The Breast Journal

Review Article

Impact of CDK4/6 Inhibitors on Aromatase Inhibitor-Associated Musculoskeletal Syndrome (AIMSS) in the Adjuvant Setting

Table 1

Phase III randomized trials of AIs in postmenopausal women with early-stage breast cancer.

Reference

Trial

Treatment arms

Study sample

Median age

Median follow-up (month)

DFS

Arthralgia (%)

Myalgia (%)

Bone pain (%)

Back pain (%)

Arthritis (%)

Osteoporosis (%)

Fracture (%)

Carpal tunnel syndrome

Colleoni et al. [21]

BIG 1–98 (NCT00004205)

Tamoxifen 5 years vs. letrozole 5 years

4922 (2459/2463)

61.7/61.9

81.1%/84% IPCW: 82.1/85.6

90.4/91.8

16.6/22.5

7/8.4

2.2/5.1

6.7/10

0.2/0.8

Regan et al. [5]

Buzdar et al. [45]

ATAC (NCT00849030)

Tamoxifen for 5 years vs. anastrozole for 5 years vs. combination for 5 years

9366 (3116/3125/3125)

64.1/64.1/64.3

575 vs. 651 events; HR: 0·87

Similar; HR: 0.97

29.4/35.6

7/11

7.7/11

1/3

Howell et al. [7]

Van de Velde et al. [6]

TEAM (NCT00036270, NCT00279448)

Tamoxifen for 2.5–3 years plus exemestane until 5 years vs. exemestane for 5 years

9779 (4875/4904)

5-year: 86%/87%; HR: 0.93

5-year: 91%/91%; HR: 1.0

20.9/24

7.4/7.5

4.8/5.4

5.7/5.7

2.9/3.6

6/10

3/5

10-year: 67%/67%; HR: 0.96

10-year: 73%/74%; HR: 0.98

Derks et al. [22]

Coombes et al. [46]

IES (NCT00038467)

Tamoxifen for 2–3 years plus exemestane until 5 years vs. tamoxifen for 5 years

4724 (2352/2372)

63.7/63/6

55.7

5-year: 354 vs. 455 events; adjusted HR: 0.75

5-year: 222 vs. 261 deaths; adjusted HR: 0.85

18.6/11.8

14.1/12

7.3/5.5

4.3/3.1

2.8/0.3

Goss et al. [23, 24]

NCIC CTG MA-17 (NCT00003140)

Letrozole vs. placebo for 5 years (after 5 years of tamoxifen)

5187 (2593/2594)

62.4/62

4-year: 94.4%/89.8%; HR:0.58

4-year: 95.4%/95%; HR: 0.82

25/21

15/12

5/6

6/5

8.1/6

5.3/4.6

Goss et al. [36]

MA.17R (NCT00754845)

Letrozole vs. placebo for 5 years (after 4.5–6 years of AI treatment preceded or not by tamoxifen)

1918 (959/959)

65.6/64.8

5-year: 96%/91%; HR: 0.66

5-year: 93%/94%; HR: 0.97

53/50

28/25

18/14

33/30

11/6

14/9

Mamounas et al. [25, 26]

NSABP-B42 (NCT00382070)

Letrozole vs. placebo for 5 years (after 5 years of tamoxifen or AI)

3966 (1983/1983)

7-year: 84.7%/81.3%; HR: 0.85

7-year: 91.8%/92.3%; HR: 1.15

18/15

8/6

2/2

3/2

Smith, et al. [28]

FACE (NCT00248170)

Letrozole vs. anastrozole for 5 years

4136 (2061/2075)

62/62

5-year: 84.9%/82.9%; HR: 0.93

5-year: 89.9%/89.2%; HR: 0.98

48.2/47.9

11.4/10.3

6.7/5.9

10.3/9.4

10.9/10.9

0/0.05

Boccardo et al. [39]

ITA trial (NCT00286117)

Tamoxifen for 2–3 years plus anastrozole until 5 years vs. tamoxifen for 5 years

448 (223/225)

63/63

94.6%/85.8%

10 deaths vs. 4 deaths

1/1.3

Jakesz et al. [42]

ABCSG 6a (NCT00300508)

Anastrozole for 3 years vs. placebo (after 5 years of tamoxifen)

856 (387/469)

67.8/68.5

62.3

5-year: 7.15 vs. 11.8%; 16 vs. 35 events (HR = 0.53; )

5-year: 40 deaths (10.3%) vs. 55 deaths (11.7%); HR: 0.89;

24.5/18.3

0.8/1.1

Dubsky et al. [27]

ABCSG-8 (NCT00291759)

Tamoxifen for 2 years plus anastrozole for 3 years vs. tamoxifen for 5 years

3714 (1865/1849)

63.6/64

5-year: 89.5%/88.5%; HR: 0.91

83 vs. 94 deaths; HR: 0.87

19/16

2.3/1.5

Jakesz et al. [40]

ABCSG-8 (NCT00291759)

Tamoxifen for 2 years plus anastrozole for 3 years vs. tamoxifen for 5 years

3224 (1618/1606)

60.9/60.5

3-year: 95.8%/92.7%; HR: 0.60

3-year: 97%/96%; HR, 0.53

2/1

ARNO 95 (NCT00287534)

Tjan-Heijnen et al. [29]

DATA (NCT00301457)

Anastrozole for 3 years vs. 6 years (after 2-3 years of tamoxifen)

1860 (929/931)

57.6/57.7

5-year: 79.4%/83.1%; HR: 0.79

5-year: 90.4%/90.8%; HR: 0.91

52.5/57.7

16.4/20.9

7.5/10

Colleoni et al. [32]

SOLE (NCT00553410)

Letrozole intermittently or continuously for 5 years (after 4–6 years of endocrine therapy)

4851 (2425/2426)

60/60

5-year: 85.8%/87.5%; HR: 1.08

5-year: 94.3%/93.7%; HR:0.85

65.7/68.7

35.9/37.1

27.2/28.7

47.4/46.8

8.1/8.8

Blok et al. [31]

IDEAL (BOOG 2006−05)

Letrozole for 2.5 years vs. 5 years (after 5 years of endocrine therapy)

1824 (909/915)

5-year: 82%/83.4%; HR: 0.92

HR: 1.04

13.2/14.7

6.1/5

7.5/12.7

2.8/5

De Placido et al. [30]

FATA-GIM3 (NCT00541086)

Anastrozole or exemestane or letrozole 5 years vs. tamoxifen for 2 years plus anastrozole or letrozole or exemestane for 3 years

3697 (1847/1850)

64/64

5-year: 89.8%/88.5%; HR: 0.89

5-year: 96.8%/95.3%; HR: 0.72

17/13

27.3/21.9

33.6/25.8

23.8/19.4

4/5

Del Mastro et al. [47]

GIM4 LEAD (NCT01064635)

Letrozole for 2–3 years vs. 5 years (after 2–3 years of tamoxifen)

2056 (1030/1026)

60/61

120

8-year: 80%/85%; HR: 0.82

4.8/8.3

0.5/0.9

NCT00295620 [48, 49]

SALSA (ABCSG 16)

Anastrozole for 2 years vs. 5 years (after 5 years of endocrine therapy)

3470 (1732/1738)

65/65

5-year: 78%/78%; HR 0.99

4/6

Mamounas et al. 2008 [43]

NSABP B-33 (NCT00016432)

Exemestane for 5 years vs. placebo for 5 years (after 5 years of tamoxifen)

1598 (799/799)

4-year: 91%/89%;

16 vs. 13 deaths

1/0.5 (Grade3/4)

0.5/0.7 (Grade 3/4)

Aihara et al. [33]

N-SAS BC03

Tamoxifen for 1–4 years plus anastrozole until 5 years vs. tamoxifen for 5 years

706 (354/3520)

59.5/60.2

3-year: 94.3%/90.7% HR: 0.69

3-year: 99.6%/98.8%

50.4/31.8

1.4/2.6

Ruiz-Borrego et al. [34]

GEICAM/2006−10 (NCT00543127)

Anastrozole vs. anastrozole plus fulvestrant

870 (437/433)

62/62

7-year: 83.3%/86.9%; HR: 0.84

5-year: 95.8%/94.3%;

14.6/13.4 (Grade 2–4)

2.7/5 (Grade 2–4)

3/6.5 (Grade 2–4)

Goss et al. [23, 64]

NCIC CTG MA.27 (NCT00066573)

Exemestane for 5 years vs. anastrozole for 5 years

7576 (3,789/3,787)

64.1

4-year: 91 vs. 91.2; HR: 1.02

4-year: 94.5%/94.1; HR: 0.93

55.4/55.4

17.716.7

10.1/10.9

12.7/13.4

7/6.4

33/36.4

4/4

NR = not reported.