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The Genomic Grade Assay Compared with Ki67 to Determine Risk Of Supplementary Online Content Ignatiadis M, Azim HA Jr, Desmedt C, et al. The Genomic Grade Assay Compared With Ki67 Prevalence to Determine Risk of Distant Breast Cancer Recurrence. JAMA Oncol. Published online December 3, 2015. doi:10.1001/jamaoncol.2015.4377. eMethods. Summary of development and validation of the Genomic Grade (GG) qRT-PCR based assay. eFigure. Comparison in Distant recurrence-free interval (DRFI) between BIG 1-98 patients included and not included in the genomic grade sub-study. eTable 1. Centrally reviewed histological grade (HG) versus genomic grade (GG) in the BIG 1- 98 sub-study. eTable 2. Cox model showing the prognostic value of the different parameters included in the CP model, in terms of distant recurrence-free interval (DRFI), disease-free survival (DFS) and overall survival (OS) eTable 3. Cox model showing the added value of genomic grade (GG) or centrally reviewed Ki67; both tested as continuous variables on Adjuvant!online (AOL) in predicting distant recurrence-free interval (DRFI), disease-free survival (DFS) and overall survival (OS). eTable 4. Cox model showing the added value of genomic grade (GG) and centrally reviewed Ki67; both tested as continuous variables on clinicopathological (CP) model in predicting disease-free (DFS) and overall survival (OS). This supplementary material has been provided by the authors to give readers additional information about their work. © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 SUPPLEMENT LEGENDS eMethods: Summary of development and validation of the Genomic Grade (GG) qRT- PCR based assay. eFigure eFigure: Comparison in Distant recurrence-free interval (DRFI) between BIG 1-98 patients included and not included in the genomic grade sub-study. eTables eTable 1: Centrally reviewed histological grade (HG) versus genomic grade (GG) in the BIG 1-98 sub-study. eTable 2: Cox model showing the prognostic value of the different parameters included in the CP model, in terms of distant recurrence-free interval (DRFI), disease-free survival (DFS) and overall survival (OS) eTable 3: Cox model showing the added value of genomic grade (GG) or centrally reviewed Ki67; both tested as continuous variables on Adjuvant!online (AOL) in predicting distant recurrence-free interval (DRFI), disease-free survival (DFS) and overall survival (OS). eTable 4: Cox model showing the added value of genomic grade (GG) and centrally reviewed Ki67; both tested as continuous variables on clinicopathological (CP) model in predicting disease-free (DFS) and overall survival (OS). © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 eMethods: Summary of development and validation of the Genomic Grade (GG) qRT- PCR based assay. Selection of genes for the GG qRT-PCR The GG qRT-PCR assay was developed from the original microarray based 97-gene Genomic Grade Index (GGI) (1), in order to improve its clinical application by testing on formalin fixed paraffin embedded tissue (FFPE). We started by selecting a subset of genes from the original GGI signature based on their performance in assessing histological grade (HG) and prognosis using 15 independent publicly available microarray datasets including 1,192 patients. Accordingly, we selected six reporter genes that were mostly overexpressed in grade 3 tumors and 3 reference genes (Table A). Table A: GG qRT-PCR composition (9 genes, 6 reporter genes and 3 control genes) Reporter genes Role in cell cycle Upregulation HG1 HG3 MCM10 Minichromosome Maintenance DNA replication √ Complex Component 10 factor, regulation of DNA synthesis CCNB2 Cyclin B2 Phosphorylation of √ proteins involved in G2/M transition ASPM ASP (abnormal spindle) homolog, Spindle √ © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 microcephaly associated organization, (Drosophilia) spindle positioning and cytokinesis PTTG1 Pituitary Tumor Transorfming 1 Control of sister √ chromatids segregation. FRY Furry Homolog (Drosophilia) Microtubule binding √ fidelity of mitotic chromosomes alignment CX3CR1 Chemokine receptor 1 √ Control Genes GUS Glucoronidase, beta TBP TATA box Binding Protein RPLP0 Ribosomal Protein, Large, P0 We tested the analytical performance of the reduced gene signature in 4 samples (5 RNA extractions and 3 qRT-PCR reactions per sample) in order to define a 95% Confidence Interval (CI) around the GG low/high (GG1/GG3) cut-off. We considered cases with a qRT-PCR GG falling into the 95% CI as equivocal (GGEq). © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Concordance between GG and the original microarray-based GGI We then assessed the concordance between GG and the original 97-gene signature in 44 paired Frozen and FFPE samples identified at the Department of Pathology, in Institut Jules Bordet, Brussels, Belgium. The frozen samples were assessed by microarray (Affymetrix U133 Plus2.0) and results were compared to GG assessed on paired FFPE samples. We found that the concordance between GG and HG was 91%. We also found a 95% overall concordance and a high correlation (r=0.87) between the frozen and FFPE samples (Figure A, Table B). Figure A © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table B: Concordance between GG and the original microarray-based GGI Microarray GGI (N=44) GGI 1 GGI 3 GG1 19 1 GG equivocal 0 0 GG3 1 23 Validation of the GG in a hospital-based series Table C: Patient characteristics of samples included in the validation set N = 388 Age Median, range 61 (31 – 91) Histology Ductal 326 (84%) Lobular 62 (16%) Nodal status N0 387 (99%) Size Mean, range 16 mm (15 – 80) ≤ 2cm 336 (85.5%) > 2cm 46 (13%) Not available 6 (1.5%) ER / PgR status ER + / PgR + 291 (75%) ER + / PgR - 97 (25%) © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Histological grade (HG) HG1 105 (27%) HG2 217 (56%) HG3 66 (17%) HER2 status Negative 388 (100%) 60 samples (15%) were excluded due to low tumor cellularity (<30% invasive tumor cells) leaving 336 samples evaluable for this analysis. RNA was extracted from two deparaffinized 10μm FFPE slides using RNAeasy FFPE (Qiagen). rTT-PCR assays were run on 384 well plates on an ABI 7900 HT instrument (Applied Biosystem) with set quality controls. GG qRT-PCR was successful in 96% of samples (n=336) (Figure B). Figure B Table 3 summarizes the concordance between genomic grade and HG. We observed an overall concordance of 90% between GG and HG. Concordance was similar according to histology, 91% for ductal and 89% for lobular cancers. 82% of HG2 tumors reclassified into 74% GG1 and 26% GG3. Overall, there was 52 (16%) of 322 evaluable samples that were considered equivocal. © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table D: Concordance between GG and HG in the validation set HG1 HG2 HG3 Total GG1 71 107 6 184 (57%) GG equivocal 9 31 12 52 (16%) GG3 6 38 42 86 (27%) Total 86 (27%) 176 (55%) 60 (18%) 322 References 1. Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 2006;98(4):262-72. © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 eFigure 1: Comparison in distant recurrence free interval (DRFI) between BIG 1-98 patients included and not included in the genomic grade (GG) sub-study. GG Sub-study 5 Year DRFI (ITT) 95% Confidence Interval No 0.90 0.89 0.91 Yes 0.94 0.93 0.96 GG Sub-study 8 Year DRFI (ITT) 95% Confidence Interval No 0.86 0.85 0.88 Yes 0.90 0.88 0.92 © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 1: Centrally reviewed histological grade (HG) versus genomic grade (GG) in the BIG 1-98 sub-study. HG1 HG2 HG3 Total GG1 92 (68%) 202(40%) 23 (10%) 317(36%) GGEq 38 (28%) 220 (44%) 94 (39%) 352 (40%) GG3 5 (4%) 80 (16%) 124 (51%) 209 (24%) Total 135 (100%) 502 (100%) 241 (100%) 878 HG1: histological grade 1; HG2: histological grade 2; HG3: histological grade 3; GG1: genomic grade 1; GG3: genomic grade 3; GGEq: genomic grade equivocal © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 eTable 2: Cox model showing the prognostic value of the different parameters of the clinicopathologiacl (CP) model, in terms of distant recurrence-free interval (DRFI), disease-free survival (DFS) and overall survival (OS). a) Distant recurrence-free survival (DRFI, n=848) Hazard ratio 95% CI p-value Age (1-unit increase) 1.03 1.00 – 1.06 0.08 Nodal status - 0 1 - 1-3 2.01 1.17 – 3.45 0.01 - > 3 2.37 1.21 – 4.64 0.01 Log2 Tumor size 1.45 1.07 – 1.96 0.02 Histological grade - 1 1 - 2 2.26 0.80 – 6.38 0.012 - 3 3.37 1.16 – 9.81 0.03 ER (1-unit increase) 0.99 1.00 – 1.00 0.18 HER2 - Negative 1 - Positive 0.84 0.39 – 1.80 0.66 Log2 PgR (1-unit increase) 0.92 0.83 – 1.01 0.08 b) Disease-free survival (DFS, n=848) Hazard ratio 95% CI p-value Age (1-unit increase) 1.06 1.04 – 1.09 <0.0001 Nodal status - 0 1 - 1-3 1.45 1.04 – 2.00 0.03 - > 3 1.77 1.14 – 2.75 0.01 Log2 Tumor size 1.27 1.03 – 2.75 0.02 Histological grade - 1 1 - 2 1.29 0.80 – 2.07 0.29 - 3 1.74 1.04 – 2.91 0.03 ER (1-unit increase) 1.00 0.99 – 1.00 0.99 HER2 - Negative 1 - Positive 1.21 0.74 – 1.99 0.44 Log2 PgR (1-unit increase) 0.99 0.92 – 1.06 0.70 © 2015 American Medical Association.
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