March 7, 2012 — In contrast to the documented increase in breast cancer risk that accompanies combined estrogen and progesterone hormone replacement therapy (HRT) in postmenopausal women, a new analysis shows that for the subgroup of postmenopausal women who have had a hysterectomy, estrogen alone is not associated with such a risk. In fact, the risk for breast cancer is reduced.
The findings, published online March 7 in the Lancet Oncology, come from an extended follow-up of a subgroup of women who took part in the Women's Health Initiative (WHI).
"These data are reassuring for postmenopausal women with a hysterectomy. They can take estrogen alone for about 5 years to control climacteric symptoms and not worry about breast cancer risk," said second author Rowan Chlebowski, MD, from the Los Angeles Medical Center in Torrance, California. He told Medscape Medical News that about 30% of postmenopausal women in the United States have had a hysterectomy.
The WHI was infamously stopped in 2002 after it showed that the harms of HRT, including an increased risk for breast cancer, outweighed its benefits. The HRT in question, used to manage climacteric symptoms, was a combination of conjugated equine estrogens and progestin (PremarinPro, Pfizer). The news led to a marked decrease in HRT use, which was followed by a decrease in the incidence of breast cancer.
However, there was a subgroup of 10,739 postmenopausal women in the WHI who had undergone hysterectomy and who were randomized to treatment with estrogen alone (Premarin, Pfizer) or placebo. After a median follow-up of 11.8 years, Dr. Chlebowski and colleagues showed that estrogen alone (taken for a median of 5.9 years) significantly lowered the risk for breast cancer in this subgroup.
In the estrogen group, the incidence of breast cancer was 0.27% per year (151 of 5310 women) for women after a hysterectomy, compared with 0.35% per year (199 cases in 5429 women) in the placebo group (hazard ratio [HR], 0.77; P = .02).
In addition, fewer women died from breast cancer in the estrogen group (6 deaths per year; 0.009%) than in the placebo group (16 deaths per year; 0.024%; HR. 0.37; P = .03).
"Our findings provide reassurance for women with hysterectomy seeking relief for climacteric symptoms, in terms of the effects of estrogen use for about 5 years on breast cancer incidence and mortality," write the researchers, led by Garnet Anderson, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.
However, they add that the use of estrogen alone was associated with an increased risk for stroke and venothromboembolism.
In an interview with Medscape Medical News, Dr. Chlebowski emphasized the decrease in breast cancer risk, and suggested that these other adverse effects are not of great concern. The risk for stroke is low in women in their 50s, he said. The risk for venothromboembolism is also low, is similar to that seen with oral contraceptives or tamoxifen, and it dissipates after about a year, so there is a "net safety profile," he explained.
Pertains Only Premarin?
The team's finding of a decreased risk for breast cancer pertains only to the 1 dose and 1 schedule of oral conjugated equine estrogen (Premarin 0.625 mg per day). "Whether these findings apply to lower doses, other estrogen preparations, or longer durations of use is not known," they report.
This point is also made in an accompanying editorial, written by Anthony Howell, MD, professor of medical oncology at the University Hospital of South Manchester, and epidemiologist Jack Cuzick, PhD, from the Wolfson Institute for Preventive Medicine, Queen Mary University of London, United Kingdom.
Whether the benefit can be translated to all estrogen-only HRT is not known; perhaps only conjugated equine estrogens should be prescribed for now, they write.
Paradoxic Finding
This decreased risk for breast cancer is in contrast to the results from the rest of the WHI, in which the HRT combination of estrogen and progesterone increased the risk for breast cancer. "The biological basis for this difference is unknown," the researchers note.
It is a paradoxic finding, Dr. Chlebowski said. He was also involved in the recent MAP.3 study, which showed that "estrogen reduction with the aromatase inhibitor exemestane decreases the risk of breast cancer in postmenopausal women, and yet now we are showing that estrogen addition in postmenopausal women [after a hysterectomy] reduces the risk of breast cancer."
Dr. Chlebowski explained that "normally estrogen acts as a mitogen, and stimulates the breast epithelium and inhibits apoptosis, so the breast grows bigger and makes milk — that is its job." However, as a woman ages, that signal stops. After a period of estrogen deprivation, the role of estrogen changes so that it induces apoptosis. So it changes its effect on the breast, depending on the environment, he said.
This explanation is also put forward by the editorialists. They note that estrogen stimulates the development and growth of breast cancer, but that breast tumor cells have a propensity to adapt to prevailing estrogen concentrations.
They refer to a preclinical study in which breast cancer cells were grown in a medium (J Natl Cancer Inst. 2001;93:1714-1723). When estrogen concentrations in the medium were reduced, the breast cancer cells stopped growing; at 3 months, they had adapted and were growing at the reduced concentrations, after which an increase in estrogen inhibited their growth. Extrapolating to the findings of the WHI, they suggest that "when estrogen concentrations decline after the menopause, any tumors present in the breast might adapt and grow at the lower concentration, but then are potentially inhibited by higher concentrations provided as replacement therapy."
The editorialists also propose an alternative explanation — that some of the 10 different estrogens in the conjugated equine estrogens product that was used in the trial have antiestrogenic activity.
At Odds With Previous Studies
Other studies of estrogen alone in postmenopausal women have produced mixed results, the editorialists note.
"Most observation studies on the use of estrogen-only hormone replacement suggest an increased risk of breast cancer, whereas some show risk neutrality and a few agree with the reduced risk reported by the WHI," write Drs. Howell and Cuzick. They also note that the WHI is the only randomized controlled trial examining estrogen therapy that supports this view.
"The WHI investigators should be congratulated for providing insight into the value of conjugated equine estrogens," the editorialists note. Provided that they are counseled about the small increases in thromboembolic disease as noted with most hormonal preparations, younger postmenopausal women (50–59 years) can be reassured of the low risks and the striking benefit of a reduced risk of breast cancer, they add.
Dr. Chlebowski reports acting as a consultant for AstraZeneca, Novartis, Amgen, and Pfizer; receiving funding support from Amgen; and serving on the speaker's bureau for AstraZeneca and Novartis. All of his coauthors and Dr. Howell and Dr. Cuzick have disclosed no relevant financial relationships.
Lancet Oncol. Published online March 7, 2012. Abstract, Editorial
The findings, published online March 7 in the Lancet Oncology, come from an extended follow-up of a subgroup of women who took part in the Women's Health Initiative (WHI).
"These data are reassuring for postmenopausal women with a hysterectomy. They can take estrogen alone for about 5 years to control climacteric symptoms and not worry about breast cancer risk," said second author Rowan Chlebowski, MD, from the Los Angeles Medical Center in Torrance, California. He told Medscape Medical News that about 30% of postmenopausal women in the United States have had a hysterectomy.
The WHI was infamously stopped in 2002 after it showed that the harms of HRT, including an increased risk for breast cancer, outweighed its benefits. The HRT in question, used to manage climacteric symptoms, was a combination of conjugated equine estrogens and progestin (PremarinPro, Pfizer). The news led to a marked decrease in HRT use, which was followed by a decrease in the incidence of breast cancer.
However, there was a subgroup of 10,739 postmenopausal women in the WHI who had undergone hysterectomy and who were randomized to treatment with estrogen alone (Premarin, Pfizer) or placebo. After a median follow-up of 11.8 years, Dr. Chlebowski and colleagues showed that estrogen alone (taken for a median of 5.9 years) significantly lowered the risk for breast cancer in this subgroup.
In the estrogen group, the incidence of breast cancer was 0.27% per year (151 of 5310 women) for women after a hysterectomy, compared with 0.35% per year (199 cases in 5429 women) in the placebo group (hazard ratio [HR], 0.77; P = .02).
In addition, fewer women died from breast cancer in the estrogen group (6 deaths per year; 0.009%) than in the placebo group (16 deaths per year; 0.024%; HR. 0.37; P = .03).
"Our findings provide reassurance for women with hysterectomy seeking relief for climacteric symptoms, in terms of the effects of estrogen use for about 5 years on breast cancer incidence and mortality," write the researchers, led by Garnet Anderson, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.
However, they add that the use of estrogen alone was associated with an increased risk for stroke and venothromboembolism.
In an interview with Medscape Medical News, Dr. Chlebowski emphasized the decrease in breast cancer risk, and suggested that these other adverse effects are not of great concern. The risk for stroke is low in women in their 50s, he said. The risk for venothromboembolism is also low, is similar to that seen with oral contraceptives or tamoxifen, and it dissipates after about a year, so there is a "net safety profile," he explained.
Pertains Only Premarin?
The team's finding of a decreased risk for breast cancer pertains only to the 1 dose and 1 schedule of oral conjugated equine estrogen (Premarin 0.625 mg per day). "Whether these findings apply to lower doses, other estrogen preparations, or longer durations of use is not known," they report.
This point is also made in an accompanying editorial, written by Anthony Howell, MD, professor of medical oncology at the University Hospital of South Manchester, and epidemiologist Jack Cuzick, PhD, from the Wolfson Institute for Preventive Medicine, Queen Mary University of London, United Kingdom.
Whether the benefit can be translated to all estrogen-only HRT is not known; perhaps only conjugated equine estrogens should be prescribed for now, they write.
Paradoxic Finding
This decreased risk for breast cancer is in contrast to the results from the rest of the WHI, in which the HRT combination of estrogen and progesterone increased the risk for breast cancer. "The biological basis for this difference is unknown," the researchers note.
It is a paradoxic finding, Dr. Chlebowski said. He was also involved in the recent MAP.3 study, which showed that "estrogen reduction with the aromatase inhibitor exemestane decreases the risk of breast cancer in postmenopausal women, and yet now we are showing that estrogen addition in postmenopausal women [after a hysterectomy] reduces the risk of breast cancer."
Dr. Chlebowski explained that "normally estrogen acts as a mitogen, and stimulates the breast epithelium and inhibits apoptosis, so the breast grows bigger and makes milk — that is its job." However, as a woman ages, that signal stops. After a period of estrogen deprivation, the role of estrogen changes so that it induces apoptosis. So it changes its effect on the breast, depending on the environment, he said.
This explanation is also put forward by the editorialists. They note that estrogen stimulates the development and growth of breast cancer, but that breast tumor cells have a propensity to adapt to prevailing estrogen concentrations.
They refer to a preclinical study in which breast cancer cells were grown in a medium (J Natl Cancer Inst. 2001;93:1714-1723). When estrogen concentrations in the medium were reduced, the breast cancer cells stopped growing; at 3 months, they had adapted and were growing at the reduced concentrations, after which an increase in estrogen inhibited their growth. Extrapolating to the findings of the WHI, they suggest that "when estrogen concentrations decline after the menopause, any tumors present in the breast might adapt and grow at the lower concentration, but then are potentially inhibited by higher concentrations provided as replacement therapy."
The editorialists also propose an alternative explanation — that some of the 10 different estrogens in the conjugated equine estrogens product that was used in the trial have antiestrogenic activity.
At Odds With Previous Studies
Other studies of estrogen alone in postmenopausal women have produced mixed results, the editorialists note.
"Most observation studies on the use of estrogen-only hormone replacement suggest an increased risk of breast cancer, whereas some show risk neutrality and a few agree with the reduced risk reported by the WHI," write Drs. Howell and Cuzick. They also note that the WHI is the only randomized controlled trial examining estrogen therapy that supports this view.
"The WHI investigators should be congratulated for providing insight into the value of conjugated equine estrogens," the editorialists note. Provided that they are counseled about the small increases in thromboembolic disease as noted with most hormonal preparations, younger postmenopausal women (50–59 years) can be reassured of the low risks and the striking benefit of a reduced risk of breast cancer, they add.
Dr. Chlebowski reports acting as a consultant for AstraZeneca, Novartis, Amgen, and Pfizer; receiving funding support from Amgen; and serving on the speaker's bureau for AstraZeneca and Novartis. All of his coauthors and Dr. Howell and Dr. Cuzick have disclosed no relevant financial relationships.
Lancet Oncol. Published online March 7, 2012. Abstract, Editorial
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