Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Goss PE, Hershman DL, Cheung AM, et al. Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial. Lancet Oncol 2014; published online March 11. http://dx.doi.org/10.1016/S1470-2045(14)70035-X.

1

Supplemental materials for online. *Throughout this appendix, Group A represents T-score of -2.0 or greater; Group B represents T-score of less than -2.0. Figure 1a

2

Figure 1b

3

Figure 2a

4

Figure 2b

5

Figure 3a

6

Figure 3b

7

Figure 4a

8

Figure 4b

9

Figure 5a

10

Figure 5b

11

Figure 6a

12

Figure 6b

13

Supplemental Table 1. Change in Group BMD at 2 Years

Exemestane Anastrozole

Percent change in BMD (g/cm2)

N Mean % P-value1 N Mean % P-value1

HIP

Group A 83 -1·69 0·34 80 -2·22 0·23

Group B 61 1·66 0·55 55 0·57 0·84

L SPINE

Group A 87 0·79 0·69 77 -3·72 0·05

Group B 63 1·43 0·57 57 0·34 0·88

T-SCORE Change N Mean N Mean

HIP

Group A 83 -0·13 0·36 80 -0·09 0·53

Group B 61 0·15 0·35 55 0·05 0·76

L SPINE

Group A 87 0·08 0·68 77 -0·35 0·05

Group B 63 0·12 0·50 57 0·04 0·82

1Based on two-sided Student t-test for Group change.

14

Supplemental Table 2. Individual patient change of bone mineral density by treatment group for patients with complete assessments at baseline, and 1 year, and 2 years Group A (T-score >= - 2.0)

Exemestane

Anastrazole P- value

N Mean% (Range)

N Mean% (Range)

Hip – Year 1

79 -0.52 (-25.78 - 9.5)

72 -1.29 (-20.55 - 40.06)

0.01

Hip – Year 2

79 -1.8 (-19.44 - 8.89)

72 -2.5 (-19.75 - 40.2)

0.11

Spine – Year 1

82 -0.27(-17.15 - 27.98)

72 -1.37 (-19.57 - 16.48)

0.52

Spine – Year 2

82 -0.74 (-22.26 - 25.88)

72 -2.57 (-18.63 -21.62)

0.03

Group B (T-score < - 2.0)

Exemestane

Anastrazole P- value

N Mean% (Range)

N Mean% (Range)

Hip – Year 1 49 1.68 (-17.73 - 15.34)

49 1.01 (-9.51 - 14.98) 0.45

Hip – Year 2 49 3.21 (-14.44 -34.87)

49 -0.04 (-94.54 - 16.31) 0.37

Spine – Year 1 53 2.95 (-8.39 - 17.36)

50 2.85 (-13.3 - 15.09) 0.86

Spine – Year 2 53 3.26 (-9.4 - 22.53)

50 4.53 (-12.67 -23.84) 0.19

15

Supplemental Table 3. Unmatched group patient change of bone mineral density by treatment group for patients with assessments at baseline, or 1 year, or 2 years

Group A (T-score >= - 2.0)

Exemestane

Anastrazole P- value

N Mean% (Range)

N Mean% (Range)

Hip – Year 1 99 -0.62 (-25.78 - 9.5)

114 -1.66 (-20.55- 40.06) 0.01

Hip – Year 2 83 -1.93 (-19.44- 8.89)

79 -2.47 (-19.75-40.2) 0.13

Spine – Year 1 102 -0.59(-17.15-27.98)

116 -1.88 (-29.22 -16.48) 0.32

Spine – Year 2 87 -0.92 (-22.26 -25.88)

77 -2.39 (-18.63- 21.62) 0.08

Group B (T-score < - 2.0)

Exemestane

Anastrazole P- value

N Mean% (Range)

N Mean% (Range)

Hip – Year 1 64 0.61 (-68.92- 15.34)

66 0.83 (-9.51- 14.98) 0.23

Hip – Year 2 61 2.09 (-89.09- 34.87)

54 0.09 (-94.54 - 16.31) 0.35

Spine – Year 1 69 3.75 (-8.39- 32.54)

66 2.6(-13.3 - 15.09) 0.67

Spine – Year 2 63 2.11 (-74.27 - 22.53)

57 3.72 (-30.34-23.84) 0.26

16

Supplemental Table 4. Clinically relevant change in BMD at 2 years N Exemestane

group N Anastrozole

group P-value1

Yes No Yes No T-score -2.0 or greater Hip 83 6 77 80 6 74 1.00 Spine 87 13 74 77 7 70 0.34 T-score less than -2.0 Hip 61 16 45 55 9 46 0.26 Spine 63 25 38 57 27 30 0.46 1 P-value is based on exact Fisher test.

17

1P-value is based on exact Fisher test.

Supplemental Table 5. Patients with clinical fractures following randomization.

Group A P-value1

Group B P-value1

Exemestane Anastrozole Total Exemestane Anastrozole

Total

# (%) # (%) # (%) # (%) # (%) # (%)

TOTAL 147 (100) 153 (100) 300 (100) 101 (100) 96 (100) 197 (100)

NO FRACTURE

143 ( 97)

145 ( 95)

288 ( 96)

96 ( 95)

90 ( 94)

186 (94)

FRAGILITY FRACTURE

2 (1)

3 (2)

5 (2)

1 (1)

5 (5)

6 (3)

OTHER FRACTURE

2 ( 1)

5 (3)

7 (2)

0·65

4 (4)

1 ( 1)

5 ( 3)

0·11

18

Supplemental Table 6. Patient Change in Biomarkers from Baseline to Year 1

Exemestane Anastrozole

N Mean % (95% CI) Mean % (95% CI) P-value1

NTX

Group A 117

Baseline 13·6 (12·9,14·3) 13·7 (13·1,14·4)

Year 1 14·9 (13·9,15·9) 14·9 (14, 15·8) 0·96

Group B 81

Baseline 15 (14·1·16) 15·1 (14·1,16·2)

Year 1 10·5 (9·6,11·4) 10·5 (9·7,11·3) 0·31

PINP

Group A 117

Baseline 52·9 (48·9,57·3) 52·3 (48·4,56·6)

Year 1 58·4 (53·5,63·7) 54·5 (49·7,59·8) 0·61

Group B 81

Baseline 58·2 (53·2,63·7) 57·3 (51·8,63·3)

Year 1 30·9 (26·3,36·3) 28·7 (25·2,32·7) 0·12 1Based on two-sided Student t-test of patient change.

19

Supplemental Table 7. NCIC CTG MA.27B Accrual by Recruiting Centre and Principal Investigator

Recruiting Centre Principal Investigator Accrual

Northern Indiana Cancer Research Consortium, South Bend, IN, USA Rafat H. Ansari 27

Swedish American Regional Cancer Center, Rockford, IL, USA Harvey E. Einhorn 19

Allan Blair Cancer Centre, Regina, SK, CA Haji Ibrahim Chalchal 14

Kansas City CCOP, Prairie Village, KS, USA Rakesh Gaur 14

New Hampshire Oncology Hematology Associates, Concord, NH, USA Frederick M. Briccetti 13

Carle Cancer Center, Urbana, IL, USA Patricia A. Johnson 12

Illinois Cancer Care-Peoria, Peoria, IL, USA John W Kugler 11

University of Vermont, Burlington, VT, USA Marie Elizabeth Wood 11

Billings Clinic, Billings, MT, USA Benjamin T. Marchello 10

San Juan City Hospital, San Juan, PR, USA Luis Baez-Diaz 10

University of Washington Medical Center, Seattle, WA, USA Saul Eugene Rivkin 10

Aurora Cancer Care-Milwaukee West, Wauwatosa, WI, USA Rubina Qamar 10

Sanford Clinic North-Fargo, Fargo, ND, USA Prestone D. Steen 9

Cedar Valley Medical Specialists, Waterloo, IA, USA Boriana Svejinova Kamenova 7

Advocate Christ Medical Center, Oak Lawn, IL, USA Thomas M. Hoeltgen 7

Washington University School of Medicine, St. Louis, MO, USA Michael J. Naughton 7

Columbus CCOP, Columbus, OH, USA John Philip Kuebler 7

Summa Akron City Hospital/Cooper Cancer Center, Akron, OH, USA Jennifer Eileen Payne 7

The Moncton Hospital, Moncton, NB, CA Sheldon Rubin 6

Cambridge Memorial Hospital, Cambridge, ON, CA Edmond Chouinard 6

Siouxland Hematology Oncology Associates LLP, Sioux City, IA, USA Donald B. Wender 6

Mercy Hospital, Portland, ME, USA Roger Charles Inhorn 6

Altru Cancer Center, Grand Forks, ND, USA Todor Dentchev 6

Columbia University Medical Center, New York, NY, USA Dawn Lauryn Hershman 6

20

Providence Saint Mary Regional Cancer Center, Walla Walla, WA, USA Robert Criag Quackenbush 6

Thunder Bay Regional Health Science Centre, Thunder Bay, ON, CA Adrian Chan 5

Desert Regional Medical Center, Palm Springs, CA, USA Cynthia Gail Leichman 5

Augusta Oncology Associates PC-Saint Sebastian, Augusta, GA, USA Mark Robert Keaton 5

West Michigan Cancer Center, Kalamazoo, MI, USA Raymond Sterling Lord 5

Essentia Health Duluth Clinic CCOP, Duluth, MN, USA Daniel A. Nikcevich 5

Alegent Health Bergan Mercy Medical Center, Omaha, NE, USA Gamini S. Soori 5

Nebraska Cancer Research Center, Lincoln, NE, USA Alan Richard Berg 5

Elliot Hospital, Hooksett, NH, USA Douglas J. Weckstein 5

LRG Healthcare-Lakes Region General Hospital, Laconia, NH, USA Charles H. Catcher 5

Saint Barnabas Medical Center, Livingston, NJ, USA Richard A. Michaelson 5

Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County, Mount Holly, NJ, USA Michael S. Entmacher 5

Albert Einstein College of Medicine, Bronx, NY, USA Joseph Anthony Sparano 5

Green Bay Oncology at Saint Vincent Hospital, Green Bay, WI, USA Thomas J. Saphner 5

Sunnybrook-Odette Cancer Centre, Toronto, ON, CA Kathleen I. Pritchard 4

Mercy Hospital Fort Smith, Fort Smith, AR, USA John Dalie Wells 4

Santa Rosa Memorial Hospital, Santa Rosa, CA, USA Ian Churchill Anderson 4

Front Range Cancer Specialists, Fort Collins, CO, USA Robert F. Marschke 4

Oncology Associates at Mercy Medical Center, Cedar Rapids, IA, USA Martin Wiesenfeld 4

Heartland Oncology and Hematology LLP, Council Bluffs, IA, USA John A. Okerbloom 4

William Beaumont Hospital-Royal Oak, Royal Oak, MI, USA Dana Zakalik 4

Aultman Health Foundation, Canton, OH, USA Kisa Ewing Weeman 4

University of Wisconsin Hospital and Clinics, Madison, WI, USA James Francis Cleary 4

CHA-Hopital Du St-Sacrement, Quebec City, QC, CA Christine Desbiens 3

University of Arkansas for Medical Sciences, Little Rock, AR, USA Laura Fulper Hutchins 3

Glendale Memorial Hospital and Health Center, Glendale, CA, USA Ghassan Al-Jazayrly 3

21

Covenant Medical Center, Waterloo, IA, USA Mohammed T. Masri 3

Indiana University Health Bloomington, Bloomington, IN, USA David Y. Lee 3

Via Christi Regional Medical Center, Wichita, KS, USA Shaker R. Dakhil 3

Mass General/North Shore Cancer Center, Danvers, MA, USA Joel H. Schwartz 3

MedStar Franklin Square Medical Center/Weinberg Cancer Institute, Baltimore, MD, USA Yvonne Lynn Ottaviano 3

Grand Rapids Clinical Oncology Program, Grand Rapids, MI, USA Martin J. Bury 3

Oncology Care Associates PLLC, Saint Joseph, MI, USA Eric P. Lester 3

Kinston Medical Specialists PA, Kinston, NC, USA Peter Robins Watson 3

Samaritan North Health Center, Dayton, OH, USA Howard M. Gross 3

University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Howard Ozer 3

Cancer Centers of Southwest Oklahoma Research, Lawton, OK, USA Nadim Fouad Nimeh 3

Cancer Care Associates, Oklahoma City, OK, USA Howard Ozer 3

Saint Luke's University Hospital-Bethlehem Campus, Bethlehem, PA, USA Sanjiv Satyanarain Agarwala 3

Pottstown Memorial Medical Center, Pottstown, PA, USA Wei (Frank) Song 3

Scott and White Memorial Hospital, Temple, TX, USA Lucas Wong 3

Aspirus Regional Cancer Center, Wausau, WI, USA Umang Gautam 3

BCCA – Vancouver Cancer Centre, Vancouver, BC, CA Hagen Kennecke 2

Kaiser Permanente Medical Center - Santa Clara, Santa Clara, CA, USA Louis Fehrenbacher 2

Northeast Georgia Medical Center, Gainesville, GA, USA Richard John LoCicero 2

Kootenai Cancer Center, Post Falls, ID, USA Haluk Tezcan 2

Snake River Oncology of Eastern Idaho PLLC, Idaho Falls, ID, USA Christian T. Shull 2

Evanston CCOP-NorthShore University Health System, Evanston, IL, USA Douglas Edward Merkel 2

Baptist Health Lexington, Lexington, KY, USA Lee G. Hicks 2

Addison Gilbert Hospital, Gloucester, MA, USA Angus P. McIntyre 2

Simonds-Sinon Regional Cancer Center, Fitchburg, MA, USA Madhavi K. Toke 2

Coborn Cancer Center at Saint Cloud Hospital, St. Cloud, MN, USA Donald James Jurgens 2

22

Great Falls Clinic, Great Falls, MT, USA Benjamin T. Marchello 2

Sanford Bismarck Medical Center, Bismarck, ND, USA Edward J. Wos 2

Nebraska Methodist Hospital, Omaha, NE, USA Robert M. Langdon 2

Alegent Health Immanuel Medical Center, Omaha, NE, USA Gamini S. Soori 2

Exeter Hospital, Exeter, NH, USA Michael S. Buff 2

Finger Lakes Hematology and Oncology, Clifton Springs, NY, USA Bruce Allan Yirinec 2

Miami Valley Hospital, Dayton, OH, USA Howard M. Gross 2

Saint Mary Medical and Regional Cancer Center, Langhome, PA, USA Robert E. Reilly 2

Lankenau Hospital, Wynnewood, PA, USA Paul B. Gilman 2

AnMed Health Cancer Center, Anderson, SC, USA James Dewitt Bearden 2

Peace-Health Saint Joseph Medical Center, Bellingham, WA, USA Saul Eugene Rivkin 2

Virginia Mason CCOP, Seattle, WA, USA Jacqueline Vuky 2

Saint Vincent Hospital, Green Bay, WI, USA Thomas J. Saphner 2

Gundersen Lutheran Health System/CCOP, Lacrosse, WI, USA Kurt Oettel 2

Green Bay Oncology Limited at Saint Mary's Hospital, Green Bay, WI, USA Thomas J. Saphner 2

Algoma District Cancer Program, Sault Ste. Marie, Sault Saint Marie, ON, CA Silvana Spadafora 1

University Health Network – Princess Margaret Hospital, Toronto, ON, CA David Warr 1

Providence Saint Joseph Medical Center/Disney Family Cancer Center, Burbank, CA, USA Raul R. Mena 1

Kaiser Permanente-Richmond, Richmond, CA, USA Louis Fehrenbacher 1

Kaiser Permanente-Santa Rosa, Santa Rosa, CA, USA Louis Fehrenbacher 1

Poudre Valley Hospital, Fort Collins, CO, USA Paolo Romero 1

Norwalk Hospital, Norwalk, CT, USA Richard C. Frank 1

23

Bone Turnover Assay Bone formation was assessed by serum levels of PINP using UniQTM: PINP RIA kits by Orion Diagnostica, Espoo, Finland, expressed as microg/l. Assays were performed as per the manufacturer’s instructions with the inclusion of a standard curve on each assay plate. Bone resorption was assessed by serum levels of NTX-I using the OSTEOMARK® NTX serum kit by Wampole Laboratories.