Hormone Replacement Therapy After a Diagnosis of Breast Cancer in Relation to Recurrence and Mortality
Abstract & Commentary
There is no compelling evidence that hormone replacement therapy (HRT) use by women who have survived breast cancer increases the likelihood of recurrence. However, it has been a general assumption, based on our mental cartoon of the pathogenesis of breast cancer, that its use carried a significant, if undefined, likelihood of harm. Breast cancer survivors, therefore, have generally been discouraged from taking HRT. No one argues that the proscription of HRT is of no clinical consequence. It has just seemed the lesser of 2 evils. As O’Meara and colleagues highlight, prior studies attempting to address this issue were seriously limited by sample size or inherent biases. Nonetheless, 4 of 5 previous studies found no increased risk of breast cancer recurrence among users of HRT compared to nonusers. The present study came to the same conclusion and it clearly used the best methodology so far. Data were assembled from 2755 women aged 35-74 years who were diagnosed with incident invasive breast cancer while they were enrolled in a large health maintenance organization from 1977 through 1994. Pharmacy data identified 174 users of HRT after diagnosis. Each HRT user was matched to 4 randomly selected nonusers of similar age, disease stage, and year of diagnosis. O’Meara et al considered and controlled for every conceivable confounding variable, including route of administration, total exposure (dose and duration), and use of a progestin. The duration of HRT use before the diagnosis of breast cancer was greater among users of HRT after the diagnosis of breast cancer. While concurrent HRT use has been linked to better survival in women who subsequently develop breast cancer, O’Meara et al state that the magnitude of this potential confounding variable is not large enough to conceal a true adverse effect of HRT use after diagnosis. The rate of breast cancer recurrence was 17 per 1000 women-years in HRT users vs. 30 in nonusers, adjusted relative risk (RR) = 0.50, confidence interval (CI) 0.30-0.85. Total mortality rates were 16 per 1000 women-years in HRT users and 30 in nonusers, adjusted RR = 0.48; CI 0.29-0.78. Beyond the first year of use, the adjusted RR = 0.37; CI 0.13-1.04 for breast cancer recurrence and 0.50; CI 0.31-0.83 for total mortality. Among women with estrogen receptor-positive tumors, the unadjusted RR for HRT use = 0.31; CI 0.10-0.98 for breast cancer recurrence, 0.16; CI 0.02-1.19 for breast cancer mortality, and 0.30; CI 0.11-0.82 for total mortality. (O’Meara ES, et al. J Natl Cancer Inst. 2001;93:754-761).
COMMENT by Sarah L. Berga, MD
I was thrilled to find that someone had finally done this study. However, after reading the report, I was even more intrigued. The present study begs the issue as to whether estrogen use by breast cancer survivors with estrogen receptor-positive tumors is protective. O’Meara et al chose not to position their results as indicating increased survival for women with breast cancer who use HRT after diagnosis, but the results could be interpreted in this way. It appears that O’Meara et al chose the more conservative interpretation due to the inherent limitations of the study design. After all, this was not a randomized, prospective trial. Likely O’Meara et al also recognized the tremendous implications of suggesting that HRT use might promote survival. The current dogma suggests that anti-estrogens like tamoxifen increase survival because they are anti-estrogens. This study would seem to contradict that dogma. Sadly, given what we now know about estrogen receptors and the multiple ligands that interact with them, it becomes increasingly difficult to hold onto the simplistic worldview that there are 2 discrete classes of steroid ligands, agonists and antagonists. Based on the presumption that anti-estrogens both exist and are needed, The National Surgical Adjuvant Breast Project (NSABP) is now conducting what is referred to as the STAR trial, Study of Tamoxifen and Raloxifene, in an attempt to determine which anti-estrogen is better as adjuvant therapy for women with recently diagnosed breast cancer. I had the privilege of addressing the NSABP last summer to talk about the risks and benefits of estrogen use by postmenopausal women. After a thorough review of the data, I wondered why the STAR trial was not the STARE trial, Study of Tamoxifen, Raloxifene, and Estrogen. I concluded it was because no one felt brave enough to challenge the underlying paradigm that supports the use of anti-estrogens. The aim of the study is simply to determine which of the 2 "anti-estrogens" is best for women who have had breast cancer. The operating assumption of the STAR trial is that anti-estrogen use by women who have breast cancer is of benefit and all we lack is data about which anti-estrogen is better. The concluding line of the discussion of the present report, however, advocates for a study like the STARE. The results of the report reviewed herein further increase the justification for such a trial. Given the multiplicity of benefits that accrue from long-term HRT use, it is literally vital to know if we should continue to deny HRT use to women who have survived breast cancer.
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