In this study of 983 cancer-free women, 299 (30.4%) had non-proliferative disease, 559 (56.9%) had proliferative disease without atypia, and 125 (12.7%) had atypical hyperplasia, consistent with previously reported distributions of these BBD subtypes [29]. Distribution of different tissue types across these subtypes in our study is presented in Supplementary Table 1. The average proportion of epithelium, stroma, and fat in our study sample was 9.1% (range 0.5–52.2%), 72.4% (range 23.6–99.0%), and 18.5% (range 0-71.3%), respectively.
In our study sample, the average age at the biopsy was 42 years (range 19–58 years). A majority of the women were premenopausal at the biopsy (62.3%). The majority of women were parous (89.9% for premenopausal and 92.8% for postmenopausal) and the majority of parous women had at least two children (87.0% for premenopausal and 93.7% for postmenopausal) and breastfed for at least one month (58.8% for premenopausal and 50.4% for postmenopausal). The average age at first birth was 25 years (range 15–40 years) for premenopausal women and 25 years (range 16–37 years) for postmenopausal women. Age-adjusted characteristics of pre- and postmenopausal women in the study by nulliparous status are presented in Table 1.
Table 1
Age-adjusted characteristics of controls at the time of the biopsy
|
Premenopausal
n = 601
|
Postmenopausal
n = 290
|
Characteristic
|
Nulliparous
n = 61
|
Parous
n = 540
|
Nulliparous
n = 21
|
Parous
n = 269
|
Mean (SD)
|
|
|
|
|
% Epithelium
|
8.8 (4.8)
|
10.4 (7.0)
|
4.6 (2.8)
|
7.2 (6.1)
|
% Stroma
|
76.1 (10.3)
|
74.5 (11.0)
|
74.0 (10.7)
|
67.3 (12.6)
|
% Fat
|
15.1 (11.2)
|
15.1 (10.9)
|
21.3 (9.9)
|
25.5 (13.5)
|
% Fibroglandular tissue a
|
84.9 (11.2)
|
84.9 (10.9)
|
78.7 (9.9)
|
74.5 (13.5)
|
Age (years)b
|
36.2 (7.4)
|
41.5 (7.3)
|
55.1 (7.5)
|
57.3 (6.5)
|
Age at menarche (years)
|
13.0 (1.1)
|
12.5 (1.4)
|
12.9 (0.8)
|
12.7(1.3)
|
Age at menopause (years)
|
NA
|
NA
|
44.5 (4.9)
|
48.4 (5.1)
|
Body mass index (kg/m2)
|
24.2 (5.4)
|
24.1 (4.5)
|
24.5 (2.4)
|
25.1 (4.0)
|
Alcohol use (grams/day)
|
4.2 (4.7)
|
5.4 (8.8)
|
4.3 (3.8)
|
5.5 (8.6)
|
Parity
|
NA
|
2.7 (1.2)
|
NA
|
3.2 (1.5)
|
Age at first birth (years)
|
NA
|
25.1 (3.6)
|
NA
|
24.9 (3.2)
|
Percentages c
|
|
|
|
|
Family history of breast cancer
|
10
|
10
|
22
|
17
|
Never smoked
|
61
|
56
|
24
|
49
|
Past smoker
|
20
|
28
|
45
|
34
|
Current smoker
|
20
|
16
|
31
|
17
|
Never used PMH
|
NA
|
NA
|
12
|
29
|
Past PMH use
|
NA
|
NA
|
3
|
21
|
Current PMH use
|
NA
|
NA
|
74
|
32
|
Unknown PMH status
|
NA
|
NA
|
12
|
18
|
Breastfeeding 0-<1 month
|
NA
|
41
|
NA
|
50
|
Breastfeeding 1-<12 months
|
NA
|
32
|
NA
|
37
|
Breastfeeding 12-<24 months
|
NA
|
18
|
NA
|
10
|
Breastfeeding ≥ 24 months
|
NA
|
10
|
NA
|
3
|
BBD subtypes
Non-proliferative
Proliferative without atypia
Proliferative with atypia
|
23
70
7
|
32
58
10
|
39
45
15
|
27
55
18
|
Abbreviations: SD = standard deviation, PMH = postmenopausal hormone, NA = not applicable |
Note: Values are means (SD) and percentages and are standardized to the age distribution of the study population.a Fibroglandular tissue represents combined epithelium and stromab Value is not age adjustedc Percentages are calculated based on non-missing values |
In multivariate analysis (Table 2), being nulliparous was significantly associated with a reduced proportion of epithelium (β= -0.26, 95% Confidence Interval [CI] -0.41, -0.11) and fat tissue (β= -0.34, 95% CI -0.54, -0.13) and an increased proportion of stroma (β = 0.04, 95% CI 0.01, 0.08). Duration of breastfeeding of 24 months or longer was associated with a reduced proportion of fat (β= -0.30, 95% CI -0.54, -0.06; p-trend = 0.04). Parity was associated with a reduced proportion of stroma (β per one child = -0.01, 95% CI -0.02, -0.00; p-trend 0.02) and having a first child at age 25–29 years was associated with a larger proportion of epithelial tissue (β = 0.12, 95% CI 0.03, 0.21), though there was no clear pattern for this association. The duration of the interval between age at menarche and first birth was not associated with the proportion of any of the tissue types. None of the reproductive factors were associated with the proportion of fibroglandular tissue. The patterns of associations of the reproductive factors with tissue types were similar in the statistical analyses with secondary modeling approaches (Supplementary Tables 2 and 3). Additionally, younger age at menarche was significantly associated with smaller proportion of stroma in the logistic regression model (p-trend = 0.01) (Supplementary Table 2).
Table 2
Associations of reproductive variables with percentage of different tissue types (log-transformed) in benign breast biopsy samples
Reproductive factor
|
N
|
Tissue type
|
% Epithelial
|
% Stroma
|
% Fat
|
% Fibroglandulara
|
Nulliparityb
Nulliparous
Parous
|
86
880
|
-0.26 (-0.41; -0.11) ref
|
0.04 (0.01; 0.08)
ref
|
-0.34 (-0.54; -0.13) ref
|
0.01 (-0.02; 0.05) ref
|
Breastfeeding, monthsc
0-<1
1-<12
12-<24
≥ 24
p-trend
|
361
279
119
57
816
|
ref
0.03 (-0.07; 0.13)
0.08 (-0.05; 0.22)
0.04 (-0.15; 0.23)
0.39
|
ref
0.02 (-0.01; 0.04)
0.01 (-0.03; 0.04)
0.02 (-0.03; 0.08)
0.43
|
ref
-0.06 (-0.18; 0.07)
-0.05 (-0.22; 0.12)
-0.30 (-0.54; -0.06)
0.04
|
ref
0.01 (-0.01; 0.04)
0.01 (-0.03; 0.04)
0.03 (-0.02; 0.07)
0.34
|
Parity d
1
2
3
≥ 4
p-trend
|
82
292
269
223
866
|
ref
0.11 (-0.05; 0.27)
0.12 (-0.05; 0.28)
0.16 (-0.02; 0.33)
0.13
|
ref
-0.02 (-0.06; 0.02) -0.03 (-0.08; 0.01)
-0.05 (-0.10; -0.00)
0.02
|
ref
-0.05 (-0.25; 0.15)
0.01 (-0.19; 0.22)
0.04 (-0.18; 0.26)
0.32
|
ref
0.01 (-0.03; 0.05)
-0.01(-0.05; 0.03)
-0.02(-0.06; 0.03)
0.17
|
Parity continuous d
|
866
|
0.03 (-0.00; 0.07)
|
-0.01 (-0.02; -0.00)
|
0.01 (-0.03; 0.06)
|
-0.01 (-0.01; 0.00)
|
Age at first child’s birth e
< 25
25–29
≥ 30
p-trend
|
445
331
90
866
|
ref
0.12 (0.03; 0.21)
0.07 (-0.08; 0.23)
0.13
|
ref
-0.01 (-0.03; 0.02)
-0.03 (-0.07; 0.01)
0.16
|
ref
-0.09 (-0.20; 0.03)
-0.04 (-0.23; 0.15)
0.44
|
ref
0.01 (-0.01; 0.03)
-0.01 (-0.05; 0.03)
0.85
|
Age at first birth continuous (years) e
|
866
|
0.01 (-0.00; 0.02)
|
-0.00 (-0.00; 0.00)
|
-0.01 (-0.02; 0.01)
|
0.00 (-0.00; 0.00)
|
Age at menarche f
< 12
12
13
> 13
p-trend
|
176
275
287
228
966
|
-0.09 (-0.22; 0.04)
-0.13 (-0.24; -0.01)
-0.06 (-0.17; 0.05)
ref
0.07
|
-0.01 (-0.05; 0.02)
-0.04 (-0.07; -0.01)
-0.03 (-0.06; -0.00)
ref
0.23
|
0.07 (-0.12; 0.25)
0.10 (-0.06; 0.26)
-0.01 (-0.17; 0.15)
ref
0.24
|
-0.01 (-0.05; 0.02)
-0.05 (-0.07; -0.02)
-0.03 (-0.05; -0.00)
ref
0.11
|
Age at menarche continuous (years) f
|
966
|
0.03 (-0.00, 0.06)
|
0.00 (-0.00, 0.01)
|
-0.02 (-0.07, 0.02)
|
0.01 (-0.00, 0.01)
|
Time between menarche and age at first birth, continuous (years) g
|
866
|
0.00 (-0.01; 0.02)
|
-0.00 (-0.00; 0.00)
|
-0.00 (-0.02; 0.01)
|
-0.00 (-0.00; 0.00)
|
a Fibroglandular tissue represents combined epithelium and stroma |
b Adjusted for age (continuous), BMI (continuous), age at menarche (< 12, 12, 13, > 13), a family history of breast cancer (Yes/No), menopausal status/postmenopausal hormone use (premenopausal, postmenopausal/no hormones, postmenopausal/past hormones, postmenopausal/current hormones, postmenopausal/unknown hormone use status), NHS cohort (NHSI, NHSII), and alcohol use (none, > 0-<5, ≥ 5 g/day) |
c Among parous women only: adjusted for age (continuous), BMI (continuous), race (White, other), age at menarche (< 12, 12, 13, > 13), parity, age at first child’s birth, a family history of breast cancer (Yes/No), menopausal status/postmenopausal hormone use (premenopausal, postmenopausal/no hormones, postmenopausal/past hormones, postmenopausal/current hormones, postmenopausal/unknown hormone use status), NHS cohort (NHSI, NHSII), and alcohol use (none, > 0-<5, ≥ 5 g/day) |
d Among parous women only: adjusted for age (continuous), BMI (continuous), age at first birth, age at menarche (< 12, 12, 13, > 13), a family history of breast cancer (Yes/No), menopausal status/postmenopausal hormone use (premenopausal, postmenopausal/no hormones, postmenopausal/past hormones, postmenopausal/current hormones, postmenopausal/unknown hormone use status), NHS cohort (NHSI, NHSII), and alcohol use (none, > 0-<5, ≥ 5 g/day) |
e Among parous women only: adjusted for age (continuous), BMI (continuous), parity, age at menarche (< 12, 12, 13, > 13), a family history of breast cancer (Yes/No), menopausal status/postmenopausal hormone use (premenopausal, postmenopausal/no hormones, postmenopausal/past hormones, postmenopausal/current hormones, postmenopausal/unknown hormone use status), NHS cohort (NHSI, NHSII), and alcohol use (none, > 0-<5, ≥ 5 g/day) |
f Adjusted for age (continuous), BMI (continuous), parous status (nulliparous, parous), a family history of breast cancer (Yes/No), menopausal status/postmenopausal hormone use (premenopausal, postmenopausal/no hormones, postmenopausal/past hormones, postmenopausal/current hormones, postmenopausal/unknown hormone use status), NHS cohort (NHSI, NHSII), and alcohol use (none, > 0-<5, ≥ 5 g/day) |
g Among parous women only: adjusted for age (continuous), BMI (continuous), parity, a family history of breast cancer (Yes/No), menopausal status/postmenopausal hormone use (premenopausal, postmenopausal/no hormones, postmenopausal/past hormones, postmenopausal/current hormones, postmenopausal/unknown hormone use status), NHS cohort (NHSI, NHSII), and alcohol use (none, > 0-<5, ≥ 5 g/day) |
Among premenopausal women (Table 3), being nulliparous was associated with a greater proportion of stroma (β = 0.06, 95% CI 0.02, 0.10) and smaller proportion of epithelium (β= -0.22, 95% CI -0.38, -0.06) and fat (β= -0.32, 95% CI -0.56, -0.08). Greater parity and older age at first birth were both associated with a greater proportion of epithelium and a smaller proportion of stroma. The duration of the interval between age at menarche and first birth was not associated with the proportion of any of the tissue types. These patterns of associations were similar with the secondary modeling approaches (Supplementary Tables 4 and 5). Additionally, we observed a marginally significant inverse association of the interval between age at menarche and age at first birth with the proportion of stroma in proc glimmix models (Odds Ratio = 0.99, 95% CI 0.98, 1.00) (Supplementary Table 5).
Table 3. Associations of reproductive variables with percentage of different tissue types (log-transformed) in benign breast biopsy samples of premenopausal women
Reproductive factor
|
N
|
Tissue type
|
% Epithelial
|
% Stroma
|
% Fat
|
% Fibroglandulara
|
Nulliparityb
Nulliparous
Parous
|
61
540
|
-0.22 (-0.38; -0.06) ref
|
0.06 (0.02; 0.10) ref
|
-0.32 (-0.56; -0.08) ref
|
0.03 (-0.01; 0.06) ref
|
Breastfeeding, monthsc
0-<1
1-<12
12-<24
≥24
p-trend
|
210
162
92
47
511
|
ref
-0.06 (-0.18; 0.06)
-0.02 (-0.17; 0.13)
-0.09 (-0.30; 0.11)
0.53
|
ref
0.04 (0.01; 0.07)
0.01 (-0.03; 0.06)
0.04 (-0.02; 0.09)
0.33
|
ref
-0.11 (-0.28; 0.06)
-0.02 (-0.24; 0.19)
-0.18 (-0.48; 0.11)
0.39
|
ref
0.03 (-0.00; 0.05)
0.00 (-0.03; 0.04)
0.02 (-0.02; 0.07)
0.57
|
Parity d
1
2
3
≥4
p-trend
|
62
190
167
108
527
|
ref
0.27 (0.10; 0.44)
0.25 (0.08; 0.43)
0.34 (0.14; 0.53)
0.01
|
ref
-0.02 ( -0.07; 0.03)
-0.04 (-0.09; 0.01)
-0.06 (-0.11; -0.00)
0.02
|
ref
-0.17 (-0.42; 0.07)
-0.03 (-0.29; 0.22)
0.03 (-0.25; 0.30)
0.25
|
ref
0.02 (-0.02; 0.06)
-0.00 (-0.04; 0.04)
-0.01 (-0.05; 0.04)
0.23
|
Parity continuous d
|
527
|
0.07 (0.02; 0.11)
|
-0.02 (-0.03; -0.00)
|
0.03 (-0.03; 0.10)
|
-0.01 (-0.02; 0.00)
|
Age at first child’s birth e
<25
25-29
≥30
p-trend
|
263
205
59
527
|
ref
0.20 (0.10; 0.31)
0.23 (0.06; 0.40)
<0.01
|
ref
-0.01 (-0.04; 0.02)
-0.05 (-0.10; -0.00)
0.05
|
ref
-0.19 (-0.34; -0.03)
0.01 (-0.24; 0.26)
0.58
|
ref
0.02 (-0.01; 0.04)
-0.01 (-0.05; 0.03)
0.99
|
Age at first birth continuous (years) e
|
527
|
0.02 (0.01; 0.03)
|
-0.00 (-0.01; 0.00)
|
-0.01 (-0.03; 0.01)
|
0.00 (-0.00; 0.00)
|
Age at menarche f
<12
12
13
>13
p-trend
|
115
174
187
125
601
|
-0.10 (-0.25; 0.06)
-0.14 (-0.28; -0.00)
-0.01 (-0.14; 0.13) ref
0.06
|
-0.01 (-0.05; 0.03)
-0.03 (-0.06; 0.01)
-0.02 (-0.05; 0.02)
ref
0.61
|
0.10 (-0.13; 0.33)
0.07 (-0.14; 0.28)
-0.02 (-0.22; 0.18) ref
0.24
|
-0.02 (-0.05; 0.02)
-0.03 (-0.07; -0.00)
-0.01 (-0.04; 0.02)
ref
0.14
|
Age at menarche continuous (years) f
|
601
|
0.03 (-0.00, 0.07)
|
0.00 (-0.01, 0.01)
|
-0.03 (-0.08, 0.03)
|
0.01 (-0.00, 0.01)
|
Time between menarche and age at first birth, continuous (years) g
|
527
|
0.01 (-0.00; 0.03)
|
-0.00 (-0.01; 0.00)
|
-0.00 (-0.02; 0.02)
|
0.00 (-0.00; 0.00)
|
a Fibroglandular tissue represents combined epithelium and stroma
b Adjusted for age (continuous), BMI (continuous), age at menarche (<12, 12, 13, >13), a family history of breast cancer (Yes/No), NHS cohort (NHSI, NHSII), and alcohol use (none, >0-<5, ≥5 g/day)
c Among parous women only: adjusted for age (continuous), BMI (continuous), race (White, other), age at menarche (<12, 12, 13, >13), parity, age at first child’s birth, a family history of breast cancer (Yes/No), NHS cohort (NHSI, NHSII), and alcohol use (none, >0-<5, ≥5 g/day)
d Among parous women only: adjusted for age (continuous), BMI (continuous), age at first birth, age at menarche (<12, 12, 13, >13), a family history of breast cancer (Yes/No), NHS cohort (NHSI, NHSII), and alcohol use (none, >0-<5, ≥5 g/day)
e Among parous women only: adjusted for age (continuous), BMI (continuous), parity, age at menarche (<12, 12, 13, >13), a family history of breast cancer (Yes/No), NHS cohort (NHSI, NHSII), and alcohol use (none, >0-<5, ≥5 g/day)
f Adjusted for age (continuous), BMI (continuous), parous status (nulliparous, parous), a family history of breast cancer (Yes/No), NHS cohort (NHSI, NHSII), and alcohol use (none, >0-<5, ≥5 g/day)
g Among parous women only: adjusted for age (continuous), BMI (continuous), parity, a family history of breast cancer (Yes/No), NHS cohort (NHSI, NHSII), and alcohol use (none, >0-<5, ≥5 g/day)