Breast Cancer

Dr. Hope Rugo gives her analysis of the TEAM trial. Kerri Wachter of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. Hope Rugo gives her analysis of the TEAM trial. Kerri Wachter of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. Hope Rugo gives her analysis of the TEAM trial. Kerri Wachter of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. Stephen Jones discusses TEAM trial findings that suggest exemestane improves breast cancer survival over tamoxifen at 2.75 years of follow-up. Kerri Wachter of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. Stephen Jones discusses TEAM trial findings that suggest exemestane improves breast cancer survival over tamoxifen at 2.75 years of follow-up. Kerri Wachter of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. Stephen Jones discusses TEAM trial findings that suggest exemestane improves breast cancer survival over tamoxifen at 2.75 years of follow-up. Kerri Wachter of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. James Ingle discusses findings that adjuvant therapy with aromatase inhibitors cuts the risk of recurrent breast cancer, compared with tamoxifen. Kerri Wachter of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. James Ingle discusses findings that adjuvant therapy with aromatase inhibitors cuts the risk of recurrent breast cancer, compared with tamoxifen. Kerri Wachter of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. James Ingle discusses findings that adjuvant therapy with aromatase inhibitors cuts the risk of recurrent breast cancer, compared with tamoxifen. Kerri Wachter of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. Jessica Frisk discusses study results that suggest acupuncture can reduce hot flashes and improve sleep in women with a history of breast cancer. Bruce Jancin of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. Jessica Frisk discusses study results that suggest acupuncture can reduce hot flashes and improve sleep in women with a history of breast cancer. Bruce Jancin of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Dr. Jessica Frisk discusses study results that suggest acupuncture can reduce hot flashes and improve sleep in women with a history of breast cancer. Bruce Jancin of Elsevier Global Medical News (EGMN) reports from the annual San Antonio Breast Cancer Symposium.

Physical therapist Nicole Stout Gergich discusses shoulder dysfunction in breast cancer patients. Bruce Jancin of Elsevier Global Medical News (EGMN) interviews Ms. Gergich at the annual San Antonio Breast Cancer Symposium.

Physical therapist Nicole Stout Gergich discusses shoulder dysfunction in breast cancer patients. Bruce Jancin of Elsevier Global Medical News (EGMN) interviews Ms. Gergich at the annual San Antonio Breast Cancer Symposium.

Physical therapist Nicole Stout Gergich discusses shoulder dysfunction in breast cancer patients. Bruce Jancin of Elsevier Global Medical News (EGMN) interviews Ms. Gergich at the annual San Antonio Breast Cancer Symposium.

Dr. Rachel Brem discusses findings that breast-specific gamma imaging can spot additional breast cancers missed by mammography and physical exam in breast cancer patients. Patrice Wendling of Elsevier Global Medical News (EGMN) reports from the annual meeting of the Radiological Society of North America.

Dr. Rachel Brem discusses findings that breast-specific gamma imaging can spot additional breast cancers missed by mammography and physical exam in breast cancer patients. Patrice Wendling of Elsevier Global Medical News (EGMN) reports from the annual meeting of the Radiological Society of North America.

Dr. Rachel Brem discusses findings that breast-specific gamma imaging can spot additional breast cancers missed by mammography and physical exam in breast cancer patients. Patrice Wendling of Elsevier Global Medical News (EGMN) reports from the annual meeting of the Radiological Society of North America.

Dr. Anees B. Chagpar discusses findings that suggest elderly breast cancer patients on hormonal therapy may not need radiation therapy after breast-conserving surgery.

Dr. Anees B. Chagpar discusses findings that suggest elderly breast cancer patients on hormonal therapy may not need radiation therapy after breast-conserving surgery.

Dr. Anees B. Chagpar discusses findings that suggest elderly breast cancer patients on hormonal therapy may not need radiation therapy after breast-conserving surgery.

<huc>A.</huc>Yes. In this study from France, the association between estrogen–progestin regimens and breast cancer varied significantly, depending on the progestin. The relative risk of invasive breast cancer was 1.08 for progesterone (95% confidence interval 0.89–1.31), 1.16 for dydrogesterone (0.94–1.43), and 1.69 for other progestins (1.50–1.91).

Expert Commentary

Fear of breast cancer discourages many women from using menopausal hormone therapy (HT), and fuels anxiety among patients and physicians alike. A large body of evidence from clinical trials and observational studies indicates that the use of estrogen-only therapy for less than 5 years has minimal, if any, impact on the risk of breast cancer.^1-5 In contrast, use of combination estrogen–progestin hormone therapy for more than 5 years is associated with an elevated risk of breast cancer,^3,6,7 and this risk is greater than the risk associated with the use of estrogen alone. This modestly increased risk is comparable to the elevated risk of breast cancer associated with lifestyle choices such as daily alcohol use, postmenopausal obesity, and lack of regular exercise.⁸

Few have focused on effects of specific progestins

Because the addition of a progestin to estrogen therapy in women with a uterus appears to play a key role in increasing the risk of breast cancer, and because a variety of progestins are available (including levonorgestrel, medroxyprogesterone acetate [MPA], norethindrone acetate, and progesterone), it makes sense to ask whether some progestins increase the risk of breast cancer more than others.

Although MPA is the most widely used progestin in menopausal practice in this country—and was the progestin used in the Women’s Health Initiative (WHI) trial of combination HT—other progestins are more common in Europe. The evidence has not definitively demonstrated that the choice of progestin affects the degree of breast cancer risk in women using HT.³

Large French population had high rate of HT use

HT is commonly used by menopausal women in France, and progesterone is the most widely prescribed progestin for endometrial protection, as Fournier and colleagues note. They conducted this large, prospective cohort study to assess HT use and breast cancer risk in almost 100,000 French teachers and wives of teachers, with intriguing results. Among the women followed in this study, 70% had used HT. The mean age at initiation was 52.4 years, and the mean duration of use and followup was 7 and 8.1 years, respectively.

Findings in regard to estrogen differ from those of other studies

Overall, the risk of being diagnosed with invasive breast cancer was significantly elevated with the use of estrogen alone, at a relative risk of 1.29 (95% confidence interval 1.02–1.65). This small elevation contrasts the findings of the WHI and Nurses’ Health studies, which identified no increased risk of breast cancer with estrogen alone.^4,5

Transdermal estrogen is widely used in menopausal women in France; route of estrogen administration did not affect breast cancer risk in this study.

Progesterone was associated with no elevated risk

The use of combination HT with MPA or norethindrone acetate was associated with higher relative risks than estrogen alone: 1.48 (1.02–2.16) and 2.11 (1.56–2.86), respectively. In contrast, combination HT with progesterone was not associated with an elevated risk of breast cancer, with a relative risk of 1.08 (0.89–1.31).

Fournier and colleagues point out that theirs is the first epidemiologic study to assess the risk of breast cancer associated with HT containing progesterone. They also cite recent data in postmenopausal primates indicating that combination HT with micronized progesterone causes lower rates of proliferation in lobular and ductal breast epithelium, compared with MPA-based hormone therapy.⁹

Clinical recommendations: For now, simply ensure adequate progestin

The findings of a single study generally should not dictate clinical practice. It remains the standard of care to ensure sufficient progestin (whether levonorgestrel, MPA, norethindrone acetate, or micronized progesterone) to prevent endometrial hyperplasia when prescribing HT for menopausal women with a uterus.

The findings of this study raise the possibility that progesterone may be safer than other progestins with respect to breast neoplasia. Additional epidemiologic data assessing the safety of progesterone in comparison with other progestins are welcome, but studies would need to be conducted in regions like France, where progesterone is widely used.

In the meantime, ObGyns who wish to prescribe micronized progesterone as part of combination HT should rule out peanut allergy and advise patients to take the micronized tablets at bedtime because of their tendency to cause sleepiness. The appropriate dosage of micronized progesterone to prevent endometrial proliferation in menopausal women using estrogen is 100 mg nightly or 200 mg cyclically for 12 or more days each month.¹⁰

<huc>A.</huc>Yes. In this study from France, the association between estrogen–progestin regimens and breast cancer varied significantly, depending on the progestin. The relative risk of invasive breast cancer was 1.08 for progesterone (95% confidence interval 0.89–1.31), 1.16 for dydrogesterone (0.94–1.43), and 1.69 for other progestins (1.50–1.91).

Expert Commentary

Fear of breast cancer discourages many women from using menopausal hormone therapy (HT), and fuels anxiety among patients and physicians alike. A large body of evidence from clinical trials and observational studies indicates that the use of estrogen-only therapy for less than 5 years has minimal, if any, impact on the risk of breast cancer.^1-5 In contrast, use of combination estrogen–progestin hormone therapy for more than 5 years is associated with an elevated risk of breast cancer,^3,6,7 and this risk is greater than the risk associated with the use of estrogen alone. This modestly increased risk is comparable to the elevated risk of breast cancer associated with lifestyle choices such as daily alcohol use, postmenopausal obesity, and lack of regular exercise.⁸

Few have focused on effects of specific progestins

Because the addition of a progestin to estrogen therapy in women with a uterus appears to play a key role in increasing the risk of breast cancer, and because a variety of progestins are available (including levonorgestrel, medroxyprogesterone acetate [MPA], norethindrone acetate, and progesterone), it makes sense to ask whether some progestins increase the risk of breast cancer more than others.

Although MPA is the most widely used progestin in menopausal practice in this country—and was the progestin used in the Women’s Health Initiative (WHI) trial of combination HT—other progestins are more common in Europe. The evidence has not definitively demonstrated that the choice of progestin affects the degree of breast cancer risk in women using HT.³

Large French population had high rate of HT use

HT is commonly used by menopausal women in France, and progesterone is the most widely prescribed progestin for endometrial protection, as Fournier and colleagues note. They conducted this large, prospective cohort study to assess HT use and breast cancer risk in almost 100,000 French teachers and wives of teachers, with intriguing results. Among the women followed in this study, 70% had used HT. The mean age at initiation was 52.4 years, and the mean duration of use and followup was 7 and 8.1 years, respectively.

Findings in regard to estrogen differ from those of other studies

Overall, the risk of being diagnosed with invasive breast cancer was significantly elevated with the use of estrogen alone, at a relative risk of 1.29 (95% confidence interval 1.02–1.65). This small elevation contrasts the findings of the WHI and Nurses’ Health studies, which identified no increased risk of breast cancer with estrogen alone.^4,5

Transdermal estrogen is widely used in menopausal women in France; route of estrogen administration did not affect breast cancer risk in this study.

Progesterone was associated with no elevated risk

The use of combination HT with MPA or norethindrone acetate was associated with higher relative risks than estrogen alone: 1.48 (1.02–2.16) and 2.11 (1.56–2.86), respectively. In contrast, combination HT with progesterone was not associated with an elevated risk of breast cancer, with a relative risk of 1.08 (0.89–1.31).

Fournier and colleagues point out that theirs is the first epidemiologic study to assess the risk of breast cancer associated with HT containing progesterone. They also cite recent data in postmenopausal primates indicating that combination HT with micronized progesterone causes lower rates of proliferation in lobular and ductal breast epithelium, compared with MPA-based hormone therapy.⁹

Clinical recommendations: For now, simply ensure adequate progestin

The findings of a single study generally should not dictate clinical practice. It remains the standard of care to ensure sufficient progestin (whether levonorgestrel, MPA, norethindrone acetate, or micronized progesterone) to prevent endometrial hyperplasia when prescribing HT for menopausal women with a uterus.

The findings of this study raise the possibility that progesterone may be safer than other progestins with respect to breast neoplasia. Additional epidemiologic data assessing the safety of progesterone in comparison with other progestins are welcome, but studies would need to be conducted in regions like France, where progesterone is widely used.

In the meantime, ObGyns who wish to prescribe micronized progesterone as part of combination HT should rule out peanut allergy and advise patients to take the micronized tablets at bedtime because of their tendency to cause sleepiness. The appropriate dosage of micronized progesterone to prevent endometrial proliferation in menopausal women using estrogen is 100 mg nightly or 200 mg cyclically for 12 or more days each month.¹⁰

<huc>A.</huc>Yes. In this study from France, the association between estrogen–progestin regimens and breast cancer varied significantly, depending on the progestin. The relative risk of invasive breast cancer was 1.08 for progesterone (95% confidence interval 0.89–1.31), 1.16 for dydrogesterone (0.94–1.43), and 1.69 for other progestins (1.50–1.91).

Expert Commentary

Fear of breast cancer discourages many women from using menopausal hormone therapy (HT), and fuels anxiety among patients and physicians alike. A large body of evidence from clinical trials and observational studies indicates that the use of estrogen-only therapy for less than 5 years has minimal, if any, impact on the risk of breast cancer.^1-5 In contrast, use of combination estrogen–progestin hormone therapy for more than 5 years is associated with an elevated risk of breast cancer,^3,6,7 and this risk is greater than the risk associated with the use of estrogen alone. This modestly increased risk is comparable to the elevated risk of breast cancer associated with lifestyle choices such as daily alcohol use, postmenopausal obesity, and lack of regular exercise.⁸

Few have focused on effects of specific progestins

Because the addition of a progestin to estrogen therapy in women with a uterus appears to play a key role in increasing the risk of breast cancer, and because a variety of progestins are available (including levonorgestrel, medroxyprogesterone acetate [MPA], norethindrone acetate, and progesterone), it makes sense to ask whether some progestins increase the risk of breast cancer more than others.

Although MPA is the most widely used progestin in menopausal practice in this country—and was the progestin used in the Women’s Health Initiative (WHI) trial of combination HT—other progestins are more common in Europe. The evidence has not definitively demonstrated that the choice of progestin affects the degree of breast cancer risk in women using HT.³

Large French population had high rate of HT use

HT is commonly used by menopausal women in France, and progesterone is the most widely prescribed progestin for endometrial protection, as Fournier and colleagues note. They conducted this large, prospective cohort study to assess HT use and breast cancer risk in almost 100,000 French teachers and wives of teachers, with intriguing results. Among the women followed in this study, 70% had used HT. The mean age at initiation was 52.4 years, and the mean duration of use and followup was 7 and 8.1 years, respectively.

Findings in regard to estrogen differ from those of other studies

Overall, the risk of being diagnosed with invasive breast cancer was significantly elevated with the use of estrogen alone, at a relative risk of 1.29 (95% confidence interval 1.02–1.65). This small elevation contrasts the findings of the WHI and Nurses’ Health studies, which identified no increased risk of breast cancer with estrogen alone.^4,5

Transdermal estrogen is widely used in menopausal women in France; route of estrogen administration did not affect breast cancer risk in this study.

Progesterone was associated with no elevated risk

The use of combination HT with MPA or norethindrone acetate was associated with higher relative risks than estrogen alone: 1.48 (1.02–2.16) and 2.11 (1.56–2.86), respectively. In contrast, combination HT with progesterone was not associated with an elevated risk of breast cancer, with a relative risk of 1.08 (0.89–1.31).

Fournier and colleagues point out that theirs is the first epidemiologic study to assess the risk of breast cancer associated with HT containing progesterone. They also cite recent data in postmenopausal primates indicating that combination HT with micronized progesterone causes lower rates of proliferation in lobular and ductal breast epithelium, compared with MPA-based hormone therapy.⁹

Clinical recommendations: For now, simply ensure adequate progestin

The findings of a single study generally should not dictate clinical practice. It remains the standard of care to ensure sufficient progestin (whether levonorgestrel, MPA, norethindrone acetate, or micronized progesterone) to prevent endometrial hyperplasia when prescribing HT for menopausal women with a uterus.

The findings of this study raise the possibility that progesterone may be safer than other progestins with respect to breast neoplasia. Additional epidemiologic data assessing the safety of progesterone in comparison with other progestins are welcome, but studies would need to be conducted in regions like France, where progesterone is widely used.

In the meantime, ObGyns who wish to prescribe micronized progesterone as part of combination HT should rule out peanut allergy and advise patients to take the micronized tablets at bedtime because of their tendency to cause sleepiness. The appropriate dosage of micronized progesterone to prevent endometrial proliferation in menopausal women using estrogen is 100 mg nightly or 200 mg cyclically for 12 or more days each month.¹⁰

<huc>A</huc>Yes, if the estrogen is oral estradiol and it is used for 5 years or longer. When Lyytinen and colleagues studied different estrogen doses, constituents, and routes of administration in a cohort representing the entire postmenopausal population of Finland, they found an additional 2 to 3 cases of breast cancer for every 1,000 women when oral estradiol was used for 5 years or more. When it was used for a shorter time, or when the estrogen was oral estriol or a vaginal formulation, there was no increase in risk.

Expert Commentary

Statistical modeling cannot adequately account for the multiple variables involved in complex conditions such as breast cancer. For example, the GAIL model, which is used to predict an individual’s chance of having breast cancer, will only correctly score 59% of women with cancer; 41% of women with cancer will have a lower score estimate than their cancer-free cohorts. In short, “current breast cancer risk prediction models perform well for populations but poorly for individuals.”¹

Breast cancer is not a single disease

Estrogen-related breast cancer is preceded histologically by atypical epithelial hyperplasia that progresses to invasive disease in some but not all women. Women who develop breast cancer while taking estrogen are more likely to have immature duct epithelium that is predominantly estrogen receptor-alpha (ERα). They are also likely to be genetically susceptible to modified physiologic cell growth and estrogen-metabolizing pathways in response to various environmental carcinogens or oncogenic promoters. In this context, exogenous estrogen may be a promoter, but not an instigator, of breast cancer.

A deficiency of vitamin D also plays a role. Vitamin D has potent antiproliferative effects that include the differentiation of breast tissue, enhanced apoptosis, and inhibition of cancer cell growth.

Untreated women with breast cancer have higher tissue levels of estrogen, which are correlated with increased breast-tissue enzymatic activity (aromatase, sulfatase, and 17β-OH dehydrogenase), especially in women with a genetic predisposition to increased or aberrant breast-tissue estrogen synthesis and metabolism. Other inherent factors include gene mutation involving cell-cycle growth (BRCA1, BRCA2, p53), and the ratio and expression of estrogen receptors; estrogen-therapy-associated breast cancer is more prevalent in women with a predominant ERα/ERβ ratio.

Mammographic density reflects the breast’s hormonal environment, the influence of background genetics, and the effect of various types, dosages, and routes of exogenous estrogen.

Not all estrogen is bioavailable

About 95% of orally administered estradiol is metabolized to estrone, estrone sulfate, and estradiol glucoronide. The bioconversion of these pro-hormones to more potent estradiol is dependent on the estrogen-metabolizing enzymes noted previously, the dose of estrogen, and the route of administration. Only 5% of orally administered estradiol is bioavailable. Because of the hepatic first-pass effect, 1 mg of oral 17β-estradiol and 25 μg of transdermal estrogen yield equivalent levels of free serum estradiol.

Variability in these and unknown factors account for the differing results of population-based studies and meta-analyses. It also may explain why, in a randomly selected group of Finnish women, only 2 to 3 extra cases of breast cancer for every 1,000 women were detected after 10 years of estrogen therapy, and at a dose twice that currently recommended.

Timing is critical, too

In the estrogen-alone arm of the Women’s Health Initiative, women aged 50 to 59 years—who are most likely to be treated with estrogen in everyday clinical practice—derived cardiovascular protection (hazard ratio [HR], 0.56), reduced colorectal cancer incidence, and a reduction in breast cancer (HR, 0.72). In contrast, most of the women in the study by Lyytinen and colleagues were over age 60. Other important risk factors not noted in their study include parity (pregnancy induces differentiation and maturation of breast ductal epithelium), pretreatment mammographic density, and vitamin D status.

Clinical recommendations

• Conduct a full clinical evaluation before initiating estrogen therapy
• Assess mammographic density before and after initiation of estrogen therapy. If density increases, stop therapy or reduce the dosage and repeat mammography in 3 to 6 months
• Measure high-sensitivity serum estradiol in women at high risk. Values in excess of 10 pg/dL may reflect an increased risk of breast cancer in untreated women—although no particular level of concern has been definitively identified
• Individualize dose and length of therapy according to age and indication.

Arbitrary restriction of estrogen therapy to 5 years is not biologically rational or clinically justifiable.

<huc>A</huc>Yes, if the estrogen is oral estradiol and it is used for 5 years or longer. When Lyytinen and colleagues studied different estrogen doses, constituents, and routes of administration in a cohort representing the entire postmenopausal population of Finland, they found an additional 2 to 3 cases of breast cancer for every 1,000 women when oral estradiol was used for 5 years or more. When it was used for a shorter time, or when the estrogen was oral estriol or a vaginal formulation, there was no increase in risk.

Expert Commentary

Statistical modeling cannot adequately account for the multiple variables involved in complex conditions such as breast cancer. For example, the GAIL model, which is used to predict an individual’s chance of having breast cancer, will only correctly score 59% of women with cancer; 41% of women with cancer will have a lower score estimate than their cancer-free cohorts. In short, “current breast cancer risk prediction models perform well for populations but poorly for individuals.”¹

Breast cancer is not a single disease

Estrogen-related breast cancer is preceded histologically by atypical epithelial hyperplasia that progresses to invasive disease in some but not all women. Women who develop breast cancer while taking estrogen are more likely to have immature duct epithelium that is predominantly estrogen receptor-alpha (ERα). They are also likely to be genetically susceptible to modified physiologic cell growth and estrogen-metabolizing pathways in response to various environmental carcinogens or oncogenic promoters. In this context, exogenous estrogen may be a promoter, but not an instigator, of breast cancer.

A deficiency of vitamin D also plays a role. Vitamin D has potent antiproliferative effects that include the differentiation of breast tissue, enhanced apoptosis, and inhibition of cancer cell growth.

Untreated women with breast cancer have higher tissue levels of estrogen, which are correlated with increased breast-tissue enzymatic activity (aromatase, sulfatase, and 17β-OH dehydrogenase), especially in women with a genetic predisposition to increased or aberrant breast-tissue estrogen synthesis and metabolism. Other inherent factors include gene mutation involving cell-cycle growth (BRCA1, BRCA2, p53), and the ratio and expression of estrogen receptors; estrogen-therapy-associated breast cancer is more prevalent in women with a predominant ERα/ERβ ratio.

Mammographic density reflects the breast’s hormonal environment, the influence of background genetics, and the effect of various types, dosages, and routes of exogenous estrogen.

Not all estrogen is bioavailable

About 95% of orally administered estradiol is metabolized to estrone, estrone sulfate, and estradiol glucoronide. The bioconversion of these pro-hormones to more potent estradiol is dependent on the estrogen-metabolizing enzymes noted previously, the dose of estrogen, and the route of administration. Only 5% of orally administered estradiol is bioavailable. Because of the hepatic first-pass effect, 1 mg of oral 17β-estradiol and 25 μg of transdermal estrogen yield equivalent levels of free serum estradiol.

Variability in these and unknown factors account for the differing results of population-based studies and meta-analyses. It also may explain why, in a randomly selected group of Finnish women, only 2 to 3 extra cases of breast cancer for every 1,000 women were detected after 10 years of estrogen therapy, and at a dose twice that currently recommended.

Timing is critical, too

In the estrogen-alone arm of the Women’s Health Initiative, women aged 50 to 59 years—who are most likely to be treated with estrogen in everyday clinical practice—derived cardiovascular protection (hazard ratio [HR], 0.56), reduced colorectal cancer incidence, and a reduction in breast cancer (HR, 0.72). In contrast, most of the women in the study by Lyytinen and colleagues were over age 60. Other important risk factors not noted in their study include parity (pregnancy induces differentiation and maturation of breast ductal epithelium), pretreatment mammographic density, and vitamin D status.

Clinical recommendations

• Conduct a full clinical evaluation before initiating estrogen therapy
• Assess mammographic density before and after initiation of estrogen therapy. If density increases, stop therapy or reduce the dosage and repeat mammography in 3 to 6 months
• Measure high-sensitivity serum estradiol in women at high risk. Values in excess of 10 pg/dL may reflect an increased risk of breast cancer in untreated women—although no particular level of concern has been definitively identified
• Individualize dose and length of therapy according to age and indication.

Arbitrary restriction of estrogen therapy to 5 years is not biologically rational or clinically justifiable.

<huc>A</huc>Yes, if the estrogen is oral estradiol and it is used for 5 years or longer. When Lyytinen and colleagues studied different estrogen doses, constituents, and routes of administration in a cohort representing the entire postmenopausal population of Finland, they found an additional 2 to 3 cases of breast cancer for every 1,000 women when oral estradiol was used for 5 years or more. When it was used for a shorter time, or when the estrogen was oral estriol or a vaginal formulation, there was no increase in risk.

Expert Commentary

Statistical modeling cannot adequately account for the multiple variables involved in complex conditions such as breast cancer. For example, the GAIL model, which is used to predict an individual’s chance of having breast cancer, will only correctly score 59% of women with cancer; 41% of women with cancer will have a lower score estimate than their cancer-free cohorts. In short, “current breast cancer risk prediction models perform well for populations but poorly for individuals.”¹

Breast cancer is not a single disease

Estrogen-related breast cancer is preceded histologically by atypical epithelial hyperplasia that progresses to invasive disease in some but not all women. Women who develop breast cancer while taking estrogen are more likely to have immature duct epithelium that is predominantly estrogen receptor-alpha (ERα). They are also likely to be genetically susceptible to modified physiologic cell growth and estrogen-metabolizing pathways in response to various environmental carcinogens or oncogenic promoters. In this context, exogenous estrogen may be a promoter, but not an instigator, of breast cancer.

A deficiency of vitamin D also plays a role. Vitamin D has potent antiproliferative effects that include the differentiation of breast tissue, enhanced apoptosis, and inhibition of cancer cell growth.

Untreated women with breast cancer have higher tissue levels of estrogen, which are correlated with increased breast-tissue enzymatic activity (aromatase, sulfatase, and 17β-OH dehydrogenase), especially in women with a genetic predisposition to increased or aberrant breast-tissue estrogen synthesis and metabolism. Other inherent factors include gene mutation involving cell-cycle growth (BRCA1, BRCA2, p53), and the ratio and expression of estrogen receptors; estrogen-therapy-associated breast cancer is more prevalent in women with a predominant ERα/ERβ ratio.

Mammographic density reflects the breast’s hormonal environment, the influence of background genetics, and the effect of various types, dosages, and routes of exogenous estrogen.

Not all estrogen is bioavailable

About 95% of orally administered estradiol is metabolized to estrone, estrone sulfate, and estradiol glucoronide. The bioconversion of these pro-hormones to more potent estradiol is dependent on the estrogen-metabolizing enzymes noted previously, the dose of estrogen, and the route of administration. Only 5% of orally administered estradiol is bioavailable. Because of the hepatic first-pass effect, 1 mg of oral 17β-estradiol and 25 μg of transdermal estrogen yield equivalent levels of free serum estradiol.

Variability in these and unknown factors account for the differing results of population-based studies and meta-analyses. It also may explain why, in a randomly selected group of Finnish women, only 2 to 3 extra cases of breast cancer for every 1,000 women were detected after 10 years of estrogen therapy, and at a dose twice that currently recommended.

Timing is critical, too

In the estrogen-alone arm of the Women’s Health Initiative, women aged 50 to 59 years—who are most likely to be treated with estrogen in everyday clinical practice—derived cardiovascular protection (hazard ratio [HR], 0.56), reduced colorectal cancer incidence, and a reduction in breast cancer (HR, 0.72). In contrast, most of the women in the study by Lyytinen and colleagues were over age 60. Other important risk factors not noted in their study include parity (pregnancy induces differentiation and maturation of breast ductal epithelium), pretreatment mammographic density, and vitamin D status.

Clinical recommendations

• Conduct a full clinical evaluation before initiating estrogen therapy
• Assess mammographic density before and after initiation of estrogen therapy. If density increases, stop therapy or reduce the dosage and repeat mammography in 3 to 6 months
• Measure high-sensitivity serum estradiol in women at high risk. Values in excess of 10 pg/dL may reflect an increased risk of breast cancer in untreated women—although no particular level of concern has been definitively identified
• Individualize dose and length of therapy according to age and indication.

Arbitrary restriction of estrogen therapy to 5 years is not biologically rational or clinically justifiable.