SUPPLEMENTARY MATERIALS
I. Tables and figures
II. BIG 1-98 Collaborative Group participants who submitted tumor blocks
11
Section I. Tables and Figures
Table S1. CYP19A1* genotyping results from DNA samples of BIG 1-98 trial participants;
HWE assessment by sites (limited to country with a N>=30, and a site with n>=10 for at least one SNP)
rs4646 (C>A) / rs10046(T>C) / rs700518(T>C) / rs700519(G>A) / rs936308(C>G) / rs28757184(G>A)Total accessable N / 4164 / 3709 / 2161 / 2875 / 2434 / 3068
Genotyping
method / TaqMan / TaqMan / SNP stream / SNP stream / SNP stream / SNP stream
Function / UTR-3 / UTR-3 / Cds-syn / Missense / Intron / Missense
Country: site / N / HWE
p-value / N / HWE
p-value / N / HWE
p-value / N / HWE
p-value / N / HWE
p-value / N / HWE
p-value
C01 : s012 / 8 / 1 / 10 / 0.2 / 10 / 0.5 / 11 / 1 / 11 / 0.1 / 12 / 0.1
C01 : s039 / 24 / 0.7 / 20 / 1 / 19 / 0.7 / 20 / 1 / 16 / 1 / 19 / NA
C15 : s014 / 29 / 1 / 25 / 0.7 / 21 / 0.6 / 28 / 1 / 26 / 0.5 / 28 / 1
C15 : s031 / 17 / 0.5 / 18 / 0.04 / 15 / 0.007 / 18 / 1 / 15 / 1 / 20 / 0.2
aSouth AM: all sites / 63 / 0.4 / 62 / 0.03 / 42 / 0.2 / 47 / 0.005 / 23 / 1 / 55 / 1
C06 : s088 / 11 / 0.3 / 11 / 0.6 / 8 / 0.5 / 12 / 1 / 12 / 1 / 12 / 1
C06 : s089 / 8 / 0.4 / 10 / 0.6 / 5 / 1 / 10 / NA / 7 / 1 / 11 / NA
C06 : s090 / 14 / 1 / 13 / 0.6 / 12 / 0.08 / 14 / 1 / 14 / 1 / 14 / 1
C12 : s046 / 164 / 0.008 / 140 / 0.02 / 120 / 0.1 / 146 / 0.2 / 98 / 1 / 148 / 3.00E-04
C18 : s182 / 35 / 0.2 / 39 / 0.5 / 30 / 1 / 39 / 1 / 38 / 0.08 / 40 / NA
C18 : s185 / 10 / 1 / 8 / 0.2 / 6 / 0.4 / 8 / 1 / 8 / NA / 9 / NA
C21 : s212 / 42 / 0.08 / 40 / 0.008 / 21 / 0.2 / 37 / 0.08 / 32 / 1 / 40 / 1
C21 : s213 / 51 / 0.5 / 57 / 0.6 / 42 / 0.06 / 55 / 0.09 / 52 / 1 / 56 / 0.009
C02 : s078 / 23 / 0.2 / 23 / 0.4 / 14 / 0.6 / 22 / NA / 21 / 0.2 / 26 / 1
C02 : s079 / 182 / 0.9 / 174 / 0.002 / 137 / 0.3 / 170 / 0.4 / 143 / 0.5 / 179 / 0.2
C02 : s231 / 79 / 0.8 / 72 / 0.01 / 46 / 0.002 / 67 / 1 / 68 / 0.6 / 79 / 1
C02 : s233 / 92 / 1 / 87 / 0.1 / 58 / 0.06 / 93 / 1 / 72 / 1 / 98 / 0.08
C02 : s235 / 22 / 0.3 / 24 / 0.03 / 13 / 0.6 / 22 / 1 / 15 / 1 / 23 / 1
C05 : s020 / 40 / 0.6 / 41 / 0.06 / 38 / 0.1 / 42 / 1 / 41 / 0.5 / 42 / 0.2
C05 : s021 / 36 / 0.7 / 37 / 0.5 / 36 / 0.09 / 39 / 0.08 / 37 / 0.6 / 39 / 1
C05 : s022 / 16 / 0.6 / 20 / 1 / 20 / 0.6 / 20 / NA / 20 / 1 / 20 / 1
C05 : s023 / 25 / 0.6 / 24 / 1 / 18 / 0.3 / 25 / 0.02 / 25 / 0.6 / 23 / NA
C05 : s024 / 91 / 0.006 / 90 / 1 / 74 / 0.5 / 90 / 1 / 93 / 1 / 92 / 0.2
C05 : s025 / 31 / 0.2 / 32 / 1 / 28 / 0.06 / 32 / 1 / 28 / 1 / 31 / 1
C05 : s026 / 54 / 0.4 / 58 / 0.1 / 51 / 1 / 58 / 1 / 59 / 0.3 / 60 / 1
C05 : s027 / 22 / 1 / 24 / 0.7 / 24 / 0.7 / 24 / 1 / 24 / 0.2 / 23 / 1
C05 : s028 / 39 / 0.08 / 40 / 0.2 / 31 / 0.1 / 42 / 1 / 40 / 1 / 42 / 0.1
C05 : s029 / 29 / 0.7 / 26 / 0.7 / 24 / 0.7 / 29 / 1 / 25 / 1 / 28 / NA
C05 : s050 / 27 / 0.7 / 23 / 0.4 / 14 / 1 / 21 / 1 / 25 / 1 / 22 / 1
C07 : s096 / 11 / 0.2 / 11 / 1 / 5 / 0.4 / 9 / 1 / 12 / 1 / 10 / 0.05
C07 : s099 / 14 / 1 / 9 / 1 / 7 / 0.5 / 10 / NA / 9 / 1 / 13 / NA
C08 : s103 / 236 / 0.2 / 197 / 0.006 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s104 / 123 / 0.1 / 95 / 0.3 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s105 / 68 / 0.8 / 52 / 0.4 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s106 / 44 / 0.5 / 30 / 1 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s107 / 118 / 0.08 / 98 / 0.2 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s108 / 43 / 0.5 / 35 / 0.07 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s109 / 117 / 0.3 / 101 / 0.1 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s110 / 55 / 0.3 / 44 / 0.8 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s111 / 74 / 0.8 / 55 / 0.1 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s112 / 31 / 0.7 / 22 / 1 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s113 / 34 / 0.6 / 25 / 0.7 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s114 / 88 / 1 / 70 / 0.6 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s115 / 20 / 0.3 / 18 / 0.1 / 0 / - / 0 / - / 0 / - / 0 / -
C08 : s116 / 75 / 0.8 / 56 / 0.3 / 0 / - / 0 / - / 0 / - / 0 / -
C10 : s123 / 69 / 0.3 / 69 / 0.3 / 47 / 0.8 / 72 / NA / 57 / 0.3 / 74 / 1
C10 : s125 / 24 / 1 / 28 / 1 / 19 / 0.6 / 28 / 1 / 21 / 0.6 / 29 / 0.05
C10 : s126 / 29 / 0.3 / 29 / 0.1 / 18 / 1 / 30 / 1 / 22 / 1 / 31 / 1
C10 : s127 / 19 / 0.03 / 15 / 0.3 / 9 / 0.5 / 17 / NA / 12 / 1 / 19 / NA
C10 : s128 / 36 / 1 / 39 / 0.1 / 27 / 0.4 / 38 / 1 / 32 / 1 / 39 / NA
C10 : s129 / 54 / 0.006 / 49 / 0.004 / 26 / 1 / 51 / 1 / 43 / 0.4 / 54 / 1
C10 : s131 / 37 / 0.4 / 39 / 0.3 / 27 / 0.7 / 41 / 1 / 37 / 1 / 39 / 1
C10 : s133 / 149 / 0.3 / 121 / 1.00E-05 / 86 / 1.00E-09 / 113 / 0.6 / 89 / 1 / 138 / 1
C10 : s134 / 96 / 0.1 / 58 / 0.004 / 39 / 0.2 / 51 / 0.09 / 41 / 1 / 75 / 1
C10 : s135 / 9 / 1 / 6 / 1 / 4 / 1 / 7 / NA / 7 / 1 / 9 / 0.06
C10 : s136 / 24 / 0.006 / 25 / 0.4 / 15 / 0.6 / 27 / 1 / 23 / 1 / 27 / 1
C10 : s138 / 16 / 1 / 16 / 1 / 11 / 0.6 / 20 / NA / 15 / 1 / 19 / 1
C11 : s141 / 28 / 0.006 / 27 / 0.02 / 19 / 1 / 22 / 0.1 / 15 / 1 / 29 / NA
C11 : s225 / 17 / 0.1 / 16 / 0.05 / 15 / 0.3 / 17 / 1 / 10 / 1 / 19 / NA
C11 : s232 / 126 / 0.02 / 116 / 1 / 95 / 0.002 / 121 / 0.001 / 88 / 1 / 135 / 1.00E-05
C11 : s241 / 33 / 0.02 / 36 / 0.01 / 26 / 0.4 / 37 / 1 / 33 / 1 / 39 / 1
C13 : s018 / 51 / 0.2 / 46 / 0.8 / 40 / 0.02 / 53 / 1 / 47 / 1 / 55 / 1
C13 : s019 / 54 / 0.2 / 45 / 0.006 / 39 / 0.09 / 45 / 1 / 48 / 0.3 / 46 / 1
C13 : s047 / 46 / 0.4 / 49 / 0.6 / 41 / 0.7 / 48 / 1 / 46 / 0.07 / 51 / 0.06
C13 : s048 / 194 / 0.1 / 197 / 0.02 / 151 / 1.00E-04 / 206 / 0.03 / 199 / 1 / 207 / 1
C13 : s052 / 31 / 0.6 / 29 / 0.5 / 23 / 1 / 31 / 1 / 20 / 0.2 / 34 / NA
C13 : s057 / 9 / 1 / 10 / 0.2 / 8 / 1 / 11 / NA / 9 / 1 / 11 / NA
C13 : s059 / 78 / 0.2 / 68 / 0.3 / 65 / 0.8 / 80 / 1 / 45 / 0.7 / 81 / 0.06
C13 : s154 / 57 / 0.5 / 48 / 0.1 / 40 / 0.07 / 56 / 0.005 / 54 / 1 / 65 / 0.05
C13 : s161 / 32 / 1 / 16 / 7.00E-04 / 11 / 1 / 22 / 1 / 20 / 0.2 / 21 / 0.07
C13 : s166 / 11 / 1 / 12 / 0.5 / 11 / 0.02 / 13 / NA / 11 / 1 / 13 / 1
C13 : s229 / 16 / 0.4 / 11 / 1 / 12 / 1 / 14 / 1 / 8 / 1 / 15 / NA
C14 : s170 / 21 / 0.2 / 6 / 0.03 / 6 / 0.09 / 11 / 0.3 / 8 / NA / 14 / 1
C14 : s171 / 17 / 1 / 4 / 0.1 / 3 / 1 / 8 / 0.07 / 4 / NA / 9 / NA
C16 : s177 / 32 / 0.4 / 7 / 0.08 / 12 / 1 / 11 / 0.06 / 13 / NA / 8 / NA
C25 : s243 / 32 / 0.05 / 31 / 0.02 / 15 / 0.5 / 30 / 1 / 27 / 0.6 / 35 / 0.09
C25 : s247 / 10 / 1 / 7 / 1 / 5 / 1 / 9 / 0.06 / 9 / 0.3 / 10 / 1
* CYP19A1 = Cytochrome P450 19A1; BIG = Breast International Group; SNP = single nucleotide polymorphism.
CYP19A1 SNPs rs4646 and rs10046 were genotyped in all 4861 patient DNA samples; other SNPs were genotyped in 3691 patient DNA samples. 224 patient DNA samples failed all CYP19A1 genotyping. Genotyping was done using polymerase chain reaction-based methods.
a: South AM= South America;
-no data available; NA=test result not available.
Table S2. Associations between CYP19A1 genotype variants and distant recurrence-free interval, in the overall cohort and in the subset of patients assigned to a 5-year monotherapy regimen in the BIG 1-98 trial*.
Overall Cohort / 5-year Letrozole / 5-year TamoxifenSNP / Genetic model / N Patients (N Events) / HR (95%CI) / P / N Patients (N Events) / HR (95%CI) / N Patients (N Events) / HR (95%CI) / Interaction P†
rs4646 / 0 vs.1 vs. 2(A) / 4164 (546) / 1.04 (0.92,1.18) / 0.55 / 1236 (156) / 1.00 (0.79,1.27) / 1173 (162) / 1.08 (0.85,1.38) / 0.63
rs10046 / 0 vs.1 vs. 2(C) / 3709 (461) / 1.00 (0.88,1.12) / 0.94 / 1084 (130) / 0.87 (0.69,1.09) / 1034 (133) / 1.02 (0.81,1.28) / 0.32
rs700518 / 0 vs.1 vs. 2(C) / 2161 (222) / 0.85 (0.68,1.05) / 0.13 / 618 (53) / 1.14 (0.75,1.75) / 587 (72) / 0.61 (0.41,0.92) / 0.17
TT(ref) vs. CC, TC / -- / -- / 1.27 (0.70,2.33) / 0.44 (0.27,0.73) / 0.07
rs700519 / 0 vs.1 vs. 2(A) / 2875 (302) / 1.04 (0.75,1.46) / 0.80 / 829 (75) / 0.53 (0.21,1.37) / 809 (93) / 1.28 (0.74,2.22) / 0.15
rs936308 / 0 vs.1 vs. 2(G) / 2434 (253) / 0.82 (0.62,1.09) / 0.17 / 720 (67) / 0.51 (0.25,1.01) / 679 (80) / 1.14 (0.72,1.79) / 0.07
rs28757184 / 0 vs.1 vs. 2(A) / 3068 (313) / 1.31 (0.91,1.89) / 0.15 / 875 (78) / 1.97 (1.02,3.81) / 856 (100) / 1.37 (0.71,2.65) / 0.57
* CYP19A1 = Cytochrome P450 19A1; BIG = Breast International Group; SNP = single nucleotide polymorphism; HR = hazard ratio; CI = confidence interval. CYP19A1 SNPs rs4646 and rs10046 were genotyped in all 4861 patient DNA samples; other SNPs were genotyped in 3691 patient DNA samples. HRs, CIs and P-values estimated using adjusted Cox proportional hazards models.
† Interaction P-value: Wald test of treatment assignment (5-year letrozole vs. 5-year tamoxifen) by genotype interaction.
11
FIGURE LEGEND
Fig S1. Kaplan–Meier estimates of distant recurrence-free interval (DRFI) according to CYP19A1 SNP rs700518(T>C) variants for patients in the Breast International Group (BIG) 1-98 trial assigned to: A) 5-years letrozole; B) 5-years tamoxifen.
Figure S1
Section II. BIG 1-98 Collaborative Group participants who submitted tumor blocks
Steering Committee: B. Thürlimann (Chair), S. Aebi, L. Blacher, H Bonnefoi, A. S. Coates, T. Cufer, B. Ejlertsen, J. F. Forbes, R. D. Gelber, A. Giobbie-Hurder, A. Goldhirsch, A. Hiltbrunner, S. B. Holmberg, R. Maibach, A. Martoni, G. MacGrogan, H. T. Mouridsen, R. Paridaens, K. N. Price, M. Rabaglio, B.B. Rasmussen, M.M. Regan, A. Santoro, I. E. Smith, A. Wardley, G. Viale. Novartis: H. A. Chaudri-Ross.
IBCSG Foundation Council (members from 1998 to 2011): S. Aebi, A. S. Coates, M. Colleoni, J. P. Collins, H. Cortés Funes, R. D. Gelber, A. Goldhirsch, M. Green, A. Hiltbrunner, S. B. Holmberg, P. Karlsson, I Kössler, I. Láng, J. Lindtner, F Paganetti, M. de Stoppani, C.-M. Rudenstam, H.-J. Senn, R. Stahel, B. Thürlimann, A. Veronesi.
Coordinating Center (Berne, Switzerland): M. Castiglione (Chief Executive Officer 1998 – 2007), A. Hiltbrunner (Director), R. Kammler, M. Rabaglio, G. Egli, H. Hawle, B. Ruepp, R. Maibach.
Statistical Center (Dana-Farber Cancer Institute, Boston, MA, USA): R. D. Gelber (Director) , M.M. Regan (Group Statistician), K. N. Price (Director of Scientific Administration), A. Giobbie-Hurder (Trial Statistician), A. Keshaviah , Z. Sun, P.K. Gray, H. Huang, L. Nickerson.
Data Management Center (Frontier Science & Technology Research Foundation, Amherst, NY, USA): L. Blacher (Director of Data Management), T. Heckman Scolese (Coordinating Data Manager), M. Belisle, M. Caporale, J. Celano, L. Dalfonso, L. Dooley, S. Fischer, K. Galloway, J. Gould, R. Hinkle, M. Holody, G. Jones, R. Krall, S. Lippert, J. Meshulam, L. Mundy, A. Pavlov-Shapiro, K. Scott, M. Scott, S. Shepard, J. Swick, L. Uhteg, D. Weinbaum, C. Westby, T. Zielinski.
Central Pathology Review Office (University of Glasgow, Glasgow, UK): B. A. Gusterson, E. Mallon; (European Institute of Oncology, Division of Pathology, Milano, Italy): G. Viale, P. Dell’Orto, M. Mastropasqua, B. Del Curto.
Study Support (Novartis Corp. Basel, Switzerland): E. Waldie, I. van Hoomissen, M. De Smet, U. Trostmann, W. Schmidt, A. Bolton, W. Hackl.
Breast International Group (BIG)
International Breast Cancer Study Group (IBCSG)
Australian New Zealand Breast Cancer Trials Group (ANZ BCTG): R. D. Snyder, J. Chirgwin, J. F. Forbes, A. S. Coates, F. Boyle, D. Lindsay, D. Preece, J. Cowell, D. Talbot, A. Whipp.
Australia: The Cancer Council Victoria, Melbourne, VIC: F. Abell, R. Basser, R. Bell, B. Brady, D. Blakey, P. Briggs, I. Burns, P. Campbell, M. Chao, J. Chirgwin, B. Chua, K. Clarke, J. Collins, R. De Boer, J. C. Din, R. Doig, A. Dowling, R. Drummond, N. Efe, S. T. Fan, M. Francis, P. Francis, V. Ganju, P. Gibbs, G. Goss, M. Green, P. Gregory, J. Griffiths, I. Haines, M. Henderson, R. Holmes, P. James, J. Kiffler, M. Lehman, M. Leyden, L. Lim, G. Lindeman, R. Lynch, B. Mann, J. McKendrick, S. McLachlan, R. McLennan, G. Mitchell, S. Mitra, C. Murphy, I. Parker, K. Phillips, I. Porter, G. Richardson, J. Scarlet, S. Sewak, J. Shapiro, R. Snyder, R. Stanley, C. Steer, D. Stoney, A. Strickland, G. Toner, C. Underhill, K. White, M. White, A. Wirth, S. Wong; W P Holman Clinic, Liverpool Hospital, Sydney, NSW: S. Della-Fiorentina, A. Goldrick, E. Hovey, E. Moylan, E. Segelov; Calvary Mater Newcastle, Newcastle, NSW: J. F. Forbes, F. Abell, S. Ackland, A. Bonaventura, S. Cox, J. Denham, R. Gourlay, D. Jackson, R. Sillar, J. Stewart; Princess Alexandra Hospital, Woollongabba, QLD: E. Walpole, D. Thompson; Royal Brisbane and Women’s Hospital, Brisbane, QLD: M. Colosimo, R. Cheuk, L. Kenny, N. McCarthy, D. Wyld; Royal Hobart Hospital, Hobart, Tasmania: R. Young, R. Harrup, R. Kimber, R. Lowenthal; Toowoomba Hospital, Toowoomba, QLD: E. A. Abdi, R. Brodribb, Z. Volobueva; Westmead Hospital, Sydney, NSW: P. Harnett, V. Ahern, H. Gurney, N. Wilcken.
New Zealand: Auckland Hospital, Auckland: V. J. Harvey, B. Evans, W. Jones, M. McCrystal, D. Porter, P. Thompson, M. Vaughan; Christchurch Hospital, Christchurch: D. Gibbs, C. Atkinson, R. Burcombe, B. Fitzharris, B. Hickey, M. Jeffery, B. Robinson; Dunedin Hospital, Dunedin: B. McLaren, S. Costello, J. North, D. Perez; Waikato Hospital, Hamilton: I. D. Campbell, L. Gilbert, R. Gannaway, M. Jameson, I. Kennedy, J. Long, G. Round, L. Spellman, D. Whittle, D. Woolerton.
Brazil: Hospital de Clinicas de Porto Alegre, Porto Alegre: C. Menke, J. Biazús, R. Cericatto, J. Cavalheiro, N. Xavier, A. Bittelbrunn, E. Rabin.