Estrogen alone in postmenopausal women and breast cancer detection by means of mammography and breast biopsy

Abstract

Purpose: As the influence of estrogen alone on breast cancer detection is not established, we examined this issue in the Women's Health Initiative trial, which randomly assigned 10,739 postmenopausal women with prior hysterectomy to conjugated equine estrogen (CEE; 0.625 mg/d) or placebo.

Methods: Screening mammography and breast exams were performed at baseline and annually. Breast biopsies were based on clinical findings. Effects of CEE alone on breast cancer detection were determined by using receiver operating characteristic (ROC) analyses of mammogram performance.

Results: After a 7.1-year mean follow-up, fewer invasive breast cancers were diagnosed in the CEE than in the placebo group, but the difference was not statistically significant. Use of CEE alone increased mammograms with short-interval follow-up recommendations (cumulative, 39.2% v 29.6.3%; P < .001) but not abnormal mammograms (ie, those suggestive of or highly suggestive of malignancy; cumulative, 7.3% v 7.0%; P = .41). Breast biopsies were more frequent in the CEE group (cumulative, 12.5% v 10.7%; P = .004) and less commonly diagnosed as cancer (8.9% v 15.8%, respectively, with positive biopsies; P = .04). Mammographic breast cancer detection in the CEE group was significantly compromised only in the early years of use.

Conclusion: CEE alone use for 5 years results in approximately one in 11 and one in 50 women having otherwise avoidable mammograms with short-interval follow-up recommendations or breast biopsies, respectively. Although the breast biopsies on CEE were less commonly diagnosed as cancer, breast cancer detection was not substantially compromised. These findings differ from estrogen-plus-progestin use, for which significantly increased abnormal mammograms and a compromise in breast cancer detection are seen.

Fig 1.

CONSORT diagram. CEE, conjugated equine estrogen.

Fig 2.

Random assignment in the Women's Health Initiative (WHI) dietary modification (DM) and calcium/vitamin D (CaD) clinical trials by random assignment group in the WHI conjugated equine estrogen (CEE) clinical trial. As women could participate in all three trials and could be randomly assigned to an intervention (I) or control (C) group in the DM trial or in the active drug (CaD) or placebo (CaD Plc) groups in the CaD trial, a total of nine categories are described.

Fig 3.

Initial report of a mammogram with (A) recommendation for short-interval follow-up or suggestive or highly suggestive of cancer and (B) initial report of breast biopsy for participants by year on study and random assignment group. Women in the conjugated equine estrogen (CEE) group had about a 4% greater risk of a mammogram with recommendation for short-interval follow-up after 1 year and 9% greater risk after 5 years of use (P < .001). Women in the CEE group had about a 2% greater risk of having a biopsy after 5 years of use (P = .004). Standard error (SE) bars were plotted at each data point but may not be visible because of their small sizes relative to the data point.

Fig 4.

Diagnostic performance of mammograms by study period and randomization group. (A) Intent-to-treat analysis conducted using receiver operating curves (ROC) and nested area under the curve (AUC) statistics. For placebo-group women, the ROC AUCs were 0.89, 0.85, and 0.92 for mammograms performed in years 1 to 2, 3 to 4, and ≥ 5, respectively. For women in the conjugated equine estrogen (CEE) group, the ROC AUCs were 0.85 (P = .027), 0.88 (P = .792), and 0.91 (P = .580) for mammograms performed in year 1 to 2, 3 to 4, and ≥ 5, respectively. P values compared abnormal versus normal mammograms for hormone-group versus placebo-group women. (B) Sensitivity analysis, excluding mammogram findings 6 months after a woman became nonadherent to study medication use. In these analyses, mammogram diagnostic performance for women in the CEE group was not significantly different from those in the placebo group for any period examined (P = .38, .49, and .06 in years 1 to 2, 3 to 4, and ≥ 5, respectively).