Combined hormone replacement therapy (HRT), which consists of estrogen plus progestin, is associated with increased risk of breast cancer. HRT promotes some breast cancer types more than others and certain women are more susceptible to the effects of HRT than others. Short-term use is safer than long-term use, but even short-term use can increase breast cancer risk. HRT increases risk more for perimenopausal and menopausal women than older women. One 2015 study reported that HRT use cancels out the benefits of exercise in reducing breast cancer risk. Generally speaking, estrogen-only HRT is safer than combined HRT, but this does not hold for high-risk women who might already have small, undetected tumors. Any form of HRT appears to be unsafe for breast cancer survivors.
Combined HRT is associated with increased breast cancer risk
Combined HRT is a well established risk factor for breast cancer. Strong evidence that combined HRT use could increase the risk of breast cancer was first published in 2002, when it was reported that participants in the Women’s Health Initiative trial who were taking combined HRT had higher rates of breast cancer than those who were not. Subsequent studies have confirmed the finding that combined HRT promotes breast cancer:
- A 2017 study which was widely reported to conclude that HRT was not associated with an increase in mortality from any cause, including cancer, nevertheless still found an increased risk of ER+ breast cancer.
- A follow-up report describing Women's Health Initiative study outcomes after an average of 11 years found that combined HRT was associated with more invasive breast cancers (compared with placebo) among HRT users (a rate of 0.42% per year) compared to nonusers (0.34% per year). Breast cancers in the combined HRT group were more likely to be lymph node-positive. There were also more breast cancer-related deaths in the combined HRT group.
- A Canadian study reported that percent mammographic density was 6% greater in postmenopausal breast cancer patients who used HRT than in never users of HRT with breast cancer. Cancer-free controls who used HRT had 1.6% greater breast density than never users of HRT. In other words, differences in percent mammographic density associated with HRT were greater in women who later developed breast cancer than in cancer-free controls. Breast density is a strong risk factor for breast cancer that changes in response to changes in hormone exposure.
- Another Canadian study that was designed to determine whether the decline in use of HRT since 2002 was followed by a concurrent decrease in breast cancer incidence reported that the largest decline in HRT use (between 2002 and 2004) took place concurrently with a 9.6% reduction in the incidence of breast cancer.
HRT promotes some breast cancer types more than others
Several studies have reported that while HRT use is associated with heightened risk of all breast cancer subtypes, it is most strongly associated with lobular breast cancer. A Chinese study reported that the risk of ER+/PR- breast cancer, a relatively rare subtype that is more common in Asia, was more than doubled by HRT use.
Increased breast cancer risk from HRT is biologically plausible
Increased risk of breast cancer as a result of HRT use is plausible. Women with menopausal symptoms have approximately half the breast cancer risk of those who do not experience them. Those with symptoms have lower estrogen levels as a result of going through menopause compared to women without symptoms. One study designed to examine whether those with menopausal symptoms have reduced breast cancer risk reported that the greater the intensity of hot flashes, the lower the risk of breast cancer. Women with the lowest levels of estrogen (who are likely to have the most severe menopausal symptoms) when starting combined HRT have been reported to experience the greatest increase in breast cancer risk from HRT.
New onset of hot flashes as a result of anti-estrogen treatments such as aromatase inhibitors and tamoxifen have also been found to be associated with favorable breast cancer prognosis. Since HRT reduces menopausal symptoms, it might also extinguish the risk advantage conferred by having a sudden and dramatic drop in estrogen and other hormones as a result of menopause. However, this does not explain why estrogen-only HRT increases breast cancer risk less than combined HRT. Also, one large prospective study found no association between hot flashes and breast cancer risk.
Certain women are more susceptible to the cancer promoting effects of HRT
Some women appear to be more susceptible to the cancer-promoting effects of combined HRT than others. For example, women with tender or dense breasts have been shown to be more vulnerable to the risk-increasing effects of combined HRT. Alcohol consumption also appears to heighten the risk of breast cancer associated with HRT.
Increased breast tenderness from combined HRT is linked to heightened breast cancer risk
One trial reported that breast tenderness during combined HRT use was associated with increased subsequent breast cancer risk, especially among women who experienced breast tenderness before beginning HRT. To conduct the study, the authors analyzed data from the Women’s Health Initiative Estrogen plus Progestin clinical trials. The trials included 16,608 cancer-free postmenopausal women who had not had hysterectomies and were randomly assigned to receive either daily estrogen plus progestin or a placebo, as well as 10,739 women on estrogen-alone or placebo. Self-reported breast tenderness was recorded at baseline and one year later.
Use of combined HRT was found to double the risk of invasive breast cancer among women with baseline breast tenderness. On the other hand, combined HRT had smaller and nonsignificant effects in women without baseline breast tenderness. The risk of new-onset breast tenderness was significantly higher among women assigned to HRT compared to placebo. New-onset breast tenderness was also associated with higher breast cancer risk among trial participants assigned to combined HRT, but not among women assigned to estrogen alone. New-onset breast tenderness during use of combined HRT was also found to be associated with increased risk of subsequent breast cancer.
Combined HRT increases the already high risk associated with dense breasts
Combined HRT increases breast cancer risk more for women with dense breasts than those with low breast density. One study that examined the associations between breast density, HRT and risk of breast cancer examined data concerning 587,369 women who underwent 1,349,027 screening mammograms. Of these women, 14,090 were eventually diagnosed with breast cancer.
Risk of breast cancer was found to be low for women with low breast density. Among women aged 55 to 59 years with low breast density, the five-year risk was 0.8% for non-HRT users and 0.9% for combined HRT users. On the other hand, breast cancer risk was relatively high among women with very high density, particularly for combined HRT users. Among women age 55 to 59 years with high breast density, the five-year risk was 2.4% for non-HRT users, 3.0% for estrogen-only HRT users, and 4.2% for combined HRT users. In addition, risk of advanced-stage breast cancer was increased 1.7-fold for postmenopausal HRT users with very high density compared to those with average breast density. In other words, combined HRT can amplify the already heightened risk of breast cancer associated with high breast density.
Alcohol consumption increases risk
Alcohol increases the breast cancer risk associated with HRT. A study of 40,680 postmenopausal women in the California Teachers Study reported increased ER+ breast cancer risk associated with alcohol intake among women who were current HRT users. Risks were similar for combined and estrogen only HRT.
Timing of HRT influences breast cancer risk
The timing of HRT, including the age at which it is started and the duration of use, determines the degree of risk. HRT use is most harmful before menopause; the excess risk of breast cancer declines with age and appears to disappear by age 65. Although HRT use appears to increase breast cancer risk almost immediately, long-term use (over five years) heightens the risk. When initiated close to menopause, even short durations of combined HRT use are associated with increased breast cancer risk.
A French prospective study reported that combined HRT use influences breast cancer risk in relation to the time that has elapsed between the onset of menopause and the initiation of HRT. The study included 53,310 postmenopausal women who were followed for an average of 8.1 years, during which time 1,726 developed breast cancer. The risk of breast cancer increased 1.5-fold for short-term (two years or less) use started during the first three years following the onset of menopause, whereas there was no increase in breast cancer risk for short-term use initiated after the three-year mark. In other words, women who started HRT at some point during the three years after menopause had an elevated risk of breast cancer even if the HRT was taken for only two years or less. Note that the combined HRT regimens typically used in France are formulated differently from U.S. regimens.
Estrogen-only HRT is safer than combined HRT
Studies that have compared combined HRT and estrogen-only HRT have consistently reported that estrogen-only HRT is associated with lower additional breast cancer risk. However, note that combined HRT is typically used in women who have not had a hysterectomy since estrogen-only HRT increases the risk of endometrial cancer and progestin minimizes this risk.
A 2012 study reported on longer-term outcomes for 7,645 surviving participants of the Women's Health Initiative (WHI) trial, which had enrolled 10,739 women (who had undergone hysterectomies) between 1993 and 1998. The women had been assigned randomly to receive either oral conjugated equine estrogen (estrogen-only HRT) or a placebo. The trial was stopped in early 2004 instead of March 2005 as intended because of increased incidence of stroke among the HRT users.
After a median follow-up of 11.8 years, estrogen-only use for a median of 5.9 years was found to be associated with lower incidence of invasive breast cancer (0.27% per year) compared with placebo (0.35% per year) with no difference between HRT intervention phase and the following period without HRT. However, the breast cancer risk reduction associated with estrogen-only HRT was found primarily in women without benign breast disease or a family history of breast cancer, both of which are high risk groups.
On the other hand, another 2012 study that included participants in the Nurses’ Health Study reported an increased risk of breast cancer among current estrogen-only users of 10 years duration.
Caution is advised
Unlike the case of many other postmenopausal breast cancer risk factors, the increased risk associated with combined HRT becomes detectable in less than two years of use and the excess risk also disappears quickly after cessation of short-term HRT use. This pattern suggests that combined HRT might act in the short term by stimulating the growth of existing micro-tumors, in addition to promoting the generation of new tumors with longer-term use.
Similarly, estrogen-only HRT appears to be protective against breast cancer only for lower-risk women. The interaction between breast cancer development and estrogen is not straightforward. For example, childhood exposure to estrogen or estrogenic compounds found in soybeans and cow's milk are known to reduce breast cancer risk in adulthood. Even in adulthood, consumption of some phytoestrogens are associated with reduced breast cancer risk whereas others increase it under certain circumstances. Therefore, it is not farfetched to suggest that estrogen-only HRT could protect against breast cancer for many women. The problem is that for women with existing but undetected tumors (some of which might not otherwise have developed into life-threatening disease), estrogen-only HRT could stimulate tumor growth. Nor are bioidentical hormones necessarily safe in this circumstance. It appears unwise for breast cancer survivors to use any form of HRT.
Below are links to recent studies on this topic. For a more complete list of studies, please click on HRT.