Hot Flashes, Hormone Therapy and Breast Cancer Risk in the Women's Health Initiative Clinical Trials Open Access

Ko, Charles Perry (2017)

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Background: The association of hot flashes with breast cancer risk is not clearly elucidated, although evidence suggests that their new onset with anti-estrogen therapy predicts breast cancer prognosis and that they modify the effects of dietary interventions on breast cancer risk and prognosis.

Objective: We investigated the association of baseline hot flash status with the subsequent development of invasive breast cancer (Aim 1) and assessed whether baseline hot flash status modifies the effect of estrogen plus progestin (E+P) and estrogen alone (E-alone) therapy on invasive breast cancer risk (Aim 2).

Methods: We performed a prospective analysis within the Women's Health Initiative Hormone Therapy Clinical Trials. The E+P trial included 16,608 women aged 50-79 years with an intact uterus and no history of breast cancer, and the E-alone trial 10,739 women aged 50-79 years with prior hysterectomy and no history of breast cancer. During an average follow-up of 14.4 years extending post intervention, 1,460 cases of breast cancer were diagnosed (960 in E+P and 500 in E-alone).

Results: For Aim 1, combining the trials' placebo groups, hot flash status was not associated with breast cancer risk. In adjusted models, the hazard ratio (HR) was 1.05 (95% CI 0.85-1.29) for women with mild hot flashes and 1.16 (95% CI 0.89-1.53) for women with moderate/severe symptoms, compared to women without symptoms. For Aim 2, breast cancer risk associated with E+P treatment tended to increase with higher severity of hot flashes (none: HR= 1.16, 95% CI 0.98-1.37; mild: HR= 1.19, 95% CI 0.88-1.63; moderate/severe: HR= 1.46, 95% CI 0.96-2.24); however, interactions of E+P with hot flash status categories were not statistically significant. Breast cancer risk associated with E-alone treatment did not vary significantly by hot flash status (none: HR=0.89, 95% CI 0.70-1.12; mild: HR=0.59, 95% CI 0.38-0.92; moderate/severe: HR=0.72, 95% CI 0.43-1.23; p-values for interaction terms >0.05).

Conclusions: In postmenopausal women, hot flashes did not predict breast cancer risk, and they did not modify the effect of E+P or E-alone therapy on breast cancer risk. Further studies are needed to evaluate the possibility that women with moderate/severe symptoms have a higher breast cancer risk with E+P treatment.

Table of Contents

Acknowledgement- vi

Table of Contents- vii

Chapter 1: Introduction- 1

Chapter 2: Review of the Literature- 7

I. Breast Cancer- 7

- Epidemiology- 7

- Subtypes- 7

- Etiology- 9

-- Family History and Reproductive Factors- 9

-- Hormonal Factors- 11

--- Endogenous Sex Hormones- 11

--- Postmenopausal Hormone Therapy- 12

--- Endogenous Sex Hormone, Postmenopausal Hormone Therapy and Breast Cancer Risk- 14

-- Other Risk Factors- 15

-- Differences in Etiology by Breast Cancer Subtype- 15

II. Menopause Transition and Vasomotor Symptoms- 16

III. Vasomotor Symptoms and Breast Cancer- 20

- Vasomotor Symptoms and Women's Health Outcomes- 20

- Vasomotor Symptoms and Breast Cancer Prognosis- 21

- Vasomotor Symptoms and Breast Cancer Risk- 23

IV. Limitations in the Existing Literature on Hot Flashes and Breast Cancer- 25

V. Purpose Statement and Research Questions- 25

VI. Significance Statement- 26

Chapter 3: Manuscript- 27

- Abstract- 27

- Background- 29

- Methods- 34

- Results- 43

- Discussion- 45

- Conclusion- 48

- Acknowledgements- 48

- References- 49

- Tables- 51

Chapter 4: Discussion and Recommendations- 54

References- 58

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