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Breast Tenderness, HRT, and Breast Cancer
Abstract & Commentary
By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff Professor of Obstetrics and Gynecology, Vice Chair for Research, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: New-onset breast tenderness in women using combined hormone replacement therapy is common, but this is not a useful predictor of future breast cancer risk.
Source: Crandall CJ, et al. New-onset breast tenderness after initiation of estrogen plus progestin therapy and breast cancer risk. Arch Intern Med 2009;169:1684-1691.
The authors analyzed data from the Women's Health Initiative (WHI) combined Estrogen/Progestin Trial to determine if new-onset breast tenderness (NOBT) was associated with the development of breast cancer. The WHI combined group randomized postmenopausal women with an intact uterus to receive either daily conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (2.5 mg; Prempro®, CEE/MPA) or placebo, and followed a number of health outcomes including breast cancer. Breast tenderness was self-reported at baseline and at the 12-month follow-up visit via a symptom inventory. Breast cancer outcomes were self-reported every 6 months using standardized questionnaires, and breast cancer diagnoses were confirmed by local physician adjudicators who reviewed medical records and pathology reports. Significantly more subjects randomized to treatment with CEE/MPA (36.1%) than placebo (11.8%; P = 0.001) experienced new-onset breast tenderness after 12 months. Among subjects randomized to CEE/MPA, the risk of breast cancer was 48% higher in users with NOBT compared to users without breast tenderness (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.08-2.03). Breast cancer risk was not increased among women randomized to placebo with NOBT. However, when treatment assignment and NOBT were included in the same Cox regression model, the observed increase in risk was no longer statistically significant (HR, 1.29; 95% CI, 0.99-1.70). Using the less precise unadjusted figures, the authors calculated that NOBT had a sensitivity of 41%, a specificity of 64%, and a positive predictive value of 2.7% for the development of invasive breast cancer risk during the intervention period (mean, 5.6 years). The authors concluded that reports of breast tenderness during CEE/MPA therapy may identify women at high risk for the development of breast cancers.
Although this article was published last fall, it deserves some commentary as these studies tend to circulate back to our offices after being posted on internet sites or in women's magazines. Dr. Speroff passed it on to me, so I thought I would follow our former editor's advice and bring it to your attention.
The basis for the study rests on two observed associations: Breast cancer diagnosis and breast tenderness are both increased in women using hormone therapy. Hormone therapy also increases breast density on mammography. Since both of these findings reflect an increase in proliferation of breast tissue, there is reason for concern. Breast tenderness is a common finding in both postmenopausal and premenopausal women. In postmenopausal women, both HRT and ERT are associated with an increase report of breast tenderness. However, while the risk of breast cancer was increased in the WHI combined therapy study, no increase in risk was reported in the estrogen-only arm.1
Crandell and colleagues report a three-fold increase in new-onset breast tenderness among women in the combined arm of the WHI study.2 This finding is nothing new. Breast tenderness is typically transient, going away after the first 3 months of therapy.3 Persistent breast tenderness at 1 year is reported by about 25% of women starting HRT.4 The type of HRT preparation may influence breast tenderness and density. Harvey reported that subjects randomized to transdermal combination therapy (50 µg E2/140 µg norethisterone acetate [NETA]) had lower rates of both breast tenderness (36% vs 58%) and increased mammographic density (61% vs 86%) than subjects using oral therapy (2 mg E2/1 mg NETA).5
In the paper by Crandell et al, subjects randomized to CEE/MPA that developed NOBT had a significant 48% increase in the risk of breast cancer compared to users that did not have breast tenderness. The risk of breast cancer was not significantly increased among women randomized to placebo that developed NOBT, suggesting that hormone therapy was responsible for the boost. However, after adjustment for potential confounders in a Cox regression model, the magnitude of the effect decreased to 29%, and this was no longer statistically significant. Unfortunately, this adjustment is buried in the results section, and not presented in the abstract. An interesting side note in the WHI combined study was that despite randomization, women in the HRT arm had a significantly increased prevalence of breast tenderness at baseline compared to the placebo arm. While subjects with baseline tenderness were excluded from the present analysis, it is interesting to reflect on what impact this might have had to the overall comparison.
Increased density represents a concern if it reduces the sensitivity of mammography. As we discussed in the January 2010 issue of OB/GYN Clinical Alerts, mammography has a fairly high false-positive rate. For every 1000 women screened annually with mammograms starting at age 50, 95 will undergo "unnecessary" biopsies. Women accept this risk as regular mammograms provide a powerful reduction in the risk of breast cancer mortality. Seven fewer deaths from breast cancer will occur in the same 1000 women screened annually starting at age 50.6 Another way to describe this relationship is the predictive value of a positive test (PPV); for mammography the PPV varies between 12% and 20%.7 It was this relatively low PPV that led the United States Preventive Health Task Force to recommend against routine annual mammography. In the present study, new onset of breast pain was found to have a PPV of a breast cancer diagnosis of only 2.8%. Recall that the overall increase in breast cancer diagnosis is represented best in absolute terms, not in relative risk. Using the actual event rates and risk estimates from the WHI, for every 10,000 women treated with CEE/MPA, the absolute increase would be 8 additional breast cancer cases. If we conservatively follow the calculations in the Crandell paper, 24% of this increase (approximately 2 cases) would be "explained" by NOBT. Another way to explain this to patients is that about 3% of women with new-onset breast tenderness that persists at 1 year will develop breast cancer within 5.6 years, but 97% will not.
While women want to be proactive to protect themselves against cancer, sending false alarms can produce unnecessary anxiety. Since breast tenderness is most prominent during the first 3 months, and resolves in nearly two-thirds of patients by 1 year, the assertion that NOBT is a useful predictor of breast cancer is highly likely to needlessly alarm women and their doctors. Women that experience breast tenderness may discontinue therapy. While women worry about breast cancer, they are much more likely to die from cardiovascular disease. According to the Centers for Disease Control and Prevention, in 2006 the mortality rate for women due to breast cancer (26.9/100,000) was about 10 times lower than that for cardiovascular disease (282.4/100,000). Although the WHI showed an increase in the rate of cardiovascular disease in women using combined CEE/MPA, this same association was not seen in women without a uterus using CEE only.1 Furthermore, data from prospective and case-control studies have shown a reduction in cardiovascular disease among women who initiate hormone therapy with the onset of menopause, and similar findings were observed among the subgroup of women in the WHI-HRT study that were recently menopausal.8 These results, along with studies from animal models and surrogate markers of cardiovascular disease in women, suggest that early initiation of HRT might provide substantial protection against the No. 1 killer of women. Needlessly frightening women by linking a common symptom like breast tenderness to breast cancer takes us in the wrong direction.
So what clinically important message does this paper provide? I believe that clinicians should use these data to reassure patients that breast tenderness is a common symptom of hormone therapy. The tenderness usually goes away within 3 months, and is related to dose. Transdermal therapy may be associated with less tenderness and less dense breasts, and also has been shown to reduce the risk of venous thrombosis.9 All postmenopausal women using HRT should undergo breast cancer screening with annual mammograms (so should those not on HRT). For the 25% of women who will complain of persistent breast tenderness after 1 year of therapy, the results of this study may apply. Your patients that are already fearful of hormone therapy may look at a 3% chance of breast cancer developing over 5.6 years and stop HRT. Patients that see the benefits of HRT might be reassured that they have a 97% chance that they won't develop breast cancer. While the basic recommendations for mammogram screening don't change, all of these women should be counseled about the importance of keeping to the screening schedule.