Journal Article
. 2019 Sep;22(10).
doi: 10.1016/j.jval.2019.05.004.

A Value of Information Analysis of Research on the 21-Gene Assay for Breast Cancer Management

Natalia R Kunst 1 Fernando Alarid-Escudero 2 A David Paltiel 3 Shi-Yi Wang 4 
  • PMID: 31563252
  •     54 References


Objectives: The 21-gene assay Oncotype DX (21-GA) shows promise as a guide in deciding when to initiate adjuvant chemotherapy in women with hormone receptor-positive early-stage breast cancer. Nevertheless, its routine use remains controversial, owing to insufficient evidence of its clinical utility and cost-effectiveness. Accordingly, we aim to quantify the value of conducting further research to reduce decision uncertainty in the use of the 21-GA.

Methods: Using value of information methods, we first generated probability distributions of survival and costs for decision making with and without the 21-GA alongside traditional risk prediction. These served as the input to a comparison of 3 alternative study designs: a retrospective observational study to update risk classification from the 21-GA, a prospective observational study to estimate prevalence of chemotherapy use, and a randomized controlled trial (RCT) of the 21-GA predictive value.

Results: We found that current evidence strongly supports the use of the 21-GA in intermediate- and high-risk women. Further research should focus on low-risk women, among whom the cost-effectiveness findings remained equivocal. For this population, we identified a high value of reducing uncertainty in the 21-GA use for all proposed research studies. The RCT had the greatest potential to efficiently reduce the likelihood of choosing a suboptimal strategy, providing a value between $162 million and $1.1 billion at willingness-to-pay thresholds of $150 000 to $200 000/quality-adjusted life years.

Conclusion: Future research to inform 21-GA decision making is of high value. The RCT of the 21-GA predictive value has the greatest potential to efficiently reduce decision uncertainty around 21-GA use in women with low-risk early-stage breast cancer.

Keywords: 21-gene assay; breast cancer; cost-effectiveness; decision making; decision uncertainty; gene expression profiling; precision medicine; research design and prioritization; value of information.

A rational framework for decision making by the National Institute For Clinical Excellence (NICE).
Karl Claxton, Mark Sculpher, Michael Drummond.
Lancet, 2002 Sep 21; 360(9334). PMID: 12241891
Value-of-information analysis to guide future research in colorectal cancer screening.
Cesare Hassan, M G Myriam Hunink, +5 authors, Emilio Di Giulio.
Radiology, 2009 Oct 01; 253(3). PMID: 19789242
A Gaussian Approximation Approach for Value of Information Analysis.
Hawre Jalal, Fernando Alarid-Escudero.
Med Decis Making, 2017 Jul 25; 38(2). PMID: 28735563
Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group.
Michael Crump, Dongsheng Tu, +3 authors, Kathleen Pritchard.
J Clin Oncol, 2003 Aug 14; 21(16). PMID: 12915595
Cost-effectiveness of the 21-gene recurrence score assay in the context of multifactorial decision making to guide chemotherapy for early-stage breast cancer.
Shelby D Reed, Michaela A Dinan, Kevin A Schulman, Gary H Lyman.
Genet Med, 2012 Sep 15; 15(3). PMID: 22975761    Free PMC article.
Influence of a 21-Gene Recurrence Score Assay on Chemotherapy Delivery in Breast Cancer.
Charles E Rutter, Xiaopan Yao, +7 authors, Suzanne B Evans.
Clin Breast Cancer, 2015 Oct 21; 16(1). PMID: 26483315
Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.
Joseph A Sparano, Robert J Gray, +27 authors, George W Sledge.
N Engl J Med, 2018 Jun 05; 379(2). PMID: 29860917    Free PMC article.
Highly Cited.
Cost-Effectiveness Analyses of the 21-Gene Assay in Breast Cancer: Systematic Review and Critical Appraisal.
Shi-Yi Wang, Weixiong Dang, +3 authors, Cary P Gross.
J Clin Oncol, 2018 Apr 17; 36(16). PMID: 29659329    Free PMC article.
Systematic Review.
Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer.
Michael J Hassett, A James O'Malley, +2 authors, Craig C Earle.
J Natl Cancer Inst, 2006 Aug 17; 98(16). PMID: 16912263
Highly Cited.
PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer.
Gordon C Wishart, Elizabeth M Azzato, +5 authors, Paul D P Pharoah.
Breast Cancer Res, 2010 Jan 08; 12(1). PMID: 20053270    Free PMC article.
Association between Time since Cancer Diagnosis and Health-Related Quality of Life: A Population-Level Analysis.
Shi-Yi Wang, Sylvia H Hsu, +4 authors, James B Yu.
Value Health, 2016 Aug 28; 19(5). PMID: 27565280    Free PMC article.
"Time Traveling Is Just Too Dangerous" but Some Methods Are Worth Revisiting: The Advantages of Expected Loss Curves Over Cost-Effectiveness Acceptability Curves and Frontier.
Fernando Alarid-Escudero, Eva A Enns, +2 authors, Hawre Jalal.
Value Health, 2019 May 21; 22(5). PMID: 31104743    Free PMC article.
Targeting adjuvant chemotherapy: a good idea that needs to be proven!
Daniel F Hayes.
J Clin Oncol, 2012 Feb 23; 30(12). PMID: 22355050
Economic analysis of targeting chemotherapy using a 21-gene RT-PCR assay in lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer.
John Hornberger, Leon E Cosler, Gary H Lyman.
Am J Manag Care, 2005 May 19; 11(5). PMID: 15898220
Incorporating Tumor Characteristics to Maximize 21-Gene Assay Utility: A Cost-Effectiveness Analysis.
Shi-Yi Wang, Tiange Chen, +3 authors, Cary P Gross.
J Natl Compr Canc Netw, 2019 Jan 20; 17(1). PMID: 30659128
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.
Association Between Use of the 21-Gene Recurrence Score Assay and Receipt of Chemotherapy Among Medicare Beneficiaries With Early-Stage Breast Cancer, 2005-2009.
Michaela A Dinan, Xiaojuan Mi, +2 authors, Lesley H Curtis.
JAMA Oncol, 2015 Aug 28; 1(8). PMID: 26313372
Gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in breast cancer management: a systematic review and cost-effectiveness analysis.
S Ward, A Scope, +4 authors, L Wyld.
Health Technol Assess, 2013 Oct 04; 17(44). PMID: 24088296    Free PMC article.
Systematic Review.
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.
Updating cost-effectiveness--the curious resilience of the $50,000-per-QALY threshold.
Peter J Neumann, Joshua T Cohen, Milton C Weinstein.
N Engl J Med, 2014 Aug 28; 371(9). PMID: 25162885
Highly Cited.
Value of Information: A Tool to Improve Research Prioritization and Reduce Waste.
Cosetta Minelli, Gianluca Baio.
PLoS Med, 2015 Sep 30; 12(9). PMID: 26418866    Free PMC article.
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.
What does the value of modern medicine say about the $50,000 per quality-adjusted life-year decision rule?
R Scott Braithwaite, David O Meltzer, +2 authors, Mark S Roberts.
Med Care, 2008 Mar 26; 46(4). PMID: 18362813
Highly Cited.
The cost-effectiveness of particle therapy in non-small cell lung cancer: exploring decision uncertainty and areas for future research.
Janneke P C Grutters, Madelon Pijls-Johannesma, +5 authors, Manuela A Joore.
Cancer Treat Rev, 2010 Mar 23; 36(6). PMID: 20303217
Cost-effectiveness of the 21-gene assay for guiding adjuvant chemotherapy decisions in early breast cancer.
Mike Paulden, Jacob Franek, +3 authors, Murray Krahn.
Value Health, 2013 Aug 21; 16(5). PMID: 23947965
Decisions on Further Research for Predictive Biomarkers of High-Dose Alkylating Chemotherapy in Triple-Negative Breast Cancer: A Value of Information Analysis.
Anna Miquel-Cases, Valesca P Retèl, Wim H van Harten, Lotte M G Steuten.
Value Health, 2016 Jun 22; 19(4). PMID: 27325334
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG).
Lancet, 2005 May 17; 365(9472). PMID: 15894097
Highly Cited.
Value of Information Analysis of Multiparameter Tests for Chemotherapy in Early Breast Cancer: The OPTIMA Prelim Trial.
Peter S Hall, Alison Smith, +16 authors, OPTIMA Trial Management Group.
Value Health, 2017 Dec 16; 20(10). PMID: 29241890
Trade-offs Between Efficacy and Cardiac Toxicity of Adjuvant Chemotherapy in Early-Stage Breast Cancer Patients: Do Competing Risks Matter?
Fernando Alarid-Escudero, Anne H Blaes, Karen M Kuntz.
Breast J, 2017 Jan 25; 23(4). PMID: 28117517
Recommendations for Conduct, Methodological Practices, and Reporting of Cost-effectiveness Analyses: Second Panel on Cost-Effectiveness in Health and Medicine.
Gillian D Sanders, Peter J Neumann, +13 authors, Theodore G Ganiats.
JAMA, 2016 Sep 14; 316(10). PMID: 27623463
Highly Cited.
Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer.
P M Ravdin, L A Siminoff, +4 authors, H L Parker.
J Clin Oncol, 2001 Feb 22; 19(4). PMID: 11181660
Highly Cited.
Cost-Effectiveness Analysis of Brentuximab Vedotin With Chemotherapy in Newly Diagnosed Stage III and IV Hodgkin Lymphoma.
Scott F Huntington, Gottfried von Keudell, +2 authors, Sapna A Prasad.
J Clin Oncol, 2018 Oct 05;. PMID: 30285558    Free PMC article.
Breast cancer specialists' views on and use of risk prediction models in clinical practice: a mixed methods approach.
Ellen G Engelhardt, Arwen H Pieterse, +4 authors, Anne M Stiggelbout.
Acta Oncol, 2014 Oct 14; 54(3). PMID: 25307407    Free PMC article.
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.
The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors.
D G Fryback, E J Dasbach, +4 authors, P A Martin.
Med Decis Making, 1993 Apr 01; 13(2). PMID: 8483408
Highly Cited.
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.
Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study.
Erin J Aiello Bowles, Robert Wellman, +13 authors, Pharmacovigilance Study Team.
J Natl Cancer Inst, 2012 Sep 06; 104(17). PMID: 22949432    Free PMC article.
Highly Cited.
Prioritizing Future Research on Allopurinol and Febuxostat for the Management of Gout: Value of Information Analysis.
Eric Jutkowitz, Fernando Alarid-Escudero, +2 authors, Hawre Jalal.
Pharmacoeconomics, 2017 Jun 21; 35(10). PMID: 28631197
Economic evaluation of genomic test-directed chemotherapy for early-stage lymph node-positive breast cancer.
Peter S Hall, Christopher McCabe, Robert C Stein, David Cameron.
J Natl Cancer Inst, 2011 Dec 06; 104(1). PMID: 22138097
A Review of Methods for Analysis of the Expected Value of Information.
Anna Heath, Ioanna Manolopoulou, Gianluca Baio.
Med Decis Making, 2017 Apr 16; 37(7). PMID: 28410564
Adjuvant! Online as a decision-making tool in early breast cancer--a UK national survey.
V Agarwal, P O'Neill.
Clin Oncol (R Coll Radiol), 2010 Nov 30; 23(2). PMID: 21112194
How much are Americans willing to pay for a quality-adjusted life year?
Milton C Weinstein.
Med Care, 2008 Mar 26; 46(4). PMID: 18362811
Model parameter estimation and uncertainty analysis: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force Working Group-6.
Andrew H Briggs, Milton C Weinstein, +4 authors, ISPOR-SMDM Modeling Good Research Practices Task Force.
Med Decis Making, 2012 Sep 20; 32(5). PMID: 22990087
Highly Cited.
The value of comparative effectiveness research: projected return on investment of the RxPONDER trial (SWOG S1007).
William B Wong, Scott D Ramsey, +2 authors, David L Veenstra.
Contemp Clin Trials, 2012 Sep 18; 33(6). PMID: 22981891    Free PMC article.
Value of information analysis in healthcare: a review of principles and applications.
Haitham W Tuffaha, Louisa G Gordon, Paul A Scuffham.
J Med Econ, 2014 Mar 22; 17(6). PMID: 24650041
Researchers consider value-of-information theory for selecting trials.
Charlie Schmidt.
J Natl Cancer Inst, 2010 Jan 29; 102(3). PMID: 20107161
Utilization and impact of 21-gene recurrence score assay for breast cancer in clinical practice across the United States: lessons learned from the 2010 to 2012 National Cancer Data Base analysis.
Amila Orucevic, Robert E Heidel, John L Bell.
Breast Cancer Res Treat, 2016 May 22; 157(3). PMID: 27206678    Free PMC article.
Racial and Ethnic Disparities in Oncotype DX Test Receipt in a Statewide Population-Based Study.
Brigette A Davis, Jenerius A Aminawung, +5 authors, Cary P Gross.
J Natl Compr Canc Netw, 2017 Mar 10; 15(3). PMID: 28275035
Myelodysplastic syndrome and acute myeloid leukemia following adjuvant chemotherapy with and without granulocyte colony-stimulating factors for breast cancer.
Gregory S Calip, Judith A Malmgren, +2 authors, Henry G Kaplan.
Breast Cancer Res Treat, 2015 Oct 10; 154(1). PMID: 26450505    Free PMC article.
Effect of a US National Institutes of Health programme of clinical trials on public health and costs.
S Claiborne Johnston, John D Rootenberg, +2 authors, Jacob S Elkins.
Lancet, 2006 Apr 25; 367(9519). PMID: 16631910
Systematic Review.
The cost-effectiveness of adjuvant chemotherapy for early breast cancer: A comparison of no chemotherapy and first, second, and third generation regimens for patients with differing prognoses.
H E Campbell, D Epstein, +16 authors, M J Sculpher.
Eur J Cancer, 2011 Jul 12; 47(17). PMID: 21741831
An Overview of R in Health Decision Sciences.
Hawre Jalal, Petros Pechlivanoglou, +3 authors, M G Myriam Hunink.
Med Decis Making, 2017 Jan 07; 37(7). PMID: 28061043
Clinical validity/utility, change in practice patterns, and economic implications of risk stratifiers to predict outcomes for early-stage breast cancer: a systematic review.
John Hornberger, Michael D Alvarado, +3 authors, William J Gradishar.
J Natl Cancer Inst, 2012 Jul 07; 104(14). PMID: 22767204
Systematic Review.
The costs of conducting clinical research.
Ezekiel J Emanuel, Lowell E Schnipper, +2 authors, Allen S Lichter.
J Clin Oncol, 2003 Oct 16; 21(22). PMID: 14559889