Use of CEE alone significantly increased mammograms with short-interval follow-up recommendations but not those with more serious findings. Significantly more breast biopsies were performed for clinical indications in the hormone group, yet they less frequently diagnosed cancer. However, mammogram diagnostic performance differences between random assignment groups were seen only in the early years of exposure. Thus, mammograms in women in the CEE-alone group were generally able to diagnose breast cancer in a timely manner at a cost of an increase in both mammograms with short-interval follow-up recommendation and breast biopsies, which were more likely to be false positive.
The influence of CEE alone on breast cancer detection in women with prior hysterectomy can be compared with that of CEE plus MPA in women with no prior hysterectomy in the parallel WHI randomized trial.1,2
There were similarities, as both increased mammograms with short-interval follow-up recommendation and both significantly increased breast biopsies that less reliably detected cancer. However, combined hormone therapy also increased abnormal mammograms with more serious findings and more commonly compromised mammogram performance.2,7
During 5.6 years of combined use of CEE plus MPA, invasive breast cancers were increased, and they were diagnosed at higher stage,2
consistent with combined hormone therapy effects to both stimulate breast cancer growth and delay breast cancer diagnosis.2,6,7
However, in the CEE-alone trial with a longer intervention duration of 7.1 years, there were fewer invasive breast cancers in the CEE group, and mammographic cancer detection was not substantially compromised.8
Breast cancers were diagnosed without substantial delay for women using CEE alone, but more breast biopsies were needed to find the tumors.
Post hoc analyses in the CEE-alone group found significantly (P = .008) fewer small invasive breast cancers ≤ 2 cm (65 v 102, respectively), and significantly fewer (P = .02) cancers with negative lymph nodes (60 v 92, respectively), whereas there was no significant increase in larger invasive breast cancers or those with positive nodes. These findings may indicate CEE reduces the incidence of smaller, early-stage cancers. Ongoing postintervention follow-up will provide additional information regarding the long-term effects of CEE exposure on breast cancer incidence.
To our knowledge, this is the first comprehensive description of the time course of the influence of CEE alone on the diagnostic performance of mammography and breast biopsy in a randomized clinical trial. The preponderance of observational studies have combined results for estrogen alone with those for estrogen plus progestin use18,19,20
or have reported no difference in performance between regimens.21,22,23
In the Million Women Study, conjugated estrogen either alone or combined with progestin had closely comparable adverse influence on the false-positive recall rate.24
However, as this end point includes both abnormal mammograms and those given a short follow-up recommendation, it did not address the difference seen in this report, for which combined hormone therapy only increased mammogram with a short-interval follow-up recommendation.
As an increase or even preservation of breast density could potentially adversely affect mammogram diagnostic performance,21,25
breast density was assessed in ancillary studies in the WHI hormone therapy trials. In 445 randomly assigned women, CEE alone use for 2 years modestly increased breast density compared with placebo (absolute difference in percent breast density, 2.9%; P
The effect of combined CEE plus MPA, in a parallel study of similar design and size, was substantially greater, with an absolute difference in percent breast density for combined hormone therapy compared with placebo after 2 years of 6.9% (P
Although additional study is needed to correlate breast density change with mammogram recommendations in individuals, breast density change may contribute to mammographic performance differences seen.
The mammography performance regarding sensitivity and specificity reported in this randomized trial reflects that of a large number of mammography centers and interpreting radiologists throughout the nation. Direct comparison to national benchmarks28
for performance is not appropriate, given substantial differences in study population and protocol directives. For example, when considering the performance of the year 1 mammogram in the WHI trial, all women were required to have a clear mammogram in the past year, information on only completed mammograms was recorded, and no reliable evidence on estrogen effects on performance was available. Nonetheless, comparisons of current results with the Breast Cancer Surveillance Consortium (BCSC) mammogram screening program are favorable. With respect to tumor size, the BCSC program found tumors less than 1 cm in 37% and tumors of 1 to 2 cm in 42%, and the mean tumor size was 1.6 cm. In the placebo arm of the WHI study, tumors less than 1 cm were found in 40%, tumors of 1 to 2 cm were found in 40%, and the mean tumor size was 1.4 cm, which is a performance similar to that of the BCSC program.28,29
Study strengths include the randomized design, large sample size, requirement for annual mammography, and the central adjudication of breast cancers by reviewers blinded to random assignment. The trial evaluated CEE at 0.625 mg/d, and the results may not apply to other oral or transdermal hormonal therapies.
These findings have clinical implications. Women using estrogen alone for climacteric symptoms for durations comparable to those in the study can be reassured regarding breast cancer risk and detection. However, they will experience more mammograms with short-interval follow-up recommendations and more false-positive breast biopsies. For mammographers, identification of the nature of the findings leading to short-interval follow-up recommendations in women on estrogen should be a priority. Given the suggestion of early interference with mammographic performance after estrogen-alone initiation, extra diligence in review of mammograms obtained in this setting also could be recommended.
In conclusion, use of CEE alone for about 5 years results in approximately one in 11 and one in 50 women who had an otherwise avoidable mammogram with recommendation for short-interval follow-up or a breast biopsy, respectively. Clinically indicated breast biopsies were significantly more frequent among CEE users but less commonly led to breast cancer diagnoses. These findings differ from those with combined CEE plus MPA use, for which abnormal mammograms were increased and for which there was strong evidence of diagnostic delay.