Sex Hormone Levels and Risk of Breast Cancer
Sex Hormone Levels and Risk of Breast Cancer
Background Although high endogenous sex hormone levels and estrogen plus progestin (E+P) therapy are associated with increased breast cancer risk, it is unknown whether pretreatment levels of sex hormones modify E+P effect on breast cancer.
Methods We conducted a nested case–control study within the Women's Health Initiative randomized clinical trial of E+P. The trial enrolled 16608 postmenopausal women aged 50 to 79 years with intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone, and sex hormone–binding globulin [SHBG]) and year 1 (estrogens and SHBG) using sensitive assays. All statistical tests were two-sided.
Results Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (Ptrend = .04), bioavailable estradiol (Ptrend = .03), estrone (Ptrend = .007), and estrone sulfate (Ptrend = .007). E+P increased all measured estrogens and SHGB at year 1 (all P < .001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval [CI] = 1.28 to 4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI = 0.44 to 2.09) in the highest total estradiol quartile; Pinteraction = .04).
Conclusions Women with lower pr-treatment endogenous estrogen levels were at greater risk of breast cancer during E+P therapy compared with those with higher levels. Further studies are warranted to confirm these findings.
Higher circulating levels of endogenous sex hormones are associated with increased breast cancer risk among postmenopausal women. A meta-analysis of nine prospective studies observed a twofold increase in breast cancer risk in women with estradiol levels in the highest, relative to the lowest, quintile, with similar associations noted for estrone, estrone sulfate, and testosterone.
In the Women's Health Initiative (WHI) randomized trial, combined estrogen plus progestin (E+P) increased both breast cancer incidence and breast cancer mortality relative to placebo. There has been ongoing interest in determining whether reproductive hormone levels can serve as predictive markers for breast cancer risk in hormone-based chemopreventive interventions. Two prior chemoprevention trials of raloxifene and tamoxifen have explored this question and yielded mixed results. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, women with higher baseline estradiol levels had the greatest risk reduction in breast cancer risk associated with raloxifene use. However, in an ancillary study within the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1), the effect of tamoxifen on breast cancer did not vary by estradiol level. Whether pretreatment levels of endogenous sex hormones modify the effect of E+P on breast cancer risk is unknown.
In a nested case–control study within the WHI E+P trial, we investigated the extent to which the effect of combined hormone therapy on breast cancer risk was modified by pretreatment levels of endogenous sex hormones (estradiol, estrone, estrone sulfate, testosterone, and progesterone) and sex hormone–binding globulin (SHBG). In addition, we assessed the association between pretreatment sex hormone levels and overall breast cancer risk. We hypothesized that women with lower levels of sex hormones have a lower overall risk of breast cancer but experience a greater increase in breast cancer during E+P use compared with women with higher levels.
Abstract and Introduction
Abstract
Background Although high endogenous sex hormone levels and estrogen plus progestin (E+P) therapy are associated with increased breast cancer risk, it is unknown whether pretreatment levels of sex hormones modify E+P effect on breast cancer.
Methods We conducted a nested case–control study within the Women's Health Initiative randomized clinical trial of E+P. The trial enrolled 16608 postmenopausal women aged 50 to 79 years with intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone, and sex hormone–binding globulin [SHBG]) and year 1 (estrogens and SHBG) using sensitive assays. All statistical tests were two-sided.
Results Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (Ptrend = .04), bioavailable estradiol (Ptrend = .03), estrone (Ptrend = .007), and estrone sulfate (Ptrend = .007). E+P increased all measured estrogens and SHGB at year 1 (all P < .001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval [CI] = 1.28 to 4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI = 0.44 to 2.09) in the highest total estradiol quartile; Pinteraction = .04).
Conclusions Women with lower pr-treatment endogenous estrogen levels were at greater risk of breast cancer during E+P therapy compared with those with higher levels. Further studies are warranted to confirm these findings.
Introduction
Higher circulating levels of endogenous sex hormones are associated with increased breast cancer risk among postmenopausal women. A meta-analysis of nine prospective studies observed a twofold increase in breast cancer risk in women with estradiol levels in the highest, relative to the lowest, quintile, with similar associations noted for estrone, estrone sulfate, and testosterone.
In the Women's Health Initiative (WHI) randomized trial, combined estrogen plus progestin (E+P) increased both breast cancer incidence and breast cancer mortality relative to placebo. There has been ongoing interest in determining whether reproductive hormone levels can serve as predictive markers for breast cancer risk in hormone-based chemopreventive interventions. Two prior chemoprevention trials of raloxifene and tamoxifen have explored this question and yielded mixed results. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, women with higher baseline estradiol levels had the greatest risk reduction in breast cancer risk associated with raloxifene use. However, in an ancillary study within the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1), the effect of tamoxifen on breast cancer did not vary by estradiol level. Whether pretreatment levels of endogenous sex hormones modify the effect of E+P on breast cancer risk is unknown.
In a nested case–control study within the WHI E+P trial, we investigated the extent to which the effect of combined hormone therapy on breast cancer risk was modified by pretreatment levels of endogenous sex hormones (estradiol, estrone, estrone sulfate, testosterone, and progesterone) and sex hormone–binding globulin (SHBG). In addition, we assessed the association between pretreatment sex hormone levels and overall breast cancer risk. We hypothesized that women with lower levels of sex hormones have a lower overall risk of breast cancer but experience a greater increase in breast cancer during E+P use compared with women with higher levels.
Source...