Review
. 2014 Dec;15(2).
doi: 10.1586/14737159.2015.983476.

The value of multigene predictors of clinical outcome in breast cancer: an analysis of the evidence

Amalia M Issa 1 Vivek S Chaudhari  Gary E Marchant  
Affiliations
  • PMID: 25479414
  •     68 References
  •     4 citations

Abstract

Objective: Multigene predictors are being used increasingly in early-stage breast cancer patients for prediction and prognosis. However, one consequence of the increased use of multigene predictors, and the heightened efforts toward their incorporation into routine clinical practice, is the potential for future malpractice litigation. It is, therefore, important to ascertain the strength of the evidence for using the different commercially available multigene predictor assays clinically. We evaluated the literature for evidence of clinical validity of four currently available gene signatures and to assess the influence of the 21-gene-expression assay on changes in treatment recommendations.

Methods: A systematic search of the peer-reviewed literature from January 2002 to March 2014 for multigene predictor assays was carried out, and a meta-analysis was conducted.

Results: The adjusted Cox hazard ratio average for studies that met the eligibility criteria was 3.538 (95% CI: 1.513-8.469). The 21-gene signature showed the highest stability in the estimation of likelihood of distant risk of recurrence. Using the recurrence scores resulted in changes in treatment recommendations in 31.8% of all patients in the studies.

Conclusion: This study may provide insight about the use of multigene predictors in clinical practice for prediction and prognosis of breast cancer.

Keywords: Cox hazard ratios; breast cancer; gene-expression profiling; meta-analysis; multigene predictors; recurrence score.

Integration of Systemic Chemotherapy in the Management of Primary Breast Cancer.
Esteva, Hortobagyi.
Oncologist, 1999 Jul 01; 3(5). PMID: 10388120
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.
Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer.
Yixin Wang, Jan G M Klijn, +11 authors, John A Foekens.
Lancet, 2005 Feb 22; 365(9460). PMID: 15721472
Highly Cited.
Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes.
Melody A Cobleigh, Bita Tabesh, +7 authors, Steven Shak.
Clin Cancer Res, 2005 Dec 20; 11(24 Pt 1). PMID: 16361546
Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer.
John A Foekens, David Atkins, +17 authors, Yixin Wang.
J Clin Oncol, 2006 Mar 01; 24(11). PMID: 16505412
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.
Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer.
Marc Buyse, Sherene Loi, +18 authors, TRANSBIG Consortium.
J Natl Cancer Inst, 2006 Sep 07; 98(17). PMID: 16954471
Highly Cited.
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.
TAILORx: trial assigning individualized options for treatment (Rx).
Joseph A Sparano.
Clin Breast Cancer, 2006 Nov 10; 7(4). PMID: 17092406
Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series.
Christine Desmedt, Fanny Piette, +18 authors, TRANSBIG Consortium.
Clin Cancer Res, 2007 Jun 05; 13(11). PMID: 17545524
Highly Cited.
Systematic review: gene expression profiling assays in early-stage breast cancer.
Luigi Marchionni, Renee F Wilson, +4 authors, Steven N Goodman.
Ann Intern Med, 2008 Feb 07; 148(5). PMID: 18252678
Systematic Review.
Comparison of gene expression profiles predicting progression in breast cancer patients treated with tamoxifen.
Marleen Kok, Sabine C Linn, +11 authors, Els M J J Berns.
Breast Cancer Res Treat, 2008 Mar 04; 113(2). PMID: 18311582
The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study.
Stella Mook, Marjanka K Schmidt, +10 authors, TRANSBIG Consortium.
Breast Cancer Res Treat, 2008 Jul 29; 116(2). PMID: 18661261
Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes.
Christine Desmedt, Benjamin Haibe-Kains, +6 authors, Christos Sotiriou.
Clin Cancer Res, 2008 Aug 14; 14(16). PMID: 18698033
Highly Cited.
Does oncotype DX recurrence score affect the management of patients with early-stage breast cancer?
Juhi Asad, Allyson F Jacobson, +7 authors, Paul I Tartter.
Am J Surg, 2008 Sep 24; 196(4). PMID: 18809056
Validation of 70-gene prognosis signature in node-negative breast cancer.
J M Bueno-de-Mesquita, S C Linn, +16 authors, M J van de Vijver.
Breast Cancer Res Treat, 2008 Sep 27; 117(3). PMID: 18819002
The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy.
Yi Zhang, Anieta M Sieuwerts, +17 authors, John A Foekens.
Breast Cancer Res Treat, 2008 Sep 30; 116(2). PMID: 18821012
Chemosensitivity and stratification by a five monoclonal antibody immunohistochemistry test in the NSABP B14 and B20 trials.
Douglas T Ross, Chung-Yeul Kim, +7 authors, Norman Wolmark.
Clin Cancer Res, 2008 Oct 18; 14(20). PMID: 18927301    Free PMC article.
The influence of a gene expression profile on breast cancer decisions.
Leonard R Henry, Alexander Stojadinovic, +3 authors, Peter W Soballe.
J Surg Oncol, 2009 Feb 11; 99(6). PMID: 19204954
Chemotherapy in older women with breast cancer.
Yue-Can Zeng.
N Engl J Med, 2009 Sep 04; 361(10). PMID: 19726778
Stage I breast cancer in a regional oncology practice in Israel 2002-2006: clinicopathologic features, risk estimation and planned therapy of 328 consecutive patients.
D B Geffen, N Amir, +7 authors, M Koretz.
Breast, 2009 Oct 13; 18(5). PMID: 19819143
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
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.
Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection.
Shelly S Lo, Patricia B Mumby, +8 authors, Kathy S Albain.
J Clin Oncol, 2010 Jan 13; 28(10). PMID: 20065191
Highly Cited.
Metastatic potential of T1 breast cancer can be predicted by the 70-gene MammaPrint signature.
Stella Mook, Michael Knauer, +5 authors, Emiel J Rutgers.
Ann Surg Oncol, 2010 Jan 23; 17(5). PMID: 20094918
The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer.
Michael Knauer, Stella Mook, +7 authors, Laura J van 't Veer.
Breast Cancer Res Treat, 2010 Mar 06; 120(3). PMID: 20204499
Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study.
Mitch Dowsett, Jack Cuzick, +11 authors, Steven Shak.
J Clin Oncol, 2010 Mar 10; 28(11). PMID: 20212256
Highly Cited.
Economic implications of 21-gene breast cancer risk assay from the perspective of an Israeli-managed health-care organization.
Shmuel H Klang, Ariel Hammerman, +3 authors, John Hornberger.
Value Health, 2010 Apr 24; 13(4). PMID: 20412544
Impact of a commercial reference laboratory test recurrence score on decision making in early-stage breast cancer.
Ruth Oratz, Dev Paul, Allen L Cohn, Scot M Sedlacek.
J Oncol Pract, 2007 Jul 01; 3(4). PMID: 20859407    Free PMC article.
Identification of a low-risk subgroup of HER-2-positive breast cancer by the 70-gene prognosis signature.
M Knauer, F Cardoso, +4 authors, L J van 't Veer.
Br J Cancer, 2010 Nov 18; 103(12). PMID: 21081926    Free PMC article.
The effects of oncotype DX recurrence scores on chemotherapy utilization in a multi-institutional breast cancer cohort.
Foluso O Ademuyiwa, Austin Miller, +5 authors, Sunil Badve.
Breast Cancer Res Treat, 2011 Jan 05; 126(3). PMID: 21197567
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.
Impact of the 21-gene recurrence score assay compared with standard clinicopathologic guidelines in adjuvant therapy selection for node-negative, estrogen receptor-positive breast cancer.
Jessica F Partin, Eleftherios P Mamounas.
Ann Surg Oncol, 2011 May 04; 18(12). PMID: 21537874
Prospective transGEICAM study of the impact of the 21-gene Recurrence Score assay and traditional clinicopathological factors on adjuvant clinical decision making in women with estrogen receptor-positive (ER+) node-negative breast cancer.
J Albanell, A González, +17 authors, A Lluch.
Ann Oncol, 2011 Jun 10; 23(3). PMID: 21652577
Gene expression profile testing for breast cancer and the use of chemotherapy, serious adverse effects, and costs of care.
Jennifer S Haas, Su-Ying Liang, +3 authors, Kathryn A Phillips.
Breast Cancer Res Treat, 2011 Jun 18; 130(2). PMID: 21681446    Free PMC article.
Physician survey of the effect of the 21-gene recurrence score assay results on treatment recommendations for patients with lymph node-positive, estrogen receptor-positive breast cancer.
Ruth Oratz, Benjamin Kim, +4 authors, Michael Broder.
J Oncol Pract, 2011 Jul 07; 7(2). PMID: 21731516    Free PMC article.
Breast medical oncologists' use of standard prognostic factors to predict a 21-gene recurrence score.
Arif H Kamal, Charles L Loprinzi, +7 authors, Matthew P Goetz.
Oncologist, 2011 Sep 22; 16(10). PMID: 21934103    Free PMC article.
Use of Oncotype DX in Women with Node-Positive Breast Cancer.
Naoko Ishibe, Sheri Schully, Andrew Freedman, Scott David Ramsey.
PLoS Curr, 2011 Oct 11; 3. PMID: 21984342    Free PMC article.
The effect of Oncotype DX recurrence score on treatment recommendations for patients with estrogen receptor-positive early stage breast cancer and correlation with estimation of recurrence risk by breast cancer specialists.
Jennifer E Joh, Nicole N Esposito, +10 authors, Geza Acs.
Oncologist, 2011 Oct 22; 16(11). PMID: 22016474    Free PMC article.
Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer.
Richard G Gray, Philip Quirke, +10 authors, David J Kerr.
J Clin Oncol, 2011 Nov 10; 29(35). PMID: 22067390
Highly Cited.
Integrating breast cancer genetics into clinical practice.
Abhik Mukherjee, Emad A Rakha.
Womens Health (Lond), 2011 Dec 17; 8(1). PMID: 22171779
Review.
Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen.
A Prat, J S Parker, +9 authors, C M Perou.
Ann Oncol, 2012 Apr 26; 23(11). PMID: 22532584    Free PMC article.
Adoption of gene expression profile testing and association with use of chemotherapy among women with breast cancer.
Michael J Hassett, Samuel M Silver, +12 authors, Jane C Weeks.
J Clin Oncol, 2012 May 16; 30(18). PMID: 22585699    Free PMC article.
Why does Oncotype DX recurrence score reduce adjuvant chemotherapy use?
Jeffrey G Schneider, Danny N Khalil.
Breast Cancer Res Treat, 2012 Jun 23; 134(3). PMID: 22723033    Free PMC article.
Treatment Choices Based on OncotypeDx in the Breast Oncology Care Setting.
Teri L Malo, Isaac Lipkus, +3 authors, Susan T Vadaparampil.
J Cancer Epidemiol, 2012 Aug 29; 2012. PMID: 22927848    Free PMC article.
Mammostrat as an immunohistochemical multigene assay for prediction of early relapse risk in the tamoxifen versus exemestane adjuvant multicenter trial pathology study.
John M S Bartlett, Kenneth J Bloom, +13 authors, Daniel Rea.
J Clin Oncol, 2012 Oct 10; 30(36). PMID: 23045591
The 21-gene recurrence score assay impacts adjuvant therapy recommendations for ER-positive, node-negative and node-positive early breast cancer resulting in a risk-adapted change in chemotherapy use.
W Eiermann, M Rezai, +13 authors, J Blohmer.
Ann Oncol, 2012 Nov 09; 24(3). PMID: 23136233    Free PMC article.
Prudent precaution in clinical trials of nanomedicines.
Gary E Marchant, Rachel A Lindor.
J Law Med Ethics, 2013 Jan 08; 40(4). PMID: 23289685
Additional prognostic value of the 70-gene signature (MammaPrint(®)) among breast cancer patients with 4-9 positive lymph nodes.
M Saghatchian, S Mook, +8 authors, L van't Veer.
Breast, 2013 Jan 26; 22(5). PMID: 23347730
A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study.
C A Drukker, J M Bueno-de-Mesquita, +10 authors, S C Linn.
Int J Cancer, 2013 Feb 02; 133(4). PMID: 23371464    Free PMC article.
Gene expression profiling in breast cancer: a clinical perspective.
Grazia Arpino, Daniele Generali, +16 authors, Luigi Dogliotti.
Breast, 2013 Mar 07; 22(2). PMID: 23462680
Review.
A prospective clinical utility and pharmacoeconomic study of the impact of the 21-gene Recurrence Score® assay in oestrogen receptor positive node negative breast cancer.
J A Davidson, I Cromwell, +15 authors, S K Chia.
Eur J Cancer, 2013 Apr 25; 49(11). PMID: 23611660
A decision impact, decision conflict and economic assessment of routine Oncotype DX testing of 146 women with node-negative or pNImi, ER-positive breast cancer in the U.K.
S Holt, G Bertelli, +12 authors, C J Phillips.
Br J Cancer, 2013 May 23; 108(11). PMID: 23695023    Free PMC article.
Is oncotype DX recurrence score (RS) of prognostic value once HER2-positive and. low-ER expression patients are removed?
Meghan Milburn, Martin Rosman, Charles Mylander, Lorraine Tafra.
Breast J, 2013 May 25; 19(4). PMID: 23701403
The impact of the 21-gene Recurrence Score assay on clinical decision-making in node-positive (up to 3 positive nodes) estrogen receptor-positive breast cancer patients.
Salomon M Stemmer, Shmuel H Klang, +7 authors, Nicky Lieberman.
Breast Cancer Res Treat, 2013 Jun 27; 140(1). PMID: 23801158    Free PMC article.
The impact of a genomic assay (Oncotype DX) on adjuvant treatment recommendations in early breast cancer.
Richard H de Boer, Caroline Baker, +3 authors, G Bruce Mann.
Med J Aust, 2013 Aug 06; 199(3). PMID: 23909545
Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.
A Goldhirsch, E P Winer, +5 authors, Panel members.
Ann Oncol, 2013 Aug 07; 24(9). PMID: 23917950    Free PMC article.
Highly Cited.
Evaluating use characteristics for the oncotype dx 21-gene recurrence score and concordance with chemotherapy use in early-stage breast cancer.
Clara Chen, Rahul Dhanda, +2 authors, Debra A Patt.
J Oncol Pract, 2013 Aug 15; 9(4). PMID: 23942918    Free PMC article.
The impact of the Oncotype Dx breast cancer assay in clinical practice: a systematic review and meta-analysis.
Josh J Carlson, Joshua A Roth.
Breast Cancer Res Treat, 2013 Aug 27; 141(1). PMID: 23974828    Free PMC article.
Highly Cited. Systematic Review.
Personalized medicine and genetic malpractice.
Gary E Marchant, Rachel A Lindor.
Genet Med, 2013 Sep 28; 15(12). PMID: 24071800    Free PMC article.
Prospective study of the effect of the 21-gene assay on adjuvant clinical decision-making in Japanese women with estrogen receptor-positive, node-negative, and node-positive breast cancer.
Hideko Yamauchi, Chizuko Nakagawa, +7 authors, Seigo Nakamura.
Clin Breast Cancer, 2013 Dec 11; 14(3). PMID: 24321102
Cancer statistics, 2014.
Rebecca Siegel, Jiemin Ma, Zhaohui Zou, Ahmedin Jemal.
CA Cancer J Clin, 2014 Jan 09; 64(1). PMID: 24399786
Highly Cited.
Oncotype dx results in multiple primary breast cancers.
Michael J Toole, Kelley M Kidwell, Catherine Van Poznak.
Breast Cancer (Auckl), 2014 Jan 24; 8. PMID: 24453493    Free PMC article.
Time to initiation of adjuvant chemotherapy for early breast cancer and outcome: the earlier, the better?
Marco Colleoni, Richard D Gelber.
J Clin Oncol, 2014 Feb 12; 32(8). PMID: 24516011
Treatment decisions in estrogen receptor-positive early breast cancer patients with intermediate oncotype DX recurrence score results.
Georgeta Fried, Mor Moskovitz.
Springerplus, 2014 Feb 26; 3. PMID: 24567880    Free PMC article.
High concordance of protein (by IHC), gene (by FISH; HER2 only), and microarray readout (by TargetPrint) of ER, PgR, and HER2: results from the EORTC 10041/BIG 03-04 MINDACT trial.
G Viale, L Slaets, +11 authors, TRANSBIG Consortium & the MINDACT Investigators.
Ann Oncol, 2014 Mar 29; 25(4). PMID: 24667714    Free PMC article.
Multigene Assays for Classification, Prognosis, and Prediction in Breast Cancer: a Critical Review on the Background and Clinical Utility.
P Sinn, S Aulmann, +6 authors, A Schneeweiss.
Geburtshilfe Frauenheilkd, 2014 Apr 29; 73(9). PMID: 24771945    Free PMC article.
Physician liability: the next big thing for personalized medicine?
Gary E Marchant, Doug E Campos-Outcalt, Rachel A Lindor.
Per Med, 2011 Jul 01; 8(4). PMID: 29783333
Implementation of the 21-gene recurrence score test in the United States in 2011.
Julie A Lynch, Brygida Berse, +5 authors, Andrew N Freedman.
Genet Med, 2016 Feb 19; 18(10). PMID: 26890451
Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: A multicenter trial.
Harry D Bear, Wen Wan, +8 authors, Amy P Sing.
J Surg Oncol, 2017 Apr 14; 115(8). PMID: 28407247    Free PMC article.
Gene Expression Profiling Tests for Early-Stage Invasive Breast Cancer: A Health Technology Assessment.
Ontario Health (Quality).
Ont Health Technol Assess Ser, 2020 Apr 15; 20(10). PMID: 32284770    Free PMC article.
Molecular profiling of transcription factors pinpoints MYC-estrogen related receptor α-regulatory factor X5 panel for characterizing the immune microenvironment and predicting the efficacy of immune checkpoint inhibitors in renal cell carcinoma.
Fei Liu, Hongxia Zhang, +2 authors, Wanchun Yan.
Oncol Lett, 2019 Aug 20; 18(2). PMID: 31423259    Free PMC article.