Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies

Abstract

Background: Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.

Methods: Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.

Findings: Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons).

Interpretation: The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.

Funding: Cancer Research UK.

Figure 1

Cumulative distribution of (A) age at menarche and (B) age at natural menopause Data are for women without breast cancer—ie, controls. Results for age at menarche are based on data from 306 068 women. Results for age at menopause are based on data from 157 272 postmenopausal women aged older than 55 years at the time of reporting their age at menopause.

Figure 2

Correlates of various factors with (A) early menarche and (B) late natural menopause Data are for women without breast cancer—ie, controls. OR calculations were stratified by study and, where appropriate, by age at diagnosis, year of birth, parity, age at first birth, smoking, alcohol consumption, height, and current BMI (results for BMI as a young adult are not stratified by current BMI). Results for age at menopause are restricted to postmenopausal women without breast cancer aged 55 years or older at the time they reported their age at menopause. OR=odds ratio. gs=group specific. BMI=body-mass index.

Figure 3

Relative risk of breast cancer by (A) age at menarche and (B) age at menopause Calculated stratifying by study, age, year of birth, parity, age at first birth, smoking, alcohol consumption, height, and current body-mass index. RR=relative risk. gs=group specific.

Figure 4

Relative risk of breast cancer (A) per year younger at menarche and (B) per year older at menopause, in various subgroups and by tumour characteristics Relative risks are calculated stratifying by study and age, and where appropriate, by year of birth, parity, age at first birth, smoking, alcohol consumption, height, and current BMI (results for BMI as a young adult are not stratified by current BMI). RR=relative risk. BMI=body-mass index. ER=oestrogen receptor. *Subgroup analyses for age at menarche are for age at menopause <50 vs ≥50 years in postmenopausal women; and for age at menopause are for age at menarche <13 vs ≥13 years. †Case-case comparisons stratified by study, age and year of birth, and adjusted by parity, age at first birth, smoking, alcohol consumption, height, and current BMI.

Figure 5

Hormone concentrations and breast cancer risk at around the time of the menopause (A) Circulating oestradiol concentrations, in the years before and after menopause, calculated from published data. (B) RR of breast cancer in women aged 45–54 years, by menopausal status. (C) RR of breast cancer in women aged 45–54 years by menopausal status and current BMI. RRs stratified by study, age at diagnosis in single years, year of birth, parity, age at first birth, smoking, alcohol consumption, height, and current BMI. RR=relative risk. gs=group specific. BMI=body-mass index. *Results for breast cancer risk are plotted against the time between menopause and the diagnosis of breast cancer for postmenopausal women, and against an estimate of that time for premenopausal and perimenopausal women. The postmenopausal women aged 45–54 years in these analyses reported that their menopause had occurred 4·6 years previously, on average. The premenopausal women aged 45–54 years in these analyses would be expected to reach their menopause in the next 2·7 years, on average (this estimate is based on the age distribution of the premenopausal women in these analyses and the age distribution of women's ages at menopause shown in figure 1B). Perimenopausal women might be expected to reach their menopause in the next 6 months, on average.

Figure 6

Breast cancer by tumour characteristics and by women's age and menopausal status (A) Oestrogen receptor-positive (ER+). (B) Lobular histology. Results are shown for age groups <40 years, 40–44 years, 45–54 years, 55–59 years, 60–64 years, and ≥65 years, and plotted against the mean age of women with breast cancer in each age group.