Intervention(s) Results primary outcome Results secondary and other outcomes

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1 Uitgangsvraag 4: evidence tables Welke nieuwe vormen van risicoprofilering zijn - in tegenstelling tot de traditionele prognostische factoren als tumorgrootte, lymfklierstatus en tumorgradering - van invloed op de keuze om al dan niet te starten met adjuvante behandeling bij patiënten met een invasief mammacarcinoom (5-30 mm) en maximaal 3 lymfkliermetastasen, en verschilt dit bij patiënten < 50 jaar, tussen 50 en 70 jaar en ouder dan 70 jaar? Systematic reviews Study Critical appraisal of review Marchio nni Full report: 2 SR Supported by Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, no conflicts of interest disclosed 2 is the full report Search date: January 2007 Searched databases: CENTRAL, Medline, Embase, CINAHL, Included study design: no restrictions Number of included studies = 20 Abbreviations: SR: systematic review Original data studies on any of three gene profiling assays in women with breast cancer, with information on prognostic accuracy and discrimination or treatment benefit prediction Genetic tests Improvement in clinical No studies identified; two ongoing RCTs identified (TAILORx and MINDACT) References were retrieved to answer clinical question Level of evidence: not applicable as no data were used Good SR, no meta-analysis Independent review and selection of studies English articles only Multiple study questions in the full report 2 : only references for relevant information retrieved (Key questions 1, 3 and 4a)

2 Randomized controlled trials Study Intervention(s) Results primary outcome Results secondary and other Albain Retrospective analysis of trial data (SWOG-8814) National Cancer Institute and by the test Several authors were employed by the 21- Sample size: N= year follow-up; inclusion period not stated Postmenopausal women with N+ and HR+ breast cancer Aged years; 25% aged <55 years 33% of tumours <20 mm 62% of patients N1- N3 Treated with tamoxifen or CAF (cyclofosfamide, doxorubicine and fluorouracil) followed by tamoxifen 21- RS 10 year disease-free survival CAF-tamoxifen vs. tamoxifen (stratified for node positivity): High RS ( 31) hazard ratio: 0.59 (95% CI ); Intermediate RS: HR: 0.72 ( ) Low-RS (<18): HR: 1.02 ( ) 10 year overall survival CAFtamoxifen vs. tamoxifen (stratified for node positivity): High RS HR: 0.56 (95% CI ); Intermediate RS: HR: 0.84 ( ) Low-RS: RR: 1.18 ( ) - Level of evidence: A2 Retrospective analysis of prospectively collected trial data Tumour material of 664 of the 1477eligible trial patients was available. s had a slightly lower number of + lymph nodes and a smaller tumour size than patients in the parent trial Blinded assessment No information on 21-signature in different age groups The significant benefit from CAF in patients with a high RS did not vary by age (data not shown) Similar were observed for breast cancer-specific survival (data presented in figures) The test for interaction between chemotherapy treatment and the 21- RS was not significant (p=0.053) in a model adjusted for node positivity, over a ten-year period, but was significant for the first five years (p=0.029)

3 Study Intervention(s) Results primary outcome Results secondary and other Paik Retrospective analysis of trial data (NSABP trial B20) National Cancer Institute and by the test All authors were employed by the 21- Sample size: N=651 Duration not stated; inclusion from 1988 to1993 Primary invasive breast cancer, N0, HR+ 44%<50 years 66% of tumours 20 mm Treated with tamoxifen or tamoxifen + chemotherapy 21- RS 10 year distant recurrence-free survival chemotherapy + tamoxifen vs. tamoxifen: High RS ( 31) relative risk: 0.26 (95% CI ); mean absolute decrease 27.6% (SE: 8.0%) Intermediate RS: RR: 0.61 ( ); mean absolute increase 1.8% Low-RS (<18): RR: 1.31 ( ); mean absolute increase 1.1% Similar trends were observed for freedom from loco-regional and/or distant recurrence and overall survival (data presented in figures) Similar results were observed when chemotherapy benefit was analyzed in different regimens grouped separately (data not given) Likelihood ratio test interaction chemotherapy treatment and age 50 years: HR: 2.02 ( ), p=0.162 Likelihood ratio test interaction chemotherapy treatment and RS increment 50 units: HR: 0.32 ( ), p=0.038 Level of evidence: A2 Retrospective analysis of prospectively collected trial data Tumour material of 670 of the 2299 clinically eligible patients was available. The patients were similar for those with available material and those without Blinded assessment No information on 21-signature in different age groups, though there was interaction between age and treatment in the entire trial population The test for interaction between chemotherapy treatment and the 21- RS was statistically significant (p=0.038) in a multivariate analysis. The magnitude of chemotherapy benefit appeared to increase continuously as the RS increased. A clear cut-off point for RS, below which there is was no demonstrable benefit from chemotherapy, could not be accurately defined Abbreviations: HR; hazard ratio; HR+: hormone receptor positive; RS: risk score; SE: standard error

4 Observationele studies Study Bueno-de- Mesquita Prospective observational cohort study Financially supported by the Dutch Health Care and Insurance Board (CVZ) Several authors were employed by the Dutch hospitals Sample size: N=427 (585 eligible patients) Duration not stated; inclusion from Primary breast carcinoma (clinical T1-4N0M0); Age <61 years, halfway changed to <55 years; 68% 50 years 25% of patients had a tumour size of 21 to 50 mm 70- Predicting disease : discordant classification of patients Dutch CBO guidelines 31% of patients classified as low risk 28% of patients classified as high risk St Gallen Guidelines 15% of patients classified as low risk 44% of patients classified as moderate or high risk were classified as good prognosis by Nottingham Prognostic Index 29% of patients classified as low risk 25% of patients classified as moderate or high risk were classified as good prognosis by Influence on treatment decisions: change in treatment regime Dutch CBO guidelines For 19% of patients, systemic adjuvant treatment management differed between that recommended by the Dutch CBO guidelines and that actually given based on the prognosis signature, Dutch CBO guidelines, and patients preferences The decision to use adjuvant systemic treatment was changed in 69 of 128 (54%) patients, which resulted in an increase of 19 (4%) patients receiving chemotherapy and 47 (37%) patients receiving endocrine treatment, when the prognosis signature and patient preferences were taken into account in addition to the CBO guidelines Level of evidence: A2 Well performed prospective study, based on a study protocol, which was reviewed by an investigative review board In 22% of included patients a sampling failure occurred and in 5% of patients the procedure was incorrect; these patients were left out of the analyses No multivariate analysis on the added value of the 70-gene signature in addition to existing classification systems Consecutive inclusion not stated, but likely given existence of protocol and review thereof 70- assessment blinded to clinical profile No information on 70-gene signature in different age groups Buyse Retrospective study of patients from five European centres European Commission and several non-profit organizations Some authors were employed by the gene signature Sample size: N=307 Duration: not stated. Median follow-up 13.6 T1-T2 N0 Age <61 years; 67% 50 years No adjuvant systemic treatment 49% 20 mm 70- Adjuvant! Online 28% of patients classified as low risk 42% of patients classified as high risk Adjuvant! Online 35% of patients classified as low risk 27% of patients classified as high risk <40 years o 11% of patients classified as low risk o 18% of patients classified as high risk were classified as good prognosis by years 70- hazard ratio (HR) for time to distant metastasis Adjusted for St Gallen criteria: HR: 2.15 (95% CI: ) Adjusted for NPI: HR: 2.15 ( ) Adjusted for Adjuvant! Online: HR: 2.13 ( ) 70- HR for overall survival Adjusted for St Gallen criteria: HR: 2.69 ( ) Adjusted for NPI: HR: 2.89 ( ) Adjusted for Adjuvant! Online: HR: 2.63 ( ) 70- HR for disease-free Level of evidence: B s from five centres combined and analysed as one study Not clear whether patients were consecutive, how outcome data were collected. Multivariate analyses of the hazard ratios

5 Study years; diagnosis made before 1999 o 38% of patients classified as low risk o 23% of patients classified as high risk were classified as good prognosis by survival Adjusted for St Gallen criteria: HR: 1.50 ( ) Adjusted for NPI: HR: 1.41 ( ) Adjusted for Adjuvant! Online: HR: 1.36 ( ) years o 38% of patients classified as low risk o 25% of patients classified as high risk were classified as good prognosis by Adjuvant! HR for time to distant metastasis, adjusted for 70-gene signature: 1.26 ( ) Adjuvant! HR for overall survival, adjusted for 70-: 1.08 ( ) Dowsett Retrospective cohort study with prospective data collection Supported by Breakthrough Breast Cancer and AstraZeneca Several authors were employed by the 21- Uses UK samples/patients from the ATAC trial Sample size: N=872 (all included patients, including N+: 1231) Duration not stated; median follow-up: 8.5 years; inclusion up to 2006 Jerevall Retrospective study based on trial patients Supported by several governmental and non-governmental not for profit organizations Two Swedish centres Sample size: N=104 Women treated between 1982 and 1995; median followup: 11.2 years Postmenopausal women with localized N0, HR+ breast cancer Age range or age groups not specified Tumours >30 mm were included (% not stated) Treated with tamoxifen or anastrozole Postmenopausal oestrogen receptor+ women Age range or age groups not specified The full cohort (N=264) included 28% nodal negative patients; and 29% with a tumour 20 mm 21- H/I ratio The 21- showed significant prognostic value for distant recurrence, beyond that provided by Adjuvant! Online. In a model adjusted for treatment, the 21- and Adjuvant! Online each provided a comparable degree of mutually independent predictive information (likelihood ratio χ2=21.9, P<0.001 for both) Similar results were observed for local grade and for Adjuvant! Online estimates of overall survival, but these data were not shown Recurrence-free survival in the lower H/I ratio group was higher for postmenopausal women treated with tamoxifen for five years vs. tamoxifen for 2 years (p=0.021). Recurrence rate ratio: 0.39 ( ) This advantage was not observed in the higher H/I ratio (p=0.09) Recurrence rate ratio: 0.95 ( ) Adjuvant! HR for disease-free survival, adjusted for 70-: 1.03 ( ) - Level of evidence: B Retrospective analysis of prospectively collected data Consecutive inclusion not stated Blinded assessment Multivariate analysis on the added value of the 21-gene signature in addition to existing classification systems Selective outcome reporting only a minor analysis in this article No information on 21-gene signature in different age groups - Level of evidence: B Retrospective study with patients from a trial in which patients were randomised to either 2 or 5 years of tamoxifen Small sample size Long follow-up Blinded assessment not stated only a minor analysis in this article

6 Study Knauer Individual patient meta-analysis Austrian Society of Surgery and the test Sample size: N=541 (patients from seven previously reported studies) Diagnosis between 1984 and 2006 Mook Retrospective cohort study Samples from two centres Sample size: N=241 Median follow-up: 7.8 years; diagnoses made between 1994 and 2001 T1-3, N0-1, M0 Age range not specified; 43% 50 years Either endocrine therapy or endocrine therapy + chemotherapy Operable T1-3 breast cancer, N1-3 Aged<71 years; 52% aged <50 years 49% 20 mm 53% received chemotherapy with or without endocrine therapy 69% received endocrine therapy with or without chemotherapy year breast cancer specific survival endocrine therapy vs. chemotherapy + endocrine therapy: High risk group hazard ratio (HR): 0.21 (95% CI: ) Low risk group HR: (0- ) Adjuvant! Online 16% of patients classified as low risk 34% of patients classified as high risk Adding chemotherapy for patients in the 70-gene high risk group could prevent 33 events per 1000 patient years, resulting in a number needed to treat of 30 (95% CI 19-64) The addition of chemotherapy for patients in the 70-gene low risk group could prevent 3 events per 1000 patient years (number needed to treat of 333) (95% CI - 78 to 83) Level of evidence: B s from seven previously reported studies included and analysed as one study Not clear whether patients came from single centre, were consecutive, how outcome data were collected. This information is probably available in the seven original articles Blinded assessment Multivariate analyses of the hazard ratio, including important confounders (age, tumour size, lymph node positivity, grade and endocrine receptor status) only a minor part of the analyses in this article; many univariate analyses presented De definition of events is not given; are events both breast cancer specific deaths as well as recurrence? No information on different age groups Several discrepancies in the article, e.g.: N0-1 patients included vs. number of positive lymph nodes (0-3) included in multivariate analysis - Level of evidence: B Outcomes retrieved from medical records Consecutive inclusion, but only of patients with frozen tumour samples Blinded assessments Unadjusted HR estimates for 70- prediction of treatment only a minor part of the analyses in this article No information on different age groups

7 Study Mook Retrospective study European Commission and the gene profile Several authors were employed by the 70- Samples from one Dutch centre Sample size: N=148 Median follow-up: 12.5 years; patients treated from 1984 to 1996 T1-T2 N0 primary invasive breast carcinoma Aged between 55 and 71 years 56% tumours 20 mm No adjuvant chemotherapy 18% endocrine therapy 70- Adjuvant! Online 16% of patients classified as low risk 39% of patients classified as high risk - Level of evidence: B Outcomes retrieved from medical records Consecutive inclusion, but only of patients with frozen tumour samples Blinded assessment of gene profiles and clinical only a minor part of the analyses in this article No information on different age groups Overlap with other patient series not stated but possible, e.g. with 6 Abbreviations: 95%CI: 95 percent confidence intervals; ATAC : Arimidex, Tamoxifen, Alone or in Combination; CBO: Kwaliteitsinstituut voor de Gezondheidszorg (Dutch); HR: hazard ratio; HR+: hormone receptor positive; RR: relative risk; RS: risk score References 1. Marchionni L, Wilson RF, Wolff AC, Marinopoulos S, Parmigiani G, Bass EB, et al. Systematic review: gene expression profiling assays in early-stage breast cancer. Ann.Intern.Med. 2008;148(5): Marchionni L, Wilson RF, Marinopoulos SS, Wolff AC, Parmigiani G, Bass EB, et al. Impact of gene expression profiling tests on breast cancer. Evid Rep Technol Assess (Full Rep). 2008(160): Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, et al. 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. Lancet Oncol. 2010;11(1): Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23): Bueno-de-Mesquita JM, van Harten WH, Retel VP, van't Veer LJ, van Dam FS, Karsenberg K, et al. Use of 70- to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER). Lancet Oncol. 2007;8(12): Buyse M, Loi S, van't Veer L, Viale G, Delorenzi M, Glas AM, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98(17): Dowsett M, Cuzick J, Wale C, Forbes J, Mallon EA, Salter J, et al. 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. J Clin Oncol. 2010;28(11): Jerevall PL, Brommesson S, Strand C, Gruvberger-Saal S, Malmstrom P, Nordenskjold B, et al. Exploring the two-gene ratio in breast cancer--independent roles for HOXB13 and IL17BR in prediction of clinical outcome. Breast Cancer Res Treat. 2008;107(2): Knauer M, Mook S, Rutgers EJ, Bender RA, Hauptmann M, van de Vijver MJ, et al. The predictive value of for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120(3): Mook S, Schmidt MK, Viale G, Pruneri G, Eekhout I, Floore A, et al. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2009;116(2): Mook S, Schmidt MK, Weigelt B, Kreike B, Eekhout I, van de Vijver MJ, et al. The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. 2010;21(4):

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