. 2010 May;7(6).
doi: 10.1038/nrclinonc.2010.61.

Gene-expression-based prognostic assays for breast cancer

Chungyeul Kim 1 Soonmyung Paik  
  • PMID: 20440284
  •     35 References
  •     46 citations


Several gene-expression-based reference laboratory tests are now available for prognostication of patients diagnosed with breast cancer. For clinical oncologists, it is important to understand the clinical contexts for which these assays were developed in order to use them properly. This Review is aimed at providing a conceptual and technical overview of the steps involved in the development of gene-expression profiling-based prognostic assays. MammaPrint and Oncotype DX, two widely utilized assays, are compared with respect to differences in the clinical contexts for their development, technologies used, and clinical utilities with the aim of providing a guide to clinical oncologists for utilization of these assays.

Analytical validation of the Oncotype DX genomic diagnostic test for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer.
Maureen Cronin, Chithra Sangli, +7 authors, Drew Watson.
Clin Chem, 2007 Apr 28; 53(6). PMID: 17463177
Highly Cited.
Direct multiplexed measurement of gene expression with color-coded probe pairs.
Gary K Geiss, Roger E Bumgarner, +18 authors, Krassen Dimitrov.
Nat Biotechnol, 2008 Feb 19; 26(3). PMID: 18278033
Highly Cited.
Analysis of the MammaPrint breast cancer assay in a predominantly postmenopausal cohort.
Ben S Wittner, Dennis C Sgroi, +9 authors, Sridhar Ramaswamy.
Clin Cancer Res, 2008 May 17; 14(10). PMID: 18483364    Free PMC article.
The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer.
Marieke E Straver, Annuska M Glas, +7 authors, Sjoerd Rodenhuis.
Breast Cancer Res Treat, 2009 Feb 14; 119(3). PMID: 19214742
Quantitative monitoring of gene expression patterns with a complementary DNA microarray.
M Schena, D Shalon, R W Davis, P O Brown.
Science, 1995 Oct 20; 270(5235). PMID: 7569999
Highly Cited.
Commercialized multigene predictors of clinical outcome for breast cancer.
Jeffrey S Ross, Christos Hatzis, +2 authors, Gabriel N Hortobágyi.
Oncologist, 2008 Jun 03; 13(5). PMID: 18515733
Supervised risk predictor of breast cancer based on intrinsic subtypes.
Joel S Parker, Michael Mullins, +17 authors, Philip S Bernard.
J Clin Oncol, 2009 Feb 11; 27(8). PMID: 19204204    Free PMC article.
Highly Cited.
The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age.
S Mook, M K Schmidt, +7 authors, L J van 't Veer.
Ann Oncol, 2009 Oct 15; 21(4). PMID: 19825882
A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients.
Laurel A Habel, Steven Shak, +12 authors, Charles P Quesenberry.
Breast Cancer Res, 2006 Jun 02; 8(3). PMID: 16737553    Free PMC article.
Highly Cited.
Molecular portraits of human breast tumours.
C M Perou, T Sørlie, +15 authors, D Botstein.
Nature, 2000 Aug 30; 406(6797). PMID: 10963602
Highly Cited.
Gene expression profiling predicts clinical outcome of breast cancer.
Laura J van 't Veer, Hongyue Dai, +13 authors, Stephen H Friend.
Nature, 2002 Feb 02; 415(6871). PMID: 11823860
Highly Cited.
The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements.
MAQC Consortium, Leming Shi, +135 authors, William Slikker.
Nat Biotechnol, 2006 Sep 12; 24(9). PMID: 16964229    Free PMC article.
Highly Cited.
Gene expression-based prognostic and predictive markers for breast cancer: a primer for practicing pathologists.
Chungyeul Kim, Yusuke Taniyama, Soonmyung Paik.
Arch Pathol Lab Med, 2009 Jun 06; 133(6). PMID: 19492877    Free PMC article.
Analysis of chemical modification of RNA from formalin-fixed samples and optimization of molecular biology applications for such samples.
N Masuda, T Ohnishi, +2 authors, K Okubo.
Nucleic Acids Res, 1999 Oct 28; 27(22). PMID: 10536153    Free PMC article.
Highly Cited.
Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer.
Julian A Schardt, Manfred Meyer, +7 authors, Christoph A Klein.
Cancer Cell, 2005 Sep 20; 8(3). PMID: 16169467
Individualization of therapy using Mammaprint: from development to the MINDACT Trial.
Stella Mook, Laura J Van't Veer, +2 authors, Fatima Cardoso.
Cancer Genomics Proteomics, 2007 Sep 20; 4(3). PMID: 17878518
Concordance among gene-expression-based predictors for breast cancer.
Cheng Fan, Daniel S Oh, +5 authors, Charles M Perou.
N Engl J Med, 2006 Aug 11; 355(6). PMID: 16899776
Highly Cited.
Technology insight: Application of molecular techniques to formalin-fixed paraffin-embedded tissues from breast cancer.
Soonmyung Paik, Chung-yeul Kim, Yong-kuk Song, Wan-seop Kim.
Nat Clin Pract Oncol, 2005 Nov 03; 2(5). PMID: 16264960
Improvement of the clinical applicability of the Genomic Grade Index through a qRT-PCR test performed on frozen and formalin-fixed paraffin-embedded tissues.
Jérôme Toussaint, Anieta M Sieuwerts, +8 authors, Christos Sotiriou.
BMC Genomics, 2009 Sep 12; 10. PMID: 19744330    Free PMC article.
TAILORx: trial assigning individualized options for treatment (Rx).
Joseph A Sparano.
Clin Breast Cancer, 2006 Nov 10; 7(4). PMID: 17092406
Genomic grade index is associated with response to chemotherapy in patients with breast cancer.
Cornelia Liedtke, Christos Hatzis, +8 authors, Lajos Pusztai.
J Clin Oncol, 2009 Apr 15; 27(19). PMID: 19364972    Free PMC article.
Converting a breast cancer microarray signature into a high-throughput diagnostic test.
Annuska M Glas, Arno Floore, +9 authors, Laura J Van't Veer.
BMC Genomics, 2006 Nov 01; 7. PMID: 17074082    Free PMC article.
Highly Cited.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Soonmyung Paik, Steven Shak, +12 authors, Norman Wolmark.
N Engl J Med, 2004 Dec 14; 351(27). PMID: 15591335
Highly Cited.
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.
Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade.
Sherene Loi, Benjamin Haibe-Kains, +14 authors, Christos Sotiriou.
J Clin Oncol, 2007 Apr 03; 25(10). PMID: 17401012
Highly Cited.
A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer.
Xiao-Jun Ma, Ranelle Salunga, +8 authors, Dennis Sgroi.
Clin Cancer Res, 2008 May 03; 14(9). PMID: 18451222
Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis.
Christos Sotiriou, Pratyaksha Wirapati, +17 authors, Mauro Delorenzi.
J Natl Cancer Inst, 2006 Feb 16; 98(4). PMID: 16478745
Highly Cited.
A gene-expression signature as a predictor of survival in breast cancer.
Marc J van de Vijver, Yudong D He, +18 authors, René Bernards.
N Engl J Med, 2002 Dec 20; 347(25). PMID: 12490681
Highly Cited.
Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
Kathy S Albain, William E Barlow, +20 authors, Breast Cancer Intergroup of North America.
Lancet Oncol, 2009 Dec 17; 11(1). PMID: 20005174    Free PMC article.
Highly Cited.
Clinical application of the 70-gene profile: the MINDACT trial.
Fatima Cardoso, Laura Van't Veer, +3 authors, Martine J Piccart-Gebhart.
J Clin Oncol, 2008 Feb 09; 26(5). PMID: 18258980
Highly Cited.
Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial.
Jan Bogaerts, Fatima Cardoso, +12 authors, TRANSBIG consortium.
Nat Clin Pract Oncol, 2006 Oct 05; 3(10). PMID: 17019432
Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
T Sørlie, C M Perou, +14 authors, A L Børresen-Dale.
Proc Natl Acad Sci U S A, 2001 Sep 13; 98(19). PMID: 11553815    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.
Measurement of gene expression in archival paraffin-embedded tissues: development and performance of a 92-gene reverse transcriptase-polymerase chain reaction assay.
Maureen Cronin, Mylan Pho, +5 authors, Joffre B Baker.
Am J Pathol, 2003 Dec 26; 164(1). PMID: 14695316    Free PMC article.
Highly Cited.
A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients.
Stephanie Roessler, Hu-Liang Jia, +8 authors, Xin Wei Wang.
Cancer Res, 2010 Dec 17; 70(24). PMID: 21159642    Free PMC article.
Highly Cited.
Molecular profiling currently offers no more than tumour morphology and basic immunohistochemistry.
Britta Weigelt, Jorge S Reis-Filho.
Breast Cancer Res, 2011 Jan 05; 12 Suppl 4. PMID: 21172089    Free PMC article.
Challenges to developing proteomic-based breast cancer diagnostics.
Richard R Drake, Lisa H Cazares, +3 authors, Christine Laronga.
OMICS, 2011 Feb 22; 15(5). PMID: 21332380    Free PMC article.
The dChip survival analysis module for microarray data.
Samir B Amin, Parantu K Shah, +5 authors, Cheng Li.
BMC Bioinformatics, 2011 Mar 11; 12. PMID: 21388547    Free PMC article.
Molecular profiling of melanoma and the evolution of patient-specific therapy.
Thomas F Gajewski.
Semin Oncol, 2011 Mar 23; 38(2). PMID: 21421113    Free PMC article.
Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes.
Jatinder K Lamba, Kristine R Crews, +12 authors, Raul C Ribeiro.
Pharmacogenomics, 2011 Apr 01; 12(3). PMID: 21449673    Free PMC article.
E2F1 and KIAA0191 expression predicts breast cancer patient survival.
Robin M Hallett, John A Hassell.
BMC Res Notes, 2011 Apr 02; 4. PMID: 21453498    Free PMC article.
Artificially induced epithelial-mesenchymal transition in surgical subjects: its implications in clinical and basic cancer research.
Kazuhiko Aoyagi, Keiko Minashi, +10 authors, Hiroki Sasaki.
PLoS One, 2011 May 03; 6(4). PMID: 21533028    Free PMC article.
Personalized medicine: new genomics, old lessons.
Kenneth Offit.
Hum Genet, 2011 Jun 28; 130(1). PMID: 21706342    Free PMC article.
Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer.
Rebecca Roylance, David Endesfelder, +12 authors, Charles Swanton.
Cancer Epidemiol Biomarkers Prev, 2011 Jul 26; 20(10). PMID: 21784954    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.
Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence.
Mary Jo Fackler, Christopher B Umbricht, +13 authors, Saraswati Sukumar.
Cancer Res, 2011 Aug 10; 71(19). PMID: 21825015    Free PMC article.
Highly Cited.
Prognostic significance of gene-specific promoter hypermethylation in breast cancer patients.
Yoon Hee Cho, Jing Shen, +11 authors, Regina M Santella.
Breast Cancer Res Treat, 2011 Aug 13; 131(1). PMID: 21837480    Free PMC article.
A new gene expression signature, the ClinicoMolecular Triad Classification, may improve prediction and prognostication of breast cancer at the time of diagnosis.
Dong-Yu Wang, Susan J Done, +3 authors, Wey Liang Leong.
Breast Cancer Res, 2011 Sep 24; 13(5). PMID: 21939527    Free PMC article.
Practical implications of gene-expression-based assays for breast oncologists.
Aleix Prat, Matthew J Ellis, Charles M Perou.
Nat Rev Clin Oncol, 2011 Dec 07; 9(1). PMID: 22143140    Free PMC article.
Highly Cited. Review.
Human genetics and genomics a decade after the release of the draft sequence of the human genome.
Nasheen Naidoo, Yudi Pawitan, +2 authors, Chee-Seng Ku.
Hum Genomics, 2011 Dec 14; 5(6). PMID: 22155605    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.
The prognostic role of RASSF1A promoter methylation in breast cancer: a meta-analysis of published data.
Yong Jiang, Lin Cui, +2 authors, Li-dong Ding.
PLoS One, 2012 May 23; 7(5). PMID: 22615811    Free PMC article.
RNA-Seq and human complex diseases: recent accomplishments and future perspectives.
Valerio Costa, Marianna Aprile, Roberta Esposito, Alfredo Ciccodicola.
Eur J Hum Genet, 2012 Jun 29; 21(2). PMID: 22739340    Free PMC article.
HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers.
Marc L Mendillo, Sandro Santagata, +7 authors, Susan Lindquist.
Cell, 2012 Aug 07; 150(3). PMID: 22863008    Free PMC article.
Highly Cited.
From drug discovery to biomarker-driven clinical trials in lymphoma.
Anas Younes, Donald A Berry.
Nat Rev Clin Oncol, 2012 Sep 12; 9(11). PMID: 22965151    Free PMC article.
FOXM1 coming of age: time for translation into clinical benefits?
Muy-Teck Teh.
Front Oncol, 2012 Oct 23; 2. PMID: 23087907    Free PMC article.
Clinical value of prognosis gene expression signatures in colorectal cancer: a systematic review.
Rebeca Sanz-Pamplona, Antoni Berenguer, +11 authors, Victor Moreno.
PLoS One, 2012 Nov 13; 7(11). PMID: 23145004    Free PMC article.
Systematic Review.
Nervous system regulation of the cancer genome.
Steven W Cole.
Brain Behav Immun, 2012 Dec 05; 30 Suppl. PMID: 23207104    Free PMC article.
Biomarkers and sustainable innovation in cardiovascular drug development: lessons from near and far afield.
Russell M Medford, T Forcht Dagi, Robert S Rosenson, Margaret K Offermann.
Curr Atheroscler Rep, 2013 Mar 21; 15(5). PMID: 23512605
Organ Specific Tumor Markers: What's New?
Kannan Vaidyanathan, D M Vasudevan.
Indian J Clin Biochem, 2013 Apr 02; 27(2). PMID: 23542399    Free PMC article.
Examining the pathogenesis of breast cancer using a novel agent-based model of mammary ductal epithelium dynamics.
Joaquin Chapa, Ryan J Bourgo, +2 authors, Gary An.
PLoS One, 2013 May 25; 8(5). PMID: 23704974    Free PMC article.
Using large-scale molecular data sets to improve breast cancer treatment.
Chad J Creighton.
Breast Cancer Manag, 2012 May 01; 1(1). PMID: 23869198    Free PMC article.
Neoadjuvant endocrine treatment for breast cancer: from bedside to bench and back again?
R R Saleh, N Bouganim, +2 authors, M Clemons.
Curr Oncol, 2014 Feb 14; 21(1). PMID: 24523609    Free PMC article.
Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer.
Thomas E Rohan, Xiaonan Xue, +10 authors, Joan G Jones.
J Natl Cancer Inst, 2014 Jun 05; 106(8). PMID: 24895374    Free PMC article.
Highly Cited.
Downregulation of DYRK2 can be a predictor of recurrence in early stage breast cancer.
Yasuko Enomoto, Shin-ichi Yamashita, +4 authors, Akinori Iwasaki.
Tumour Biol, 2014 Aug 07; 35(11). PMID: 25095982
Biological subtypes of breast cancer: Prognostic and therapeutic implications.
Ozlem Yersal, Sabri Barutca.
World J Clin Oncol, 2014 Aug 13; 5(3). PMID: 25114856    Free PMC article.
Highly Cited. Review.
A program to identify prognostic and predictive gene signatures.
Sam D Chorlton, Robin M Hallett, John A Hassell.
BMC Res Notes, 2014 Aug 20; 7. PMID: 25135081    Free PMC article.
The predictive accuracy of PREDICT: a personalized decision-making tool for Southeast Asian women with breast cancer.
Hoong-Seam Wong, Shridevi Subramaniam, +7 authors, Nirmala Bhoo-Pathy.
Medicine (Baltimore), 2015 Feb 26; 94(8). PMID: 25715267    Free PMC article.
A microRNA code for prostate cancer metastasis.
D Bonci, V Coppola, +15 authors, R De Maria.
Oncogene, 2015 Jun 16; 35(9). PMID: 26073083    Free PMC article.
Omics Profiling in Precision Oncology.
Kun-Hsing Yu, Michael Snyder.
Mol Cell Proteomics, 2016 Apr 22; 15(8). PMID: 27099341    Free PMC article.
An international comparability study on quantification of mRNA gene expression ratios: CCQM-P103.1.
Alison S Devonshire, Rebecca Sanders, +41 authors, Carole A Foy.
Biomol Detect Quantif, 2016 Jun 24; 8. PMID: 27335807    Free PMC article.
Specificity of Genetic Biomarker Studies in Cancer Research: A Systematic Review.
Garrett Green, Ruben Carmona, +5 authors, Loren K Mell.
PLoS One, 2016 Jul 08; 11(7). PMID: 27383192    Free PMC article.
Systematic Review.
Liquid biopsy and therapeutic response: Circulating tumor cell cultures for evaluation of anticancer treatment.
Bee Luan Khoo, Gianluca Grenci, +5 authors, Chwee Teck Lim.
Sci Adv, 2016 Jul 28; 2(7). PMID: 27453941    Free PMC article.
Breast cancer classification and prognostication through diverse systems along with recent emerging findings in this respect; the dawn of new perspectives in the clinical applications.
Vida Pourteimoor, Samira Mohammadi-Yeganeh, Mahdi Paryan.
Tumour Biol, 2016 Sep 22; 37(11). PMID: 27651157
Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack.
Michela Bulfoni, Matteo Turetta, +3 authors, Daniela Cesselli.
Int J Mol Sci, 2016 Oct 27; 17(10). PMID: 27783057    Free PMC article.
Performance Characteristics of the BluePrint® Breast Cancer Diagnostic Test.
Lorenza Mittempergher, Leonie Jmj Delahaye, +7 authors, Annuska M Glas. Electronic address:
Transl Oncol, 2020 Mar 26; 13(4). PMID: 32208353    Free PMC article.
A Comparison Between the Online Prediction Models CancerMath and PREDICT as Prognostic Tools in Thai Breast Cancer Patients.
Nuanphan Polchai, Doonyapat Sa-Nguanraksa, +3 authors, Pornchai O-Charoenrat.
Cancer Manag Res, 2020 Aug 06; 12. PMID: 32753968    Free PMC article.
Metformin Reshapes the Methylation Profile in Breast and Colorectal Cancer Cells
Hussein Sabit, Shimaa E Abdel-Ghany, +2 authors, Mokhtar El-Zawahry.
Asian Pac J Cancer Prev, 2018 Oct 30; 19(10). PMID: 30371994    Free PMC article.
Advances in liquid biopsy using circulating tumor cells and circulating cell-free tumor DNA for detection and monitoring of breast cancer.
Xiaofen Zhang, Shaoqing Ju, Xudong Wang, Hui Cong.
Clin Exp Med, 2019 Jun 14; 19(3). PMID: 31190187
Prognostic gene expression signatures of breast cancer are lacking a sensible biological meaning.
Kalifa Manjang, Shailesh Tripathi, +3 authors, Frank Emmert-Streib.
Sci Rep, 2021 Jan 10; 11(1). PMID: 33420139    Free PMC article.