Breast Cancer: Balancing Risks and Benefits of Postmenopausal Estrogen Therapy. Caution Still Called For.

When the Women’s Health Initiative (WHI) began in 1993, hormone therapy (HT) was prescribed for a variety of reasons that ranged from the management of menopausal symptoms to the prevention of chronic disease. The WHI was a randomized controlled trail aimed at documenting the risks and benefits of several different approaches to prevention, including estrogen by itself (also called estrogen-alone, or unopposed estrogen) in women who had a hysterectomy; estrogen plus progestin in women who still have their uterus; and vitamin D and other diet changes (like, eating low fat) to reduce risk of breast and other cancers. Many results from the WHI have been published, and we have commented on several of them in previous posts. This week, an important additional report follows women from the estrogen-only component of the trial that documents the risks and benefits of hormone therapy over time after women stopped taking hormones.
The balance of risks and benefits during active intervention for women taking unopposed estrogen was published in 2004 (Anderson, Limacher et al. 2004). Women who were currently taking estrogen had a significantly increased risk of stroke and reduced risk of hip fracture and possibly breast cancer compared with women receiving placebo. There was no overall effect of estrogen on a global index of risks and benefits including coronary heart disease (Anderson, Limacher et al. 2004).
LaCroix and colleagues now report follow-up of women who completed the intervention phase of the WHI estrogen-only study (LaCroix and al 2011). Seventy-eight percent of eligible women gave consent for continued follow-up, through a mean 10.7 years from when the study started. The increased risk of stroke observed when women were current users of estrogen did not persist after they stopped taking it. Likewise, the previously observed significant reduction in hip fractures was eliminated.
The reduced incidence of breast cancer, though, persisted. This finding is inconsistent with a longstanding and extensive body of evidence. (Steinberg, Thacker et al. 1991; Collaborative Group on Hormonal Factors in Breast Cancer 1997) There is growing evidence that important factors modify breast cancer risk among women using hormone therapy. A recent report by Beral et al from the Million Women Study demonstrates an adverse effect of postmenopausal estrogen use on breast cancer risk. Risk is significantly increased among women beginning therapy within 5 years of menopause, and there is little or no increased risk among those beginning therapy 5 or more years after menopause (Beral, Reeves et al. 2011). These findings are based on data from over a million women and 15,759 new cases of breast cancer. Risk increased with duration of use but was stronger among women who began use of estrogen alone within 5 years of menopause. Like usual medical practice, the vast majority of UK women began hormone therapy within 5 years of menopause. Overall the relative risk was 1.43 indicating a significant increase in risk of breast cancer with us of estrogen therapy. Risk was even higher in current users of hormone therapy
Figure 1
Beral and colleagues also noted that obese women using hormone therapy had little additional adverse effect from hormones when they are added to the underlying increased risk due to obesity. Among lean women the relative risk was 1.65 compared to never users (Figure 2). This translates to an increase in risk that is 65% higher than the non-users – this increase is at least comparable to the impact of family history on breast cancer risk. Among overweight and obese women the risk was still elevated at 1.2 times the risk of never users. If women began therapy more than 5 years after menopause the increase in risk was reduced.
Figure 2
In contrast with the majority of clinical practice, sixty-eight percent of women enrolled in the WHI were older than age 60 at randomization to using estrogen or placebo. In fact, 46% of the women were between 60 and 69 at the time they were started on estrogen and over 20% were between 70 and 79. Given this fact and the findings from the Million Women Study, an important question that emerges is whether the WHI population is appropriate for reaching definitive conclusions regarding younger women and the risk of breast cancer associated with hormone thereapy. (Jungheim and Colditz 2011)
As a concensus statement from the Endocrine Society – a collection of leading scientists, researchers and clinicians – says when summarizing the totality of medical science on this issue: “estrogen increases the risk of breast cancer after more than five years of use, particularly evident in those who are using hormones recently after menopause.” (Santen, Allred et al. 2010)
As we note in our editorial in JAMA that accompanies the LaCroix and colleague study (link), the lack of an adverse effect of unopposed estrogen when used for a short period in the WHI does not counter the larger body of evidence of an elevated risk of breast cancer with increasing duration of use (Steinberg, Thacker et al. 1991), the greater adverse effect among leaner women (Beral, Reeves et al. 2011), and randomized, controlled trial evidence that estrogen agonist/antagonists (e.g. tamoxifen) reduce the incidence of estrogen receptor positive breast cancer by more than 50% (LaCroix, Powles et al. 2010; Vogel, Costantino et al. 2010) This body of evidence has led the International Agency for Research on Cancer (IARC) to conclude that unopposed estrogen hormone therapy (International Agency for Research on Cancer 1999) and estrogen plus progestin hormone therapy are carcinogenic (International Agency for Research on Cancer 2008). Hormone therapy should be used with extreme caution, if at all.

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Literature Cited
Anderson, G. L., M. Limacher, et al. (2004). “Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.” Jama 291(14): 1701-1712.
Beral, V., G. Reeves, et al. (2011). “Breast Cancer Risk in Relation to the Interval Between Menopause and Starting Hormone Therapy.” Journal of the National Cancer Institute 103(4): 296-305.
Collaborative Group on Hormonal Factors in Breast Cancer (1997). “Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiologic studies of 52,705 women with breast cancer and 108,411 women without breast cancer.” Lancet 350: 1047-1059.
International Agency for Research on Cancer (1999). Monograph on the evlaaution of carcinogenic risk to humans. Hormonal Contraception and Post-menopausal Hormonal Therapy. Lyon, France, IARC Press. 72: 660.
International Agency for Research on Cancer (2008). Monograph on the evaluation of carcinogenic risk to humans: Combined estrogen/progestogen contraceptives and combined esteogen/progestogen menopausal therapy. Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. Lyon, France, IARC Press. 91.
Jungheim, E. and G. Colditz (2011). “Short-term use of unoppsoed estrogen. A balance of inferred risks and benefits.” JAMA 305(13).
LaCroix, A. and e. al (2011). “Health Risks and Benefits after stopping the Women’s Health Initiative trial of conjugated equine estrogens in postmenopausal women with prior hysterectomy.” JAMA 305: 1305-.
LaCroix, A. Z., T. Powles, et al. (2010). “Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women.” Journal of the National Cancer Institute 102(22): 1706-1715.
Santen, R. J., D. C. Allred, et al. (2010). “Postmenopausal hormone therapy: an Endocrine Society scientific statement.” J Clin Endocrinol Metab 95(7 Suppl 1): s1-s66.
Steinberg, K. K., S. B. Thacker, et al. (1991). “A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer.” JAMA 265: 1985-1990.
Vogel, V. G., J. P. Costantino, et al. (2010). “Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer.” Cancer Prev Res (Phila) 3(6): 696-706.

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