New-onset breast tenderness after initiation of estrogen plus progestin therapy and breast cancer risk

Abstract

Background: Estrogen plus progestin therapy increases breast cancer incidence and breast tenderness. Whether breast tenderness during estrogen plus progestin therapy is associated with breast cancer risk is uncertain.

Methods: We analyzed data from the Women's Health Initiative Estrogen + Progestin Trial, which randomized postmenopausal women with an intact uterus to receive daily conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg (n = 8506), or placebo (n = 8102). At baseline and annually, participants underwent mammography and clinical breast examination. Self-reported breast tenderness was assessed at baseline and at 12 months. The incidence of invasive breast cancer was confirmed by medical record review (mean follow-up of 5.6 years).

Results: Of women without baseline breast tenderness (n = 14,538), significantly more assigned to receive conjugated equine estrogens plus medroxyprogesterone vs placebo experienced new-onset breast tenderness after 12 months (36.1% vs 11.8%, P < .001). Of women in the conjugated equine estrogens plus medroxyprogesterone group, breast cancer risk was significantly higher in those with new-onset breast tenderness compared with those without (hazard ratio, 1.48; 95% confidence interval, 1.08-2.03; P = .02). In the placebo group, breast cancer risk was not significantly associated with new-onset breast tenderness (P = .97).

Conclusions: New-onset breast tenderness during conjugated equine estrogens plus medroxyprogesterone therapy was associated with increased breast cancer risk. The sensitivity and specificity of the association between breast tenderness and breast cancer were similar in magnitude to those of the Gail model. Trial Registration clinicaltrials.gov Identifier: NCT00000611.

Figure 1. Risk of invasive breast cancer by new-onset of breast tenderness

Survival times for Kaplan-Meier estimates of cumulative hazard function beginning at the year 1 follow-up visit (i.e. survival time t=0 at the year 1 follow-up visit). Adjusted for age, ethnicity, prior menopausal hormone therapy use, and Gail breast cancer risk score. Seventeen women in the active arm (6 with breast tenderness at year 1, 11 without breast tenderness at year 1) and 26 women in the placebo arm (10 with breast tenderness at year 1, 16 without breast tenderness at year 1) were excluded from the Figure because they either developed breast cancer prior to the year 1 follow-up assessment or had no follow-up after their annual visit.