Abstract 127: Hormonal and reproductive risk factors for fatal breast cancer.
Authors: Poole Elizabeth M. , Eliassen A. Heather , Hankinson Susan E. , Rosner Bernard A. , Willett Walter C. , Tamimi Rulla M. , Tworoger Shelley S. 
Published: August 2014

Introduction: Although survival from breast cancer is high (5-year survival: 88%), a subset of breast cancers are ultimately fatal. Pre-diagnosis lifestyle factors may influence which patients will die due to their disease. Examining the incidence of fatal breast cancer specifically is important for elucidating these factors, because most women with breast cancer do not die of the disease, and a specific effect on aggressiveness could be missed. Thus, in the Nurses’ Health Study cohorts (NHS and NHSII), we evaluated risk factors for fatal breast cancer.

Methods: Any woman who died due to breast cancer at any time post-diagnosis was considered a fatal case. Hazards ratios (HRs) and 95% confidence intervals (CIs) for the association of reproductive and hormonal factors with incidence of fatal breast cancer were calculated using Cox proportional hazards regression. NHS and NHSII were combined using meta-analysis. Fatal and non-fatal cases were also compared for heterogeneity using competing risks analysis. For this analysis, we restricted to women who had had 15 years of post-diagnosis follow-up and defined a fatal case as any case for whom death due to breast cancer occurred within 15 years of diagnosis.

Results: We documented 1,736 fatal cases of breast cancer over 30 years of follow-up in NHS and 275 cases over 20 years of follow-up in NHSII. Similar to incidence of total breast cancer, increasing parity, younger age at first birth, and older age at menarche, and younger age at menopause tended to be associated with decreased risk of fatal breast cancer (Table). Compared to non-fatal cases, increasing age, age at first birth, age at natural menopause and time since quitting smoking were more strongly associated with fatal breast cancer than with non-fatal breast cancer(p-heterogeneity&lt;0.05).

Table. Associations between reproductive and hormonal factors and risk of fatal breast cancer in the Exposure Total cases Fatal cases HR (95% CI) HR (95% CI) N = 12,262 N = 2,011 Parity Ever Parous 1.01 (0.94–1.09) 0.87 (0.72–1.04) Number of children among parous 0.95 (0.94–0.97) 0.97 (0.94–1.00) Age at first birth (among parous women) continuous, per 5 year increase 1.15 (1.12–1.19) 1.15 (1.07–1.22) Duration of breastfeeding (among parous women), per 1 year increase 0.98* (0.92–1.04) 1.03 (0.99–1.06) Age at menarche, continuous, per 1 year increase 0.97 (0.96–0.98) 0.97 (0.94–1.00) Age at natural menopause Pre/Unknown 1.03 (0.95–1.13) 0.85 (0.70–1.04) &lt;45 0.77* (0.51–1.16) 0.71 (0.38–1.35) 45-&lt;50 0.90 (0.84–0.97) 0.96 (0.58–1.60) 50-&lt;53 1.00 (ref.) 1.00 (ref.) 53+ 1.03 (0.88–1.20) 1.05 (0.86–1.27) Oral contraceptive use Ever use 1.01 (0.96–1.05) 1.02 (0.92–1.13) Duration of use, per 5 year increase 1.03 (1.00–1.07) 1.07 (1.00–1.14) Tubal ligation 1.01 (0.96–1.06) 0.97 (0.81–1.16) Oophorectomy None 1.00 (ref.) 1.00 (ref.) 1 ovary removed 0.95 (0.88–1.04) 0.67 (0.52–0.87) both ovaries removed 0.86 (0.66–1.13) 0.95 (0.79–1.14) unknown number of ovaries removed 1.04 (0.76–1.41) 1.55 (0.89–2.72) Hysterectomy None 1.00 (ref.) 1.00 (ref.) Hysterectomy with no oophorectomy 0.96 (0.89–1.04) 0.86 (0.67–1.11) Hysterectomy with at least one ovary removed 0.80* (0.58–1.10) 0.80 (0.66–0.98) Smoking Never 1.00 (ref.) 1.00 (ref.) Former 1.07 (1.03–1.11) 0.97 (0.88–1.08) Current 1.02 (0.97–1.08) 1.02 (0.90–1.15) Time since quitting Current smoker 1.00 (ref.) 1.00 (ref.) &lt;10 years 1.06 (0.98–1.14) 0.93 (0.78–1.11) 10–19 years 1.10 (0.94–1.29) 1.10 (0.81–1.50) 20+ years 0.97 (0.86–1.09) 0.90 (0.75–1.07) Never smoker 0.96 (0.92–1.02) 0.98 (0.87–1.10) Family history of breast cancer Any 1st degree family history 1.67 (1.50–1.85) 1.47 (1.28–1.68) Per number of relatives with breast cancer 1.62 (1.45–1.80) 1.47 (1.30–1.67) All models are adjusted for age, birth index, family history of breast cancer, history of benign breast disease, BMI, alcohol intake, age at menarche, physical activity, duration of OC use, menopause status, PMH use (by type), and age at menopause *p-heterogeneity between NHS and NHSII &gt;0.05

Conclusion: Increasing age, age at first birth, and time since quitting smoking are more strongly associated with fatal breast cancer, suggesting that these factors may help predict which women are at risk of more aggressive breast cancers.

Citation Format: Elizabeth M. Poole, A. Heather Eliassen, Susan E. Hankinson, Bernard A. Rosner, Walter C. Willett, Rulla M. Tamimi, Shelley S. Tworoger. Hormonal and reproductive risk factors for fatal breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 127. doi:10.1158/1538-7445.AM2013-127