Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.
BACKGROUND
In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported.


OBJECTIVE
To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009.


METHODS
A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants.


METHODS
Invasive breast cancer incidence and breast cancer mortality.


RESULTS
In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group.


CONCLUSIONS
Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.


BACKGROUND
clinicaltrials.gov Identifier: NCT00000611.
Chlebowski
Rowan T
RT
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W Carson St, Torrance, CA 90502, USA. rchlebowski@gmail.com
Anderson
Garnet L
GL
Gass
Margery
M
Lane
Dorothy S
DS
Aragaki
Aaron K
AK
Kuller
Lewis H
LH
Manson
JoAnn E
JE
Stefanick
Marcia L
ML
Ockene
Judith
J
Sarto
Gloria E
GE
Johnson
Karen C
KC
Wactawski-Wende
Jean
J
Ravdin
Peter M
PM
Schenken
Robert
R
Hendrix
Susan L
SL
Rajkovic
Aleksandar
A
Rohan
Thomas E
TE
Yasmeen
Shagufta
S
Prentice
Ross L
RL
D000368:Aged; D001943:Breast Neoplasms / Q000401:mortality* / Q000473:pathology*; D004338:Drug Combinations; D004966:Estrogens, Conjugated (USP) / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D006801:Humans; D015994:Incidence; D008207:Lymphatic Metastasis; D017258:Medroxyprogesterone Acetate / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D017698:Postmenopause; D011379:Prognosis; D014481:United States / Q000453:epidemiology
D004338:Drug Combinations; D004966:Estrogens, Conjugated (USP); C466383:Prempro; D017258:Medroxyprogesterone Acetate