Table 2.

Risk of breast cancer (95% CI) over time in women receiving estrogen-only (CEE) or estrogen (CEE) plus progestin (MPA) menopausal hormone treatment (MHT) in the Women’s Health Initiative (WHI) study

Study	Overall BC risk	Cumulative BC risk	Statistical analysis
WHI CEE (Anderson 2004) [117] Mean FU 6.8 yr	Overall HR 0.77 (0.57–1.06)	Cumulative Hazard (8 yr) HR 0.77 (0.59–1.01)	HR (adjusted) vs Placebo
WHI CEE (Chlebowski 2020) [118] Median FU 16.2 yr		Cumulative Hazard (22 yr) HR 0.78 (0.65–0.93)	P = 0.005 versus placebo
WHI CEE/MPA (Rossouw 2002) [65] Mean FU 5.2 yr	Overall HR 1.26 (0.83–1.92)	Subgroup FU ≥ 10 yr HR 1.81 (0.60–5.43)	HR (adjusted) versus Placebo Z score for trend 2.56
WHI CEE/MPA (Hodis 2018) [66] Mean FU 5.6 yr	HT naïve patients (75% of cohort) HR 1.02 (0.77–1.36)*	Subgroup with prior HT HR 1.96 (1.17–3.27)	HR versus Placebo Difference naïve vs prior HT: P = 0.027
WHI CEE/MPA (Chlebowski 2020) [118] Median FU 18.9 yr		Cumulative Hazard (22 yr) HR 1.28 (1.13–1.45)	P < 0.001 versus placebo
Study	BC mortality
WHI CEE (Manson 2017) [68] Cumulative FU 18 yr	Overall HR 0.55 (0.33–0.92)		P = 0.02 versus placebo
WHI CEE/MPA (Manson 2017) [68] Cumulative FU 18 yr	Overall HR 1.44 (0.97–2.15)		HR (adjusted) versus Placebo

CEE conjugated equine estrogens, CI confidence interval, FU follow-up, HR hazard ratio, MPA medroxyprogesterone acetate, WHI Women’s Health Initiative, yr years

*Comment authors: an increased risk of de novo development of breast cancer during the mean 5.6 years of randomized treatment in the WHI CEE/MPA trial is biologically implausible (Santen [59])