Bilateral oophorectomy is widely recognized to reduce breast cancer risk when performed before the onset of menopause.1–8 Among premenopausal women, risk reduction associated with oophorectomy can approach 50%, a magnitude comparable with chemoprevention with tamoxifen.9 In the United States, bilateral oophorectomy is a common elective procedure undertaken to reduce ovarian cancer risk during hysterectomy for nonmalignant conditions such as uterine fibroids, prolapse, and endometriosis. Between the ages of 35 and 45, approximately 11% of United States women undergo hysterectomy, and 40% of these surgeries include bilateral oophorectomy.10
Removal of the ovaries in premenopausal women can result in severe menopausal symptoms including, but not limited to, vasomotor symptoms, sexual dysfunction, depression, and bone loss.11,12 Women who undergo concurrent hysterectomy have the option of using estrogen-only hormone therapy to mitigate some of these symptoms. However, an ongoing concern for women and their health care providers is whether the use of unopposed estrogens may negate the benefit of oophorectomy for breast cancer prevention or perhaps even increase breast cancer risk, as has been reported in some observational studies.13–16
The Women's Health Initiative randomized placebo-controlled trial recently reported an overall 23% decrease in breast cancer risk among postmenopausal hysterectomized women assigned to conjugated equine estrogen compared with placebo (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.62–0.95). However, the average age of women in the Women's Health Initiative was 63.6 years and more than 80% of participants were 10 or more years beyond menopause at trial enrollment.17 United States women undergoing hysterectomy for benign conditions are frequently younger and premenopausal.10 Whether the association between unopposed estrogens and breast cancer risk differs when therapy is initiated by premenopausal women undergoing an abrupt surgical menopause, perimenopausal women who are seeking to ameliorate menopausal symptoms, or women who have been postmenopausal for several years is not yet clearly understood.14,18
To evaluate unopposed estrogen therapy after total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO) and breast cancer risk, we pooled information collected from more than 10,000 women with invasive postmenopausal breast cancer diagnosed and 10,000 population control group participants who participated in the Collaborative Breast Cancer Studies.
MATERIALS AND METHODS
This analysis was performed using data from the Collaborative Breast Cancer Studies, a series of four population-based case–control studies of invasive breast cancer conducted continuously between 1992 and 2007 by investigators at the University of Wisconsin–Madison, the Harvard School of Public Health, and Dartmouth Medical School. Participant identification, enrollment, and data collection procedures were maintained across studies. Each study was conducted according to institutionally approved protocols.19,20
All case group participants had an incident diagnosis of invasive breast cancer and date of diagnosis was reported to the statewide cancer registry at the study site. During 1992–2001, cases were identified in three states: Wisconsin, Massachusetts, and New Hampshire; during 2002–2007 case group participants were enrolled in Wisconsin only. In total, 21,713 eligible breast cancer case group participants were identified. Among identified case group participants, physicians refused contact with 359 (1.7%), 743 (3.4%) were deceased, 624 (2.9%) could not be located, and 2,794 (12.9%) refused to participate. Physician refusals indicated that an eligible participant should not be contacted to participate in a 20- to 30-minute telephone interview. Interviews were conducted for 17,193 (79.2%) eligible case group women. Thirty-eight women eligible for the case group were considered to have provided unreliable information by the interviewers, leaving 17,155 case group interviews available for analysis.
Population control group participants were identified in each state from lists of licensed drivers (younger than 65 years) and Medicare beneficiaries (65–79 years). Control group participants were randomly selected within 5-year age strata to yield an age distribution similar to the case group participants enrolled in each state and were required to have no personal history of breast cancer. Of the 26,269 potential control group participants identified, 316 (1.2%) were deceased, 1,198 (4.6%) could not be located, and 5,446 (20.7%) refused to participate. Interviews were obtained for 19,309 (73.5%) women. Forty-one control group interviews were considered unreliable by the interviewer, leaving 19,268 control group interviews available for analysis.
All case and control group participants provided information on medical history, hormone use, lifestyle, and demographic factors during a structured telephone interview. Questions pertaining to postmenopausal hormone use queried information on formulation, routes of administration, age started, frequency of each episode of use, total duration, and time since last use. Study participants also reported whether they had undergone surgery to remove the uterus or ovaries, the type of surgery (hysterectomy or oophorectomy or both, including number of ovaries removed), and age at surgery. Information about personal and first-degree family history of cancer was obtained at the end of the interview to maintain interviewer blinding of case–control status.
For each case group participant, a reference date was defined as the registry-reported date of invasive breast cancer diagnosis. For comparability, the control group participants interviewed contemporaneously with case group participants were assigned an individual reference date corresponding to the average time from diagnosis to interview for the case group. Reference age was defined as age at diagnosis for case group participants or on the reference date given to control group participants. Only exposures that occurred before the assigned reference date were included in analyses.
In three of the four pooled studies (1992–1995; 1997–2001; 2001–2004), natural menopause was defined as the absence of menses for 6 consecutive months not attributable to surgery, chemotherapy, radiation, or other reasons. In the most recent study (2004–2007), menopause was defined as 12 consecutive months without menses not attributable to surgery, chemotherapy, radiation, or other reasons. In all studies, women who reported bilateral oophorectomy before the reference date were categorized as postmenopausal. Women who reported hysterectomy without bilateral oophorectomy were categorized as premenopausal if their reference age was in the first decile of age at natural menopause among control group participants (younger than 42 years of age for current smokers and younger than 43 years of age for nonsmokers), were reported to be postmenopausal if the reference age was in the highest decile for age at natural menopause among controls (older than 55 years of age), and were otherwise reported to have an unknown age at menopause. Participants who had started postmenopausal hormone use before cessation of menses were categorized as postmenopausal with unknown age at menopause.
The pooled analysis was limited to women aged 50 year and older (n=13,253 case group participants and 14,900 control group participants). We further excluded women who were premenopausal (n=1,352 case group participants and 1,462 control group participants) or had unknown menopausal status (n=620 case group participants and 661 control group participants), or who had a history of cancer (except nonmelanoma skin cancer; n=614 case group participants and 726 control group participants). Women with discordant ages at bilateral oophorectomy and hysterectomy (93 case group participants and 155 control group participants) or missing ages for both procedures (41 case group participants and 45 control group participants) also were excluded. Finally, 84 case group participants and 64 control group participants who reported bilateral oophorectomy or hysterectomy or both at the same age or older compared with the reference age were excluded. After these exclusions, 10,449 case group participants and 11,787 control group participants contributed information to our analyses.
Odds ratios (ORs) and 95% CIs for breast cancer were calculated using multivariable logistic regression models. The reference group comprised women with an intact uterus and ovaries who reported undergoing a natural menopause for estimates of breast cancer odds after TAHBSO. For estimates of breast cancer odds according to estrogen therapy use after TAHBSO, the reference group was additionally restricted to never-users of hormone therapy. This allowed us to jointly assess the protective effect of early ovarian removal on breast cancer risk and potential variation according to estrogen therapy use after surgery. In sensitivity analyses, we additionally required that women in the reference group reported ages at menopause between 50 and 51 years (the median age of menopause among control group participants). Results were similar when age at menopause was and was not specified for the reference group; therefore, we present results with the more expansive definition that did not specify age at menopause to maximize the sample size for the reference group.
Covariates in multivariable models were selected a priori as factors conceptually related to both gynecologic surgery and breast cancer risk. Preliminary multivariable models were adjusted for age (5-year groups), study enrollment period (1992–1995; 1997–2001; 2001–2004; 2004–2007), and study site. Final models additionally included the following covariates: age at menarche (younger than 12 years, 12 years, 13 years, 14 years or older, unknown), age at first birth (younger than 20 years, 20–24 years, 25–29 years, 30 years or older, unknown), parity (0–1 live birth, 2–3 live births, 4 or more live births, unknown), postmenopausal hormone use (never, estrogen only, estrogen plus progestin only, combination of estrogen and estrogen plus progestin, other or unknown), first-degree family history of breast cancer (yes, no, unknown), mammography screening (yes, no, unknown), and body mass index (calculated as weight (kg)/[height (m)]2; underweight, normal, overweight, obese, unknown). P≤.05 was considered to be statistically significant. P trends represent P values from the Wald test for the categorical variable included as an ordinal term in regression models (the reference group is the lowest level). All analyses were performed using SAS 9.2 software.
We conducted two additional sensitivity analyses to evaluate whether the definitional change of natural menopause from 6 to 12 months of amenorrhea during 2004–2007 and whether the enrollment of participants in Wisconsin only during 2001–2007 influenced our results. In analyses restricted to participants who were defined as menopausal after 6 months amenorrhea (n=9,051 case group participants and 10,216 control group participants) and those residing in Wisconsin (n=7,310 case group participants and 7,892 control group participants), our findings were essentially unchanged compared with the overall analysis.
Participant characteristics by case–control status are shown in Table 1. The average age of study participants was 63 years. In brief, case group participants tended to be more highly educated, had lower parity, had a positive family history of breast cancer, had a body mass index in the obese range, and were more likely to have used postmenopausal hormones compared with control group participants. Approximately 9.5% of case group participants and control group participants reported having a hysterectomy alone, and 17% of case group participants and 19% of control group participants reported undergoing TAHBSO (Table 1).
Table 2 presents the association between gynecologic surgery and breast cancer risk. To directly compare breast cancer associations with hysterectomy alone compared with TAHBSO, we defined a common reference group comprising women with an intact uterus and ovaries who underwent natural menopause. Overall, hysterectomy alone was not associated with breast cancer risk (OR 1.03, 95% CI 0.93–1.14) regardless of age at surgery (P trend=.9).
Hysterectomy with removal of one ovary (OR 0.81, 95% CI 0.70-.95) or both ovaries (OR 0.87, 95% CI 0.80–0.95) was associated with 13–19% reductions in the odds of breast cancer (Table 2).
Younger ages at TAHBSO were associated with a greater reduction in the overall odds of development of breast cancer (P trend<.001). Effect estimates ranged from a 46% reduction in breast cancer odds for TAHBSO before age 30 (OR 0.54, 95% CI 0.36–0.82) to a 21% reduction for surgeries performed at ages 40–44 years (OR 0.79, 95% CI 0.67–0.92). No reduction in breast cancer risk was observed in women who had TAHBSO at age 45 or older. Bilateral oophorectomy without concurrent hysterectomy was reported by less than 1% of case group participants and control group participants and was associated with an OR of 1.39 for breast cancer (95% CI 0.97–2.00; Table 2).
Breast cancer risk associations for hysterectomy alone and TAHBSO according to estrogen therapy use, duration, and the interval between surgery and start of estrogen therapy are shown in Table 3. All comparisons were made relative to women with an intact uterus and ovaries who experienced natural menopause and never used hormones (n=4,442 case group participants and 5,303 control group participants). This reference group allowed us to account for the protective effect of early ovarian removal on breast cancer risk and to assess variation according to estrogen therapy use after surgery. After multivariable adjustment, postmenopausal women who reported undergoing hysterectomy alone had a 29% increase in breast cancer odds if they reported using unopposed estrogens after surgery (95% CI 1.11–1.49). This increase did not appear to vary significantly based on former compared with current use, years of use, or the interval between surgery and initiation of estrogen use (Table 3).
Compared with the reference group, ever-use of estrogen therapy after TAHBSO was associated with a 9% increase in breast cancer odds (OR 1.09, 95% CI 0.99–1.19) that was not statistically significant. This increase appeared driven by a 14% increase in breast cancer odds among current estrogen users (OR 1.14, 95% CI 1.03–1.28), former use of estrogen was not associated with breast cancer risk (OR 0.95, 95% CI 0.80–1.12). Among current estrogen users, breast cancer odds were increased 32% among those who had used estrogen therapy for 0.5–9.9 years (OR 1.32, 95% CI 1.11–1.57), longer durations of use were not associated with statistically significant increases in breast cancer risk (OR 1.09, 95% CI 0.92–1.29 for 10–19.9 years and OR 1.00, 95% CI 0.82–1.23 for 20 years or more). Estrogen use that was initiated within 5 years of TAHBSO was associated with a 22% increase in breast cancer odds compared with the referent group (OR 1.22, 95% CI 1.09–1.37), whereas a 54% reduction was observed among women who started estrogen use 5 years or more after TAHBSO (OR 0.46, 95% CI 0.30–0.71; Table 3). However, on average, women who started using estrogen 5 years or more after oophorectomy were younger (40–41 years) than women who started using estrogens closer to surgery (45–46 years).
Table 4 displays ORs for breast cancer according to age at surgery and diagnosis for never and current estrogen users. Among women who never used hormones, TAHBSO before age 40 was associated with a 30% decrease in breast cancer odds (OR 0.70, 95% CI 0.55–0.88), and TAHBSO at age 40–44 was associated with a 36% decrease in breast cancer odds (OR 0.64, 95% CI 0.49–0.84) compared with the reference group. No significant associations between TAHBSO at older ages and breast cancer were observed in women who never used postmenopausal hormones (Table 4).
Overall increases in breast cancer risk were observed among women who reported currently using unopposed estrogens and having TAHBSO surgery at older ages. However, among current estrogen users, TAHBSO at the youngest ages (younger than 40 years) remained associated with an overall decrease (24%) in breast cancer odds (OR 0.76, 95% CI 0.61–0.96). The ORs ranged from 1.19 for surgeries at 40–44 years (95% CI 0.96–1.48) to 1.26 for surgeries at age 50 and older (95% CI 1.05–1.52; Table 4).
Our findings provide detailed estimates of the association between estrogen therapy and breast cancer risk for women who have undergone hysterectomy with concomitant bilateral oophorectomy (TAHBSO). Among women who reported TAHBSO before age 40, estrogen use did not negate the usual reduction in breast cancer risk conferred by early removal of the ovaries. Among women who initiated estrogen after TAHBSO at older ages, no reduction in breast cancer risk was observed. Instead, current use of unopposed estrogens was associated with a 14% increase in breast cancer odds.
Our findings confirm previous reports of 25–50% reductions in breast cancer risk associated with bilateral oophorectomy, with greater magnitudes of risk reduction for surgeries performed at younger ages and no apparent benefit after age 45.1–8 In contrast to some previous studies,5,7,8,13,21 we did not observe an association between hysterectomy alone and breast cancer risk, irrespective of age at surgery. We did observe a 29% increase in breast cancer odds associated with using unopposed estrogens after hysterectomy alone.
Few studies of the relation between unopposed estrogen use and breast cancer risk have reported estimates specific to hysterectomized women who underwent concurrent oophorectomy.16,22 In the Women's Health Initiative randomized trial, 76 incident breast cancers developed among women who had undergone bilateral oophorectomy (33 assigned to estrogen, 43 assigned to placebo); estrogen use was associated with an estimated 14% reduction in breast cancer risk (HR 0.86, 95% CI 0.55–1.36).22 In the Nurses' Health Study, 366 incident breast cancers were investigated among women who had undergone bilateral oophorectomy: 55 among never-users of hormone and 311 among current estrogen users. The authors reported a 71% increase in breast cancer risk associated with long-term (20 years or more) estrogen therapy use (95% CI 1.16–2.53).16 Among BRCA1/2 carriers, breast cancer risk reduction estimates associated with bilateral oophorectomy were similar among 50 women who used estrogen therapy (HR 0.44, 95% CI 0.12–1.61) and 50 women who did not (HR 0.59, 95% CI 0.14–2.52) over an average 3.6-year follow-up.23 These disparate findings may be caused, in part, by younger ages at bilateral oophorectomy among BRCA1/2 mutation carriers and differences in the timing of estrogen therapy relative to menopause between observational population-based studies and the Women's Health Initiative randomized trial.
The interval between menopause and start of estrogen therapy is emerging as an important factor in determining the risks and benefits of hormone use for breast cancer incidence.18 In the Women's Health Initiative, the protective effect of estrogen therapy appeared more strongly among women who started estrogen therapy further from menopause (HR 0.65, 95% CI 0.48–0.89) compared with within 5 years of menopause (HR 0.89, 95% CI 0.66–1.20); however, the difference between these estimates was not statistically significant.17 In the Million Women Study screening cohort, increased risk of breast cancer associated with current use of estrogen therapy was restricted to women who initiated hormone use within 5 years of menopause (HR 1.43, 95% CI 1.36–1.49 for intervals less than 5 years compared with HR 1.05, 95% CI 0.89–1.23 for 5 years or more).14 In our data, we observed a 58% decrease in breast cancer odds among women who initiated estrogen therapy 5 years or more after TAHBSO compared with women who underwent natural menopause and never used hormones. It is possible that unopposed estrogen therapy administered in a postmenopausal state of relative estrogen deprivation induces apoptosis and exhibits antitumor effects.24,25 However, only 29 case group participants and 86 control group participants reported initiating estrogen therapy 5 years or more after TAHBSO, making it an unusual occurrence.
Conversely, estrogen use among perimenopausal women or postmenopausal women with recent exposure to ovarian-produced estrogens could instead contribute to breast cancer growth, particularly among estrogen receptor–positive tumors. Among women who initiated estrogen therapy within 5 years of TAHBSO, we observed a 22% increase in breast cancer risk. This increase was limited to the first 10 years of use. The relation of estrogen therapy to breast cancer risk may be dependent on the presence of initiated cells as well as the estrogen environment surrounding tumor cells.26 For example, close to menopause, estrogen therapy may have a greater effect on the promotion of initiated breast cancer cells by prolonging a relatively estrogen-rich environment; the increased risk may not continue beyond 10 years because of an absence or depletion of transformed cells. Growth of tumor cells that arise in a low-estrogen environment after menopause may be inhibited by the introduction of exogenous estrogen.24,25 This potential dynamic, however, does not explain the increased risk of breast cancer with long durations of estrogen therapy observed in other observational studies.13–16
The case–control design and large sample size of the pooled studies allowed us to estimate breast cancer odds, specifically among women who reported TAHBSO, and to examine variation according to age at surgery and estrogen therapy use. Despite the large sample and extensive covariate information available in these data, some limitations should be considered in the interpretation of our results. The number of case group participants and control group participants was small for some analyses. In our report, we have used the abbreviation TAHBSO to reflect surgeries in which the uterus and both ovaries were removed simultaneously. Based on information from the study interview, we are unable to confirm whether these procedures were performed vaginally or abdominally, or whether the fallopian tubes were removed. However, based on clinical practice at the time, the majority of surgeries were likely to be abdominal and to include salpingectomy.27
Exposure status was self-reported by case and control participants, introducing the potential for recall bias. In a subset of these data19 and other studies,28–33 self-reported postmenopausal hormone use has been shown to be a reliable and valid measure for use in epidemiologic studies. In our data, self-reported hysterectomy and oophorectomy status had high reliability (κ=0.98, 95% CI 0.95–1.00) among a sequential sample of 195 control participants who were interviewed again.34 Although validation data are unavailable for the studies analyzed here, a 1988 validation study of 128 breast cancer case participants and 154 control participants enrolled in the Breast Cancer Detection and Demonstration Project reported 90% agreement between medical reports and self-reported TAHBSO status for case participants and 84% among control participants.2 Validity of self-reported hysterectomy status was also high in the Nurses' Health Study; among 69 women who reported TAHBSO, medical record confirmation was obtained for 66 (95.7%).35 However, among 49 women enrolled in the Breast Cancer Screening Program, the percent agreement was only 74% between medical record review and self-reported bilateral oophorectomy status.36
Breast cancer risk associations with unopposed estrogen use may be attenuated in analyses that do not restrict to ER+/PR+ cancers;16 we were unable to assess hormone receptor status in these data. The protective effect of TAHBSO for breast cancer risk also may vary according to hormone receptor subtypes. In the Women's Contraceptive and Reproductive Experiences Study, bilateral oophorectomy was more strongly associated with reduced risk of ER+/PR+ breast cancer (OR 0.55, 95% CI 0.45–0.68) compared with ER−/PR− tumors (OR 0.82, 95% CI 0.63–1.07).8 In our study, all breast cancer case group participants were postmenopausal and 50 years of age or older, suggesting that the majority of tumors were likely to be hormone receptor–positive.37
We observed a suggested positive association between bilateral oophorectomy without hysterectomy and breast cancer risk, although this finding was not statistically significant. One potential explanation for this finding is that our statistical adjustment for first-degree family history of breast cancer was unable to protect against residual confounding according to strong family histories of breast and ovarian cancer.38 Women with known BRCA1/2 gene mutations are counseled to consider bilateral oophorectomy after age 35 or completion of childbearing (although some women elect to undergo surgery at younger ages) for ovarian and breast cancer prevention (www.nccn.org).
The present findings are reassuring to younger women who undergo oophorectomy and elect to use estrogen therapy and are concerned about future breast cancer risk. Our results suggest a precautionary approach for women undergoing TAHBSO at older ages. Benefits of estrogen therapy should be weighed against the possibility of increased breast cancer risk.
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