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.
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.
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).
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).
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.
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).
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.
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.
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.
1. Miller VM, Kling JM, Files JA, et al. What's in a name: “hot flashes
” a symptom of menopause or a manifestation of neurovascular dysregulation? Menopause
2. Freedman RR. Menopausal hot flashes
: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol
3. Archer DF, Sturdee DW, Baber R, et al. Menopausal hot flushes and night sweats: where are we now? Climacteric
4. Grant MD, Marbella A, Wang AT, et al. Menopausal symptoms: comparative effectiveness of therapies [Internet]. 2015; Rockville, MD: Agency for Healthcare Research and Quality (US), Report No.: 15-EHC005-EF.
5. Key T, Appleby P, Barnes I, Reeves G. Endogenous Hormones and Breast Cancer
Collaborative Group. Endogenous sex hormones and breast cancer
in postmenopausal women
: reanalysis of nine prospective studies. J Natl Cancer Inst
6. Huang Y, Malone KE, Cushing-Haugen KL, Daling JR, Li CI. Relationship between menopausal symptoms and risk of postmenopausal breast cancer
. Cancer Epidemiol Biomarkers Prev
7. Fei C, DeRoo LA, Sandler DP, Weinberg CR. Menopausal symptoms and the risk of young-onset breast cancer
. Eur J Cancer
8. Hart V, Sturgeon SR, Reich N, et al. Menopausal vasomotor symptoms
and incident breast cancer
risk in the Study of Women's Health Across the Nation. Cancer Causes Control
9. Van den Berg J, Mishra GD, Van der Schouw YT, Herber-Gast GC. Vasomotor symptoms
are not associated with the incidence of breast cancer
in a population-based cohort of middle aged women. Eur J Cancer
10. Women's Health Initiative
Study Group. Design of the Women's Health Initiative
clinical trial and observational study. Control Clin Trials
11. Anderson GL, Manson J, Wallace R, et al. Implementation of the Women's Health Initiative
study design. Ann Epidemiol
12. Curb JD, McTiernan A, Heckbert SR, et al. WHI Morbidity and Mortality Committee. Outcomes ascertainment and adjudication methods in the Women's Health Initiative
. Ann Epidemiol
13. National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: http://seer.cancer.gov/
. Accessed December 16, 2015.
14. Carpenter JS, Andrykowski MA, Freedman RR, Munn R. Feasibility and psychometrics of an ambulatory hot flash monitoring device. Menopause
15. Muka T, Oliver-Williams C, Colpani V, et al. Association of vasomotor and other menopausal symptoms with risk of cardiovascular disease: a systematic review and meta-analysis. PLoS One
16. Szmuilowicz ED, Manson JE, Rossouw JE, et al. Vasomotor symptoms
and cardiovascular events in postmenopausal women
17. Gast GC, Grobbee DE, Pop VJ, et al. Menopausal complaints are associated with cardiovascular risk factors. Hypertension
18. Franco OH, Muka T, Colpani V, et al. Vasomotor symptoms
in women and cardiovascular risk markers: Systematic review and meta-analysis. Maturitas
19. Kagitani H, Asou Y, Ishihara N, Hoshide S, Kario K. Hot flashes
and blood pressure in middle-aged Japanese women. Am J Hypertens
20. Kwon DH, Lee JH, Ryu KJ, Park HT, Kim T. Vasomotor symptoms
and the homeostatic model assessment of insulin-resistance in Korean postmenopausal women
. Obstet Gynecol Sci
21. Ryu KJ, Park HT, Kwon DH, et al. Vasomotor symptoms
and metabolic syndrome in Korean postmenopausal women
22. Braithwaite D, Tammemagi CM, Moore DH, et al. Hypertension is an independent predictor of survival disparity between African-American and white breast cancer
patients. Int J Cancer
23. Agnoli C, Grioni S, Sieri S, et al. Metabolic syndrome and breast cancer
risk: a case-cohort study nested in a multicenter Italian cohort. PLoS One
24. Byrne C, Ursin G, Martin CF, et al. Mammographic density change with estrogen and progestin therapy and breast cancer
risk. J Natl Cancer Inst
2017; 109: djx001.
25. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women
. N Engl J Med
26. Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer
in high-risk postmenopausal women
(IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet
27. Mortimer JE, Flatt SW, Parker BA, et al. Tamoxifen, hot flashes
and recurrence in breast cancer
. Breast Cancer Res Treat
28. Chen Y, Dorjgochoo T, Bao PP, et al. Menopausal symptoms among breast cancer
patients: a potential indicator of favorable prognosis. PLoS One
29. Cuzick J, Sestak I, Cella D, et al. Treatment-emergent endocrine symptoms and the risk of breast cancer
recurrence: a retrospective analysis of the ATAC trial. Lancet Oncol
30. Fontein DBY, Seynaeve C, Hadji P, et al. Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis. J Clin Oncol
31. Huober J, Cole BF, Rabaglio M, et al. Symptoms of endocrine treatment and outcome in the BIG 1-98 study. Breast Cancer Res Treat
32. Stearns V, Chapman JAW, Ma CX, et al. Treatment-associated musculoskeletal and vasomotor symptoms
and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer
aromatase inhibitor trial. J Clin Oncol
33. Mieong JS, Morden JP, Bliss JM, Coonbes RC, Van de Velde CJ. IES Steering Committee. Carpal tunnel syndrome and musculoskeletal symptoms in postmenopausal women
with early breast cancer
treated with exemestane or tamoxifen after 2-3 years of tamoxifen a retrospective analysis of the Intergroup Exemestane Study. Lancet Oncol
34. Yoo T, Jang M, Eunshin L, Moon H, Noh D, Han W. Endocrine treatment-related symptoms and patient outcome in breast cancer
: a meta-analysis. J Breast Cancer
Breast cancer; Hot flashes; Postmenopausal women; Vasomotor symptoms; Women's Health Initiative
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© 2019 by The North American Menopause Society.