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Persistent vasomotor symptoms and breast cancer in the Women's Health Initiative

Chlebowski, Rowan T., MD, PhD1; Mortimer, Joanne E., MD1; Crandall, Carolyn J., MD2; Pan, Kathy, MD3; Manson, JoAnn E., MD, Dr.PH4; Nelson, Rebecca, PhD1; Johnson, Karen C., MD5; Vitolin, Mara Z., Dr.PH6; Lane, Dorothy, MD, MPH7; Wactawski-Wende, Jean, PhD8; Kwan, Karen, MD9; Stefanick, Marcia L., PhD10

doi: 10.1097/GME.0000000000001283
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Objective: Vasomotor symptoms (VMS) including hot flashes and night sweats are common during the menopausal transition and may persist. Although VMS pathophysiology is complex, estrogen's efficiency as VMS therapy suggests hormonal environment change may influence this process. As studies of VMS and breast cancer are inconsistent, we examined associations between persistent VMS and breast cancer incidence and mortality.

Methods: The analytic sample included 25,499 postmenopausal women aged 50 to 79 in the Women's Health Initiative (WHI) without current/former menopausal hormone therapy use with information on VMS status (never vs persistent). Breast cancers were verified by medical record review. Cause of death attribution was enhanced by serial National Death Index queries. Associations between VMS status and breast cancer incidence and mortality was determined using time dependent Cox regression analyses adjusted for breast cancer risk factors.

Results: Through 17.9 years (median) follow-up, 1,399 incident breast cancers were seen. Women with persistent VMS (VMS median duration 10+ years) (n = 9,715), compared to women with never VMS (n = 15,784), had a higher breast cancer incidence (hazard ratio [HR] 1.13 95% confidence interval [CI] 1.02-1.27). While breast cancer-specific mortality was higher in women with persistent VMS (HR 1.33 95% CI 0.88-2.02), the difference was not statistically significant. Persistent VMS status had no influence on breast cancer overall survival (HR 1.02 95% CI 0.81-1.29).

Conclusion: Women with persistent VMS are more likely to be diagnosed with breast cancer than women who never experienced VMS, but not more likely to die from breast cancer.

1City of Hope National Medical Center, Duarte, CA

2David Geffen School of Medicine at UCLA, Los Angeles, CA

3Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA

4Brigham and Women's Hospital, Harvard Medical School, Boston, MA

5University of Tennessee Health Science Center, Memphis, TN

6Wake Forest Baptist Medical Center, Winston Salem, NC

7Stony Brook University School of Medicine, Stony Brook, NY

8University of Buffalo, Buffalo, NY

9Southern California Permanente Medical Group, Los Angeles, CA

10Stanford Prevention Research Center, Stanford, CA.

Address correspondence to: Rowan T. Chlebowski, MD, PhD, City of Hope National Medical Center, Duarte, CA 91010. E-mail: rowanchlebowski@gmail.com

Received 8 April, 2018

Revised 31 August, 2018

Accepted 31 August, 2018

Funding/Support: The WHI program is reported by the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.

Financial disclosure/conflicts of interest: R.T.C. has received honoraria from Novartis and AstraZeneca and consulting fees from Novartis, AstraZeneca, Pfizer, and Genentech. J.E.M. has received honoraria from Novartis and consulting fees from Puma Biotechnology, Pfizer, and Novartis. Remaining authors report no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.menopause.org).

Online date: December 28, 2018

Vasomotor symptoms (VMS) including hot flashes and/or night sweats are common in women during the menopause transition and may persist. The etiology of VMS is complex, involving overactivity of the sympathetic nervous system. The symptoms follow small elevations in core body temperature related, at least in part, to ovarian senescence and the resulting estrogen decline.1,2 However, as plasma estrogen levels between women with and without VMS do not consistently differ,3 other factors must be involved. Nonetheless, exogenous hormone therapy is the most effective VMS intervention,4 suggesting hormonal environment change may play a role in this process.1 As endogenous sex hormones levels are related to postmenopausal breast cancer risk,5 there has been interest in examining associations between VMS status and breast cancer incidence and outcome.

At the present time, studies examining the association between VMS frequency and persistence with breast cancer incidence have been limited and provide conflicting results. VMS were associated with lower breast cancer risk in 2 case-control studies comparing findings in ever VMS to never VMS groups6,7 and in 1 cohort study,8 the latter including only 108 incident breast cancer cases. In contrast, a larger cohort study with 348 incident breast cancer cases found no association between VMS and breast cancer incidence.9

As the nature of the association between the VMS and breast cancer risk has not been settled, with long term, persistent VMS receiving limited attention and associations with breast cancer mortality not reported, we examined associations between persistent VMS and breast cancer incidence and breast cancer mortality in postmenopausal women participating in the Women's Health Initiative (WHI) clinical trials and observational study. In addition, we examined associations among breast cancer incidence and outcome with breast cancer risk factors more generally to facilitate comparisons with findings related to persistent VMS.

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METHODS

The design and implementation of the WHI clinical trials and the WHI observational study have been described10,11 including methods for breast cancer case ascertainment and adjudication.12 Briefly, the WHI enrolled 161,808 postmenopausal women at 40 US clinical centers between 1993 and 1998 to one of four clinical trials (N = 68,132) or an observational study (N = 93,676). Postmenopausal women between 50 and 79 years of age who were unlikely to die within 3 years were eligible for participation. The clinical trials had additional eligibility criteria related to prior cancer history and adherence or retention concerns. Written informed consent was required and study procedures were approved by the Institutional Review Boards at participating clinical centers.

Trial registration: clinicaltrials.gov Identifier NCT00000611.

Demographics and breast cancer risk factors including age, age at menarche, age at menopause, age at first birth, parity, breast feeding, contraceptive use, menopausal hormone therapy use (estrogen plus progestin, estrogen alone), family history of breast cancer, comorbidity, recreational physical activity, alcohol intake, smoking, years of education, income, neighborhood socioeconomic status, and mammography screening history were collected at baseline using study-specific questionnaires. Medication use was assessed by interview including review of medication containers. Height, weight, and waist circumference were measured at baseline clinical visits and body mass index (BMI, kg/m2) was calculated.

A negative mammography was required for clinical trial entry. In addition, mammography was required for clinical trial participants every 2 years and yearly for those participating in one of the two hormone therapy trials. Ongoing mammography was not required for observational study participants but information on mammography history and on study frequency was collected.

Clinical trial participants were contacted at 6-month intervals for outcome ascertainment during the 8.5 years (mean) active clinical trial period with subsequent contact yearly. Observational study participants were contacted yearly. Breast cancer self-reports were verified by medical record review by centrally trained WHI physician adjudicators at each clinical center. Determination of breast cancer subtype (estrogen receptor [ER], progesterone receptor, and human epidermal growth factor receptor 2) was based on local laboratory results. Final adjudication and coding for stage were performed at the Clinical Coordinating Center using Surveillance, Epidemiology and End Results coding system.13

Information on VMS was collected by a self-administered questionnaire at baseline to ascertain whether participants had ever experienced hot flashes and/or night sweats (yes/no) and their age at first and last VMS episodes. In addition, at baseline, information on VMS in the prior 4 weeks was collected with symptoms rated as mild (no interference with usual activities), moderate (interfered with usual activities), or severe (usual activities could not be performed).

Women were categorized as “persistent VMS” if they reported having moderate or severe hot flashes and/or night sweats within the last 4 weeks before WHI entry and also reported having ever experienced VMS. The duration of persistent VMS was determined from the participant's history of VMS before baseline. Women were categorized as “never VMS” if they answered “no” to the question “had you ever experienced hot flashes and/or night sweats? ” and also reported no VMS within the last 4 weeks. Also considered without persistent VMS were women reporting mild VMS as there is about a 33% false-positive rate in those reporting only mild symptoms.14

The analyses excluded participants with missing information on VMS severity, those with current menopausal hormone therapy of any kind (including those randomized to active therapy groups of the WHI Hormone Therapy trials), those missing information on hormone therapy use, and those reporting ever VMS use but no VMS within the past 4 weeks (Fig. 1). As a result, the categories for the current analysis were persistent VMS (n = 9,715) and never VMS (n = 15,784).

FIG. 1

FIG. 1

FIG. 1

FIG. 1

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Statistical analysis

Baseline characteristics were examined for all eligible participants and breast cancer cases across categories of VMS status using t tests for normally distributed continuous data, Wilcoxon rank-sum tests for non-normally distributed continuous data, Pearson X2 tests for categorical nominal data and Jonckheere-Terpstra nonparametric tests for categorical ordinal data.

In the current analyses, we examined VMS status (persistent vs never) association with breast cancer incidence, breast cancer-specific mortality (breast cancer followed by death attributed to the cancer), and breast cancer overall survival (breast cancer followed by death from any cause). Associations between VMS status and breast cancer outcomes were examined using multivariate Cox proportional hazards models, with results reported using hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariate models were adjusted for age (5-year categories), BMI group, waist circumference group (≥88 cm vs <88 cm), first-degree family history of breast cancer (yes/no/unknown), smoking status (never smokers, former smokers, current smokers, and unknown smoking status), alcohol consumption (never users, former users, and current users), and parity. The incidence model also included adjustment for the 5-year calculated breast cancer risk using the Breast Cancer Risk Assessment Tool (Gail Model). Exploratory analyses examined VMS associations with breast cancer characteristics including histology, ER, progesterone receptor, human epidermal growth factor receptor 2 status, stage, grade, tumor size, and lymph node status.

Follow-up time for breast cancer incidence was calculated from the date of enrollment. Follow-up time for breast cancer-specific survival and breast cancer overall survival was calculated from the date of breast cancer diagnosis. For analyses of breast cancer incidence, all participants were included and those not diagnosed with breast cancer were censored at date of death or last contact. Participants not diagnosed with breast cancer were not included in analyses examining breast cancer mortality. For analyses of breast cancer-specific survival, those who were alive or died from other causes were censored at the date of last contact or death. All analyses were performed using SAS, with two-sided P values of 0.05 or lesser considered statistically significant.

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RESULTS

Baseline characteristics

Of 25,499 women included in the analysis, after 17.9 years median follow-up, the 9,715 (38%) with persistent VMS, compared to the 15,784 (62%) with never VMS, were younger, closer to menopause, more likely to be Black, less likely to have an education beyond high school, and be at lower calculated breast cancer risk (median interquartile range 1 [0.9-1.8] vs 2 [1.2-2.1] P < 0.001) (Table 1). Compared to women who never experienced VMS, women with persistent VMS at the time of WHI enrollment had experienced symptoms for a duration of 10+ years (median, interquartile range 4+ to 17+ years). Women aged 70 years and older comprised 11% of the participants who reported persistent VMS.

TABLE 1

TABLE 1

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Breast cancer incidence

Of the 1,399 (5.5%) women with incident invasive breast cancers, those with persistent VMS had a higher breast cancer incidence compared to women with never VMS (adjusted HR 1.13, 95% CI 1.02-1.27) (Fig. 2). No significant interactions were seen in subgroup analyses evaluating age (50-54, 55-59, 60-69, 70-79), BMI, and alcohol consumption. Considering all 1,399 incident breast cancer cases, breast cancer incidence was greater with increasing BMI, current alcohol use (HR 1.26, CI 1.07-1.48), nulliparous status (HR 1.24, CI 1.08-1.43), and increasing calculated Breast Cancer Risk Assessment Tool breast cancer risk (HR 1.16, CI 1.1000-1.22) (Fig. 2).

FIG. 2

FIG. 2

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Breast cancer characteristics

When characteristics of the breast cancer cases were considered, compared to women with never VMS, women with persistent VMS were more likely to have ER negative cancers (P = 0.018) and to have regional or distant involvement (P = 0.002) compared to women with never VMS (Table 2).

TABLE 2

TABLE 2

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Breast cancer-specific mortality and breast cancer overall survival

During 18.7 years median total follow-up from enrollment and 9.0 years median follow-up from breast cancer diagnosis, breast cancer- specific mortality and breast cancer overall survival were examined in multivariate analyses with the following factors included in the model: VMS status, age at enrollment, BMI group, waist circumference group, family history of breast cancer, smoking status, alcohol consumption status, and parity.

Findings for breast cancer-specific mortality (breast cancer followed by death attributed to the cancer) in the 1,399 women with incident breast cancer are provided in Figure 3. Risk of breast cancer-specific mortality was higher in women with persistent VMS compared with women who never experienced VMS (HR 1.33 95% CI 0.88-2.02), but the difference was not statistically significant. Multivariate Cox proportional hazards risk of breast cancer-specific mortality stratified by tumor characteristics are outlined in supplemental Table 1 (http://links.lww.com/MENO/A364) with no differences seen.

FIG. 3

FIG. 3

Findings for breast cancer overall survival (breast cancer followed by death from any cause) are provided in Figure 4. Overall, the risk of death after breast cancer was substantially higher in older compared to younger women and in those with breast cancer family history. VMS status (persistent vs never) was not associated with breast cancer overall survival (HR 1.02 95% CI 0.81-1.29) (Fig. 4).

FIG. 4

FIG. 4

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DISCUSSION

Women with persistent VMS, compared with women who never experienced VMS, had a higher breast cancer incidence and the cancers were more likely to be ER negative with regional or distant spread. However, breast cancer-specific survival and breast cancer overall survival did not differ by VMS status.

The findings in the current report, comparing breast cancer incidence and outcome in women with persistent VMS to women who never experienced VMS, are in contrast to several previous studies addressing different but related questions. In one case-control study in postmenopausal women with 988 breast cancer cases and 449 controls, those with ever VMS had significantly lower breast cancer risk compared to the never VMS group.6 In the two sister study, when findings in 1,422 women with breast cancer diagnosed before the age of 50 years were compared to their 1,669 cancer-free sisters, ever having VMS was associated with substantially lower risk of breast cancer (odds ratio 0.49; 95% CI 0.40-0.61).7

To our review, only two prior cohort studies have examined VMS status and breast cancer risk. This issue was addressed throughout the menopausal transition in 2,468 participants with hormone therapy use by 1,120. After 108 breast cancers, incidence was lower in the ever VMS group (adjusted HR 0.63 95% CI 0.39-1.00).8 In a report from the Australian Longitudinal Study in Women's Health, 11,297 women, 47 to 52 years of age were followed over 13 years. With 348 incident breast cancer cases, breast cancer incidence was similar in the ever and never VMS groups (HR 1.09 95% CI 0.87-1.5 for hot flashes).9 Thus, these two cohort studies addressed substantially different questions than in the current report. In this study breast cancer incidence and breast cancer mortality were compared in women with persistent VMS, with long-term, 10+ year (median) VMS exposure, to findings in women with never VMS.

In contrast to the limited number of prior cohort studies addressing breast cancer associations with VMS (with a total of 456 incident cases),8,9 more evidence is available regarding VMS and cardiovascular disease risk. The association of VMS and other menopausal symptoms with risk of cardiovascular disease has been explored in a systematic review and meta-analysis of cohort studies and randomized clinical trials. Ten studies with 213,976 women and 10,037 cardiovascular disease outcomes were identified. In women with menopausal symptoms, compared to women without symptoms, significant associations were seen for higher risk of coronary heart disease, stroke, and cardiovascular disease.15 In contrast, findings were different for analyses in WHI Observational Study participants focused on early VMS (history of prior VMS but no VMS at WHI enrollment). In that setting, early VMS was associated with lower risk of cardiovascular disease and a lower risk for all-cause mortality.16

Presence of VMS and other menopausal symptoms has been associated with cardiovascular disease risk factors17-19 including homeostatic model assessment of insulin resistance20 and the metabolic syndrome,21 factors which are also associated with higher breast cancer risk.22,23 The association of VMS with risk factors common to both cardiovascular disease and breast cancer provides a plausible explanation for an association of persistent VMS with higher breast cancer seen in the current report. However, the mixed findings from studies regarding VMS and both breast cancer and cardiovascular disease indicate further studies are needed in larger populations with accompanying assessment of serial determination of sensitive assays of reproductive hormone levels and physiological assessments to reconcile the observational study differences. Also, it may well be that, relatively short-term VMS in the perimenopausal or early menopausal state may have different implications regarding chronic disease risk compared to conditions related to persistent VMS in the postmenopausal period.

In another context, presence or development of VMS while on adjuvant endocrine therapy in women with early stage breast cancer has been evaluated as prognostic for breast cancer outcome.24-26 Mortimer et al27 reported that women with early breast cancer using tamoxifen in the Women's Healthy Eating and Living study who had hot flashes were at lower recurrence risk. Findings were similar in the Shanghai Breast Cancer Survival Study where, in a cohort of 4,842 women with early stage breast cancer, tamoxifen use was also associated with a lower risk of recurrence only in women who developed hot flashes.28

Also in the setting of adjuvant breast cancer therapy, associations of emergent VMS and/or joint symptoms after initiation of adjuvant therapy which included tamoxifen and/or aromatase inhibitor use, with breast cancer outcome has been examined in six randomized clinical trials. In four studies,27,29-31 emergent symptoms on endocrine therapy were associated with improved outcome. However, findings differed in the National Cancer Institute of Canada Clinical Trials Group MA.27 trial in which symptoms were collected using an established questionnaire and no association with favorable clinical outcome was seen32 and Intergroup Exemestane Study investigators also reported negative findings.33 A recent meta-analysis of the six analyses in randomized trials addressing this issue concluded endocrine treatment-related symptoms significantly predicted lower recurrence rate in women with breast cancer regardless of symptom category or consideration of baseline symptoms.34

Study strengths include the large study population with 17.9-year median follow-up, the 1,399 incident invasive breast cancers verified by medical record review, information on deaths and cause of death enhanced by serial National Death Index queries, and detailed information on breast cancer risk factors. Representing a limitation are differences in baseline characteristics of women in the two VMS groups, a finding which could result in residual confounding despite adjustment in analyses for many breast cancer risk factors. Although measuring breast cancer specific mortality and breast cancer overall survival from cancer diagnosis could be considered a limitation, we feel it is appropriate since the exposure was persistent VMS which could have resulted in the characteristic or aggressiveness of breast cancers ultimately playing out following diagnosis. This hypothesis is supported by the fact that breast cancers in women with persistent VMS were more likely to have poor prognosis ER-negative cancers and the cancers were more likely to be regional or metastatic.

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CONCLUSIONS

Women with persistent VMS are more likely to be diagnosed with breast cancer than women who never experienced VMS, but not more likely to die from breast cancer. Given the mixed findings regarding VMS and breast cancer incidence and outcome, further study of this important question is needed.

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Acknowledgments

Women's Health Initiative Investigators

Program Office: (National Heart, Lung, and Blood Institute, Bethesda, MD) Jacques Roscoe, Shari Ludlum, Dale Burden, Joan McGowan, Leslie Ford, and Nancy Geller.

Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kopperberg.

Investigators and Academic Centers: (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E, Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thompson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (City of Hope National Medical Center, Duarte, CA) Rowan T. Chlebowski; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker.

A full list of all the investigators who have contributed to Women's Health Initiative science appears at: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf.

The authors thank the Women's Health Initiative investigators, staff, and the trial participants for their outstanding dedication and commitment.

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Keywords:

Breast cancer; Hot flashes; Postmenopausal women; Vasomotor symptoms; Women's Health Initiative

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© 2019 by The North American Menopause Society.