Wednesday, October 27, 2010

New Evidence, Same Conclusion: Postmenopausal Hormones Cause Breast Cancer

Last week new data were released adding to the evidence on the harmful effects of hormone therapy on breast cancer incidence and mortality (story). This timely report released in October when so much media attention focuses on breast cancer detection, treatment and prevention, brings further evidence to show how hormones cause breast cancer. Here I put these results in some perspective of findings from studies over the past 20 years.

Numerous studies that have evaluated trends in breast cancer over time consistently show that since the result of the Women’s Health Initiative were published in 2002 rates of breast cancer have declined in parallel with the drop in use of combination estrogen plus progestin (Prempro). Combination therapy, estrogen plus progestin, causes breast cancer and is classified as a carcinogen by the IARC (International Agency for Research on Cancer 2007). Strong evidence that use of hormone therapy can act as a late promoter of cancer in women comes from evidence relating unopposed estrogen and endometrial cancer. With the acknowledgment of this cause and effect relation in the 1970s, a sharp drop in estrogen prescribing led to a parallel rapid decrease in incidence of endometrial cancer (Austin and Roe 1982). Uptake of estrogen plus progestin therapy was somewhat slow, and epidemiologic data in the US were limited in their ability to separate effects of combination therapy from that of unopposed estrogen. However, by 1995 prospective data from the Nurses’ Health Study indicated that estrogen plus progestin therapy was not protective against breast cancer and the increase in risk may be greater than for estrogen alone (Colditz, Hankinson et al. 1995). Furthermore, mortality from breast cancer was significantly elevated in women who had used hormones prior to diagnosis. Estrogen alone remained the treatment of choice for women without a uterus. Between the mid-1970s and the mid-1980s, incidence of estrogen receptor-positive tumors increased an average of 131% in the population-based tumor registry of Kaiser Permanente in the United States (Portland, OR), perhaps implicating hormonal factors in the rising incidence of breast cancer (Glass and Hoover 1990).

Epidemiologic studies (Ross, Paganini-Hill et al. 2000; Schairer, Lubin et al. 2000) during the 1990s show that combination E&P therapy significantly increased risk, and that this was most evident among leaner women who would have lower starting estrogen levels prior to use of postmenopausal hormone therapy. Recommendations based on these findings were for women to avoid progestins if possible (Willett, Colditz et al. 2000). A broad range of epidemiologic studies continue to support the causal relation between combination E&P and total breast cancer. Meanwhile, some investigators focused on the increase in lobular cancer (Li, Weiss et al. 2000; Li, Anderson et al. 2003) – these tumors are predominantly estrogen receptor positive and so would reflect a signal from hormone therapy more precisely than the more common form of breast cancer, ductal cancer, that is estrogen receptor positive only about 70 percent of the time. Overall, studies of receptor positive tumors show that combination therapy clearly increases risk (Glass and Hoover 1990).

In 2002, the Women’s Health Initiative confirmed the epidemiologic findings relating combination hormone therapy to increased risk for breast cancer. In this trial there was substantial non-adherence to therapy, which would reduce the ability of the study to detect an effect. In fact some 40% of the women randomized to take estrogen plus progestin (PremPro), stopped taking the drug. The independent Data Safety Monitoring Board stopped the trial early due to the adverse effect of therapy on breast cancer (Rossouw, Anderson et al. 2002). The results were consistent with the HERS trial and epidemiologic data showing an increase in risk of breast cancer in the initial 2 to 5 years of use. Importantly, risk increased significantly with duration of use; the longer a woman used hormones the greater her risk of breast cancer.

Based on data from the San Francisco mammography registry, prescribing of E&P peaked in 1999. Before publication of HERS the use of hormone therapy was increasing at 1% per quarter, but declined by 1% per quarter after the publication (Haas, Kaplan et al. 2004). This decline in prescribing continued until the publication of the WHI in 2002, at which point a more substantial decline of 18% per quarter was observed. The peak and decline through 1999 to 2002 is concordant with the HERS report (Hulley, Grady et al. 1998) in 1998 showing a significant increase in CHD in the first year of therapy among women with prevalent coronary disease, and in addition, no long-term benefit in reducing CHD (Grady, Herrington et al. 2002). The growing epidemiologic evidence published since 2000 on the adverse effects of combination therapy on breast cancer added further evidence against the use of this therapy. Bases on the level of use of combination hormone therapy in California, Tina Clarke and colleagues estimate that 11 percent of all breast cancer was being caused by use of hormone therapy (Clarke, Purdie et al. 2006). Since risk increases with duration of use, this estimate of the proportion of cancers caused by hormone therapy is likely conservative.

The most recent report from the Women’s Health Initiative, addressing mortality from breast cancer, shows that risk is elevated among the women who took estrogen plus progestin therapy (study). Investigators followed participants for 11 years. Among the 16,000 women in the study those randomized to estrogen plus progestin had twice as many deaths from breast cancer as seen in the women who took placebo. This, of course, is counter to the substantial marketing effort by the manufacturers who have been shown to have ghost written articles for gynecologists to advocate for hormone therapy as safe since it only causes “good cancers” that respond adequately to treatment. This literature and the academic physicians paid to write for the industry are summarized by Dr. Fugh-Berman and is available online (article). She summarizes evidence from industry documents showing how the pharmaceutical company Wyeth used ghostwritten medical journal articles to mitigate the perceived risks of breast cancer associated with hormone therapy. The WHI results published last week confirm previous epidemiologic data on the mortality effect of hormone therapy and rule the reassurance from the industry as only a marketing ploy not a truthful message for women.

With the evidence at hand, use of hormone therapy for menopausal symptoms should be extremely limited, if used at all. Combination therapy is more harmful than unopposed estrogen and is not indicated for women who do not have a uterus. As we have noted previously, hormone levels within a woman after menopause are directly related to risk of breast cancer. Weight loss through energy restriction and increase in physical activity is the best natural way to reduce these hormone levels and significantly reduce risk of breast cancer (related post).

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Literature Cited
Austin, D. F. and K. M. Roe (1982). "The decreasing incidence of endometrial cancer: public health implications." Am J Public Health 72(1): 65-68.

Clarke, C. A., D. M. Purdie, et al. (2006). "Population attributable risk of breast cancer in white women associated with immediately modifiable risk factors." BMC Cancer6: 170.

Colditz, G. A., S. E. Hankinson, et al. (1995). "The use of estrogens and progestins and the risk of breast cancer in postmenopausal women." N Engl J Med 332: 1589-1593.

Glass, A. G. and R. N. Hoover (1990). "Rising incidence of breast cancer: relationship to stage and receptor status." J Natl Cancer Inst 82(8): 693-696.

Grady, D., D. Herrington, et al. (2002). "Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II)." Jama 288(1): 49-57.

Haas, J. S., C. P. Kaplan, et al. (2004). "Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results." Ann Intern Med140(3): 184-188.

Hulley, S., D. Grady, et al. (1998). "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group."Jama 280(7): 605-613.

International Agency for Research on Cancer (2007). Combined estrogen-progestogen postmenopausal therapy. Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. Lyon, France, International Agency for Research on Cancer. 91.

Li, C. I., B. O. Anderson, et al. (2003). "Trends in incidence rates of invasive lobular and ductal breast carcinoma." JAMA 289(11): 1421-1424.

Li, C. I., N. S. Weiss, et al. (2000). "Hormone replacement therapy in relation to risk of lobular and ductal breast carcinoma in middle-aged women." Cancer 88(11): 2570-2577.

Ross, R. K., A. Paganini-Hill, et al. (2000). "Effect of hormone replacement therapy on breast cancer: estrogen versus estrogen plus progestin." JNCI 92: 328-332.

Rossouw, J. E., G. L. Anderson, et al. (2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial." JAMA 288(3): 321-333.

Schairer, C., J. Lubin, et al. (2000). "Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk." JAMA 283: 485-491.

Willett, W. C., G. Colditz, et al. (2000). "Postmenopausal estrogens--opposed, unopposed, or none of the above." Jama 283(4): 534-535.

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