Journal Article
. 2006 Mar;24(11).
doi: 10.1200/JCO.2005.03.9115.

Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer

John A Foekens 1 David Atkins  Yi Zhang  Fred C G J Sweep  Nadia Harbeck  Angelo Paradiso  Tanja Cufer  Anieta M Sieuwerts  Dmitri Talantov  Paul N Span  Vivianne C G Tjan-Heijnen  Alfredo F Zito  Katja Specht  Heinz Hoefler  Rastko Golouh  Francesco Schittulli  Manfred Schmitt  Louk V A M Beex  Jan G M Klijn  Yixin Wang  
Affiliations
  • PMID: 16505412
  •     80 citations

Abstract

Purpose: We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an independent more diverse population of LNN patients from multiple institutions.

Patients And Methods: Using custom-designed DNA chips we analyzed the expression of the 76 genes in RNA of frozen tumor samples from 180 LNN patients who did not receive adjuvant systemic treatment.

Results: In this independent validation, the 76-gene signature was highly informative in identifying patients with distant metastasis within 5 years (hazard ratio, [HR], 7.41; 95% CI, 2.63 to 20.9), even when corrected for traditional prognostic factors in multivariate analysis (HR, 11.36; 95% CI, 2.67 to 48.4). The actuarial 5- and 10-year distant metastasis-free survival were 96% (95% CI, 89% to 99%) and 94% (95% CI, 83% to 98%), respectively, for the good profile group and 74% (95% CI, 64% to 81%) and 65% (53% to 74%), respectively for the poor profile group. The sensitivity for 5-yr distant metastasis-free survival was 90%, and the specificity was 50%. The positive and negative predictive values were 38% (95% CI, 29% to 47%) and 94% (95% CI, 86% to 97%), respectively. The 76-gene signature was confirmed as a strong prognostic factor in subgroups of estrogen receptor-positive patients, pre- and postmenopausal patients, and patients with tumor sizes 20 mm or smaller. The subgroup of patients with estrogen receptor-negative tumors was considered too small to perform a separate analysis.

Conclusion: Our data provide a strong methodologic and clinical multicenter validation of the predefined prognostic 76-gene signature in LNN breast cancer patients.

[Future of chemotherapy].
M-O Grimm, F H Hartmann, R Ackermann.
Urologe A, 2006 May 20; 45(5). PMID: 16710676
Review.
A consensus prognostic gene expression classifier for ER positive breast cancer.
Andrew E Teschendorff, Ali Naderi, +5 authors, Carlos Caldas.
Genome Biol, 2006 Nov 02; 7(10). PMID: 17076897    Free PMC article.
Expression genomics in breast cancer research: microarrays at the crossroads of biology and medicine.
Lance D Miller, Edison T Liu.
Breast Cancer Res, 2007 Apr 03; 9(2). PMID: 17397520    Free PMC article.
Review.
Molecular profiling in breast cancer.
Shannon R Morris, Lisa A Carey.
Rev Endocr Metab Disord, 2007 Apr 28; 8(3). PMID: 17464566
Review.
An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer.
Andrew E Teschendorff, Ahmad Miremadi, +2 authors, Carlos Caldas.
Genome Biol, 2007 Aug 09; 8(8). PMID: 17683518    Free PMC article.
Highly Cited.
Pathway analysis of gene signatures predicting metastasis of node-negative primary breast cancer.
Jack X Yu, Anieta M Sieuwerts, +5 authors, John A Foekens.
BMC Cancer, 2007 Sep 27; 7. PMID: 17894856    Free PMC article.
Gene arrays for diagnosis, prognosis and treatment of breast cancer metastasis.
Keltouma Driouch, Thomas Landemaine, +2 authors, Rosette Lidereau.
Clin Exp Metastasis, 2007 Nov 02; 24(8). PMID: 17973194
Review.
Systems biology and cancer stem cells.
Nathan D Price, Greg Foltz, +2 authors, Qiang Tian.
J Cell Mol Med, 2007 Nov 23; 12(1). PMID: 18031300    Free PMC article.
Review.
Prognostic relevance of glucosylceramide synthase (GCS) expression in breast cancer.
Eugen Ruckhäberle, Thomas Karn, +5 authors, Achim Rody.
J Cancer Res Clin Oncol, 2008 Jun 19; 135(1). PMID: 18560890
A comparative study of survival models for breast cancer prognostication based on microarray data: does a single gene beat them all?
B Haibe-Kains, C Desmedt, C Sotiriou, G Bontempi.
Bioinformatics, 2008 Jul 19; 24(19). PMID: 18635567    Free PMC article.
Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures.
Pratyaksha Wirapati, Christos Sotiriou, +10 authors, Mauro Delorenzi.
Breast Cancer Res, 2008 Jul 30; 10(4). PMID: 18662380    Free PMC article.
Highly Cited.
Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features.
Lori J Goldstein, Robert Gray, +12 authors, Joseph A Sparano.
J Clin Oncol, 2008 Aug 06; 26(25). PMID: 18678838    Free PMC article.
Highly Cited.
A decade of genome-wide gene expression profiling in acute myeloid leukemia: flashback and prospects.
Bas J Wouters, Bob Löwenberg, Ruud Delwel.
Blood, 2008 Aug 16; 113(2). PMID: 18703705    Free PMC article.
Review.
Combining biological gene expression signatures in predicting outcome in breast cancer: An alternative to supervised classification.
Dimitry S A Nuyten, Trevor Hastie, +2 authors, Marc J van de Vijver.
Eur J Cancer, 2008 Aug 22; 44(15). PMID: 18715778    Free PMC article.
Comparison of prognostic gene expression signatures for breast cancer.
Benjamin Haibe-Kains, Christine Desmedt, +6 authors, Christos Sotiriou.
BMC Genomics, 2008 Aug 23; 9. PMID: 18717985    Free PMC article.
Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer.
John A Foekens, Anieta M Sieuwerts, +6 authors, John W M Martens.
Proc Natl Acad Sci U S A, 2008 Aug 30; 105(35). PMID: 18755890    Free PMC article.
Highly Cited.
Age-related behaviors have distinct transcriptional profiles in Caenorhabditis elegans.
Tamara R Golden, Alan Hubbard, +2 authors, Simon Melov.
Aging Cell, 2008 Sep 10; 7(6). PMID: 18778409    Free PMC article.
Gene expression profiling of breast cancer.
Ting Bao, Nancy E Davidson.
Adv Surg, 2008 Oct 29; 42. PMID: 18953822    Free PMC article.
Review.
Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature.
Andrew Tutt, Alice Wang, +21 authors, Fred Waldman.
BMC Cancer, 2008 Nov 26; 8. PMID: 19025599    Free PMC article.
Haptoglobin phenotype is not a predictor of recurrence free survival in high-risk primary breast cancer patients.
Marie-Christine W Gast, Harm van Tinteren, +10 authors, Jos H Beijnen.
BMC Cancer, 2008 Dec 26; 8. PMID: 19108738    Free PMC article.
Gene expression of ceramide kinase, galactosyl ceramide synthase and ganglioside GD3 synthase is associated with prognosis in breast cancer.
Eugen Ruckhäberle, Thomas Karn, +5 authors, Manfred Kaufmann.
J Cancer Res Clin Oncol, 2009 Jan 07; 135(8). PMID: 19125296
Prediction of breast cancer metastasis by genomic profiling: where do we stand?
Ulrich Pfeffer, Francesco Romeo, Douglas M Noonan, Adriana Albini.
Clin Exp Metastasis, 2009 Mar 25; 26(6). PMID: 19308665    Free PMC article.
Review.
Identification of a putative protein profile associated with tamoxifen therapy resistance in breast cancer.
Arzu Umar, Hyuk Kang, +8 authors, Ljiljana Pasa-Tolić.
Mol Cell Proteomics, 2009 Mar 31; 8(6). PMID: 19329653    Free PMC article.
Gene expression profiles and breast cancer metastasis: a genetic perspective.
Kent W Hunter, Jude Alsarraj.
Clin Exp Metastasis, 2009 Apr 07; 26(6). PMID: 19347591    Free PMC article.
Review.
Metastatic gene signatures and emerging novel prognostic tests in the management of early stage breast cancer.
Attila Tordai, Cornelia Liedtke, Lajos Pusztai.
Clin Exp Metastasis, 2009 Apr 22; 26(7). PMID: 19381845
Review.
The MINDACT trial: the first prospective clinical validation of a genomic tool.
Fatima Cardoso, Martine Piccart-Gebhart, +2 authors, TRANSBIG Consortium.
Mol Oncol, 2007 Dec 01; 1(3). PMID: 19383299    Free PMC article.
A mouse mammary gland involution mRNA signature identifies biological pathways potentially associated with breast cancer metastasis.
Torsten Stein, Nathan Salomonis, +2 authors, Barry A Gusterson.
J Mammary Gland Biol Neoplasia, 2009 May 02; 14(2). PMID: 19408105
Review.
Recent advances in systemic therapy: new diagnostics and biological predictors of outcome in early breast cancer.
Catherine Oakman, Silvia Bessi, +3 authors, Angelo Di Leo.
Breast Cancer Res, 2009 May 14; 11(2). PMID: 19435470    Free PMC article.
Review.
Genomic predictors of outcome and treatment response in breast cancer.
Lara Dunn, Angela Demichele.
Mol Diagn Ther, 2009 Jun 23; 13(2). PMID: 19537843
Review.
Latent bone metastasis in breast cancer tied to Src-dependent survival signals.
Xiang H-F Zhang, Qiongqing Wang, +5 authors, Joan Massagué.
Cancer Cell, 2009 Jul 04; 16(1). PMID: 19573813    Free PMC article.
Highly Cited.
Current potential and limitations of molecular diagnostic methods in head and neck cancer.
Magdy E Mahfouz, Juan P Rodrigo, +4 authors, Alfio Ferlito.
Eur Arch Otorhinolaryngol, 2009 Dec 29; 267(6). PMID: 20037788
Review.
Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20.
Eleftherios P Mamounas, Gong Tang, +7 authors, Norman Wolmark.
J Clin Oncol, 2010 Jan 13; 28(10). PMID: 20065188    Free PMC article.
Highly Cited.
A fuzzy gene expression-based computational approach improves breast cancer prognostication.
Benjamin Haibe-Kains, Christine Desmedt, +3 authors, Gianluca Bontempi.
Genome Biol, 2010 Feb 17; 11(2). PMID: 20156340    Free PMC article.
Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery.
Sabine Tejpar, Monica Bertagnolli, +18 authors, Arnaud Roth.
Oncologist, 2010 Mar 31; 15(4). PMID: 20350999    Free PMC article.
Review.
Attitudes toward information about genetic risk for cognitive impairment after cancer chemotherapy: breast cancer survivors compared with healthy controls.
Michael A Andrykowski, Jessica L Burris, +2 authors, Paul B Jacobsen.
J Clin Oncol, 2010 May 26; 28(21). PMID: 20498392    Free PMC article.
Overexpression of POLQ confers a poor prognosis in early breast cancer patients.
Geoff S Higgins, Adrian L Harris, +3 authors, Francesca M Buffa.
Oncotarget, 2010 Aug 12; 1(3). PMID: 20700469    Free PMC article.
In silico models of cancer.
Lucas B Edelman, James A Eddy, Nathan D Price.
Wiley Interdiscip Rev Syst Biol Med, 2010 Sep 14; 2(4). PMID: 20836040    Free PMC article.
Review.
ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2.
Ekaterina V Kalashnikova, Alexey S Revenko, +6 authors, Hong-Wu Chen.
Cancer Res, 2010 Sep 25; 70(22). PMID: 20864510    Free PMC article.
Node-Negative Breast Cancer: Which Patients Should Be Treated?
Marcus Schmidt.
Breast Care (Basel), 2008 Jan 01; 3(4). PMID: 21076603    Free PMC article.
Comparison of the prognostic and predictive utilities of the 21-gene Recurrence Score assay and Adjuvant! for women with node-negative, ER-positive breast cancer: results from NSABP B-14 and NSABP B-20.
Gong Tang, Steven Shak, +6 authors, Norman Wolmark.
Breast Cancer Res Treat, 2011 Jan 12; 127(1). PMID: 21221771    Free PMC article.
Breast cancer at bone metastatic sites: recent discoveries and treatment targets.
Osama Hussein, Svetlana V Komarova.
J Cell Commun Signal, 2011 Apr 13; 5(2). PMID: 21484191    Free PMC article.
Prospective evaluation of prognostic factors uPA/PAI-1 in node-negative breast cancer: phase III NNBC3-Europe trial (AGO, GBG, EORTC-PBG) comparing 6×FEC versus 3×FEC/3×Docetaxel.
Eva J Kantelhardt, Martina Vetter, +12 authors, Nadia Harbeck.
BMC Cancer, 2011 Apr 19; 11. PMID: 21496284    Free PMC article.
Microarrays in the 2010s: the contribution of microarray-based gene expression profiling to breast cancer classification, prognostication and prediction.
Pierre-Emmanuel Colombo, Fernanda Milanezi, Britta Weigelt, Jorge S Reis-Filho.
Breast Cancer Res, 2011 Jul 27; 13(3). PMID: 21787441    Free PMC article.
Review.
Postoperative serum proteomic profiles may predict recurrence-free survival in high-risk primary breast cancer.
Marie-Christine W Gast, Marc Zapatka, +7 authors, Jos H Beijnen.
J Cancer Res Clin Oncol, 2011 Sep 14; 137(12). PMID: 21913038    Free PMC article.
Improving communication of breast cancer recurrence risk.
Noel T Brewer, Alice R Richman, +2 authors, Lisa A Carey.
Breast Cancer Res Treat, 2011 Oct 04; 133(2). PMID: 21964579    Free PMC article.
'Omic approaches to preventing or managing metastatic breast cancer.
Obi L Griffith, Joe W Gray.
Breast Cancer Res, 2012 Jan 06; 13(6). PMID: 22216753    Free PMC article.
Review.
Maximizing biomarker discovery by minimizing gene signatures.
Chang Chang, Junwei Wang, +7 authors, Tieliu Shi.
BMC Genomics, 2012 Mar 06; 12 Suppl 5. PMID: 22369133    Free PMC article.
Comparison of data-merging methods with SVM attribute selection and classification in breast cancer gene expression.
Vitoantonio Bevilacqua, Paolo Pannarale, +3 authors, Stefania Tommasi.
BMC Bioinformatics, 2012 May 25; 13 Suppl 7. PMID: 22595006    Free PMC article.
Proteomic studies in breast cancer (Review).
Xian-Ju Qin, Bruce X Ling.
Oncol Lett, 2012 Jun 29; 3(4). PMID: 22740985    Free PMC article.
Network analysis of gene lists for finding reproducible prognostic breast cancer gene signatures.
Ulykbek Kairov, Tatyana Karpenyuk, Erlan Ramanculov, Andrei Zinovyev.
Bioinformation, 2012 Oct 12; 8(16). PMID: 23055628    Free PMC article.
Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer.
Bas Franken, Marco R de Groot, +4 authors, Leon W M M Terstappen.
Breast Cancer Res, 2012 Oct 24; 14(5). PMID: 23088337    Free PMC article.
Non-invasive proteomics-thinking about personalized breast cancer screening and treatment.
Manuel Debald, Matthias Wolfgarten, +2 authors, Michael Braun.
EPMA J, 2010 Sep 01; 1(3). PMID: 23199085    Free PMC article.
Prediction and prognosis: impact of gene expression profiling in personalized treatment of breast cancer patients.
Michael R Mallmann, Andrea Staratschek-Jox, +5 authors, Joachim L Schultze.
EPMA J, 2010 Sep 01; 1(3). PMID: 23199086    Free PMC article.
KLF6-SV1 drives breast cancer metastasis and is associated with poor survival.
Raheleh Hatami, Anieta M Sieuwerts, +13 authors, Goutham Narla.
Sci Transl Med, 2013 Jan 25; 5(169). PMID: 23345610    Free PMC article.
Translating metastasis-related biomarkers to the clinic--progress and pitfalls.
François-Clément Bidard, Jean-Yves Pierga, Jean-Charles Soria, Jean Paul Thiery.
Nat Rev Clin Oncol, 2013 Feb 06; 10(3). PMID: 23381003
Review.
A data similarity-based strategy for meta-analysis of transcriptional profiles in cancer.
Qingchao Qiu, Pengcheng Lu, +6 authors, Yajun Yi.
PLoS One, 2013 Feb 06; 8(1). PMID: 23383020    Free PMC article.
Detection of cancer before distant metastasis.
Frank A W Coumans, Sabine Siesling, Leon W M M Terstappen.
BMC Cancer, 2013 Jun 15; 13. PMID: 23763955    Free PMC article.
Molecular profiling for breast cancer: a comprehensive review.
Muaiad Kittaneh, Alberto J Montero, Stefan Glück.
Biomark Cancer, 2013 Nov 20; 5. PMID: 24250234    Free PMC article.
Review.
Systematic assessment of prognostic gene signatures for breast cancer shows distinct influence of time and ER status.
Xi Zhao, Einar Andreas Rødland, +5 authors, Anne-Lise Børresen-Dale.
BMC Cancer, 2014 Mar 22; 14. PMID: 24645668    Free PMC article.
Evaluation and correlation of risk recurrence in early breast cancer assessed by Oncotype DX®, clinicopathological markers and tumor cell dissemination in the blood and bone marrow.
Bahriye Aktas, Agnes Bankfalvi, +2 authors, Sabine Kasimir-Bauer.
Mol Clin Oncol, 2014 Mar 22; 1(6). PMID: 24649291    Free PMC article.
Bioinformatics for precision medicine in oncology: principles and application to the SHIVA clinical trial.
Nicolas Servant, Julien Roméjon, +20 authors, Philippe Hupé.
Front Genet, 2014 Jun 10; 5. PMID: 24910641    Free PMC article.
Review.
Cross-study validation for the assessment of prediction algorithms.
Christoph Bernau, Markus Riester, +4 authors, Lorenzo Trippa.
Bioinformatics, 2014 Jun 17; 30(12). PMID: 24931973    Free PMC article.
Más-o-menos: a simple sign averaging method for discrimination in genomic data analysis.
Sihai Dave Zhao, Giovanni Parmigiani, Curtis Huttenhower, Levi Waldron.
Bioinformatics, 2014 Jul 26; 30(21). PMID: 25061068    Free PMC article.
The value of multigene predictors of clinical outcome in breast cancer: an analysis of the evidence.
Amalia M Issa, Vivek S Chaudhari, Gary E Marchant.
Expert Rev Mol Diagn, 2014 Dec 06; 15(2). PMID: 25479414    Free PMC article.
Review.
Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity.
Biswanath Majumder, Ulaganathan Baraneedharan, +20 authors, Pradip K Majumder.
Nat Commun, 2015 Feb 28; 6. PMID: 25721094    Free PMC article.
Highly Cited.
Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.
Wies van Roosmalen, Sylvia E Le Dévédec, +15 authors, Bob van de Water.
J Clin Invest, 2015 Mar 17; 125(4). PMID: 25774502    Free PMC article.
Highly Cited.
Identifying patients at high risk of breast cancer recurrence: strategies to improve patient outcomes.
Yehoda M Martei, Jennifer M Matro.
Breast Cancer (Dove Med Press), 2015 Oct 28; 7. PMID: 26504408    Free PMC article.
Review.
Prognostic signatures of breast cancer: Perou's molecular subtypes and Schmidt's metagenes.
Cristina Cadenas.
EXCLI J, 2012 Jan 01; 11. PMID: 27231466    Free PMC article.
Personalized chemotherapy selection for breast cancer using gene expression profiles.
Kaixian Yu, Qing-Xiang Amy Sang, +6 authors, Jinfeng Zhang.
Sci Rep, 2017 Mar 04; 7. PMID: 28256629    Free PMC article.
Clinical utility of multigene profiling assays in early-stage breast cancer.
M C Chang, L H Souter, +6 authors, Molecular Oncology Advisory Committee.
Curr Oncol, 2017 Nov 02; 24(5). PMID: 29089811    Free PMC article.
21-Gene Recurrence Score for prognosis and prediction of taxane benefit after adjuvant chemotherapy plus endocrine therapy: results from NSABP B-28/NRG Oncology.
Eleftherios P Mamounas, Gong Tang, +14 authors, Norman Wolmark.
Breast Cancer Res Treat, 2017 Nov 13; 168(1). PMID: 29128898    Free PMC article.
The 21-gene Recurrence Score® assay predicts distant recurrence in lymph node-positive, hormone receptor-positive, breast cancer patients treated with adjuvant sequential epirubicin- and docetaxel-based or epirubicin-based chemotherapy (PACS-01 trial).
Frédérique Penault-Llorca, Thomas Filleron, +12 authors, Henri Roché.
BMC Cancer, 2018 May 08; 18(1). PMID: 29728098    Free PMC article.
Differential impact of classical and non-canonical NF-κB pathway-related gene expression on the survival of breast cancer patients.
Nancy Adriana Espinoza-Sánchez, Balázs Győrffy, Ezequiel M Fuentes-Pananá, Martin Götte.
J Cancer, 2019 Oct 12; 10(21). PMID: 31602271    Free PMC article.
Amplification of Stem Genes: New Potential Metastatic Makers in Patients with an Early Form of Breast Cancer.
Matvey M Tsyganov, Marina K Ibragimova, +3 authors, Nikolai V Litviakov.
J Korean Med Sci, 2019 Dec 21; 34(49). PMID: 31858753    Free PMC article.
Upcoming Revolutionary Paths in Preclinical Modeling of Pancreatic Adenocarcinoma.
Mirna Swayden, Philippe Soubeyran, Juan Iovanna.
Front Oncol, 2020 Feb 11; 9. PMID: 32038993    Free PMC article.
Review.
Indications for prognostic gene expression profiling in early breast cancer.
Erin F Cobain, Daniel F Hayes.
Curr Treat Options Oncol, 2015 May 02; 16(5). PMID: 25929335
Review.
A Competing Risk Analysis Model to Determine the Prognostic Value of Isolated Tumor Cells in Axillary Lymph Nodes for T1N0M0 Breast Cancer Patients Based on the Surveillance, Epidemiology, and End Results Database.
Yijun Li, Huimin Zhang, +7 authors, Can Zhou.
Front Oncol, 2020 Oct 20; 10. PMID: 33072606    Free PMC article.
Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.
Iris Schrijver, Nazneen Aziz, +16 authors, Jane S Gibson.
J Mol Diagn, 2012 Aug 25; 14(6). PMID: 22918138    Free PMC article.
A multiple breast cancer stem cell model to predict recurrence of T1-3, N0 breast cancer.
Yan Qiu, Liya Wang, +8 authors, Hong Bu.
BMC Cancer, 2019 Jul 26; 19(1). PMID: 31340763    Free PMC article.
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Ainhoa Arana Echarri, Mark Beresford, +6 authors, James E Turner.
Front Immunol, 2021 Feb 19; 11. PMID: 33597950    Free PMC article.
Review.