Long-term influence of estrogen plus progestin and estrogen alone use on breast cancer incidence: The Women’s Health Initiative randomized trials. Chlebowski RT, Anderson GL, Aragaki AK, et al

Oral presentation at the San Antonio Breast Cancer Symposium; December 10-14, 2019
San Antonio, Texas

Researchers from the Women Health Initiative Randomised Trial (WHI) presented on the long-term breast cancer risk with HRT in women who took part in the WHI study at the San Antonio Breast Cancer Symposium (SABCS) in Texas on 13th December 2019.

A total of 27,347 women were included in this randomised study. Of these, 10,739 women who had undergone a hysterectomy were randomised to receive conjugated equine estrogen alone or placebo for an average of 7.2 years, while 16,608 women were randomised to receive conjugated equine estrogen plus medroxyprogesterone acetate or placebo for an average of 5.6 years.

Women in the estrogen only trial were followed up for an average of 16.1 years and had 520 breast cancer incidents included in the study. Women who received estrogen only HRT were noted to have a significant reduction in breast cancer incidence (HR 0.77, 95%CI 0.65-0.92. p=0.005) and a significant reduction in breast mortality (44% reduction) compared to placebo.

Women in the combined estrogen progestogen randomised trial were followed up for an average of 18.3 years and had 1003 breast cancer incidents included in the study. Women who received conjugated equine estrogen plus medroxyprogesterone acetate were noted to have a significant increase in breast cancer incidence (HR 1.29, 95%CI 1.14-1.47. p<0.001) as noted in the earlier reports from the WHI study. This increased risk persisted more than 10 years after discontinuing HRT. (HR 1.29, 95%CI 1.14-1.47. p<0.001). No statistically significant increase in breast cancer mortality was noted in women receiving conjugated equine estrogen plus medroxyprogesterone acetate compared to those who received placebo.

Miss Melanie Davies, Consultant Gynaecologist and Member of the Medical Advisory Council of the British Menopause Society commented on these findings for the Science Media Centre. This could be accessed through the following link:

https://www.sciencemediacentre.org/expert-reaction-to-conference-abstract-about-types-of-hrt-and-breast-cancer-risk/

The presentation summary from the report is included below:

Oral presentation: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS5-00: Long-term influence of estrogen plus progestin and estrogen alone use on breast cancer incidence: The Women’s Health Initiative randomized trials.

Chlebowski RT, Anderson GL, Aragaki AK, et al.

Background: Breast cancer outcomes from the Women’s Health Initiative (WHI) Estrogen plus Progestin and Estrogen alone trials have been reported but issues remain regarding long- term, post-intervention influence on breast cancer incidence and the influence of time from menopause to hormone therapy initiation (gap time) on breast cancer findings.

Design and methods: Postmenopausal women aged 50 to 79 years with no prior breast cancer and with mammogram clearance enrolled in one of two randomized clinical trials at 40 US centers from 1993 to1998, with follow up through September, 2016. The randomized, placebo-controlled trial interventions were: conjugated equine estrogens (CEE, 0.625mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8,506) vs placebo (n = 8,102) for 5.6 years (median) for women with a uterus or CEE-alone (n = 5,310) vs placebo (n = 5,429) for 7.2 years (median) for women with prior hysterectomy. Annual mammography was mandated through the originally specified completion date in both trials (March 31, 2005). Incident breast cancers were verified by medical record review. Hazard ratios (HRs) were estimated using multivariable Cox proportional hazards models. The primary outcome for these analyses was time-specific invasive breast cancer incidence rates. In each trial, participants were instructed to stop all study pills coincident with the publication of each trial’s results, in 2002 and 2004, respectively.

Results: During the intervention period, with 238 incident breast cancers, CEE-alone significantly reduced breast cancer incidence (hazard ratio [HR] 0.76 95% confidence interval [CI] 0.58, 0.98, P = 0.04). As previously reported, subgroup analyses indicated CEE-alone was particularly beneficial for women with no prior HT use (interaction P = 0.04) and women with gap time >= 5 years (interaction P = 0.01). Post-intervention, through 16.1 years of cumulative follow-up, with 520 incident breast cancers, CEE-alone use continued to significantly reduce breast cancer incidence (HR 0.77 95% CI 0.65-0.92, P = 0.005) while subgroup differences were attenuated and were no longer statistically significant. During the intervention period, with 360 incident breast cancers, CEE plus MPA use significantly increased breast cancer incidence (HR 1.26 95% CI 1.02, 1.56, P = 0.04) with increase in breast cancer incidence greater in women with prior HT use (interaction P = 0.02) and women with gap time < 5 years (interaction P = 0.002). Post-intervention, through 18.3 years cumulative follow-up, with 1,003 incident breast cancers, CEE plus MPA continued to significantly increase breast cancer incidence (HR 1.29 95% CI 1.14, 1.47, P < 0.001) while subgroup differences were attenuated and were no longer statistically significant.

Conclusions: CEE-alone and CEE plus MPA use have opposite effects on breast cancer incidence. CEE alone significantly decreases breast cancer incidence which is long term and persists over a decade after discontinuing use. CEE plus MPA use significantly increases breast cancer incidence which is long term and persists over a decade after discontinuing use. As a result of the attenuation of subgroup interactions: all postmenopausal women with prior hysterectomy using CEE-alone have the potential benefit of experiencing a reduction in breast cancer incidence while all postmenopausal women using CEE plus MPA have the potential risk of experiencing an increase in breast cancer incidence.