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
Authors: Chlebowski Rowan T , Anderson Garnet L , Aragaki Aaron K , Manson JoAnn E , Stefanick Marcia , Pan Kathy , Barrington Wendy , Kuller Lewis H , Simon Michael S. , Lane Dorothy , Johnson Karen C , Rohan Thomas E. , Gass Margery L.S. , Cauley Jane A , Paskett Electra D. , Sattari Maryam , Prentice Ross L 
Published: March 2020

Abstract
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, 0.625 mg/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 multi-variable 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 &gt;= 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 &lt; 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 &lt; 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.
Citation Format: Rowan T Chlebowski, Garnet L Anderson, Aaron K Aragaki, JoAnn E Manson, Marcia Stefanick, Kathy Pan, Wendy Barrington, Lewis H Kuller, Michael S. Simon, Dorothy Lane, Karen C Johnson, Thomas E. Rohan, Margery L.S. Gass, Jane A Cauley, Electra D. Paskett, Maryam Sattari, Ross L Prentice. Long-term influence of estrogen plus progestin and estrogen alone use on breast cancer incidence: The Women's Health Initiative randomized trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-00.