Circulating Steroid Hormone Levels and Risk of Breast Cancer for Postmenopausal Women

Laura Baglietto; Gianluca Severi; Dallas R. English; Kavitha Krishnan; John L. Hopper; Catriona McLean; Howard A. Morris; Wayne D. Tilley; Graham G. Giles

doi:10.1158/1055-9965.EPI-09-0532

DOI: 10.1158/1055-9965.EPI-09-0532 Published February 2010

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Table 1.

Characteristics and hormone levels of subjects (cases and subcohort) at baseline

		Breast cancer cases*	Subcohort
		n = 197	n = 857
Age, y; mean, SD (range)		62, 5 (48-70)	61, 6 (46-70)
Country of birth, n (%)	Australia/New Zealand	144 (73.1)	569 (66.4)
	United Kingdom	9 (4.6)	47 (5.5)
	Italy	26 (13.2)	134 (15.6)
	Greece	18 (9.1)	107 (12.5)
Age at menarche, n (%)	Less than 12 y	27 (13.7)	109 (12.7)
	12 y	35 (17.8)	160 (18.7)
	13 y	56 (28.4)	217 (25.3)
	14 y or more	79 (40.1)	371 (43.3)
Parity and age at first pregnancy (live birth or gestation >24 wk), n (%)	Nulliparous	30 (15.2)	100 (11.7)
	1 and <25	5 (2.5)	15 (1.8)
	>1 and <25	75 (38.1)	358 (41.8)
	1 and ≥25	11 (5.6)	52 (6.1)
	>1 and ≥25	76 (38.6)	332 (38.7)
Lactation, n (%)	Never	63 (32.0)	214 (25.0)
	Up to 6 mo	35 (17.8)	184 (21.5)
	7-12 mo	32 (16.2)	147 (17.2)
	13-24 mo	43 (21.8)	173 (20.2)
	>24 mo	24 (12.2)	139 (16.2)
Oral contraceptive use, n (%)	Never user	123 (62.4)	492 (57.4)
Oral contraceptive use, n (%)	Past user	74 (37.6)	365 (42.6)
HRT use, n(%)	Never user	174 (88.3)	760 (88.7)
HRT use, n(%)	Past user	23 (11.7)	97 (11.3)
Physical activity, n (%)	None	38 (19.3)	182 (21.2)
	Low	45 (22.8)	176 (20.5)
	Medium	78 (39.6)	341 (39.8)
	High	36 (18.3)	158 (18.4)
Alcohol, n (%)	Abstainers	89 (45.2)	403 (47.0)
	Exdrinkers	6 (3.0)	31 (3.6)
	1-19 g/d	82 (41.6)	339 (39.6)
	20-39 g/d	14 (7.1)	69 (8.1)
	40 g/d or more	6 (3.0)	15 (1.8)
Smoking, n (%)	Never	150 (76.1)	612 (71.4)
	Current	11 (5.6)	74 (8.6)
	Past	36 (18.3)	171 (20.0)
Education, n (%)	Primary school	46 (23.4)	247 (28.8)
	Some high school	98 (49.7)	378 (44.1)
	Completed high school	33 (16.8)	130 (15.2)
	Degree/diploma	20 (10.2)	102 (11.9)
BMI (kg/m²); mean, SD		27.7, 4.7	27.3, 4.7
Energy from diet (MJ/d); mean, SD		8.3, 2.7	8.5, 2.9
Hormones and SHBG, median (interquartile range)^†
Total estradiol (pmol/L)		57.00 (46.00-74.00)	57.00 (45.35-71.00)
Free estradiol (pmol/L)		0.87 (0.63-1.13)	0.80 (0.60-1.05)
Estrone sulfate (nmol/L)		3.22 (2.29-4.41)	2.95 (2.15-4.03)
Testosterone (nmol/L)		0.70 (0.50-1.10)	0.70 (0.50-1.10)
DHEAS (μmol/L)		1.50 (1.00-2.30)	1.50 (0.90-2.40)
Androstenedione (nmol/L)		2.19 (1.60-3.17)	2.16 (1.41-3.06)
SHBG (nmol/L)		43.10 (32.90-57.30)	51.10 (38.55-67.80)

↵*Nineteen breast cancer cases were also in the subcohort.
↵^†The number of missing measures among cases and in the subcohort were as follows: 2 and 15 for total estradiol, 2 and 16 for free estradiol, 5 and 16 for estrone sulfate, 1 and 4 for testosterone, 0 and 3 for DHEAS, 1 and 3 for androstenedione, 0 and 1 for SHBG.

Table 2.

HRs and 95% CIs of breast cancer by quartiles of steroid hormone levels

	Quartiles*				Doubling hormone concentration^†	P_trend^‡
	Q1	Q2	Q3	Q4	Doubling hormone concentration^†	P_trend^‡
Total estradiol
Cases/PY^§	39/1,950	47/1,946	49/1,917	60/1,904
HR (95% CI)	Reference	1.09 (0.66-1.79)	1.21 (0.74-1.99)	1.44 (0.89-2.35)	1.45 (0.91-2.30)	0.12
Free estradiol
Cases/PY^§	37/1,934	39/1,948	53/1,904	66/1,923
HR (95% CI)	Reference	1.05 (0.62-1.77)	1.49 (0.90-2.44)	1.75 (1.06-2.89)	1.61 (1.12-2.33)	0.01
Estrone sulfate
Cases/PY^§	35/1,954	48/1,914	43/1,939	66/1,898
HR (95% CI)	Reference	1.53 (0.93-2.52)	1.20 (0.71-2.03)	2.05 (1.24-3.37)	1.52 (1.11-2.07)	<0.01
Testosterone
Cases/PY^§	45/2,007	47/1,934	48/1,930	56/1,946
HR (95% CI)	Reference	1.09 (0.68-1.74)	1.10 (0.68-1.78)	1.25 (0.78-2.01)	1.11 (0.88-1.40)	0.37
DHEAS
Cases/PY^§	45/1,984	47/1,940	44/1,957	61/1,948
HR (95% CI)	Reference	1.06 (0.65-1.74)	1.06 (0.64-1.73)	1.41 (0.88-2.27)	1.15 (0.94-1.42)	0.17
Androstenedione
Cases/PY^§	36/1,958	49/1,944	56/1,950	55/1,970
HR (95% CI)	Reference	1.39 (0.85-2.28)	1.66 (1.03-2.69)	1.49 (0.91-2.44)	1.24 (0.97-1.57)	0.08
SHBG
Cases/PY^§	79/1,985	51/1,960	36/1,940	31/1,955
HR (95% CI)	Reference	0.57 (0.37-0.88)	0.38 (0.24-0.61)	0.33 (0.19-0.55)	0.41 (0.29-0.60)	<0.01

NOTE: HRs from the Cox model were adjusted for country of birth, age at menarche, parity and age at first pregnancy, duration of lactation, oral contraceptive use, HRT use, alcohol consumption, energy from diet, smoking, BMI, level of education, and level of physical activity. Estimates were based on the following number of women (cases): total estradiol, 1,019 (195); free estradiol, 1,018 (195); estrone sulfate, 1,014 (192); testosterone, 1,031 (196); DHEAS, 1,032 (197); androstenedione, 1,031 (196); SHBG, 1,034 (197).

↵*Quartiles were adjusted for variations between batches and by age at time of blood collection, according to the procedure described in the method section.
↵^†Estimates from the model including the pseudocontinuous variable log₂ transformed.
↵^‡Test for linear trend using the pseudocontinuous variable log₂ transformed.
↵^§Breast cancer cases and person-years (PY).

Table 3.

HRs (95% CIs in parentheses) of breast cancer associated with a doubling of hormone levels in relation to tumor characteristics

ER status	HR (95% CI)*	P^†	PR status	HR (95% CI)*	P^†	ER/PR status	HR (95% CI)*	P^†
Total estradiol
ER+	1.46 (0.86-2.48)	0.79	PR+	1.52 (0.82-2.81)	1.00	ER+/PR+	1.68 (0.90-3.14)	0.69
ER−	1.67 (0.70-3.99)		PR−	1.52 (0.80-2.89)		ER+/PR−	1.23 (0.54-2.82)
						ER−/PR−	2.02 (0.82-4.96)
Free estradiol
ER+	1.69 (1.11-2.56)	1.00	PR+	1.99 (1.21-3.28)	0.34	ER+/PR+	2.29 (1.38-3.79)	0.16
ER−	1.69 (0.87-3.25)		PR−	1.46 (0.90-2.39)		ER+/PR−	1.13 (0.60-2.13)
						ER−/PR−	2.12 (1.07-4.19)
Estrone sulfate
ER+	1.38 (0.96-2.00)	0.50	PR+	1.54 (0.99-2.41)	0.74	ER+/PR+	1.55 (0.99-2.43)	0.59
ER−	1.70 (0.99-2.91)		PR−	1.41 (0.93-2.11)		ER+/PR−	1.20 (0.69-2.07)
						ER−/PR−	1.74 (1.00-3.00)
Testosterone
ER+	1.14 (0.86-1.50)	0.53	PR+	1.09 (0.78-1.53)	0.95	ER+/PR+	1.14 (0.81-1.60)	0.92
ER−	0.99 (0.66-1.47)		PR−	1.11 (0.82-1.49)		ER+/PR−	1.17 (0.79-1.73)
						ER−/PR−	1.05 (0.70-1.58)
DHEAS
ER+	1.09 (0.86-1.39)	0.86	PR+	1.22 (0.93-1.60)	0.27	ER+/PR+	1.22 (0.92-1.60)	0.44
ER−	1.13 (0.77-1.67)		PR−	1.00 (0.74-1.34)		ER+/PR−	0.91 (0.62-1.34)
						ER−/PR−	1.12 (0.74-1.69)
Androstenedione
ER+	1.27 (0.96-1.68)	0.64	PR+	1.27 (0.91-1.76)	0.75	ER+/PR+	1.29 (0.92-1.80)	0.92
ER−	1.14 (0.73-1.76)		PR−	1.18 (0.85-1.64)		ER+/PR−	1.23 (0.80-1.87)
						ER−/PR−	1.15 (0.73-1.82)
SHBG
ER+	0.41 (0.27-0.63)	0.85	PR+	0.33 (0.19-0.56)	0.18	ER+/PR+	0.30 (0.17-0.51)	0.11
ER−	0.44 (0.23-0.83)		PR−	0.51 (0.32-0.81)		ER+/PR−	0.64 (0.35-1.14)
						ER−/PR−	0.37 (0.19-0.71)

NOTE: Estimates from the Cox's model including the pseudocontinuous variable log₂ transformed and fitted using a data duplication method. All estimates were adjusted for country of birth, age at menarche, parity and age at first pregnancy, duration of lactation, oral contraceptive use, HRT use, alcohol consumption, energy from diet, smoking, BMI, level of education, and physical activity.

↵*Estimates from the model including the pseudocontinuous variable log₂ transformed.
↵^†Test for heterogeneity in HRs between groups.

Table 4.

HRs and 95% CIs of breast cancer for a doubling of hormone concentration by attained age during follow-up

	HR (95% CI)*	P_trend^†	P^‡
Total estradiol
<65 y	1.14 (0.55-2.37)	0.72	0.59
65-69 y	1.40 (0.64-3.04)	0.40
>69 y	1.93 (0.93-4.01)	0.08
Free estradiol
<65 y	1.27 (0.73-2.21)	0.40	0.48
65-69 y	2.00 (1.10-3.66)	0.02
>69 y	1.75 (0.98-3.15)	0.06
Estrone sulfate
<65 y	1.34 (0.84-2.14)	0.22	0.20
65-69 y	1.16 (0.68-1.96)	0.58
>69 y	2.10 (1.28-3.44)	<0.01
Testosterone
<65 y	0.92 (0.66-1.29)	0.65	0.01
65-69 y	0.83 (0.55-1.25)	0.37
>69 y	1.70 (1.16-2.48)	<0.01
DHEAS
<65 y	1.05 (0.76-1.45)	0.75	<0.01
65-69 y	0.79 (0.55-1.13)	0.20
>69 y	1.74 (1.26-2.42)	<0.01
Androstenedione
<65 y	1.03 (0.74-1.45)	0.85	0.02
65-69 y	0.92 (0.61-1.39)	0.70
>69 y	1.91 (1.26-2.88)	<0.01
SHBG
<65 y	0.59 (0.35-0.98)	0.04	0.07
65-69 y	0.25 (0.13-0.46)	<0.01
>69 y	0.43 (0.24-0.76)	<0.01

NOTE: HRs from the Cox model were obtained by splitting the data into the specified age bands and fitting an interaction of hormones with age band. All estimates were adjusted for country of birth, age at menarche, parity and age at first pregnancy, duration of lactation, oral contraceptive use, HRT use, alcohol consumption, energy from diet, smoking, BMI, level of education, and physical activity.

↵*Estimates from the model including the pseudocontinuous variable log₂ transformed.
↵^†Test for linear trend using the pseudocontinuous variable log₂ transformed.
↵^‡Test for heterogeneity in HRs for hormone concentration (pseudocontinuous log₂ transformed) in the three age groups.

Table 5.

HRs and 95% CIs (in parentheses) for breast cancer associated with a doubling in androgen level with and without adjustment for estrogens

	Unadjusted	Adjusted for
	Unadjusted	Total estradiol	Estrone sulfate
Testosterone
All	1.11 (0.88-1.40)	1.04 (0.81-1.35)	0.92 (0.68-1.23)
<65 y	0.92 (0.66-1.29)	0.89 (0.59-1.33)	0.75 (0.45-1.23)
65-69 y	0.83 (0.55-1.25)	0.73 (0.47-1.14)	0.71 (0.44-1.16)
>69 y	1.70 (1.16-2.48)	1.63 (1.09-2.43)	1.36 (0.88-2.11)
DHEAS
All	1.15 (0.94-1.42)	1.12 (0.91-1.39)	0.98 (0.76-1.27)
<65 y	1.05 (0.76-1.45)	1.04 (0.74-1.44)	0.92 (0.61-1.38)
65-69 y	0.79 (0.55-1.13)	0.75 (0.52-1.08)	0.65 (0.43-0.99)
>69 y	1.74 (1.26-2.42)	1.68 (1.20-2.34)	1.50 (0.99-2.27)
Androstenedione
All	1.24 (0.97-1.57)	1.17 (0.91-1.50)	1.08 (0.81-1.44)
<65 y	1.03 (0.74-1.45)	1.01 (0.69-1.46)	0.90 (0.57-1.43)
65-69 y	0.92 (0.61-1.39)	0.83 (0.55-1.28)	0.85 (0.54-1.34)
>69 y	1.91 (1.26-2.88)	1.80 (1.19-2.73)	1.60 (1.00-2.54)

NOTE: All estimates were from the Cox's regression model including the pseudocontinuous variable log₂ transformed and adjusted for country of birth, age at menarche, parity and age at first pregnancy, duration of lactation, oral contraceptive use, HRT use, alcohol consumption, energy from diet, smoking, BMI, level of education, and physical activity.