Table 2.

Summary of key clinical trials, systemic reviews, and meta-analyses that investigated the role of adjuvant endocrine therapy in breast cancer ER+ HER2−.

Study and Treatment	Interval	Recurrence Outcome (95% CI)	Survival Outcome (95% CI)
Endocrine Therapy 5 Years Standard Duration
5 years of Tamoxifen vs. none EBCTCG (2011) [3] meta-analysis of 20 trials (n = 21,457)	Years 0–4 Years 5–9 Years 10–14	Breast cancer recurrence RR 0.53 (0.48–0.57), p < 0.0001 RR 0.68 (0.60–0.78), p < 0.0001 -	Mortality RR 0.71 (0.62–0.80), p < 0.0001 RR 0.66 (0.58–0.75), p < 0.0001 RR 0.68 (0.56–0.83), p < 0.0001
5 years of AI vs. 5 years of Tamoxifen EBCTCG (2015) [44] meta-analysis of 9 trials (n = 31,920 of postmenopausal women)	Years 0–4 Years 5–9	Breast cancer recurrence RR 0.70 (0.64–0.77), p < 0.0001 RR 0.92 (0.83–1.01), p = 0.082	Mortality RR 0.79 (0.67–0.92), p = 0.002 RR 0.60 (0.50–0.72), p < 0.0001
5 years of Letrozole vs. Tamoxifen BIG 1-98 (2018) [87] randomised control trial (n = 8010)	At 8 years At 14 years Years 0–5 Years 5–10 >10 years	DFS HR 0.82 (0.74–0.92), p = 0.0002 DFS HR 0.91 (0.81–1.01), p = 0.08 Contralateral breast cancer HR 0.62 (0.36–1.09) HR 0.47 (0.23–0.97) HR 1.35 (0.53–3.41)	OS HR 0.79 (0.69–0.90), p = 0.0006 OS HR 0.89 (0.77–1.02), p = 0.087 -
Extended Endocrine Therapy Beyond 5 years
5 years of Tamoxifen vs. 10 years of Tamoxifen ATLAS (2013) [58] randomised control trial (n = 12,894)	Years 5–9 ≥10 years	Breast cancer recurrence RR 0.90 (0.79–1.02), p = 0.10 RR 0.75 [0.62–0.90], p = 0.003	Mortality RR 0.97 (0.79–1.18), p = 0.74 RR 0.71 (0.58–0.88), p = 0.0016
5 years of Tamoxifen vs. 10 years of Tamoxifen aTTom (2013) [88] randomised control trial (n = 6953)	Years 5–6 Years 7–9 >10 years	Breast cancer recurrence RR 0.99 (0.86–1.15) RR 0.84 (0.73–0.95) RR 0.75 (0.66–0.86)	Mortality During 5–9 years: RR 1.03 (0.84–1.27) - > 10 years: RR 0.94 (0.82–1.07)
5 years of Tamoxifen, followed by 5 years of Letrozole vs. placebo NCIC CTG MA.17 (2012) [89] randomised control trial (n= 5187)	At 5 years	DFS HR 0.52 (0.45–0.61), p = 0.001	OS HR 0.61 (0.52–0.71), p = 0.001
5 years of ET, followed by 5 years of Letrozole vs. placebo NCIC CTG MA.17R (2016) [90] randomised control trial (n = 1918 postmenopausal women)	At 5 years	DFS HR 0.80 (0.63–1.01), p = 0.06 DFS rate: 90% (0.88–0.92), with letrozole vs. 88% (0.86–0.90) with placebo	OS HR 0.97 (0.73–1.28), p = 0.83 OS rate: 93% (0.92–0.95) with letrozole vs. 94% (0.92–0.95) with placebo
5 years of Letrozole versus Tamoxifen, and then their sequences (2 years of one treatment followed by 3 years of the other) BIG 1-98 (2011) [91] randomised control trial (n = 3086)	At 8 years	Letrozole followed by Tamoxifen vs. Letrozole: DFS HR 1.06 (0.91–1.23), p = 0.48 Tamoxifen followed by Letrozole vs. Tamoxifen: DFS HR 1.07 (0.92–1.25), p = 0.36	Letrozole followed by Tamoxifen vs. Letrozole: OS HR 0.97 (0.80–1.19), p = 0.79 Tamoxifen followed by Letrozole vs. Tamoxifen: OS HR 1.10 (0.90–1.33), p = 0.36
5 years of AI (or Tamoxifen for 2–3 years) followed by 5 years of AI NSABP B-42 (2019, 2020) [92,93] randomised control trial (n = 3903 of postmenopausal women)	At 7 years At 10 years	DFS HR 0.85 (0.73–0.999), p = 0.048 DFS HR 0.84 (0.74–0.96), p = 0.011	- OS HR 0.97 (0.82–1.16), p = 0.77
5 years of ET*, followed by EET with AI vs. placebo/none Goldvaser et al. (2017) [56] systematic review and meta-analysis of 7 trials (n = 16,349 patients) *prior duration of ET varied from 2.5–5 years	Median time 12.4 years	Sub-group analysis of LN positive DFS HR 0.72 (0.63–0.83), p < 0.001 Sub-group analysis of LN negative DFS HR 0.83 (0.64–1.08), p = 0.16	Non-significant DFS among patients with: tumors (cm) >2 vs. ≤ 2 (HR 0.77 vs. HR 0.88) Patients previously treated with chemotherapy: (HR 0.71 vs. HR 0.80), p = 0.51
5 years of ET, followed by EET with AI vs. placebo/none Clement et al. (2018) [57] meta-analysis of 8 trials (n = 17,179 postmenopausal women)	At 5 years	DFS OR 1.049 (0.93–1.18), p = 0.43 ⋅Contralateral breast cancer: OR 1.094 (0.92–1.30), p = 0.31	OS OR 1.033 (0.92–1.15), p = 0.56 -
5 years of ET, followed by EET with AI vs. placebo/none Chen et al. (2021) [64] meta-analysis of 9 trials (n = 22,313 postmenopausal women only)	5 to 7–8 years 7–8 to 10 years	Any ET: DFS HR 0.79 (0.69–0.91) Sequential Tamoxifen followed by AI: DFS HR 0.82 (0.71–0.95), DFS HR 0.79 (0.69–0.91)	OS HR 0.90 (0.69–1.17) OS HR 1.02 (0.86–1.20) - OS HR 1.05 (0.90–1.13)
5 years of ET, followed by EET with Tamoxifen vs. placebo/none Al-Mubarak et al. (2014) [63] meta-analysis of 5 trials (n = 21,554)	Median time 9 years	Breast cancer recurrence: OR 0.89 (0.76–1.05), p = 0.17 Subgroup of LN-: OR 0.93 (0.76–1.14) Subgroup of LN+: OR 0.76 (0.63–0.92)	No association between EET and all-cause of death, OR 0.99 (0.84–1.16), p = 0.88
Endocrine Therapy in combination with OFS
5 years of OFS + Exemestane vs. OFS vs. Tamoxifen SOFT and TEXT (2014, 2016) [54,94] randomised control trial (n= 4690 premenopausal women)	At 5 years	DFS HR 0.72 (0.60–0.85), p < 0.001	OS HR 1.14 (0.86–1.51), p = 0.03
5 years of AI + OFS vs. 3–5 years of Tamoxifen + OFS EBCTCG (2022) [55] meta-analysis of 4 trials (n = 7030 of premenopausal women)	Years 0–4 Years 5–9 At 10 years	Disease recurrence RR 0.68, (0.55–0.85); p < 0.0001 RR 0.98, (0.73–1.33); p = 0.89 RR 0.79, (0.69–0.90); p = 0.0005	Mortality RR 1.33, (1.00–1.76) RR 0.84, (0.64–1.11) RR 1.01 (0.82–1.24), p = 0.94
5 years of OFS + ET vs. ET alone Cochrane (Bui et al., 2020) [52] systematic review and meta-analysis of 15 trials (n = 11,538 premenopausal women)	At 5 years	DFS HR 0.83 (0.77–0.90), p < 0.001 Sub-group: OFS + Tamoxifen vs. Tamoxifen DFS HR 0.76 (0.63–0.92), p = 0.005	OS HR 0.86 (0.78–0.94), p = 0.001 Sub-group: OFS + Tamoxifen vs. Tamoxifen DFS HR 0.74 (0.59–0.93), p = 0.009

ET: Endocrine Therapy, EET: Extended Endocrine Therapy AI: Aromatase Inhibitor, OFS: Ovarian Function Suppression, LN: Lymph Node, OS: Overall Survival, DFS: Disease-free Survival, CI: Confidence Interval, HR: Hazard Ratio, OR: Odds Ratio, RR: Risk Ratio.