N. Stability of estrogen receptor status in breast carcinoma: a comparison between primary and metastatic tumors with regard to disease course and intervening systemic therapy. Cancer. 2011;117(4):705–13.CrossRefPubMed
3.
Amir E, Miller N, Geddie W, Freedman O, Kassam F, Simmons C, et al. Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol. 2012;30(6):587–92.CrossRefPubMed
4.
Pancholi S, Lykkesfeldt AE, Hilmi C, Banerjee S, Leary A, Drury S, et al. ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2. Endocr Relat Cancer. 2008;15(4):985–1002.CrossRefPubMed
5.
6.
Reijm EA, Jansen MP, Ruigrok-Ritstier K, van Staveren IL, Look MP, van Gelder ME, et al. Decreased expression of EZH2 is associated with upregulation of ER and favorable outcome to tamoxifen in advanced breast cancer. Breast Cancer Res Treat. 2011;125(2):387–94.CrossRefPubMed
7.
Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467(7319):1109–13.PubMedCentralCrossRefPubMed
8.
Xiao C, Gong Y, Han EY, Gonzalez-Angulo AM, Sneige N. Stability of HER2-positive status in breast carcinoma: a comparison between primary and paired metastatic tumors with regard to the possible impact of intervening trastuzumab treatment. Ann Oncol. 2011;22(7):1547–53.CrossRefPubMed
9.
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781–91.CrossRefPubMed
10.
Cristofanilli M, Hayes DF, Budd GT, Ellis MJ, Stopeck A, Reuben JM, et al. Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol. 2005;23(7):1420–30.CrossRefPubMed
11.
Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res. 2006;12(14 Pt 1):4218–24.CrossRefPubMed
12.
Bidard FC, Peeters DJ, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15(4):406–14.CrossRefPubMed
13.
Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A'Hern R, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69(7):2912–8.CrossRefPubMed
14.
Fehm T, Muller V, Aktas B, Janni W, Schneeweiss A, Stickeler E, et al. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat. 2010;124(2):403–12.CrossRefPubMed
15.
Riethdorf S, Muller V, Zhang L, Rau T, Loibl S, Komor M, et al. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res. 2010;16(9):2634–45.CrossRefPubMed
16.
Gasch C, Bauernhofer T, Pichler M, Langer-Freitag S, Reeh M, Seifert AM, et al. Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer. Clin Chem. 2013;59(1):252–60.CrossRefPubMed
17.
Smirnov DA, Zweitzig DR, Foulk BW, Miller MC, Doyle GV, Pienta KJ, et al. Global gene expression profiling of circulating tumor cells. Cancer Res. 2005;65(12):4993–7.CrossRefPubMed
18.
Sieuwerts AM, Mostert B, Bolt-de Vries J, Peeters D, de Jongh FE, Stouthard JM, et al. mRNA and microRNA expression profiles in circulating tumor cells and primary tumors of metastatic breast cancer patients. Clin Cancer Res. 2011;17(11):3600–18.CrossRefPubMed
19.
Onstenk W, Gratama JW, Foekens JA, Sleijfer S. Towards a personalized breast cancer treatment approach guided by circulating tumor cell (CTC) characteristics. Cancer Treat Rev. 2013;39(7):691–700.CrossRefPubMed
20.
Sieuwerts AM, Kraan J, Bolt-de Vries J, van der Spoel P, Mostert B, Martens JW, et al. Molecular characterization of circulating tumor cells in large quantities of contaminating leukocytes by a multiplex real-time PCR. Breast Cancer Res Treat. 2009;118(3):455–68.CrossRefPubMed
21.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, et al. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005;97(16):1180–4.CrossRefPubMed
22.
Mostert B, Sieuwerts AM, Kraan J, Bolt-de Vries J, van der Spoel P, van Galen A, et al. Gene expression profiles in circulating tumor cells to predict prognosis in metastatic breast cancer patients. Ann Oncol. 2015;26(3):510–6.CrossRefPubMed
23.
Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, Schutte M, et al. Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst. 2009;101(1):61–6.PubMedCentralCrossRefPubMed
24.
Mostert B, Kraan J, Bolt-de Vries J, van der Spoel P, Sieuwerts AM, Schutte M, et al. Detection of circulating tumor cells in breast cancer may improve through enrichment with anti-CD146. Breast Cancer Res Treat. 2011;127(1):33–41.CrossRefPubMed
25.
Kraan J, Sleijfer S, Strijbos MH, Ignatiadis M, Peeters D, Pierga JY, et al. External quality assurance of circulating tumor cell enumeration using the Cell Search((R)) system: a feasibility study. Cytometry B Clin Cytom. 2011;80(2):112–8.CrossRefPubMed
26.
Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P. Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer. 2005;104(8):1742–50.CrossRefPubMed
27.
Kiely BE, Soon YY, Tattersall MH, Stockler MR. How long have I got? Estimating typical, best-case, and worst-case scenarios for patients starting first-line chemotherapy for metastatic breast cancer: a systematic review of recent randomized trials. J Clin Oncol. 2011;29(4):456–63.CrossRefPubMed
28.
Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A. 1998;95(25):14863–8.PubMedCentralCrossRefPubMed
29.
Molinaro AM, Simon R, Pfeiffer RM. Prediction error estimation: a comparison of resampling methods. Bioinformatics. 2005;21(15):3301–7.CrossRefPubMed
30.
Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982;31(1):11–24.CrossRefPubMed
31.
Ferrando J, Galve J, Torres-Puente M, Santillan S, Nogues S, Grimalt R. Monilethrix: A New Family with the Novel Mutation in KRT81 Gene. Int J Trichol. 2012;4(1):53–5.CrossRef
32.
Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6(1):17–32.CrossRefPubMed
33.
Nicholson RI, Hutcheson IR, Harper ME, Knowlden JM, Barrow D, McClelland RA, et al. Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer. Endocr Relat Cancer. 2001;8(3):175–82.CrossRefPubMed
34.
Morrison MM, Hutchinson K, Williams MM, Stanford JC, Balko JM, Young C, et al. ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. J Clin Invest. 2013;123(10):4329–43.PubMedCentralCrossRefPubMed
35.
Jansa P, Mason SW, Hoffmann-Rohrer U, Grummt I. Cloning and functional characterization of PTRF, a novel protein which induces dissociation of paused ternary transcription complexes. EMBO J. 1998;17(10):2855–64.PubMedCentralCrossRefPubMed
36.
Metivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M, et al. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell. 2003;115(6):751–63.CrossRefPubMed
37.
Foekens JA, Rio MC, Seguin P, van Putten WL, Fauque J, Nap M, et al. Prediction of relapse and survival in breast cancer patients by pS2 protein status. Cancer Res. 1990;50(13):3832–7.PubMed
38.
Foekens JA, van Putten WL, Portengen H, de Koning HY, Thirion B, Alexieva-Figusch J, et al. Prognostic value of PS2 and cathepsin D in 710 human primary breast tumors: multivariate analysis. J Clin Oncol. 1993;11(5):899–908.PubMed
39.
Foekens JA, Portengen H, Look MP, van Putten WL, Thirion B, Bontenbal M, et al. Relationship of PS2 with response to tamoxifen therapy in patients with recurrent breast cancer. Br J Cancer. 1994;70(6):1217–23.PubMedCentralCrossRefPubMed
40.
Lee MH, Choi BY, Cho YY, Lee SY, Huang Z, Kundu JK, et al. Tumor suppressor p16(INK4a) inhibits cancer cell growth by downregulating eEF1A2 through a direct interaction. J Cell Sci. 2013;126(Pt 8):1744–52.PubMedCentralCrossRefPubMed
41.
Pinke DE, Kalloger SE, Francetic T, Huntsman DG, Lee JM. The prognostic significance of elongation factor eEF1A2 in ovarian cancer. Gynecol Oncol. 2008;108(3):561–8.CrossRefPubMed
42.
Tomlinson VA, Newbery HJ, Wray NR, Jackson J, Larionov A, Miller WR, et al. Translation elongation factor eEF1A2 is a potential oncoprotein that is overexpressed in two-thirds of breast tumours. BMC Cancer. 2005;5:113.PubMedCentralCrossRefPubMed
43.
Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet. 2005;365(9460):671–9.CrossRefPubMed
44.
Zhang Y, Sieuwerts AM, McGreevy M, Casey G, Cufer T, Paradiso A, et al. The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy. Breast Cancer Res Treat. 2009;116(2):303–9.CrossRefPubMed
45.
Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, et al. Protein tyrosine phosphatases in the human genome. Cell. 2004;117(6):699–711.CrossRefPubMed
46.
Sun PH, Ye L, Mason MD, Jiang WG. Protein tyrosine phosphatase kappa (PTPRK) is a negative regulator of adhesion and invasion of breast cancer cells, and associates with poor prognosis of breast cancer. J Cancer Res Clin Oncol. 2013;139(7):1129–39.CrossRefPubMed
47.
Vesuna F, Lisok A, Kimble B, Domek J, Kato Y, van der Groep P, et al. Twist contributes to hormone resistance in breast cancer by downregulating estrogen receptor-alpha. Oncogene. 2012;31(27):3223–34.PubMedCentralCrossRefPubMed
48.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7):927–39.CrossRefPubMed
49.
Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, et al. Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 2010;101(2):293–9.CrossRefPubMed
50.
van der Gun BT, Melchers LJ, Ruiters MH, de Leij LF, McLaughlin PM, Rots MG. EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis. 2010;31(11):1913–21.CrossRefPubMed
51.
Babayan A, Hannemann J, Spotter J, Muller V, Pantel K, Joosse SA. Heterogeneity of estrogen receptor expression in circulating tumor cells from metastatic breast cancer patients. PLoS One. 2013;8(9):e75038.PubMedCentralCrossRefPubMed
Metadata
Title
An 8-gene mRNA expression profile in circulating tumor cells predicts response to aromatase inhibitors in metastatic breast cancer patients
Authors
Esther A. Reijm
Anieta M. Sieuwerts
Marcel Smid
Joan Bolt-de Vries
Bianca Mostert
Wendy Onstenk
Dieter Peeters
Luc Y. Dirix
Caroline M. Seynaeve
Agnes Jager
Felix E. de Jongh
Paul Hamberg
Anne van Galen
Jaco Kraan
Maurice P. H. M. Jansen
Jan W. Gratama
John A. Foekens
John W. M. Martens
Els M. J. J. Berns
Stefan Sleijfer
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2155-y

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