Association of Hormone-Related Characteristics and Breast Cancer Risk by Estrogen Receptor/Progesterone Receptor Status in the Shanghai Breast Cancer Study

Abstract

Etiologic differences between subtypes of breast cancer defined by estrogen receptor (ER) and progesterone receptor (PR) status are not well understood. The authors evaluated associations of hormone-related factors with breast cancer subtypes in a population-based case-control study involving 1,409 ER-positive (ER+)/PR-positive (PR+) cases, 712 ER-negative (ER−)/PR-negative (PR−) cases, 301 ER+/PR− cases, 254 ER−/PR+ cases, and 3,474 controls aged 20–70 years in Shanghai, China (phase I, 1996–1998; phase II, 2002–2005). Polytomous logistic regression and Wald tests for heterogeneity across subtypes were conducted. Breast cancer risks associated with age at menarche, age at menopause, breastfeeding, age at first livebirth, waist-to-hip ratio, and oral contraceptive use did not differ by hormone receptor status. Among postmenopausal women, higher parity (≥2 children vs. 1) was associated with reduced risk (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.52, 0.91) and higher body mass index (BMI; weight (kg)/height (m)²) with increased risk (highest quartile: OR = 2.40, 95% CI: 1.65, 3.47) of the ER+/PR+ subtype but was unrelated to the ER−/PR− subtype (for parity, P_{heterogeneity} = 0.02; for BMI, P_{heterogeneity} < 0.01). Hormone replacement therapy (OR = 2.25, 95% CI: 1.40, 3.62) and alcohol consumption (OR = 1.59, 95% CI: 1.01, 2.51) appeared to be preferentially associated with the ER+/PR− subtype. These findings indicate that BMI, parity, hormone replacement therapy, and alcohol consumption may play different roles in subtypes of breast cancer. More research is needed to better understand the etiology of 2 relatively rare subtypes, ER+/PR− tumors and ER−/PR+ tumors.

Epidemiologic and biologic evidence suggests a pivotal role for estrogen and progesterone in the development of breast cancer. The effects of these hormones are mediated by their respective receptors, estrogen receptor (ER) and progesterone receptor (PR). ER and PR status are biologic markers considered to be a crucial factor in treatment recommendations (1). Furthermore, it has been hypothesized that hormone-related risk factors that reflect exposure to estrogen and progesterone may be predominantly associated with breast tumors that express ER and PR but not with tumors that are hormone receptor-negative (2–4). Given the evidence for differential associations, it is important to take into account the ER/PR status of breast tumors with respect to risk and prognosis prediction and therapeutic decision-making.

In a systematic review of publications on the etiology of hormone receptor-defined breast cancer, Althuis et al. (5) concluded in 2004 that nulliparity, later age at first livebirth, and early age at menarche were associated with increased risk of ER-positive (ER+) tumors but not ER-negative (ER−) tumors. Althuis et al. also reported that postmenopausal obesity was more consistently associated with an increased risk of ER+/PR-positive (PR+) tumors compared with ER−/PR-negative (PR−) tumors. Another meta-analysis published in 2006 (6) suggested that each birth reduced the risk of ER+/PR+ cancer by 11% (relative risk = 0.89, 95% confidence interval (CI): 0.84, 0.94) and that women who were older at the time of their first birth had a greater risk of ER+/PR+ cancer than women whose first livebirth occurred at a younger age (relative risk = 1.27, 95% CI: 1.07, 1.50). Neither parity nor age at first birth was associated with the risk of ER−/PR− cancer (6). The protective effects of longer duration of breastfeeding and later age at menarche did not differ by ER/PR status (6). Recent studies have also found that the associations of some hormone-related factors with breast cancer risk, such as parity, age at first livebirth, age at menarche, and obesity, differed by ER/PR status (3, 7–9). However, inconsistent results have also been reported (10, 11). Although most previous studies have included a large number of ER+/PR+ breast cancer patients, only a few have included a sizable number (n = 500) of ER−/PR− patients. Sample sizes for patients with ER+/PR− and ER−/PR+ cancer are even smaller, yielding limited evidence for these 2 subtypes of breast cancer.

Results on breast cancer risk factors among subgroups defined by ER/PR status have been predominantly derived from studies of Western populations, and few studies have been conducted among other racial or ethnic groups. It has been suggested that ER/PR status varies significantly across racial/ethnic groups, and Chinese women are more often diagnosed with hormone receptor-negative tumors than Caucasian women (12, 13). However, few studies have investigated etiologic differences for subtypes of breast cancer among Chinese women (14, 15). In this study, we conducted a comprehensive evaluation of hormone-related breast cancer risk factors among breast cancer subgroups defined by ER/PR status, using data from the Shanghai Breast Cancer Study.

MATERIALS AND METHODS

Study population

The Shanghai Breast Cancer Study is a large, population-based case-control study of 3,443 cases and 3,474 controls being conducted in Shanghai, China. The study had 2 phases of recruitment, phase I (August 1996–March 1998) and phase II (April 2002–February 2005). The study design has been described in detail elsewhere (16). Briefly, eligible breast cancer patients were identified through a rapid case ascertainment system based on the population-based Shanghai Cancer Registry. All participants were permanent residents of urban Shanghai, were between 20 and 70 years of age, and had no prior history of cancer. Controls were randomly selected from the general female population using the Shanghai Resident Registry and were frequency-matched to cases on age distribution in 5-year groups. In phase I of the study, 1,455 (90.8%) cases and 1,556 (90.3%) controls were recruited, and in phase II, 1,988 (83.2%) cases and 1,918 (70.4%) controls were recruited. All participants in the study provided written informed consent, and the study protocol was approved by the institutional review boards of all participating study institutions.

Data collection

In-person interviews were conducted by trained interviewers using a structured questionnaire to collect information on demographic characteristics, family history of cancer, detailed menstrual and reproductive history, use of oral contraceptives, use of hormone replacement therapy (HRT), behavioral and dietary habits, and regular physical exercise during the 10 years preceding the interview. Current weight, waist and hip circumferences, and sitting and standing heights were measured. Body mass index (BMI; weight (kg)/height (m)²) and waist-to-hip ratio (WHR) were computed from these measurements.

We reviewed medical and pathology records from the hospital where patients were originally diagnosed to obtain information on the ER and PR status of cases, which was primarily measured by the immunohistochemical method. Among patients whose ER/PR status could not be obtained from medical charts, tumor slides were available for 299. For these 299 patients, ER and PR status was evaluated by the Vanderbilt Molecular Epidemiology Laboratory using a double immunohistochemical staining method. Of the total of 3,443 cases, data on ER status were available for 2,700 (78.4%) cases, PR status for 2,679 (77.8%) cases, and joint ER/PR status for 2,676 (77.7%) cases.

Data analysis

Patients were grouped into the following joint categories: ER+/PR+ (receptor-positive), ER−/PR− (receptor-negative), ER+/PR−, and ER−/PR+. Analysis of variance and Pearson χ² tests were used to compare differences in continuous and categorical variables in the frequency distributions between cases and controls and across case subgroups.

Multiple polytomous unconditional logistic regression analysis was used to calculate odds ratios and corresponding 95% confidence intervals for hormone-related factors in association with breast cancer case subtypes (ER+/PR+, ER−/PR−, ER+/PR−, and ER−/PR+). Included in the models were the following variables: age at diagnosis for cases and age at interview for controls (years; continuous variable), educational level (college or above, senior high school, junior high school, or elementary school or below), first-degree family history of breast cancer (yes, no), history of breast fibroadenoma (yes, no), regular physical exercise during the 10 years preceding the interview (at least twice a week; yes, no), BMI, WHR, years of menstruation, history of livebirth (never, ever), parity, and study phase (I, II). For premenopausal women, total years of menstruation were calculated by taking age at diagnosis (cases) or interview (controls) and subtracting age at menarche. For postmenopausal women, total years of menstruation were calculated by taking age at menopause and subtracting age at menarche. We also extended our analysis and stratified the results by the menopausal status of participants, because risk factor profiles for breast cancer may differ between pre- and postmenopausal women.

Tests for trend were conducted by fitting ordinal values corresponding to exposure categories. We used multivariable polytomous unconditional logistic regression to conduct Wald tests to evaluate the heterogeneity of the associations across breast cancer subtypes. All statistical tests were based on 2-sided probability with a significance level of 0.05 and were performed using SAS, version 9.2 (SAS Institute Inc., Cary, North Carolina).

RESULTS

Table 1 shows the frequency distributions of sociodemographic and study variables for cases by joint ER/PR status and for controls. Controls tended to have a lower educational level, later age at menarche, younger age at first livebirth, a greater percentage of breastfeeding, lower BMI, less HRT use, more regular exercise, and less frequent family history of breast cancer than cases and were less likely to have a personal history of breast fibroadenoma than cases. Among cases with known receptor status, 1,409 (52.7%) were ER+/PR+, 712 (26.6%) were ER−/PR−, 301 (11.2%) were ER+/PR−, and 254 (9.5%) were ER−/PR+. Age at breast cancer diagnosis (F test: P < 0.01), menopausal status (χ² test: P < 0.01), duration of oral contraceptive use (F test: P = 0.03), and HRT use (χ² test: P_χ2 < 0.01) differed across the 4 case groups with known ER/PR information. Overall, we had information on joint ER/PR status for 2,676 (77.7%) breast cancer cases. Cases with missing data on ER/PR status were similar to those with known ER/PR status with respect to most known breast cancer risk factors, with a few exceptions. Cases with known ER/PR status appeared to have a slightly lower percentage of livebirths (93.22% vs. 95.44%) and lower BMI (23.33 vs. 23.74) and WHR (0.817 vs. 0.824) than those with unknown ER/PR status (see Web Table 1, which appears on the Journal’s Web site (http://aje.oxfordjournals.org/)). We adjusted for these variables throughout subsequent analyses.

Table 1.

Characteristics of Cases and Controls by Estrogen Receptor and Progesterone Receptor Status, Shanghai Breast Cancer Studies I (1996–1998) and II (2002–2005), Shanghai, China

	Controls (n = 3,474)		ER/PR Status										P Valuea	P Valueb
			ER+/PR+ (n = 1,409)		ER−/PR− (n = 712)		ER+/PR− (n = 301)		ER−/PR+ (n = 254)		Unknown (n = 767)
	%	Mean (SD)	%	Mean (SD)	%	Mean (SD)	%	Mean (SD)	%	Mean (SD)	%	Mean (SD)
Age, years		49.90 (8.76)		49.77 (8.12)		50.01 (8.51)		51.18 (8.21)		48.09 (7.65)		49.33 (8.43)	0.37	<0.01
Educational level
Elementary school or below	12.58		7.31		8.99		7.31		6.69		11.34
Junior high school	41.02		39.46		39.47		37.87		38.98		39.37
Senior high school	35.29		37.26		37.64		36.54		38.58		36.25
College or above	11.11		15.97		13.90		18.27		15.75		13.04		<0.01	0.80
Age at menarche, years		14.66 (1.74)		14.38 (1.62)		14.39 (1.62)		14.43 (1.59)		14.33 (1.76)		14.54 (1.67)	<0.01	0.89
Postmenopausal	43.49		37.26		42.42		49.83		29.53		41.07		<0.01	<0.01
Age at menopause (postmenopausal women), years		47.92 (4.71)		48.39 (4.29)		48.40 (4.53)		48.40 (4.48)		48.40 (4.64)		48.29 (4.49)	0.01	1.00
Ever had a livebirth	96.20		95.03		96.63		94.68		95.28		93.22		0.01	0.35
No. of livebirths		1.47 (0.82)		1.35 (0.70)		1.39 (0.75)		1.42 (0.76)		1.29 (0.60)		1.49 (0.85)	<0.01	0.11
Age at first livebirth, years		26.35 (3.82)		27.03 (3.73)		26.75 (3.86)		26.77 (3.75)		27.28 (3.72)		26.81 (4.05)	<0.01	0.17
Ever breastfed	79.44		75.80		77.33		81.05		76.03		78.18		0.02	0.28
Body mass indexc		23.31 (3.30)		23.85 (3.31)		23.51 (3.36)		23.70 (3.12)		23.77 (3.48)		23.33 (3.32)	<0.01	0.18
Waist-to-hip ratio		0.81 (0.06)		0.82 (0.05)		0.82 (0.05)		0.83 (0.06)		0.82 (0.06)		0.82 (0.06)	<0.01	0.25
Ever consumed alcohol	5.50		4.47		4.63		7.64		4.33		4.04		0.13	0.13
Ever used oral contraceptives	20.03		18.45		19.24		24.25		15.35		20.60		0.50	0.05
Duration of oral contraceptive use (among users), months		42.74 (58.49)		38.53 (59.04)		55.83 (76.55)		34.25 (48.43)		54.36 (70.11)		45.31 (57.86)	0.67	0.03
Ever used hormone replacement therapy	3.02		3.55		4.07		7.97		1.57		3.66		0.04	<0.01
Regular exercised	30.20		25.20		26.12		26.25		22.05		23.21		<0.01	0.61
History of breast fibroadenoma	5.47		10.31		7.62		8.64		10.63		10.99		<0.01	0.20
First-degree family history of breast cancer	2.76		4.40		4.63		6.64		5.12		4.30		<0.01	0.42

Abbreviations: ER, estrogen receptor; PR, progesterone receptor; SD, standard deviation.

^aP for cases versus controls from a χ² test (categorical variables) or analysis of variance (continuous variables).

^bP for comparison across the 4 known hormone receptor status groups for cases.

^cWeight (kg)/height (m)².

^dAt least twice a week (yes, no).

Table 2 presents associations between menstrual factors and breast cancer by joint ER/PR status. No differences in risk were found across the 4 ER/PR breast cancer subtypes for age at menarche, age at menopause, or years of menstruation. Later age at menarche was inversely associated with risk for the ER+/PR+ and ER−/PR− subtypes of breast cancer (P-trend < 0.01 for both). Compared with women who were younger at menarche (age ≤13 years), there was a 34% reduction (odds ratio (OR) = 0.66, 95% CI: 0.53, 0.82) in risk of ER+/PR+ cancer and a 38% reduction (OR = 0.62, 95% CI: 0.46, 0.83) in risk of ER−/PR− cancer for women who were older at menarche (age ≥17 years). Later age at menarche was associated with a statistically nonsignificantly reduced risk of ER+/PR− and ER−/PR+ cancers. Women in the highest quartile of years of menstruation had increased risk of all 4 subtypes of breast cancer, although trend tests were significant only for the ER+/PR+ and ER−/PR− subtypes. However, the association with menopausal status differed between subtypes defined by ER/PR status (heterogeneity test: P < 0.01), with menopausal status being associated with a reduced risk of ER+/PR+ and ER−/PR+ breast cancer.

Table 2.

Odds Ratios for Breast Cancer According to Menstrual Factors, by Estrogen Receptor and Progesterone Receptor Status (n = 6,150), Shanghai Breast Cancer Studies I (1996–1998) and II (2002–2005), Shanghai, China^a

	No. of Controls	ER/PR Status												P Valueb
		ER+/PR+			ER−/PR−			ER+/PR−			ER−/PR+
		No. of Cases	OR	95% CI	No. of Cases	OR	95% CI	No. of Cases	OR	95% CI	No. of Cases	OR	95% CI
Age at menarche, yearsc
≤13	981	479	1.0d		240	1.0d		95	1.0d		89	1.0d
14	743	292	0.84	0.70, 1.01	156	0.87	0.70, 1.09	63	0.92	0.66, 1.29	52	0.81	0.57, 1.17
15–16	1,244	493	0.88	0.76, 1.03	241	0.83	0.68, 1.01	108	0.99	0.74, 1.33	82	0.80	0.58, 1.10
≥17	495	140	0.66	0.53, 0.82	71	0.62	0.46, 0.83	34	0.79	0.52, 1.20	29	0.77	0.49, 1.20
Ptrend			<0.01			<0.01			0.46			0.14		0.66
Menopausale
No	1,957	882	1.0d		409	1.0d		151	1.0d		178	1.0d
Yes	1,508	522	0.58	0.47, 0.71	299	0.89	0.69, 1.15	150	1.05	0.73, 1.51	74	0.54	0.35, 0.82	<0.01
Age at menopause (among women with natural menopause), yearse
≤46	303	77	1.0d		50	1.0d		17	1.0d		12	1.0d
47–49	412	146	1.32	0.95, 1.83	69	0.96	0.64, 1.43	38	1.60	0.87, 2.94	19	1.35	0.63, 2.92
50–51	319	112	1.25	0.88, 1.77	72	1.24	0.82, 1.87	38	2.07	1.12, 3.85	16	1.47	0.67, 3.28
≥52	276	102	1.23	0.85, 1.76	65	1.33	0.87, 2.04	30	1.89	0.97, 3.67	16	1.61	0.70, 3.68
Ptrend			0.42			0.09			0.05			0.26		0.46
Years of menstruation (interval between age at menarche and age at menopause/current age)
≤27	841	257	1.0d		142	1.0d		55	1.0d		60	1.0d
28–31	863	365	1.40	1.14, 1.72	168	1.12	0.86, 1.46	64	0.99	0.67, 1.47	70	1.40	0.94, 2.09
32–34	805	323	1.38	1.10, 1.73	175	1.26	0.94, 1.67	68	1.03	0.67, 1.57	50	1.25	0.78, 2.02
≥35	951	458	1.66	1.30, 2.11	223	1.38	1.01, 1.87	113	1.31	1.85, 2.02	72	1.71	1.03, 2.86
Ptrend			<0.01			0.03			0.15			0.08		0.91

Abbreviations: CI, confidence interval; ER, estrogen receptor; OR, odds ratio; PR, progesterone receptor.

^aResults were adjusted for age, education, history of breast fibroadenoma, first-degree family history of breast cancer, regular exercise (yes/no), body mass index, waist-to-hip ratio, history of livebirth, parity, and study phase (I or II). Missing values (<0.6%) were excluded from the model.

^bTest for heterogeneity of P_trend values between the 4 hormone receptor groups, calculated using multivariable polytomous logistic regression.

^cAlso adjusted for menopausal status (yes/no).

^dReference category.

^eAlso adjusted for age at menarche.

Associations of breast cancer risk with never having a livebirth were confined to women with ER+ breast cancer, although the tests for heterogeneity across subtypes of breast cancer were not significant (Table 3). Later age at first livebirth was associated with both ER+/PR+ and ER−/PR+ breast cancer. Having multiple children was significantly related to a reduced risk of ER+/PR+ breast cancer (P-trend = 0.02). Longer duration of breastfeeding was significantly and inversely related to the ER+/PR+ subtype (P-trend = 0.01). However, the test for heterogeneity was not significant for any of these factors.

Table 3.

Odds Ratios for Breast Cancer According to Reproductive Factors, by Estrogen Receptor and Progesterone Receptor Status (n = 6,150), Shanghai Breast Cancer Studies I (1996–1998) and II (2002–2005), Shanghai, China^a

	No. of Controls	ER/PR Status												P Valueb
		ER+/PR+			ER−/PR−			ER+/PR−			ER−/PR+
		No. of Cases	OR	95% CI	No. of Cases	OR	95% CI	No. of Cases	OR	95% CI	No. of Cases	OR	95% CI
History of livebirth
Ever	3,330	1,333	1.0c		684	1.0c		284	1.0c		241	1.0c
Never	130	70	1.40	1.03, 1.90	24	0.90	0.57, 1.41	16	1.53	0.89, 2.63	11	1.07	0.56, 2.04	0.25
Parity (among parous women)
1	2,279	1,009	1.0c		495	1.0c		200	1.0c		186	1.0c
2	693	220	0.71	0.58, 0.88	142	0.90	0.70, 1.17	58	0.75	0.51, 1.10	44	1.05	0.69, 1.61
≥3	358	104	0.80	0.58, 1.12	47	0.61	0.40, 0.95	26	0.76	0.42, 1.37	11	0.68	0.31, 1.51
Ptrend			0.02			0.06			0.22			0.61		0.96
Age at first livebirth (among parous women), years
≤24	959	311	1.0c		182	1.0c		65	1.0c		50	1.0c
25–26	859	300	0.89	0.72, 1.10	164	0.85	0.65, 1.10	79	1.29	0.88, 1.89	50	0.88	0.56, 1.37
27–28	745	335	1.14	0.92, 1.41	157	0.92	0.70, 1.20	63	1.20	0.79, 1.82	66	1.36	0.88, 2.10
≥29	758	386	1.24	1.00, 1.54	178	0.98	0.74, 1.28	76	1.32	0.87, 1.99	74	1.49	0.96, 2.33
Ptrend			<0.01			0.84			0.31			0.01		0.13
Lifetime duration of breastfeeding (among parous women), months
Never breastfed	685	324	1.0c		155	1.0c		54	1.0c		58	1.0c
<9	839	381	0.96	0.80, 1.15	186	0.98	0.77, 1.25	85	1.29	0.90, 1.84	70	0.98	0.68, 1.41
9–17	1,044	407	0.79	0.66, 0.94	222	0.91	0.72, 1.15	95	1.05	0.74, 1.50	73	0.85	0.59, 1.23
≥18	762	221	0.71	0.53, 0.95	121	0.76	0.52, 1.11	50	0.65	0.38, 1.12	40	1.23	0.65, 2.34
Ptrend			0.01			0.18			0.30			0.72		0.59

Abbreviations: CI, confidence interval; ER, estrogen receptor; OR, odds ratio; PR, progesterone receptor.

^aResults were adjusted for age, education, history of breast fibroadenoma, first-degree family history of breast cancer, regular exercise (yes/no), years of menstruation, body mass index, waist-to-hip ratio, parity, and study phase (I or II). Missing values (<0.6%) were excluded from the model.

^bTest for heterogeneity of P_trend values between the 4 hormone receptor groups, calculated using multivariable polytomous logistic regression.

^cReference category.

As shown in Table 4, we found no association between oral contraceptive use (ever use or duration of use) and breast cancer for any subtype defined by ER and PR status. Risk was higher for women with ER+/PR− tumors who had used HRT (OR = 2.25, 95% CI: 1.40, 3.62), and associations differed statistically across the 4 subtypes (heterogeneity test: P = 0.01), mainly between the ER+/PR− and ER−/PR+ subgroups.

Table 4.

Odds Ratios for Breast Cancer According to Contraceptive Factors and Alcohol Consumption, by Estrogen Receptor and Progesterone Receptor Status (n = 6,150), Shanghai Breast Cancer Studies I (1996–1998) and II (2002–2005), Shanghai, China^a

	No. of Controls	ER/PR Status												P Valueb
		ER+/PR+			ER−/PR−			ER+/PR−			ER−/PR+
		No. of Cases	OR	95% CI	No. of Cases	OR	95% CI	No. of Cases	OR	95% CI	No. of Cases	OR	95% CI
Ever used oral contraceptives
No	2,767	1,144	1.0c		571	1.0c		228	1.0c		213	1.0c
Yes	694	259	0.92	0.78, 1.09	137	0.97	0.79, 1.20	72	1.19	0.89, 1.59	39	0.84	0.58, 1.20	0.36
Duration of oral contraceptive use, months
No use	2,767	1,144	1.0c		571	1.0c		228	1.0c		213	1.0c
<12	248	101	1.01	0.79, 1.29	47	0.93	0.67, 1.30	29	1.39	0.92, 2.11	16	0.94	0.55, 1.59
12–47	242	95	0.97	0.75, 1.26	36	0.74	0.51, 1.06	24	1.12	0.71, 1.77	7	0.44	0.20, 0.95
≥48	203	62	0.74	0.55, 1.00	53	1.29	0.93, 1.78	19	1.03	0.62, 1.70	16	1.19	0.69, 2.06
Ptrend			0.12			0.75			0.55			0.54		0.36
Hormone use
Never	3,355	1,351	1.0c		679	1.0c		276	1.0c		248	1.0c
Ever	105	50	1.05	0.74, 1.50	29	1.24	0.81, 1.91	24	2.25	1.40, 3.62	4	0.51	0.19, 1.41	0.01
Alcohol consumption
Never	3,270	1,340	1.0c		675	1.0c		277	1.0c		241	1.0c
Ever	180	63	0.89	0.66, 1.20	33	0.89	0.61, 1.31	23	1.59	1.01, 2.51	11	0.87	0.47, 1.63	0.12

Abbreviations: CI, confidence interval; ER, estrogen receptor; OR, odds ratio; PR, progesterone receptor.

^aResults were adjusted for age, education, history of breast fibroadenoma, first-degree family history of breast cancer, regular exercise (yes/no), years of menstruation, body mass index, waist-to-hip ratio, history of livebirth, parity, and study phase (I or II). Missing values (<0.6%) were excluded from the model.

^bTest for heterogeneity of P_trend values between the 4 hormone receptor groups, calculated using multivariable polytomous logistic regression.

^cReference category.

Alcohol intake was not associated with risk of the ER+/PR+, ER−/PR−, or ER−/PR+ subtypes of breast cancer but was related to increased risk of ER+/PR− breast cancer (OR = 1.59, 95% CI: 1.01, 2.51) (Table 4). However, the heterogeneity test did not reach statistical significance (P = 0.12). The percentage of alcohol intake (5.09%) was low in our study population.

BMI was associated with a significantly increased risk of ER+/PR+ breast cancer (P-trend < 0.01), and the test for heterogeneity across the 4 subtypes of breast cancer was statistically significant (P = 0.01) (Table 5). Increasing WHR substantially increased the risk of all 4 tumor subtypes. Compared with women in the lowest quartile of WHR, women in the highest quartile (≥0.843) had more than double the risk of breast cancer for all subtypes (OR range = 2.20–2.72).

Table 5.

Odds Ratios for Breast Cancer According to Measures of Obesity, by Estrogen Receptor and Progesterone Receptor Status (n = 6,150), Shanghai Breast Cancer Studies I (1996–1998) and II (2002–2005), Shanghai, China^a

	No. of Controls	ER/PR Status												P Valueb
		ER+/PR+			ER−/PR−			ER+/PR−			ER−/PR+
		No. of Cases	OR	95% CI	No. of Cases	OR	95% CI	No. of Cases	OR	95% CI	No. of Cases	OR	95% CI
Quartile of body mass indexc
<21.00	864	266	1.0d		159	1.0d		53	1.0d		55	1.0d
21.00–23.02	865	319	1.09	0.90, 1.32	183	1.00	0.78, 1.27	77	1.24	0.85, 1.80	60	1.03	0.70, 1.53
23.03–25.15	866	385	1.25	1.03, 1.52	177	0.89	0.69, 1.14	85	1.23	0.84, 1.80	56	0.93	0.62, 1.40
≥25.16	865	433	1.37	1.12, 1.68	189	0.89	0.68, 1.15	85	1.14	0.76, 1.69	81	1.31	0.87, 1.96
Ptrend			<0.01			0.25			0.66			0.24		0.01
Quartile of waist-to-hip ratio
<0.772	871	229	1.0d		113	1.0d		41	1.0d		48	1.0d
0.772–0.805	854	310	1.32	1.08, 1.61	162	1.45	1.11, 1.89	63	1.45	0.96, 2.19	47	1.04	0.68, 1.60
0.806–0.842	882	362	1.51	1.23, 1.85	186	1.72	1.32, 2.24	83	1.95	1.30, 2.92	67	1.53	1.02, 2.30
≥0.843	853	503	2.20	1.78, 2.71	247	2.48	1.88, 3.26	113	2.72	1.80, 4.11	90	2.29	1.51, 3.49
Ptrend			<0.01			<0.01			<0.01			<0.01		0.68

Abbreviations: CI, confidence interval; ER, estrogen receptor; OR, odds ratio; PR, progesterone receptor.

^aResults were adjusted for age, education, history of breast fibroadenoma, first-degree family history of breast cancer, regular exercise (yes/no), years of menstruation, history of livebirth, parity, and study phase (I or II); results were also mutually adjusted for body mass index and waist-to-hip ratio. Missing values (<0.6%) were excluded from the model.

^bTest for heterogeneity of P_trend values between the 4 hormone receptor groups, calculated using multivariable polytomous logistic regression.

^cWeight (kg)/height (m)².

^dReference category.

We further analyzed associations of hormone-related factors with ER+/PR+ and ER−/PR− breast cancer by menopausal status. Results for WHR and other factors that had significant heterogeneity are presented in Table 6. Because the numbers of patients with ER+/PR− and ER−/PR+ tumors were too small to provide stable estimates, we did not include them in the stratified analyses. We found that parity was significantly and inversely associated with both ER+/PR+ and ER−/PR− tumors among premenopausal women (heterogeneity test: P = 0.56). Among postmenopausal women, the heterogeneity test for parity between ER+/PR+ and ER−/PR− was significant (P = 0.02). Compared with women who had 1 livebirth, having 2 or more livebirths was associated with a substantially lower risk of ER+/PR+ breast cancer in postmenopausal women (OR = 0.69, 95% CI: 0.52, 0.91). The inverse association of breastfeeding with ER+/PR+ and ER−/PR− breast cancer was mainly confined to postmenopausal women. BMI was positively associated with ER+/PR+ breast cancer in postmenopausal women (P-trend < 0.01), and the odds ratio for the highest quartile was 2.40 (95% CI: 1.65, 3.47). Statistically significant differences for ER+/PR+ and ER−/PR− subtypes were found for BMI in postmenopausal women (heterogeneity test: P < 0.01). WHR was positively associated with ER+/PR+ and ER−/PR− tumors in both pre- and postmenopausal women. There were no statistically significant ER+/PR+ and ER−/PR− subgroup differences for age at menarche, age at first livebirth, oral contraceptive use, or alcohol consumption among pre- or postmenopausal women (data not shown).

Table 6.

Odds Ratios for Breast Cancer According to Selected Hormone-Related Factors and Menopausal Status (n = 5,593), Shanghai Breast Cancer Studies I (1996–1998) and II (2002–2005), Shanghai, China^a

	Premenopausal Women								Postmenopausal Women
	No. of Controls	ER+/PR+			ER−/PR−			P Valueb	No. of Controls	ER+/PR+			ER−/PR−			P Valueb
		No. of Cases	OR	95% CI	No. of Cases	OR	95% CI			No. of Cases	OR	95% CI	No. of Cases	OR	95% CI
Parity (among parous women)
1	1,723	786	1.0c		370	1.0c			556	223	1.0c		125	1.0c
≥2	162	55	0.70	0.49, 0.99	25	0.60	0.37, 0.96	0.56	889	269	0.69	0.52, 0.91	164	1.12	0.79, 1.58	0.02
Lifetime duration of breastfeeding (among parous women), months
Never breastfed	506	244	1.0c		101	1.0c			179	80	1.0c		54	1.0c
<9	608	293	1.01	0.82, 1.26	134	1.12	0.84, 1.50		231	88	0.82	0.56, 1.19	52	0.73	0.47, 1.14
9–17	679	269	0.78	0.63, 0.97	144	1.05	0.79, 1.39		365	138	0.76	0.54, 1.08	78	0.65	0.43, 0.97
≥18	92	35	1.02	0.56, 1.84	16	1.11	0.49, 2.49		670	186	0.66	0.44, 0.99	105	0.48	0.30, 0.77
Ptrend			0.04			0.77		0.09			0.04			<0.01		0.25
Quartile of body mass indexd
<21.00	586	212	1.0c		113	1.0c			278	54	1.0c		46	1.0c
21.00–23.02	537	219	0.96	0.76, 1.21	116	0.98	0.73, 1.31		328	100	1.59	1.09, 2.33	67	1.10	0.72, 1.68
23.03–25.15	455	233	1.09	0.86, 1.39	90	0.81	0.59, 1.11		411	152	1.93	1.34, 2.79	87	1.06	0.70, 1.60
≥25.16	378	218	1.07	0.82, 1.39	90	0.84	0.59, 1.19		487	215	2.40	1.65, 3.47	99	1.00	0.66, 1.53
Ptrend			0.45			0.19		0.08			<0.01			0.88		<0.01
Quartile of waist-to-hip ratio
<0.772	621	169	1.0c		89	1.0c			250	60	1.0c		25	1.0c
0.772–0.805	513	217	1.49	1.17, 1.89	107	1.46	1.07, 2.00		341	93	0.96	0.66, 1.40	56	1.53	0.91, 2.57
0.806–0.842	474	242	1.76	1.37, 2.25	106	1.62	1.17, 2.24		408	118	1.06	0.74, 1.54	80	2.02	1.22, 3.34
≥0.843	348	254	2.41	1.84, 3.14	107	2.31	1.62, 3.28		505	249	1.73	1.21, 2.48	141	2.92	1.78, 4.79
Ptrend			<0.01			<0.01		0.78			<0.01			<0.01		0.16

Abbreviations: CI, confidence interval; ER, estrogen receptor; OR, odds ratio; PR, progesterone receptor.

^aResults were adjusted for age, education, history of breast fibroadenoma, first-degree family history of breast cancer, regular exercise (yes/no), years of menstruation, body mass index, waist-to-hip ratio, history of livebirth, parity, and study phase (I or II). Missing values (<0.6%) were excluded from the model.

^bTest for heterogeneity of P_trend values between the 2 hormone receptor groups, calculated using multivariable polytomous logistic regression.

^cReference category.

^dWeight (kg)/height (m)².

DISCUSSION

In this large study of 2,676 breast cancer cases with hormone receptor information and 3,474 controls from the Shanghai Breast Cancer Study, we found that parity and BMI were differently associated with ER+/PR+ breast cancers but not ER−/ER− breast cancers among postmenopausal Chinese women (heterogeneity test: P < 0.05) and that HRT and alcohol consumption were associated only with ER+/PR− breast cancer. There were no differences in associations between the 4 breast cancer subtypes and age at menarche, age at menopause, breastfeeding, age at first livebirth, oral contraceptive use, or WHR.

Many previous studies have shown that menstrual and reproductive factors, including age at menarche, age at first livebirth, and parity, are mainly associated with hormone receptor-positive tumors and not with hormone receptor-negative tumors (5, 8). Some investigators have also reported no significant differences in risk associated with delayed first livebirth (2, 17) or early menarche (2, 6, 18) for ER+/PR+ and ER−/PR− breast cancer. In our study, it was only among postmenopausal women that we observed significant differences in the risk of subtypes of breast cancer associated with parity. The associations of other reproductive factors did not appear to differ by the ER/PR status of the tumor. Consistent with previous reviews (5, 6), we found that the inverse association with long-duration breastfeeding did not vary according to the receptor status of the tumor. This finding supports the notion that, in addition to hormonal mechanisms, breastfeeding may act through other, nonhormonal mechanisms—such as differentiation of breast epithelial cells induced by lactation—to reduce the risk of breast cancer (19).

Evidence has shown that the association between obesity and breast cancer risk may vary by menopausal status (20) and hormone receptor status (3, 5). Multiple studies have found that excess endogenous estrogen due to obesity contributes to an increased risk of ER+/PR+ breast cancer in postmenopausal women (8, 9, 21). In a recent meta-analysis that included 9 cohort studies and 22 case-control studies, Suzuki et al. (9) concluded that excessive BMI was associated with differences in risk of developing ER+/PR+ tumors according to menopausal status, with a 10% (95% CI: −18, −1) reduction in risk for every 5-unit increase in BMI among premenopausal women and a 33% (95% CI: 20, 48) increase in risk for every 5-unit increase in BMI among postmenopausal women. Consistent with these results, we found that BMI was more strongly associated with receptor-positive tumors among postmenopausal women. However, BMI was unrelated to either ER+/PR+ or ER−/PR− breast cancer among premenopausal women. We observed no heterogeneity across tumor subtypes for associations with WHR in analyses with and without stratification by menopausal status. Our findings are supported by 2 (10, 22) of 3 other published studies on WHR (10, 22, 23) that took into account joint ER/PR status.

Our finding that higher BMI was differentially associated with the risk of ER+/PR+ and ER−/PR− breast tumors among postmenopausal women while the WHR associations were observed across subtypes of breast cancer suggests that different biologic mechanisms may be involved. It has been suggested that higher BMI increases levels of circulating steroids (21, 24) and reduces levels of sex hormone-binding globulin among postmenopausal women (25, 26). This may increase the overall level of bioavailable estrogen, which binds estrogen receptors to promote the development of hormone receptor-positive breast cancer. In addition to being inversely correlated with sex hormone-binding globulin (26), WHR is also associated with increased insulin levels and insulin-like growth factors (27), which may stimulate the growth of breast cancer cells, an effect that does not depend on ER/PR status.

Data have accumulated linking use of HRT solely to ER+/PR+ tumors (8, 18, 28–31), although null findings have also been observed (17, 23, 32, 33). Slanger et al. (30) suggested that associations between HRT use and histologic type could potentially be attributed to ER/PR status. In our study, interestingly, the increased risk for HRT use was associated with ER+/PR− tumors. This finding is consistent with the French E3N cohort study (34), which found that the use of some HRT was more markedly associated with the risk of ER+/PR− tumors than with ER+/PR+ tumors and suggested that progestogens might have increased the potency of growth factors and hence preferentially affected the risk of ER+/PR− tumors. Potter et al. (32) also suggested that there were differences in risk associated with HRT for ER+/PR− tumors as compared with the other 3 ER/PR categories in the Iowa Women’s Health Study.

There is increasing evidence that ER+/PR− tumors may be a distinct subgroup of breast cancers that occur more frequently than ER+/PR+ tumors in older patients and patients with a higher frequency of overexpression of human epidermal growth factor receptors 1 and 2 (35). Our finding that alcohol consumption increased the risk of ER+/PR− breast cancer supports the notion that the ER+/PR− subtype may be etiologically distinct. However, all previous studies, including the current study, have had relatively small sample sizes for a comprehensive evaluation of the etiology of ER+/PR− breast cancer tumors. The same applies to ER−/PR+ breast cancer. Further studies with larger sample sizes are needed to confirm our findings and to further elucidate the risk profiles of the 2 mixed ER/PR subgroups and the potential mechanisms underlying them.

Several potential limitations of this study should be noted. Hormone receptor information for patients was collected primarily from medical records. Hence, misclassification of hormone receptor status was unavoidable. The percentage of ER/PR positivity previously reported in Chinese populations has varied. The percentage of ER+ breast cancer in our study was similar to that reported for the largest hospital-based study conducted in China (63.8% vs. 64.1%), while the percentage of PR+ breast cancer was lower (62.1% vs. 70.2%) (36). However, these rates were higher than rates reported from a hospital-based study conducted in China (49.3% for ER+ and 46.1% for PR+) (37) and a study conducted in Hong Kong (54.1% for ER+ and 47.4% PR+) (13). The ER/PR distribution of our patients, however, more closely resembled that of Chinese women in the United States (52.7% vs. 60.6% for ER+/PR+ tumors and 26.6% vs. 22.6% for ER−/PR− tumors), according to a Surveillance, Epidemiology, and End Results report (38). To further evaluate the possible bias introduced by misclassification of ER/PR status, we compared ER/PR status distributions between cases diagnosed by teaching hospitals or municipal hospitals (third-tier hospitals, the highest quality) and those diagnosed by district hospitals (second-tier hospitals) and found no major differences (Web Table 2). We also analyzed associations for hormone-related factors and breast cancer subgroups by including ER/PR information on cases from only the teaching or municipal hospitals and observed similar association patterns (Web Table 3). Another limitation was missing data on ER/PR status for 22% of our cases. Although the differences between cases with and without known data on receptor status were small (Web Table 1), potential bias could not be completely ruled out. Last, statistical power was limited for our ER+/PR− and ER−/PR+ analyses. However, compared with previous published reports, our study had the largest number of cases for these 2 subgroups.

Our study is one of the largest to date with the capacity to conduct an in-depth investigation of the association between hormonal risk factors and breast cancer risk characterized by ER/PR status. The comprehensively collected exposure information also allowed for adjustment for multiple potential confounders during the analysis. The high response rate minimized selection bias. Additionally, over 98% of Chinese women living in Shanghai belong to a single ethnic group (Han Chinese), thus greatly reducing potential confounding by unknown and/or unmeasured factors related to ethnic differences in culture, heritage, lifestyle, etc.

In summary, our study found that associations of BMI, parity, HRT use, and alcohol consumption with breast cancer risk differed by ER/PR status and by menopausal status. However, the association of other hormone-related factors with breast cancer did not vary by ER/PR status. More research is needed to better understand the etiologic differences and underlying mechanisms for subtypes of breast cancer, particularly the 2 relatively rare subtypes, ER+/PR− and ER−/PR+.

Glossary

Abbreviations

BMI

body mass index

CI

confidence interval

ER

estrogen receptor

HRT

hormone replacement therapy

OR

odds ratio

PR

progesterone receptor

WHR

waist-to-hip ratio