Introduction
First trials: oophorectomy
Adjuvant tamoxifen
First trials
Tamoxifen and the Oxford overview
Tamoxifen and age, menopausal status, nodal status, size, and grade
Tamoxifen with chemotherapy
Significance of progesterone receptor
Tamoxifen in ER-negative and ER-low breast cancer
Duration: 5 years or less
Toxicities
CYP2D6 genotyping and tamoxifen efficacy
Adjuvant ovarian suppression
Adjuvant aromatase inhibitor trials
Study | Design | Arms | Number | Population (post-menopausal women) | Primary endpoint (s) |
---|---|---|---|---|---|
Monotherapy (versus tamoxifen) | |||||
ATAC [42] | Double-blind | A versus T versus T + A (5 years) | 9,366 | HR+ EBC | DFSa, occurrence of AEs |
BIG 1-98 [43] | Double-blind | L versus T versus L→T versus T→L (5 years) | 8,010 | HR+ EBC | DFSb |
Open-label, multinational | Upfront T versus E (2.75 years) | 9,775 | HR+ EBC | DFSc | |
Sequential T→E versus E (5 years) | |||||
Sequential therapy | |||||
IES [46] | Double-blind | T→E versus T→T (5 years) | 4,724 | HR+ EBC | DFSd |
ARNO 95 [47] | Open-label | T (2 years) → earsabears) versus T (2 years) → T (3 years) | 979 | HR+ EBC who received 2 years of T | DFSa |
ABCSG Trial 8 [48] | Open-label | T (5 years) versus T (2 years)→A (3 years) | 3,714 | HR+ EBC who received 2-3 years of T | RFSe |
ITA [49] | Open-label, multi-center | T (2-3 years)→A (5 years) versus T (5 years) | 448 | HR+ (or unknown) node+ EBC who received 2-3 years of T | RFSf |
BIG 1-98 [43] | Double-blind | L versus T versus L→T versus T→L (5 years) | 8,010 | HR+ EBC | DFSb |
TEAM [44] | Open-label, multinational | Upfront E (2.75 years) versus T | 9,779 | HR+ EBC | DFSc |
E (5 years) versus sequential T→E | |||||
Extended therapy | |||||
MA.17 [50] | Double-blind | L versus placebo | 5,187 | HR+ EBC who had received 4.5 to 6 years of adjuvant T therapy | DFSg |
ABCSG Trial 6a [51] | Open-label | A (3 years) versus no further treatment | 856 | HR+ EBC who had received 5 years of adjuvant T, with or without AG, for the first 2 years of therapy | RFSh |
NSABP-33 [52] | Double-blind | E (5 years) versus placebo (5 years) | 1,598 | HR+ T1-3N1M0 EBC who were disease-free after 5 years of adjuvant T | DFSa |
Study | Arms | DFS hazard ratio (95% CI) | TTR or RFS hazard ratio (95% CI) | TTDR or DRFI or DRFS or DDFS hazard ratio (95% CI) | BCFI or BCFS hazard ratio (95% CI) | OS hazard ratio (95% CI) |
---|---|---|---|---|---|---|
Monotherapy analysis (versus tamoxifen) | ||||||
ATAC [53] 120-month follow-up | A versus T versus T + A (5 years) | 0.91 (0.83-0.99) P = 0.04 | TTR 0.84 (0.75-0.93) P = 0.001 | TTDR 0.87 (0.77-0.99) P = 0.03 | NA | 0.97 (0.88-1.08) P = 0.6 |
HR+ patients 0.86 (0.78-0.95) P = 0.003 | HR+ patients 0.79 (0.70-0.89) P = 0.0002 | HR+ patients 0.85 (0.73-0.98) P = 0.02 | HR+ patients 0.95 (0.84-1.06) P = 0.4 | |||
BIG 1-98 [54] 8.1-year follow-up | L versus T | 0.53 (0.78-0.96) P = 0.007 | NA | DRFI 0.86 (0.74-0.998) P = 0.047 | BCFI 0.86 (0.76-0.98) P = 0.03 | 0.87 (0.77-0.999) P = 0.048 |
IPCW 0.82 (0.74-0.92) P <0.0002 | IPCW 0.79 (0.68-0.92) P = 0.003 | IPCW 0.80 (0.70-0.92) P = 0.002 | IPCW 0.79 (0.69-0.90) P <0.0006 | |||
TEAM [45] 2.75-year follow-up (before the switch) | Upfront E (2.75 years) versus T | 0.89 (0.77-1.03) P = 0.12 | NA | NA | NA | NA |
Sequential therapy analysis | ||||||
IES [46] 91-month follow-up | T→ E versus T→ T (5 years) | 0.81 (0.72-0.91) P <0.001 | NA | TTDR 0.84 (0.73-0.97) P = 0.01 | BCFS 0.81 (0.71-0.92) P <0.001 | 0.53 (0.75-0.99) P <0.04 |
ARNO 95 [47] 30.1-month follow-up | T (2 years)→A (3 years) versus T (2 years)→T (3 years) | 0.66 (0.44-1.00) P = 0.049 | NA | NA | NA | 0.53 (0.28-0.99) P = 0.045 |
ABCSG Trial 8 [48] 60-month follow-up | T (2 years)→A (3 years) versus T (5 years) | 0.91 (0.75-1.103) P = 0.33 | RFS 0.80 (0.631-1.013) P = 0.06 | DRFS 0.78 (0.60-0.99) P = 0.046 | NA | 0.87 (0.64-1.16) P = 0.33 |
ITA [49] 128-month follow-up | T (2-3 years)→A (5 years) versus T (5 years) | NA | RFS 0.64 (0.44-0.94) P = 0.02 | NA | BCFS 0.72 (0.44-1.17) P = 0.2 | 0.79 (0.52-1.21) P = 0.3 |
BIG 1-98 [54] 8.1-year follow-up | L→T versus T→L (5 years) | L→T 1.06 (0.91-1.23) P = 0.48 | NA | L→T DRFI 1.14 (0.92-1.42) P = 0.24 | L→T BCFI 1.10 (0.91-1.32) P = 0.34 | L→T 0.97 (0.80-1.19) P = 0.79 |
T→L 1.07 (0.92-1.25) P = 0.36 | T→L 1.23 (0.99-1.53) P = 0.06 | T→L 1.16 (0.96-1.40) P = 0.12 | T→L 1.10 (0.90-1.33) P = 0.36 | |||
TEAM [55] 5-year follow-up (after the switch) | E (5 years) versus sequential T→E | 1.06 (0.91-1.24) P = 0.42 | RFS 1.06 (0.88-1.28) P = 0.53 | NA | NA | 1.00 (0.89-1.14) P >0.99 |
Extended therapy analysis | ||||||
MA.17 [56] 64-month follow-up | L versus placebo | 0.68 (0.56-0.83) P <0.001 | NA | DDFS 0.81 (0.63-1.04) P = 0.09 | NA | 0.99 (0.79-1.24) P = 0.83 |
IPCW 0.52 (0.45-0.61) P <0.001 | IPCW 0.51 (0.42-0.61) P <0.001 | IPCW 0.61 (0.52-0.71) P <0.001 | ||||
SCC 0.58 (0.47-0.72) P <0.001 | SCC 0.68 (0.52-0.88) P = 0.004 | SCC 0.76 (0.60-0.96) P = 0.02 | ||||
ABCSG Trial 6 [51] 62.3-month follow-up | A (3 years) versus no further treatment | NA | RFS 0.62 (0.40-0.96) P = 0.031 | DFRS 0.53 (0.29-0.96) P = 0.034 | NA | 0.89 (0.59-1.34) P = 0.57 |
NSABP-33 [52] 30-month follow-up | E (5 years) versus placebo (5 years) | 0.68 P = 0.07 | RFS 0.44 P = 0.004 | NA | NA | NA |
Arimidex, tamoxifen, alone or in combination
Breast international group 1-98
Sequential aromatase inhibitor treatment after tamoxifen
Sequential tamoxifen after an aromatase inhibitor
Aromatase inhibitor toxicities and comparative toxicities with tamoxifen
Study | Arms numberaMSK: % (comparative P value)b | Arms numberaBMD (T-score): % (comparative P value)b | Arms numberaCV events: % (comparative P value) | Arms numberaGynae: % (comparative Pvalue) | Arms numberaHot flashes : % (comparative P value) |
---|---|---|---|---|---|
ATAC | A versus T 6,241 | A versus T (5 years) 197 | A versus T 6,186 | A versus T (5 years) 6,186 | A versus T (5 years) 6,186 |
Arthralgia: 35.6 versus 29.4 (<0.0001) | LS: −6.1 versus +2.8 (<0.0001) | Ischemic CV event: 4.1 versus 3.4 (0.1) | Gynecologic eventd: 3.0 versus 10.0 (<0.0001) | 35.7 versus 40.9 (<0.0001) | |
Ischemic CerebroV event: 2.0 versus 2.8 (0.03) | Vaginal bleeding. 5.4 versus 10.2 (<0.0001) | ||||
CTS: 3.0 versus 1.0 (<0.0001) | Hip: −7.2 versus +0.7 (<0.0001) | Venous TE event: 2.8 versus 4.5 (0.0004) | Vaginal discharge: 3.5 versus 13.2 (<0.0001) | ||
DVT event: 1.6 versus 2.4 (0.02) | Reduced libido: 1.0 versus 0.4 (<0.0001) | ||||
CV deathc: 2.0 versus 2.0 (NR) | |||||
CerebroV deathc: 0.8 versus 0.9 (NR) | |||||
Hypercholesterolemia: 9.0 versus 3.0 (<0.0001) | |||||
BIG 1-98 | L versus T 8,028 (4,992)a | NA | L versus T 4,895 | L versus T (6 years) 3,074 | L versus T (6 years) 3,074 |
Arthralgia: 20.0 versus 13.5 (<0.001) | Cardiac event: 5.5 versus 5.0 (0.48) | Vaginal bleeding: 5.1 versus 9.9 (<0.001) | 37.7 versus 42.9 (NR) | ||
Myalgia: 7.1 versus 6.1 (0.19) | CerebroV accident or TIA: 1.4 versus 1.4 (0.90) | Night sweating: 15.6 versus 19.4 (NR) | |||
TE event: 2.0 versus 3.8 (<0.001) | |||||
Hypercholesterolemia: 50.6 versus 24.6 (<0.001) | |||||
TEAM | E versus T 9,779 | E versus T (1 year) 161 | E versus T 9,779 | E versus T (2.75 years) 9,779 | NA |
Arthralgia: 17.9 versus 9.2 (≤0.001) | LS: −2.8 versus +0.5 (0.0008) | Ischemic CV event/MI: 0.8 versus 0.7 (NR) | Endometrial hyperplasia: 0.0 versus 2.0 (<0.0001) | ||
Vaginal hemorrhage: 1.6 versus 3.1 (<0.0001) | |||||
Hip: −2.2 versus +0.4 (0.04) | |||||
Vaginal discharge: 2.3 versus 6.8 (<0.0001) | |||||
FN: +0.3 versus −1.8 (0.414) | Vaginal infection: 0.7 versus 2.2 (<0.0001) | ||||
MA.17 | L versus placebo 5,187 | L versus placebo 226 | L versus placebo 5,187 | L versus placebo (2.5 years) 5,187 | L versus placebo 5,187 |
Arthralgia: 25.0 versus 21.0 (<0.001) | LS: −5.4 versus −0.7 (0.008) | CV disease: 5.8 versus 5.6 (0.76) | Vaginal bleeding: 6 versus 8 (0.005) | 58 versus 54 (0.003) | |
Arthritis: 6.0 versus 5.0 (0.07) | Hip: −3.6 versus −0.7 (0.044) | MI: 0.3 versus 0.4 (NR) Stroke/TIA: 0.7 versus 0.6 (NR) | Vaginal dryness: 6 versus 5 (0.26) | ||
Myalgia: 15.0 versus 12.0 (0.0041) | TE event: 0.4 versus 0.2 (NR) Hypercholesterolemia: 16 versus 16 (0.79) |
Outcome measure | AE | Number of AEs (yes versus no AE) | Hazard ratio | 95% CI | P value |
---|---|---|---|---|---|
DFS | VMS | 249 versus 837 | 0.731 | 0.618-0.866 | <0.001 |
MSAE | 239 versus 847 | 0.826 | 0.694-0.982 | 0.030 | |
VVS | 89 versus 997 | 0.769 | 0.585-1.01 | 0.058 | |
Overall | 418 versus 668 | 0.735 | 0.632-0.855 | <0.001 | |
OS | VMS | 147 versus 617 | 0.583 | 0.424-0.803 | 0.001 |
MSAE | 151 versus 613 | 0.811 | 0.654-1.005 | 0.055 | |
VVS | 51 versus 713 | 0.570 | 0.391-0.831 | 0.003 | |
Overall | 268 versus 496 | 0.680 | 0.565-0.819 | <0.001 | |
DM | VMS | 165 versus 490 | 0.813 | 0.664-0.996 | 0.046 |
MSAE | 138 versus 517 | 0.749 | 0.601-0.934 | 0.010 | |
VVS | 54 versus 601 | 0.687 | 0.435-1.085 | 0.107 | |
Overall | 261 versus 394 | 0.783 | 0.651-0.942 | 0.010 |
Cognitive function with aromatase inhibitors
Predictive factors of benefit from an aromatase inhibitor
Extended adjuvant endocrine therapy
NCIC CTG MA.17/BIG 1-97
Other extended adjuvant therapy trials with aromatase inhibitors
Ongoing studies
Study | Number | Population (treatment received pre-enrollment) | Arms at random assignment | Study number |
---|---|---|---|---|
MA.17R | 1,918 | Prior 4.5-6 years of AI, with or without prior Ta | L (5 years) versus placebo (5 years) | NCT00754845 |
Completed AI ≤2 years prior random assignment | ||||
SALSA | 3,486 | Any endocrine therapy (5 years) | A (5 years) versus A (2 years) | NCT00295620 |
LEAD | 4,050 | T (4-6 years) | L (5 years) versus L (2-3 years) | NCT01064635 |
DATA | 1,900 | T (2-3 years) | A (6 years) versus A (3 years) | NCT00301457 |
NSABP-B42 | 3,966 | AI or T→AIb (to 5 years) | L (5 years) versus placebo (5 years) | NCT00382070 |
SOLE | 4,800 | Any endocrine therapyc (5 years) | L (5 years) versus intermittentd L (5 years) | NCT00553410 |
Tamoxifen beyond 5 years
Study | Number | Population | Arms | Disease-free survival hazard ratio (95% CI) | Overall survival hazard ratio (95% CI) |
---|---|---|---|---|---|
ATLAS [113] Open-label | 6,846a | Pre- and post-menopausal women with ER+ EBC who already received T for 5 years (in the context of ATLAS trial total number = 12,894) | T for additional 5 years (10 years) versus stop T (5 years) | 5-9 years RR 0.90 (0.79-1.02) P = 0.10 > 10 years RR 0.75 (0.62-0.90) P = 0.01 | BC mortality: 5-9 years RR 0.97 (0.79-1.18) P = 0.74 BC mortality: >10 years RR 0.71 (0.58-0.88) P = 0.002 |
All years log-rank = 0.002 | |||||
Absolute reduction at years 15: 3.7% | |||||
aTToM [114]b Open-label | 6,953 | Invasive EBC who had already been taking T for 5 years. 2,755 ER+ (39%) and 4,198 ER untested (61%) (estimated 80% ER+ if status unknown) | T for additional 5 years versus no further treatment | RR 0.85 (0.76-0.95) P = 0.003 | BC mortality: 5-9 years RR 1.08 (0.85-1.38) |
Absolute reduction 4% | BC mortality: >10 years RR 0.75 (0.63-0.90) P = 0.007 BC mortality: all years RR 0.88 (0.74-1.03) P = 0.1 | ||||
Pooled analysis ATLAS + aTToM [114]b | 17,477 | 10,543c ER+ from ATLAS plus 6,934 ER+ from aTTom | T 10 versus 5 years | NA | BC mortality: 5-9 years RR 0.97 (0.84-1.15) |
BC mortality: >10 years RR 0.75 (0.65-0.86) P = 0.00004 | |||||
BC mortality: all years RR 0.85 (0.77-0.94) P = 0.001 |