Tumor Gene Expression Profiling in Women with Breast Cancer



Differences in the expression of specific genes within breast tumors have been associated with risk of recurrence after treatment. Most women with Stage I or II node-negative breast cancer (especially when estrogen-receptor positive and treated with tamoxifen) remain disease-free at 10 years. Information on risk of recurrence could help identify women most likely to benefit from chemotherapy. Several clinically available gene expression profiles (GEP) provide “recurrence risk scores” that are intended to supplement information used by clinicians and patients in treatment decision-making.

Clinical Scenario

Tumor gene expression profiling in women with Stage I or II node-negative breast cancer to predict recurrence risk and guide decisions about chemotherapy.

Test Description

Reverse transcription PCR is used by Oncotype DX and the H:I Ratio Test (Breast cancer Gene Expression Ratio Assay) for the detection and quantification of mRNA in formalin fixed, paraffin-embedded breast cancer tissue. Oncotype DX analyzes the expression of 21 genes (16 cancer related and 5 normative). The H:I Ratio Test measures the ratio of the expression of the homeobox gene-B13 (HOXB13) and the interleukin-17B receptor gene (IL17BR). MammaPrint uses micro-array technology to test for 70 cancer related and about 1800 normative genes in unfixed (fresh or frozen) breast cancer tissue. [1][2]

Public Health Importance

Breast cancer is the most commonly diagnosed cancer in U.S. women with an estimated 207,090 new cases in 2010. Among U.S. women, it is the second leading cause of cancer-related deaths (estimated 39,840 deaths in 2010). [3] Stage I/II accounts for over 50% of all diagnoses, and is associated with a 5 year survival rate of 98%. [4] Among women with early stage node-negative disease, the majority elect to receive chemotherapy on the basis of standard recurrence risk classification using tumor characteristics. [5][6] Approximately 60%, 5%, and 0.5% of women respectively will experience minor, major or fatal toxicity from chemotherapy. [7][8] Studies of use of breast cancer GEP suggest changes in treatment decisions in approximately 25-30% of cases, most commonly selection of endocrine therapy alone due to reclassification of women from high to low-risk of recurrence . [9][10] If tumor gene expression profiles are conclusively shown to result in more accurate classification of women into low and high recurrence risk categories, theoretical benefits would include avoidance of unnecessary chemotherapy and reduced disease recurrence rates.

Published Reviews, Recommendations and Guidelines

Systematic evidence reviews

Agency for Healthcare Research and Quality, Evidence Report/Technology Assessment [2] Blue Cross and Blue Shield Association, Technology Assessment [11]

Recommendations by independent group*

Available data have been systematically reviewed and evaluated, providing the basis for a recommendation statement: “The Evaluation of Genomics in Practice and Prevention (EGAPP) Working Group found insufficient evidence to make a recommendation for or against the use of tumor gene expression profiles to improve outcomes in defined populations of women with breast cancer.” [1]

Guidelines by professional groups

  • National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology – Breast Cancer [12] American Society of Clinical Oncology: 2007 Update of Recommendations for the use of tumor markers in breast cancer [13] ECRI Institute: Policy Statement [14]
  • American Society of Clinical Oncology: 2007 Update of Recommendations for the use of tumor markers in breast cancer [13]
  • ECRI Institute: Policy Statement [14]

* independent groups include the US Preventive Services Task Force (USPSTF) and Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.

Evidence Overview

Analytic Validity :
Test accuracy and reliability in measuring differences in expression of relevant genes (analytic sensitivity and specificity).

  • A 2009 EGAPP Working Group recommendation statement [1]suggested that:

    • limited published data are available regarding assay performance of clinically available GEP,
    • analytic sensitivity and specificity cannot be estimated because no reference technology (“gold standard”) is available for comparison,
    • initial test failure rates ranged from 12-19%, partly because of problems with tissue sampling and processing.
  • One published reference on Oncotype DX analytical validity sponsored by the test manufacturer is available. [15]
  • he FDA summary of MammaPrint provided information on result and classification accuracy [16]

Clinical Validity :
Test accuracy and reliability in predicting breast cancer recurrence and benefit from chemotherapy (predictive value).

  • Several studies have reported on the clinical validity for Oncotype DX.[17][18][19][20]
  • A recent study reported an association between the Oncotype DX recurrence score and risk of locoregional recurrence using data from the NSABP B-14 and B-20 trials.[21]
  • Published studies regarding MammaPrint have suggested a significant association between the MammaPrint Index (high vs. low risk) and 5 and 10 year distant recurrence rates.[22][23][24]However:

    • efficacy in ER positive vs. negative cases is unclear,[1]
    • added value beyond standard risk stratification is unclear.[1]
  • A parallel, prospective evaluation was recently published comparing three gene expression profile tests analogous to Oncotype DX, Mammaprint and the H:I Ratio Test.
  • All were significantly associated with time to progression; however, concordance of results among the three classifiers was relatively low, classifying only 45-61% of patients in the same category.[25]

Clinical Utility: Net benefit of test in improving health outcomes.

  • Retrospective analysis of one arm of a single prospective trial (NSABP B-20) showed that chemotherapy (in addition to tamoxifen) was most beneficial in women in the Oncotype DX high risk category.[20]
  • A prospective multicenter study published in 2010 reported on the impact of Oncotype DX on patient and physician adjuvant chemotherapy decisions.[9]
  • Analyses of economic implications of Oncotype DX have been published. [5][26]
  • 2010 publication explored women’s experiences with genomic testing for breast cancer recurrence risk in terms of how scores were received and understood.[27]
  • A 2009 EGAPP recommendation reported that no direct evidence linked the use of MammaPrint or the H:I test to clinical outcomes.[1]
  • Ongoing trials include:

    • TAILORx trial (Oncotype DX)[28]
    • INDACT trial (MammaPrint)[29]


For recent additions to the literature, see PubMed special query (2007-present).

U.S. Food and Drug Administration : Search FDA 510(k) database

Last updated: June 8, 2010


  • Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can tumor gene expression profiling improve outcomes in patients with breast cancer? Genet Med. 2009 Jan;11(1):66-73. PubMed PMID: 19125125; PubMed Central PMCID: PMC2743614.
  • Marchionni L, Wilson RF, Marinopoulos SS, Wolff AC, Parmigiani G, Bass EB, Goodman SN. Impact of gene expression profiling tests on breast cancer outcomes. Evid Rep Technol Assess (Full Rep). 2007 Dec;(160):1-105. Review. PubMed PMID: 18457476.
  • Cancer Facts and Figures 2010. Accessed 5/18/10:
    Reference Link
  • SEER Breast Cancer Statistics. Accessed 5/18/10:
    Reference Link
  • Hornberger J, Cosler LE, Lyman GH. Economic analysis of targeting chemotherapy using a 21-gene RT-PCR assay in lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer. Am J Manag Care. 2005 May;11(5):313-24. Erratum in: Am J Manag Care. 2005 Aug;11(8):476. PubMed PMID: 15898220.
  • Cole BF, Gelber RD, Gelber S, Coates AS, Goldhirsch A. Polychemotherapy for early breast cancer: an overview of the randomised clinical trials with quality-adjusted survival analysis. Lancet. 2001 Jul 28;358(9278):277-86. Review. PubMed PMID: 11498214.
  • Desch CE, Hillner BE, Smith TJ, Retchin SM. Should the elderly receive chemotherapy for node-negative breast cancer? A cost-effectiveness analysis examining total and active life-expectancy outcomes. J Clin Oncol. 1993 Apr;11(4):777-82. PubMed PMID: 8478671.
  • Hillner BE, Smith TJ. Efficacy and cost effectiveness of adjuvant chemotherapy in women with node-negative breast cancer. A decision-analysis model. N Engl J Med. 1991 Jan 17;324(3):160-8. PubMed PMID: 1898533.
  • Lo SS, Mumby PB, Norton J, Rychlik K, Smerage J, Kash J, Chew HK, Gaynor ER, Hayes DF, Epstein A, Albain KS. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010 Apr 1;28(10):1671-6. Epub 2010 Jan 11. PubMed PMID: 20065191.
  • Henry LR, Stojadinovic A, Swain SM, Prindiville S, Cordes R, Soballe PW. The influence of a gene expression profile on breast cancer decisions. J Surg Oncol. 2009 May 1;99(6):319-23. PubMed PMID: 19204954.
  • Piper MA. Gene expression profiling of breast cancer to select women for adjuvant chemotherapy. Technology Evaluation Center. Assessment Program 2008;22:1-51. Accessed October 26, 2009:
    Reference Link
  • National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology – Breast Cancer, v 1.2010. Accessed 5/18/10:
    Reference Link
  • Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr; American Society of Clinical Oncology. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007 Nov 20;25(33):5287-312. Epub 2007 Oct 22. Review. PubMed PMID: 17954709.
  • ECRI Institute, Gene expression profiling of breast cancer to predict the likelihood of recurrence, August 2007. ECRI Institute. To subscribers only:
    Reference Link
  • Cronin M, Sangli C, Liu ML, Pho M, Dutta D, Nguyen A, Jeong J, Wu J, Langone KC, Watson D. Analytical validation of the Oncotype DX genomic diagnostic test for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer. Clin Chem. 2007 Jun;53(6):1084-91. Epub 2007 Apr 26. PubMed PMID: 17463177.
  • 501(k) Submission for MammaPrint Service in the US Section 5: 501(k) Summary. Accessed 5/18/10:
    Reference Link
  • Habel LA, Shak S, Jacobs MK, Capra A, Alexander C, Pho M, Baker J, Walker M, Watson D, Hackett J, Blick NT, Greenberg D, Fehrenbacher L, Langholz B, Quesenberry CP. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8(3):R25. Epub 2006 May 31. PubMed PMID: 16737553; PubMed Central PMCID: PMC1557737.
  • Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004 Dec 30;351(27):2817-26. Epub 2004 Dec 10. PubMed PMID: 15591335.
  • Esteva FJ, Sahin AA, Cristofanilli M, Coombes K, Lee SJ, Baker J, Cronin M, Walker M, Watson D, Shak S, Hortobagyi GN. Prognostic role of a multigene reverse transcriptase-PCR assay in patients with node-negative breast cancer not receiving adjuvant systemic therapy. Clin Cancer Res. 2005 May 1;11(9):3315-9. PubMed PMID: 15867229.
  • Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Geyer CE Jr, Wickerham DL, Wolmark N. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006 Aug 10;24(23):3726-34. Epub 2006 May 23. PubMed PMID: 16720680.
  • Mamounas EP, Tang G, Fisher B, Paik S, Shak S, Costantino JP, Watson D, Geyer CE Jr, Wickerham DL, Wolmark N. 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. J Clin Oncol. 2010 Apr 1;28(10):1677-83. Epub 2010 Jan 11. PubMed PMID: 20065188; PubMed Central PMCID: PMC2849763.
  • Glas AM, Floore A, Delahaye LJ, Witteveen AT, Pover RC, Bakx N, Lahti-Domenici JS, Bruinsma TJ, Warmoes MO, Bernards R, Wessels LF, Van't Veer LJ. Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics. 2006 Oct 30;7:278. PubMed PMID: 17074082; PubMed Central PMCID: PMC1636049.
  • Buyse M, Loi S, van't Veer L, Viale G, Delorenzi M, Glas AM, d'Assignies MS, Bergh J, Lidereau R, Ellis P, Harris A, Bogaerts J, Therasse P, Floore A, Amakrane M, Piette F, Rutgers E, Sotiriou C, Cardoso F, Piccart MJ; TRANSBIG Consortium. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006 Sep 6;98(17):1183-92. PubMed PMID: 16954471.
  • van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002 Jan 31;415(6871):530-6. PubMed PMID: 11823860.
  • Kok M, Linn SC, Van Laar RK, Jansen MP, van den Berg TM, Delahaye LJ, Glas AM, Peterse JL, Hauptmann M, Foekens JA, Klijn JG, Wessels LF, Van't Veer LJ, Berns EM. Comparison of gene expression profiles predicting progression in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat. 2009 Jan;113(2):275-83. Epub 2008 Mar 4. PubMed PMID: 18311582.
  • Klang SH, Hammerman A, Liebermann N, Efrat N, Doberne J, Hornberger J. Economic Implications of 21-Gene Breast Cancer Risk Assay from the Perspective of an Israeli-Managed Health-Care Organization. Value Health. 2010 Apr 15. [Epub ahead of print] PubMed PMID: 20412544.
  • Tzeng JP, Mayer D, Richman AR, Lipkus I, Han PK, Valle CG, Carey LA, Brewer NT. Women's experiences with genomic testing for breast cancer recurrence risk. Cancer. 2010 Apr 15;116(8):1992-2000. PubMed PMID: 20213682.
  • National Cancer Institute, National Institutes of Health. TAILORx Breast Cancer Trial. National Cancer Institute. Accessed October 26, 2009:
    Reference Link
  • European Organisation for Research and Treatment of Cancer. Microarray in node negative disease may avoid chemotherapy (MINDACT) Trial. European Organisation for Research and Treatment of Cancer. Acessed October 26, 2009:
    Reference Link

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