Breast Cancer Research and Treatment

TOP2A RNA Expression and Recurrence in Estrogen Receptor-Positive Breast Cancer

Joseph A. Sparano, Lori J. Goldstein, Nancy E. Davidson, George W. Sledge, Jr., and Robert Gray5

Corresponding author: Joseph A. Sparano, MD, Montefiore-Einstein Cancer Center, Montefiore Medical Center-Weiler Division, 1825 Eastchester Rd. Bronx, NY 10461; Phone 718-904-2555; Fax 718-904-2892; Email: [email protected]

Supplemental Tables 1-4

Supplemental Table 1. Cutoffs and number of positive cases/total cases for Her2, ER and PgR ERBB2 ESR1 PGR # HR+, HER2- cases (# events) Wang et al 12.8 (51/286) 10.0 (207/286) 4.6 (151/286) 192 (73) Van de Vijver 0.0 (53/295) -0.65 (226/295) -0.40 (226/295) 212 (68) et al Desmedt et al 7.7 (39/198) 10.0 (136/198) 4.6 (125/198) 124 (33) Loi et al 0.8 (39/263) -- -- 224 (70) Supplemental Table 2. Estimated hazard ratios and 95% confidence intervals for TOP2A and simRS.

Data Set Model Effect Estimated 95% Confidence P-value

Ratio Intervals Wang et al simRS simRs 1.69 (1.38, 2.08) <0.0001 TOP2A TOP2A 1.58 (1.21, 2.05) 0.001 TOP2A + simRS TOP2A 1.2 (0.90, 1.61) 0.21 TOP2A + simRS simRS 1.54 (1.20, 1.98) 0.0007

Van de Sim RS simRS 1.7 (1.41, 2.04) <0.0001 Vijver et al TOP2A TOP2A 1.62 (1.27,2.07) 0.0001 TOP2A + simRS TOP2A 1.3 (0.99,1.69) 0.06 TOP2A + simRS simRS 1.55 (1.26, 1.92) <0.0001

Desmedt et simRS simRS 1.49 (1.13, 1.96) 0.004 al TOP2A TOP2A 1.83 (1.27, 2.64) 0.001 TOP2A+simRS TOP2A 1.63 (1.09, 2.44) 0.02 TOP2A+simRS simRS 1.23 (0.90, 1.67) 0.2

Loi et al simRS simRS 1.49 (1.22, 1.81) 0.0001 TOP2A TOP2A 1.41 (1.11, 1.78) 0.004 TOP2A+simRS TOP2A 1.15 (0.87, 1.52) 0.33 TOP2A+simRS simRS 1.37 (1.07, 1.77) 0.01

Supplemental Table 3. Five-year relapse free survival by high vs. low TOP2A (overall median split) within classical RS risk groups, with logrank p-values for the TOP2A comparison in each group Low TOP2A High TOP2A Classical SimRS Data Set Group No. 5-yr RFS SE No. 5-yr RFS SE P Value

Wang et al Low 61 78.6 5.3 29 79.3 7.5 0.99 Intermediate 31 87.1 6 34 49.5 8.6 0.02 High 4 25 21.7 33 39.4 8.5 0.19

Vijver et al Low 62 93.4 3.2 38 83.5 6.2 0.41 Intermediate 34 79.4 6.9 37 69.5 7.7 0.88 High 10 40 15.5 31 47 9.1 0.61

Desmedt et al Low 37 80.8 6.5 21 85.7 7.6 0.61 Intermediate 23 86.3 7.4 19 57.9 11.3 0.03 High 2 50 35.4 22 50 10.7 0.85

Loi et al Low 73 83.8 4.5 32 81.8 7.4 0.2 Intermediate 32 86.7 6.2 44 80.1 6.3 0.24 High 7 42.9 18.7 36 56.2 9 0.46 Abbreviations: RFS – relapse free survival; SE – standard error Note: RS groups use the proportions from the E2197 HR-positive, HER2- negative subset (47% low <18, 34%, intermediate 18-30, 19% high > 30). Supplemental Table 4. Five-year relapse free survival by high vs. low TOP2A (overall median split) within TAILORx RS risk groups, with logrank p-values for the TOP2A comparison in each group

Low High TOP2A TOP2A Data Set TAILORx No. 5-yr RFS SE No. 5-yr RFS SE simRS Group

Wang et al Low 20 79.3 9.2 13 92.3 7.4 0.68 Intermedia te 67 83.6 4.5 36 60.9 8.2 0.04 High 9 44.4 16.6 47 40.1 7.2 0.54

Van de P Value Vijver et al Low 24 100 0 12 73.3 13.2 0.05 Intermedia te 66 86 4.3 48 85 5.2 0.62 High 16 50 12.5 46 48 7.5 0.97

Desmedt et al Low 11 90.9 8.7 10 90 9.5 0.92 Intermedia te 45 79.4 6.1 22 72.7 9.5 0.62 High 6 83.3 15.2 30 50 9.1 0.15

Loi et al Low 30 81.6 7.4 8 100 0 0.22 Intermedia te 65 85.4 4.5 56 78.2 5.9 0.16 High 17 70.6 11.1 48 63.4 7.4 0.24 Abbrevia tions: RFS – relapse free survival; S.E. – standard error Note: TAILORx RS groups use the proportions from the E2197 HR-positive, HER2-negative subset (17% low <11, 54%, intermediate 11-25, 29% high > 25)