Cancer Causes Control (2014) 25:881–889 DOI 10.1007/s10552-014-0388-0
ORIGINAL PAPER
Reproductive history and the risk of molecular breast cancer subtypes in a prospective study of Norwegian women Julie Horn • Signe Opdahl • Monica J. Engstrøm • Pa˚l R. Romundstad Steinar Tretli • Olav A. Haugen • Anna M. Bofin • Lars J. Vatten • ˚ svold Bjørn Olav A
•
Received: 9 December 2013 / Accepted: 16 April 2014 / Published online: 1 May 2014 Ó Springer International Publishing Switzerland 2014
Abstract Purpose Breast cancer can be classified into molecular subtypes that differ in clinical characteristics and prognosis. There is some but conflicting evidence that reproductive risk factors may differ between distinct breast cancer subtypes. Methods We investigated associations of reproductive factors with the risk for six molecular breast cancer subtypes in a cohort of 21,532 Norwegian women who were born between 1886 and 1928 and followed up for breast cancer incidence between 1961 and 2008. We obtained stored tumor tissue from incident breast cancers and used immunohistochemistry and in situ hybridization to classify 825 invasive tumors into three luminal subtypes [Luminal A, Luminal B (HER2-) and Luminal B (HER2?)] and
J. Horn (&) S. Opdahl P. R. Romundstad S. Tretli ˚ svold L. J. Vatten B. O. A Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway e-mail: [email protected] J. Horn Department of Gynecology and Obstetrics, Levanger Hospital, Health Trust Nord-Trøndelag, Levanger, Norway M. J. Engstrøm O. A. Haugen A. M. Bofin Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway S. Tretli Cancer Registry of Norway, Institute of Population-based Cancer Research, Oslo, Norway ˚ svold B. O. A Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
three non-luminal subtypes [human epidermal growth factor receptor 2 (HER2) subtype, basal-like phenotype (BP) and five negative phenotype (5NP)]. We used Cox regression to assess reproductive factors and risk for each subtype. Results We found that young age at menarche, old age at first birth and low parity were associated with increased risk for luminal breast cancer subtypes. For the HER2 subtype, we either found no association or associations in the opposite direction compared to the luminal subtypes. The BP subtype appeared to have a similar reproductive risk profile as the luminal subtypes. Breastfeeding was associated with a reduced risk for HER2 and 5NP subtypes, but was not associated with any other subtype. Conclusions The results suggest that molecular breast cancer subtypes differ in their reproductive risk factors, but associations with non-luminal subtypes are still poorly understood and warrant further study. Keywords Breast cancer Molecular subtype Reproductive factors Epidemiology
Introduction Reproductive factors, including early menarche, a late first birth, low parity and lack of breastfeeding, are established risk factors for breast cancer [1, 2], but the underlying biological mechanisms that link these reproductive factors to breast cancer development are still poorly understood. Except for breastfeeding, these reproductive factors seem to be most strongly associated with the risk for luminal (hormone-receptor positive) breast cancers that exhibit receptors for estrogen and/or progesterone, whereas the associations with non-luminal (hormone-receptor negative)
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tumors are not clear [3]. Recently, gene expression profiling studies have shown that breast cancer can be further classified into molecularly defined subtypes [4] that may differ in clinical characteristics and prognosis [5]. Emerging evidence suggests that risk for different subtypes may also differ with respect to reproductive factors [6–8]. However, few prospective studies have examined reproductive risk factors and risk for molecular breast cancer subtypes, and results have not been consistent [6, 8, 9]. Also, most studies have applied tumor information obtained from medical records instead of using a standardized classification of molecular subtypes. Tissue microarray (TMA) can be used to ensure standardized staining conditions and immunohistochemistry and in situ hybridization can be used as surrogates for gene expression profiling [10, 11]. This technology was applied to breast cancer tissue in a historic cohort of Norwegian women who were followed up for breast cancer incidence since 1961 [12]. In this cohort, we assessed associations of reproductive factors with the risk of molecular subtypes of breast cancer.
Methods Study population and follow-up Between 1956 and 1959, all women living in NordTrøndelag County in Norway were invited to participate in a breast cancer screening program carried out by the Norwegian Cancer Society. The eligible women were born between 1886 and 1928 and were invited to a clinical breast examination conducted by a physician and to have an interview based on a standardized questionnaire. Thus, information on history of breast disease, age at menarche, reproductive history and history of breastfeeding was collected. In addition, information on place of residence, marital status and occupation (own or husband’s) was collected from the national population register and added to the data set. The study has been described in more detail elsewhere [13]. A unique 11-digit identification number, allocated to each Norwegian citizen at a population census in 1960, enabled individual linkage of information on study participants to breast cancer incidence data at the Cancer Registry of Norway and to data on vital status and emigration provided by Statistics Norway. Based on mandatory reporting and regulated by law, incident cases of cancer have been registered in the Cancer Registry of Norway since 1952. A total of 25,897 invited women were still alive at the census in 1960, and among them, 21,662 women (83.6 %) had participated at the breast examination and were eligible
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for breast cancer follow-up. We excluded 130 participants with a history of breast cancer before follow-up started, and therefore, 21,532 women were followed from 1 January 1961 until the date of a first breast cancer diagnosis, death or emigration, or until 31 December 2008, whichever event occurred first. Tissue microarray (TMA) construction and immunohistochemical analysis TMA construction, assay methods and the molecular subtypes classification algorithm applied to the tumors of the patients in this cohort, have been described in detail in a previous publication [12]. Briefly, for women recorded with incident breast cancer during follow-up, tumor tissue was obtained from the archives of the Department of Pathology at St. Olav’s Hospital, which is the primary pathology center serving Nord-Trøndelag County. Two independent pathologists revised the original breast tissues and confirmed invasive breast carcinoma on hematoxylin-eosin-saffron stained sections. The tumors were then classified according to histopathological type [14] and graded according to the Nottingham criteria [15]. Three representative tissue cores, 1 mm in diameter, were taken from peripheral regions of each tumor sample and inserted into TMA blocks. The sections cut from the TMA blocks were immunostained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5 (CK5), epidermal growth factor receptor (EGFR) and the proliferation marker Ki67. In addition, chromogenic in situ hybridization (CISH) with probes for the HER2 gene and chromosome 17 centromere was used to determine HER2 status, but if CISH was unsuccessful, the result from the immunohistochemical analysis was used. ER positive and/or PR positive tumors (C1 % of tumor cells showed positive nuclear staining [11]) were considered luminal breast cancers, and tumors negative for both ER and PR were considered non-luminal breast cancers. The luminal tumors were sub-classified as Luminal A if they were HER2 negative and Ki67 \ 15 %. Luminal B subtype was sub-classified into Luminal B (HER2-) (negative for HER2 and Ki67 C 15 %), or Luminal B (HER2 ?). On the other hand, non-luminal tumors were classified as HER2 subtype if they were HER2 positive, as basal-like phenotype (BP) if they were HER2 negative and positive for CK5 and/or EGFR and as five negative phenotype (5NP) if they were negative for all five markers (ER, PR, HER2, CK5 and EGFR). Statistical analysis We used Cox proportional hazards regression to estimate hazard ratios (HR) with 95 % confidence intervals (CI) for
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breast cancer subtypes by age at menarche, age at first birth, parity and duration of breastfeeding. First, we examined associations with the broad subtypes luminal and non-luminal breast cancer, which allowed comparisons with studies that have examined breast cancer risk according to hormone-receptor status of the tumors. Second, we assessed the associations for each of the molecular breast cancer subtypes. In the analyses, we assessed each reproductive factor separately, both as continuous variables and in categories (age at menarche \14 or C14 years; age at first birth \25 or C25 years; number of births 1, 2, 3 or C4 and duration of breastfeeding (cumulative duration for all births) \4, 4–12, 13–24 or [24 months). For each analysis, we excluded participants with missing information on the exposure or on relevant confounding factors. Thus, the analyses of age at first birth, number of births and breastfeeding were restricted to parous women with known age at first birth. The analysis of breastfeeding was further restricted to women with 1–4 children to avoid residual confounding by parity. All associations were examined in two different models. In the first model, we adjusted for age (by using age as the time scale) and birth cohort (10-year categories). The analysis of number of births was also adjusted for age at first birth, and the analysis of breastfeeding was adjusted for age at first birth and number of births. In a second model, we additionally adjusted for all other reproductive factors and used place of residence and occupational status as proxies for socioeconomic status. These adjustments did not materially influence the results, and in the tables, we therefore report the results obtained from the first model. We repeated all analyses using 10 % positively stained tumor cells as the cut-off point to define ER and PR status, but the associations of reproductive factors with risk of breast cancer subtypes remained similar to those of the main analyses (data not shown). As associations of reproductive factors with risk of luminal breast cancer may differ by PR status [16, 17], we also examined the associations with each luminal subtype according to the tumor’s PR status, but the estimates for PR positive and PR negative tumors did not substantially differ (data not shown). To examine if the associations between each reproductive factor and breast cancer risk differed by breast cancer subtype, we used the data augmentation method described by Lunn and McNeil [18]. We conducted likelihood ratio tests to compare two models: one that allowed the association to differ between tumor subtypes, and one that assumed a common association across subtypes. These tests yielded p values for heterogeneity, where a small p value would indicate that the association of the reproductive factor with breast cancer risk may differ between tumor subtypes. The proportional hazard assumption was
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met in all analyses as evaluated by log minus log plots and by Schoenfeld residuals. All analyses were performed using STATA for Windows (Version12.1Ó Stata Corp LP). The study was approved by the regional committee for medical research ethics, the Norwegian Data Inspectorate and the Norwegian Directorate of Health.
Results A total of 21,532 women without breast cancer at baseline were followed for 667,461 person years, and a total of 1,226 women developed breast cancer during follow-up. Among 825 breast cancer cases that were successfully subtyped, 392 (47.5 %) were classified as Luminal A, 226 (27.4 %) as Luminal B (HER2-), 64 (7.8 %) as Luminal B (HER2?), 53 (6.4 %) as HER2 subtype, 58 (7.0 %) as BP and 32 (3.9 %) as 5NP phenotype. The remaining 401 cases were not subtyped, either because no pathological examination had been performed (n = 52), the tumor sample had been sent to another hospital (n = 259) and was not available to us, or the tumor sample was of insufficient size or quality (n = 90). These 401 patients were more likely to be diagnosed in the 1960s and 1970s than later (64.1 % vs. 28.7 % among cases with subtype information) and breast cancer stage at diagnosis was consistently higher (14 % at stage 4 vs. 5.4 % among cases with subtype information). However, age at menarche and reproductive and lactation histories did not differ from patients with tumors that could be subtyped (data not shown), suggesting that the patients who were subtyped do not represent a particularly selected group. Clinical characteristics by breast cancer subtype Baseline characteristics of the study population as well as baseline and tumor characteristics for each case group are presented in Table 1. HER2 subtype tumors were more often diagnosed at a younger age and at higher stages (stage 3 or 4, 18.9 %) compared to other breast cancer subtypes (9.3 % for Luminal A and 10.4 % for BP) and HER2 and BP subtypes more often had higher histopathological grade. Reproductive risk factors for luminal and non-luminal breast cancer We first examined associations of reproductive risk factors with risk for luminal and non-luminal breast cancer, without further subdivision into molecular subtypes. Age at menarche, age at first birth and parity were associated with the risk for luminal breast cancer (Table 2). Thus, older age
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Table 1 Baseline characteristics of the study population (21,532 Norwegian women followed up from 1961 to 2008) overall and by breast cancer subtype Study population n = 21,532
Luminal A n = 392
Luminal B (HER-) n = 226
Luminal B (HER?) n = 64
HER2 subtype n = 53
Basal-like phenotype n = 58
Five negative phenotype n = 32
1886–1899
19.0
9.2
11.1
1.6
7.6
8.6
6.3
1900–1909
24.6
22.2
25.2
18.8
18.9
20.7
40.6
1910–1919
29.9
33.7
31.0
37.5
39.6
32.8
31.3
1920–1928
26.5
35.0
32.7
42.2
34.0
37.9
21.9
Age at start of follow-up (years), median (IQR)
48 (40, 58)
44 (39, 52)
46 (38, 53)
43 (38, 50)
45 (39, 51)
44 (39, 52)
50 (41, 56)
\14
29.1
34.7
30.1
34.4
17.0
27.6
37.5
C14
64.9
58.7
62.4
57.8
79.2
60.3
59.4
7.5
7.8
3.8
12.1
3.1
Birth cohort, %
Age at menarche (years), %
Missing 6.0 6.6 Age at first birth among parous women (years), % \25
41.9
39.9
31.4
42.3
57.5
28.6
40.7
C25
53.1
55.2
65.1
48.1
42.5
63.2
51.9
Missing
5.0
4.9
3.5
9.6
0
8.2
7.4
Nulliparous
16.5
19.4
21.2
17.2
11.3
13.8
15.6
1 birth
14.6
17.1
21.7
21.9
15.1
24.1
6.3
2 births
23.1
24.7
23.0
25.0
24.5
25.9
25.0
3 births
18.8
19.9
16.4
20.3
17.0
19.0
31.3
Parity (%)
C4 births
24.8
16.8
15.0
14.1
32.1
15.5
21.9
Missing
2.2
2.0
2.7
1.6
0
1.7
0
Urban
10.0
9.7
15.5
6.3
11.3
12.1
9.4
Rural
90.0
90.3
84.5
93.7
88.7
87.9
90.6
Occupation (own or husband’s, %) Professional, private 23.1 enterprise
28.3
28.3
26.6
30.2
25.9
31.3
Manual
47.3
47.7
38.5
48.4
37.7
39.7
40.6
Domestic, others
29.6
Place of residence (%)
24.0
33.2
25.0
32.1
34.5
28.1
Age at diagnosis (years), median (IQR)
75 (68, 82)
73 (66, 80)
72 (59, 77)
66 (58, 74)
72 (65, 80)
74 (67, 85)
Year at diagnosis, median (IQR)
1990 (1980, 1997)
1985 (1978, 1994)
1986 (1978, 1992)
1981 (1972, 1990)
1986 (1976, 1995)
1988 (1976, 1996)
I
54.9
49.6
43.8
32.1
46.6
50.0
II
35.0
35.0
40.6
49.1
43.1
37.5
III
6.1
7.1
4.7
11.3
5.2
6.3
IV
3.2
7.5
7.8
7.6
5.2
6.3
Missing
0.8
0.9
3.1
0
0
0
Invasive ductal
68.6
73.9
81.3
77.4
58.6
40.6
Invasive lobular
15.6
13.7
7.8
1.9
3.5
34.4
Medullary
0
2.7
0
11.3
12.1
9.4
Others
15.8
9.7
10.9
9.4
25.8
15.6
20.4
8.4
3.1
0
6.9
0
Stage at diagnosis (%)
Histology (%)
Tumor grade (%) 1
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Cancer Causes Control (2014) 25:881–889
885
Table 1 continued Study population n = 21,532
Luminal A n = 392
Luminal B (HER-) n = 226
Luminal B (HER?) n = 64
HER2 subtype n = 53
Basal-like phenotype n = 58
Five negative phenotype n = 32
2
69.6
47.4
48.4
20.7
10.3
65.6
3
9.7
43.8
48.4
79.3
82.8
34.4
Missing
0.3
0.4
0
0
0
0
IQR, inter quartile range
Table 2 Reproductive factors in relation to luminal and non-luminal breast cancer among 21,532 Norwegian women followed up from 1961 to 2008 Luminal n
Non-luminal HR
95 % CI
n
HR
95 % CI
p for heterogeneity
Age at menarche (years)a, n = 20,244 \14
226
1
Referent
37
1
Referent
C14 per 2 year increase
408
0.85 0.91
(0.72–1.00) (0.81–1.03)
96
1.21 0.93
(0.83–1.78) (0.72–1.20) Referent
0.09 0.91
Age at first birth (years)a, n = 16,625 \25
199
1
Referent
52
1
C25
307
1.19
(1.00–1.43)
65
0.95
(0.66–1.38)
0.26
1.15
(1.05–1.26)
0.99
(0.82–1.20)
0.16
per 5 year increase Nulliparous versus parousa, n = 21,062 Nulliparous
135
1
Referent
Parous
532
0.72
(0.60–0.87)
19 123
1
Referent
1.19
(0.73–1.94)
0.05
Number of births among parous womenb, n = 16,625 1
124
1
Referent
22
1
Referent
2
159
0.76
(0.60–0.96)
35
0.94
(0.55–1.60)
3
122
0.73
(0.57–0.94)
30
0.99
(0.57–1.74)
C4
101
0.53
(0.40–0.70)
30
0.88
(0.49–1.57)
0.53
0.85
(0.79–0.91)
0.94
(0.82–1.06)
0.20
Breastfeeding (ever versus never)c, n = 13,423 Never 25 0.84
(0.56–1.27)
11
2.13
(1.11–4.07)
Ever (C1 month)
Referent
92
1
Referent
per birth
438
1
0.02
d
Breastfeeding (total duration) , n = 12,607 1–3 month
56
1.01
(0.74–1.38)
13
1.25
(0.65––2.40)
4–12 month
168
1
Referent
34
1
Referent
13–24 month
141
1.14
(0.89–1.47)
23
0.80
(0.45–1.41)
73
0.98
(0.70–1.39)
22
1.24
(0.63–2.46)
0.31
1.01
(0.94–1.08)
1.02
(0.88–1.18)
0.89
[24 month per 6 month increase a
adjusted for age and birth cohort
b
adjusted for age, birth cohort and age at first birth
c
among women with 1–4 children, adjusted for age, birth cohort, age at first birth and number of births
d
among women with 1–4 children who ever breastfed, adjusted for age, birth cohort, age at first birth and number of births
at menarche was associated with lower risk (HR 0.85, 95 % CI 0.72–1.00, comparing menarche at C14 vs. \14 years), and parous women were at lower risk (HR 0.72, 95 % CI 0.60–0.87) compared to nulliparous women. Among parous
women, higher age at first birth was associated with increased risk (HR 1.15, 95 % CI 1.05–1.26, for each 5-year increase in age), and a high number of births was associated with a reduced risk (HR 0.53, 95 % CI
123
123
230
C14
0.87
0.79
1
(0.74–1.02)
(0.63–0.98)
Referent
170
C25
1.09
1.07
1
(0.97–1.23)
(0.84–1.35)
Referent
76
308
0.74
1
(0.57–0.95)
Referent 172
48
112
54
141
68
0.67
1
1.28
1.58
1
1.02
0.96
1
74
62
3
C4
0.88
0.61
0.84
1 0.85
(0.81–0.96)
(0.42–0.88)
(0.60–1.18)
Referent (0.62–1.17)
13
253
0.80
1
(0.45–1.41)
Referent
94
87 42
4–12 month
13–24 month [24 month
d
c
b
a
1.00
1.18 0.90
1
1.01
(0.66–1.53)
(0.91–1.10)
(0.85–1.63) (0.58–1.41)
Referent 40 24
59
23
146
0.99
1.01 1.06
1
1.15
1
0.65
0.80
0.47
0.60
1 0.67
(0.87–1.12)
(0.64–1.58) (0.57–1.96)
Referent
(0.70–1.88)
Referent
(0.30–1.40)
(0.71–0.91)
(0.29–0.76)
(0.39–0.94)
Referent (0.45–1.00)
(0.49–0.93)
Referent
(1.10–1.49)
(1.14–2.20)
Referent
(0.84–1.25)
(0.72–1.29)
Referent
95 % CI
14 7
15
3
39
5
7
12
13 15
52
11
25
22
37
22
n
1.09
1.45 1.41
1
0.54
1
1.93
0.78
0.35
0.64
1 0.64
0.81
1
0.99
0.95
1
0.83
0.86
1
HR
(0.86–1.37)
(0.63–3.36) (0.45–4.38)
Referent
(0.15–1.88)
Referent
(0.73–5.05)
(0.61–1.00)
(0.13–0.92)
(0.28–1.43)
Referent (0.30–1.35)
(0.42–1.56)
Referent
(0.72–1.37)
(0.53–1.69)
Referent
(0.56–1.23)
(0.51–1.46)
Referent
95 % CI
7 9
11
6
33
5
17
9
8 13
47
6
20
27
42
9
n
0.93
0.67 1.28
1
1.88
1
2.99
1.01
1.19
0.74
1 0.90
1.42
1
0.83
0.58
1
1.27
2.28
1
HR
(0.73–1.18)
(0.25–1.81) (0.41–3.98)
Referent
(0.68–5.17)
Referent
(1.12–7.98)
(0.84–1.22)
(0.49–2.92)
(0.28–1.96)
Referent (0.37–2.18)
(0.60–3.33)
Referent
(0.60–1.15)
(0.32–1.04)
Referent
(0.85–1.89)
(1.11–4.69)
Referent
95 % CI
8 8
17
7
40
3
8
11
12 14
49
8
31
14
35
16
n
1.09
0.69 1.43
1
1.18
1
1.06
0.85
0.53
0.76
1 0.73
1.09
1
1.25
1.78
1
0.80
1.03
1
HR
(0.86–1.38)
(0.28–1.71) (0.47–4.41)
Referent
(0.48–2.89)
Referent
(0.32–3.51)
(0.68–1.08)
(0.21–1.38)
(0.33–1.76)
Referent (0.34–1.58)
(0.52–2.31)
Referent
(0.93–1.69)
(0.94–3.37)
Referent
(0.52–1.21)
(0.56–1.86)
Referent
95 % CI
Basal-like phenotype
among women with 1–4 children who ever breastfed, adjusted for age, birth cohort, age at first birth and number of births
among women with 1–4 children, adjusted for age, birth cohort, age at first birth and number of births
adjusted for age, birth cohort and age at first birth
adjusted for age and birth cohort
Per 6 month increase
30
1–3 month
Breastfeeding (total duration)d, n = 12,607
Ever (C1 month)
Never
7
32
36
47 51
Breastfeeding (ever versus never)c, n = 13,423
Per birth
64 93
1 2
Number of births among parous womenb, n = 16,625
Parous
Nulliparous
Nulliparous versus parousa, n = 21,062
per 5 year increase
123
\25
Age at first birth (years)a, n = 16,625
per 2 year increase
136
\14
Age at menarche (years)a, n = 20,244
HR
n
95 % CI
n
HR
HER2 subtype
Luminal B (HER2-)
Luminal A
Luminal B (HER2?)
Non-luminal
Luminal
Table 3 Reproductive factors in relation to molecular breast cancer subtypes among 21,532 Norwegian women followed up from 1961 to 2008
8 5
6
0
19
3
5
10
2 8
27
5
14
11
19
12
n
1.06
1.11 0.87
1
–
1
3.85
0.91
1.43
3.50
1 2.40
1.08
1
0.90
0.86
1
0.71
0.68
1
HR
(0.79–1.43)
(0.36–3.42) (0.22–3.49)
Referent
–
Referent
(1.10–13.56)
(0.70–1.20)
(0.27–7.64)
(0.76–16.13)
Referent (0.51–11.35)
(0.41–2.83)
Referent
(0.60–1.35)
(0.39–1.92)
Referent
(0.41–1.21)
(0.33–1.42)
Referent
95 % CI
Five negative phenotype
0.92
0.55
0.06
0.40
0.66
0.50
0.10
0.03
0.38
0.09
p for heterogeneity
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Cancer Causes Control (2014) 25:881–889
0.40–0.70 for C4 births vs. 1 birth). We observed no corresponding associations with the risk for non-luminal breast cancer. For the comparison of nulliparous versus parous women (p for heterogeneity = 0.05), but not for the other associations, there was some statistical evidence that the associations of reproductive factors differed between the risk for luminal and non-luminal tumors (Table 2). We found no association of breastfeeding with the risk for luminal breast cancer. However, breastfeeding was associated with the risk for non-luminal tumors. Thus, among parous women, never having breastfed was associated with an increased risk (HR 2.13, 95 % CI 1.11–4.07), compared to ever having breastfed, and the association of breastfeeding (ever vs. never) was statistically different between non-luminal and luminal tumors (p for heterogeneity = 0.02). Among women who had breastfed, there was no evidence that longer duration of breastfeeding was associated with a further reduction in risk for non-luminal breast cancer. Reproductive factors and the risk for each molecular breast cancer subtype We examined reproductive factors and risk for each of the luminal [Luminal A, Luminal B (HER2-) and Luminal B (HER2?)] and non-luminal (HER2 subtype, BP and 5NP) breast cancer subtypes (Table 3). Early age at menarche, late age at first birth and low parity were associated with a similar increase in breast cancer risk for all tumor subtypes except for HER2 subtype. For HER2 subtype, the results suggested that older age at menarche was associated with increased risk (HR 2.28, 95 % CI 1.11–4.69, comparing menarche at C14 vs. \14 years of age), that late age at first birth was associated with a reduced risk (HR 0.58, 95 % CI 0.32–1.04, comparing first birth at C25 vs.\25 years of age), and that a high number of births was not associated with reduced risk. For age at first birth (p for heterogeneity = 0.03), but not for age at menarche and parity, there was statistical evidence to suggest heterogeneity across subtypes. Among parous women, never having breastfed was associated with increased risk for HER2 (HR 2.99, 95 % CI 1.12–7.98) and 5NP subtypes (HR 3.85, 95 % CI 1.10–13.56), compared to ever having breastfed. For the other breast cancer subtypes, there was no association with breastfeeding, and there was some statistical evidence to suggest heterogeneity across subtypes (p for heterogeneity = 0.06).
Discussion In this population-based cohort of more than 21,000 Norwegian women, we examined reproductive factors and the risk of breast cancer subtypes. We found that young age at
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menarche, high age at first birth and low parity were associated with increased risk for luminal breast cancer subtypes, but for HER2 subtype of breast cancer (a nonluminal form), we found either no associations, or associations that tended to be in the opposite direction of associations with the luminal subtypes. The BP subtype of nonluminal breast cancer appeared to have a similar reproductive risk factor profile as the luminal subtypes. Breastfeeding was associated with a reduced risk for HER2 subtype and 5NP breast cancer, but was not associated with risk for any other subtype. Strengths of this study include the population-based prospective design with long-term follow-up, the high attendance and the high comparability at baseline between women who participated and women who declined to participate [13]. As the participants were born between 1886 and 1928, few of them have been exposed to menopausal hormone treatment, and they have not been invited to systematic mammography screening, which are factors that most likely influence breast cancer incidence and tumor characteristics at diagnosis in more recent cohorts [19–22]. The original breast cancer diagnoses were revised by two pathologists, and the use of TMA technology enabled standardized conditions for immunohistochemical analyses. Unlike most previous studies, we analyzed the proliferation marker Ki67, yielding a better differentiation between luminal A and B tumors than in some other studies [10]. Also, the analyses of EGFR and CK5 enabled us to separate the BP subtype from the broader subgroup of triple-negative (ER negative, PR negative, HER2 negative) breast cancer [23]. Similar to previous studies, the relatively low number of HER2 subtype, BP and 5NP tumors precluded precise risk estimates for these subtypes and restricted the power to obtain statistical evidence for heterogeneity across subtypes. In this population, some of the cases could not be subtyped, but the distributions of hormone-receptor status, HER2 status and Ki67 among the subtyped cases were quite similar to those observed in other Scandinavian studies [24]. Also, the distribution of reproductive factors did not differ between breast cancer cases that either could, or could not be subtyped, which is reassuring in relation to possible selection bias of cases in the analysis. Due to the observational design of this study, we cannot rule out the possibility of uncontrolled confounding. For example, we had no available information on family history of breast cancer, history of benign breast disease or current alcohol consumption, and baseline measurements of height and weight were not conducted. Reproductive factors have been more strongly associated with risk for luminal than non-luminal breast cancer in other studies, whereas breastfeeding has been associated with a reduced risk for both luminal and non-luminal tumors [3,
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25–28]. Associations appear to be similar across subtypes of luminal breast cancer [6, 7, 29], but may differ between subtypes of non-luminal breast cancer [7, 30, 31]. Neither age at first birth nor parity have been associated with the risk of HER2 subtype breast cancer [6, 7, 29], except in one study that reported increased risk among women with a late first birth [8]. In contrast, a high age at first birth and low parity have been associated with a reduced risk for the BP [6, 7] or the triple-negative subtype that includes BP and 5NP tumors [9, 32]. However, other studies have reported no such associations [8, 26, 29, 33], consistent with the similar reproductive risk profile between BP and luminal subtypes in our data. Similar to our results, breastfeeding has been associated with a reduced risk for the HER2 subtype or HER2 gene amplified breast cancer (Luminal B (HER2?) and HER2 subtype) in some [30, 34] but not in other studies [6, 7, 33]. It has been suggested that the combination of multiparity and no breastfeeding may be associated with a particularly high risk for BP [7] and other non-luminal tumors [27, 30], but we could not examine that combination of exposures, because few (8 %) of the parous women in our cohort had never breastfed. The reasons why reproductive risk factors for nonluminal breast cancer subtypes differ between studies are not known, but could be related to different models for classifying the various subtypes or to differences between study populations. Compared to others, our cohort was homogenously Caucasian and not affected by menopausal hormonal treatment or organized mammography screening, and a high proportion of breast cancer cases were diagnosed in old age. The relatively low number of non-luminal breast cancer cases in each study is also likely to contribute to the inconsistencies in results, and meta-analyses of available data may increase our understanding of how reproductive risk factors are related to risk for the nonluminal breast cancer subtypes. In conclusion, this prospective population-based study provides evidence that the associations of reproductive factors with the risk for breast cancer may vary according to breast cancer subtypes. For luminal breast cancers, early menarche, a late first birth and low parity were associated with increased risk. For the HER2 subtype of non-luminal breast cancer, there was either no association, or the associations were in the opposite direction of associations with the luminal subtypes. For HER2 and 5NP subtypes, breastfeeding was associated with a reduced risk. Differences in reproductive risk factor profiles between non-luminal breast cancer subtypes are still poorly understood and warrant further study. Acknowledgments Cancer Society.
This study was funded by The Norwegian
Conflict of interest of interest.
The authors declare that they have no conflict
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ORIGINAL PAPER
Reproductive history and the risk of molecular breast cancer subtypes in a prospective study of Norwegian women Julie Horn • Signe Opdahl • Monica J. Engstrøm • Pa˚l R. Romundstad Steinar Tretli • Olav A. Haugen • Anna M. Bofin • Lars J. Vatten • ˚ svold Bjørn Olav A
•
Received: 9 December 2013 / Accepted: 16 April 2014 / Published online: 1 May 2014 Ó Springer International Publishing Switzerland 2014
Abstract Purpose Breast cancer can be classified into molecular subtypes that differ in clinical characteristics and prognosis. There is some but conflicting evidence that reproductive risk factors may differ between distinct breast cancer subtypes. Methods We investigated associations of reproductive factors with the risk for six molecular breast cancer subtypes in a cohort of 21,532 Norwegian women who were born between 1886 and 1928 and followed up for breast cancer incidence between 1961 and 2008. We obtained stored tumor tissue from incident breast cancers and used immunohistochemistry and in situ hybridization to classify 825 invasive tumors into three luminal subtypes [Luminal A, Luminal B (HER2-) and Luminal B (HER2?)] and
J. Horn (&) S. Opdahl P. R. Romundstad S. Tretli ˚ svold L. J. Vatten B. O. A Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway e-mail: [email protected] J. Horn Department of Gynecology and Obstetrics, Levanger Hospital, Health Trust Nord-Trøndelag, Levanger, Norway M. J. Engstrøm O. A. Haugen A. M. Bofin Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway S. Tretli Cancer Registry of Norway, Institute of Population-based Cancer Research, Oslo, Norway ˚ svold B. O. A Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
three non-luminal subtypes [human epidermal growth factor receptor 2 (HER2) subtype, basal-like phenotype (BP) and five negative phenotype (5NP)]. We used Cox regression to assess reproductive factors and risk for each subtype. Results We found that young age at menarche, old age at first birth and low parity were associated with increased risk for luminal breast cancer subtypes. For the HER2 subtype, we either found no association or associations in the opposite direction compared to the luminal subtypes. The BP subtype appeared to have a similar reproductive risk profile as the luminal subtypes. Breastfeeding was associated with a reduced risk for HER2 and 5NP subtypes, but was not associated with any other subtype. Conclusions The results suggest that molecular breast cancer subtypes differ in their reproductive risk factors, but associations with non-luminal subtypes are still poorly understood and warrant further study. Keywords Breast cancer Molecular subtype Reproductive factors Epidemiology
Introduction Reproductive factors, including early menarche, a late first birth, low parity and lack of breastfeeding, are established risk factors for breast cancer [1, 2], but the underlying biological mechanisms that link these reproductive factors to breast cancer development are still poorly understood. Except for breastfeeding, these reproductive factors seem to be most strongly associated with the risk for luminal (hormone-receptor positive) breast cancers that exhibit receptors for estrogen and/or progesterone, whereas the associations with non-luminal (hormone-receptor negative)
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tumors are not clear [3]. Recently, gene expression profiling studies have shown that breast cancer can be further classified into molecularly defined subtypes [4] that may differ in clinical characteristics and prognosis [5]. Emerging evidence suggests that risk for different subtypes may also differ with respect to reproductive factors [6–8]. However, few prospective studies have examined reproductive risk factors and risk for molecular breast cancer subtypes, and results have not been consistent [6, 8, 9]. Also, most studies have applied tumor information obtained from medical records instead of using a standardized classification of molecular subtypes. Tissue microarray (TMA) can be used to ensure standardized staining conditions and immunohistochemistry and in situ hybridization can be used as surrogates for gene expression profiling [10, 11]. This technology was applied to breast cancer tissue in a historic cohort of Norwegian women who were followed up for breast cancer incidence since 1961 [12]. In this cohort, we assessed associations of reproductive factors with the risk of molecular subtypes of breast cancer.
Methods Study population and follow-up Between 1956 and 1959, all women living in NordTrøndelag County in Norway were invited to participate in a breast cancer screening program carried out by the Norwegian Cancer Society. The eligible women were born between 1886 and 1928 and were invited to a clinical breast examination conducted by a physician and to have an interview based on a standardized questionnaire. Thus, information on history of breast disease, age at menarche, reproductive history and history of breastfeeding was collected. In addition, information on place of residence, marital status and occupation (own or husband’s) was collected from the national population register and added to the data set. The study has been described in more detail elsewhere [13]. A unique 11-digit identification number, allocated to each Norwegian citizen at a population census in 1960, enabled individual linkage of information on study participants to breast cancer incidence data at the Cancer Registry of Norway and to data on vital status and emigration provided by Statistics Norway. Based on mandatory reporting and regulated by law, incident cases of cancer have been registered in the Cancer Registry of Norway since 1952. A total of 25,897 invited women were still alive at the census in 1960, and among them, 21,662 women (83.6 %) had participated at the breast examination and were eligible
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for breast cancer follow-up. We excluded 130 participants with a history of breast cancer before follow-up started, and therefore, 21,532 women were followed from 1 January 1961 until the date of a first breast cancer diagnosis, death or emigration, or until 31 December 2008, whichever event occurred first. Tissue microarray (TMA) construction and immunohistochemical analysis TMA construction, assay methods and the molecular subtypes classification algorithm applied to the tumors of the patients in this cohort, have been described in detail in a previous publication [12]. Briefly, for women recorded with incident breast cancer during follow-up, tumor tissue was obtained from the archives of the Department of Pathology at St. Olav’s Hospital, which is the primary pathology center serving Nord-Trøndelag County. Two independent pathologists revised the original breast tissues and confirmed invasive breast carcinoma on hematoxylin-eosin-saffron stained sections. The tumors were then classified according to histopathological type [14] and graded according to the Nottingham criteria [15]. Three representative tissue cores, 1 mm in diameter, were taken from peripheral regions of each tumor sample and inserted into TMA blocks. The sections cut from the TMA blocks were immunostained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5 (CK5), epidermal growth factor receptor (EGFR) and the proliferation marker Ki67. In addition, chromogenic in situ hybridization (CISH) with probes for the HER2 gene and chromosome 17 centromere was used to determine HER2 status, but if CISH was unsuccessful, the result from the immunohistochemical analysis was used. ER positive and/or PR positive tumors (C1 % of tumor cells showed positive nuclear staining [11]) were considered luminal breast cancers, and tumors negative for both ER and PR were considered non-luminal breast cancers. The luminal tumors were sub-classified as Luminal A if they were HER2 negative and Ki67 \ 15 %. Luminal B subtype was sub-classified into Luminal B (HER2-) (negative for HER2 and Ki67 C 15 %), or Luminal B (HER2 ?). On the other hand, non-luminal tumors were classified as HER2 subtype if they were HER2 positive, as basal-like phenotype (BP) if they were HER2 negative and positive for CK5 and/or EGFR and as five negative phenotype (5NP) if they were negative for all five markers (ER, PR, HER2, CK5 and EGFR). Statistical analysis We used Cox proportional hazards regression to estimate hazard ratios (HR) with 95 % confidence intervals (CI) for
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breast cancer subtypes by age at menarche, age at first birth, parity and duration of breastfeeding. First, we examined associations with the broad subtypes luminal and non-luminal breast cancer, which allowed comparisons with studies that have examined breast cancer risk according to hormone-receptor status of the tumors. Second, we assessed the associations for each of the molecular breast cancer subtypes. In the analyses, we assessed each reproductive factor separately, both as continuous variables and in categories (age at menarche \14 or C14 years; age at first birth \25 or C25 years; number of births 1, 2, 3 or C4 and duration of breastfeeding (cumulative duration for all births) \4, 4–12, 13–24 or [24 months). For each analysis, we excluded participants with missing information on the exposure or on relevant confounding factors. Thus, the analyses of age at first birth, number of births and breastfeeding were restricted to parous women with known age at first birth. The analysis of breastfeeding was further restricted to women with 1–4 children to avoid residual confounding by parity. All associations were examined in two different models. In the first model, we adjusted for age (by using age as the time scale) and birth cohort (10-year categories). The analysis of number of births was also adjusted for age at first birth, and the analysis of breastfeeding was adjusted for age at first birth and number of births. In a second model, we additionally adjusted for all other reproductive factors and used place of residence and occupational status as proxies for socioeconomic status. These adjustments did not materially influence the results, and in the tables, we therefore report the results obtained from the first model. We repeated all analyses using 10 % positively stained tumor cells as the cut-off point to define ER and PR status, but the associations of reproductive factors with risk of breast cancer subtypes remained similar to those of the main analyses (data not shown). As associations of reproductive factors with risk of luminal breast cancer may differ by PR status [16, 17], we also examined the associations with each luminal subtype according to the tumor’s PR status, but the estimates for PR positive and PR negative tumors did not substantially differ (data not shown). To examine if the associations between each reproductive factor and breast cancer risk differed by breast cancer subtype, we used the data augmentation method described by Lunn and McNeil [18]. We conducted likelihood ratio tests to compare two models: one that allowed the association to differ between tumor subtypes, and one that assumed a common association across subtypes. These tests yielded p values for heterogeneity, where a small p value would indicate that the association of the reproductive factor with breast cancer risk may differ between tumor subtypes. The proportional hazard assumption was
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met in all analyses as evaluated by log minus log plots and by Schoenfeld residuals. All analyses were performed using STATA for Windows (Version12.1Ó Stata Corp LP). The study was approved by the regional committee for medical research ethics, the Norwegian Data Inspectorate and the Norwegian Directorate of Health.
Results A total of 21,532 women without breast cancer at baseline were followed for 667,461 person years, and a total of 1,226 women developed breast cancer during follow-up. Among 825 breast cancer cases that were successfully subtyped, 392 (47.5 %) were classified as Luminal A, 226 (27.4 %) as Luminal B (HER2-), 64 (7.8 %) as Luminal B (HER2?), 53 (6.4 %) as HER2 subtype, 58 (7.0 %) as BP and 32 (3.9 %) as 5NP phenotype. The remaining 401 cases were not subtyped, either because no pathological examination had been performed (n = 52), the tumor sample had been sent to another hospital (n = 259) and was not available to us, or the tumor sample was of insufficient size or quality (n = 90). These 401 patients were more likely to be diagnosed in the 1960s and 1970s than later (64.1 % vs. 28.7 % among cases with subtype information) and breast cancer stage at diagnosis was consistently higher (14 % at stage 4 vs. 5.4 % among cases with subtype information). However, age at menarche and reproductive and lactation histories did not differ from patients with tumors that could be subtyped (data not shown), suggesting that the patients who were subtyped do not represent a particularly selected group. Clinical characteristics by breast cancer subtype Baseline characteristics of the study population as well as baseline and tumor characteristics for each case group are presented in Table 1. HER2 subtype tumors were more often diagnosed at a younger age and at higher stages (stage 3 or 4, 18.9 %) compared to other breast cancer subtypes (9.3 % for Luminal A and 10.4 % for BP) and HER2 and BP subtypes more often had higher histopathological grade. Reproductive risk factors for luminal and non-luminal breast cancer We first examined associations of reproductive risk factors with risk for luminal and non-luminal breast cancer, without further subdivision into molecular subtypes. Age at menarche, age at first birth and parity were associated with the risk for luminal breast cancer (Table 2). Thus, older age
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Cancer Causes Control (2014) 25:881–889
Table 1 Baseline characteristics of the study population (21,532 Norwegian women followed up from 1961 to 2008) overall and by breast cancer subtype Study population n = 21,532
Luminal A n = 392
Luminal B (HER-) n = 226
Luminal B (HER?) n = 64
HER2 subtype n = 53
Basal-like phenotype n = 58
Five negative phenotype n = 32
1886–1899
19.0
9.2
11.1
1.6
7.6
8.6
6.3
1900–1909
24.6
22.2
25.2
18.8
18.9
20.7
40.6
1910–1919
29.9
33.7
31.0
37.5
39.6
32.8
31.3
1920–1928
26.5
35.0
32.7
42.2
34.0
37.9
21.9
Age at start of follow-up (years), median (IQR)
48 (40, 58)
44 (39, 52)
46 (38, 53)
43 (38, 50)
45 (39, 51)
44 (39, 52)
50 (41, 56)
\14
29.1
34.7
30.1
34.4
17.0
27.6
37.5
C14
64.9
58.7
62.4
57.8
79.2
60.3
59.4
7.5
7.8
3.8
12.1
3.1
Birth cohort, %
Age at menarche (years), %
Missing 6.0 6.6 Age at first birth among parous women (years), % \25
41.9
39.9
31.4
42.3
57.5
28.6
40.7
C25
53.1
55.2
65.1
48.1
42.5
63.2
51.9
Missing
5.0
4.9
3.5
9.6
0
8.2
7.4
Nulliparous
16.5
19.4
21.2
17.2
11.3
13.8
15.6
1 birth
14.6
17.1
21.7
21.9
15.1
24.1
6.3
2 births
23.1
24.7
23.0
25.0
24.5
25.9
25.0
3 births
18.8
19.9
16.4
20.3
17.0
19.0
31.3
Parity (%)
C4 births
24.8
16.8
15.0
14.1
32.1
15.5
21.9
Missing
2.2
2.0
2.7
1.6
0
1.7
0
Urban
10.0
9.7
15.5
6.3
11.3
12.1
9.4
Rural
90.0
90.3
84.5
93.7
88.7
87.9
90.6
Occupation (own or husband’s, %) Professional, private 23.1 enterprise
28.3
28.3
26.6
30.2
25.9
31.3
Manual
47.3
47.7
38.5
48.4
37.7
39.7
40.6
Domestic, others
29.6
Place of residence (%)
24.0
33.2
25.0
32.1
34.5
28.1
Age at diagnosis (years), median (IQR)
75 (68, 82)
73 (66, 80)
72 (59, 77)
66 (58, 74)
72 (65, 80)
74 (67, 85)
Year at diagnosis, median (IQR)
1990 (1980, 1997)
1985 (1978, 1994)
1986 (1978, 1992)
1981 (1972, 1990)
1986 (1976, 1995)
1988 (1976, 1996)
I
54.9
49.6
43.8
32.1
46.6
50.0
II
35.0
35.0
40.6
49.1
43.1
37.5
III
6.1
7.1
4.7
11.3
5.2
6.3
IV
3.2
7.5
7.8
7.6
5.2
6.3
Missing
0.8
0.9
3.1
0
0
0
Invasive ductal
68.6
73.9
81.3
77.4
58.6
40.6
Invasive lobular
15.6
13.7
7.8
1.9
3.5
34.4
Medullary
0
2.7
0
11.3
12.1
9.4
Others
15.8
9.7
10.9
9.4
25.8
15.6
20.4
8.4
3.1
0
6.9
0
Stage at diagnosis (%)
Histology (%)
Tumor grade (%) 1
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Cancer Causes Control (2014) 25:881–889
885
Table 1 continued Study population n = 21,532
Luminal A n = 392
Luminal B (HER-) n = 226
Luminal B (HER?) n = 64
HER2 subtype n = 53
Basal-like phenotype n = 58
Five negative phenotype n = 32
2
69.6
47.4
48.4
20.7
10.3
65.6
3
9.7
43.8
48.4
79.3
82.8
34.4
Missing
0.3
0.4
0
0
0
0
IQR, inter quartile range
Table 2 Reproductive factors in relation to luminal and non-luminal breast cancer among 21,532 Norwegian women followed up from 1961 to 2008 Luminal n
Non-luminal HR
95 % CI
n
HR
95 % CI
p for heterogeneity
Age at menarche (years)a, n = 20,244 \14
226
1
Referent
37
1
Referent
C14 per 2 year increase
408
0.85 0.91
(0.72–1.00) (0.81–1.03)
96
1.21 0.93
(0.83–1.78) (0.72–1.20) Referent
0.09 0.91
Age at first birth (years)a, n = 16,625 \25
199
1
Referent
52
1
C25
307
1.19
(1.00–1.43)
65
0.95
(0.66–1.38)
0.26
1.15
(1.05–1.26)
0.99
(0.82–1.20)
0.16
per 5 year increase Nulliparous versus parousa, n = 21,062 Nulliparous
135
1
Referent
Parous
532
0.72
(0.60–0.87)
19 123
1
Referent
1.19
(0.73–1.94)
0.05
Number of births among parous womenb, n = 16,625 1
124
1
Referent
22
1
Referent
2
159
0.76
(0.60–0.96)
35
0.94
(0.55–1.60)
3
122
0.73
(0.57–0.94)
30
0.99
(0.57–1.74)
C4
101
0.53
(0.40–0.70)
30
0.88
(0.49–1.57)
0.53
0.85
(0.79–0.91)
0.94
(0.82–1.06)
0.20
Breastfeeding (ever versus never)c, n = 13,423 Never 25 0.84
(0.56–1.27)
11
2.13
(1.11–4.07)
Ever (C1 month)
Referent
92
1
Referent
per birth
438
1
0.02
d
Breastfeeding (total duration) , n = 12,607 1–3 month
56
1.01
(0.74–1.38)
13
1.25
(0.65––2.40)
4–12 month
168
1
Referent
34
1
Referent
13–24 month
141
1.14
(0.89–1.47)
23
0.80
(0.45–1.41)
73
0.98
(0.70–1.39)
22
1.24
(0.63–2.46)
0.31
1.01
(0.94–1.08)
1.02
(0.88–1.18)
0.89
[24 month per 6 month increase a
adjusted for age and birth cohort
b
adjusted for age, birth cohort and age at first birth
c
among women with 1–4 children, adjusted for age, birth cohort, age at first birth and number of births
d
among women with 1–4 children who ever breastfed, adjusted for age, birth cohort, age at first birth and number of births
at menarche was associated with lower risk (HR 0.85, 95 % CI 0.72–1.00, comparing menarche at C14 vs. \14 years), and parous women were at lower risk (HR 0.72, 95 % CI 0.60–0.87) compared to nulliparous women. Among parous
women, higher age at first birth was associated with increased risk (HR 1.15, 95 % CI 1.05–1.26, for each 5-year increase in age), and a high number of births was associated with a reduced risk (HR 0.53, 95 % CI
123
123
230
C14
0.87
0.79
1
(0.74–1.02)
(0.63–0.98)
Referent
170
C25
1.09
1.07
1
(0.97–1.23)
(0.84–1.35)
Referent
76
308
0.74
1
(0.57–0.95)
Referent 172
48
112
54
141
68
0.67
1
1.28
1.58
1
1.02
0.96
1
74
62
3
C4
0.88
0.61
0.84
1 0.85
(0.81–0.96)
(0.42–0.88)
(0.60–1.18)
Referent (0.62–1.17)
13
253
0.80
1
(0.45–1.41)
Referent
94
87 42
4–12 month
13–24 month [24 month
d
c
b
a
1.00
1.18 0.90
1
1.01
(0.66–1.53)
(0.91–1.10)
(0.85–1.63) (0.58–1.41)
Referent 40 24
59
23
146
0.99
1.01 1.06
1
1.15
1
0.65
0.80
0.47
0.60
1 0.67
(0.87–1.12)
(0.64–1.58) (0.57–1.96)
Referent
(0.70–1.88)
Referent
(0.30–1.40)
(0.71–0.91)
(0.29–0.76)
(0.39–0.94)
Referent (0.45–1.00)
(0.49–0.93)
Referent
(1.10–1.49)
(1.14–2.20)
Referent
(0.84–1.25)
(0.72–1.29)
Referent
95 % CI
14 7
15
3
39
5
7
12
13 15
52
11
25
22
37
22
n
1.09
1.45 1.41
1
0.54
1
1.93
0.78
0.35
0.64
1 0.64
0.81
1
0.99
0.95
1
0.83
0.86
1
HR
(0.86–1.37)
(0.63–3.36) (0.45–4.38)
Referent
(0.15–1.88)
Referent
(0.73–5.05)
(0.61–1.00)
(0.13–0.92)
(0.28–1.43)
Referent (0.30–1.35)
(0.42–1.56)
Referent
(0.72–1.37)
(0.53–1.69)
Referent
(0.56–1.23)
(0.51–1.46)
Referent
95 % CI
7 9
11
6
33
5
17
9
8 13
47
6
20
27
42
9
n
0.93
0.67 1.28
1
1.88
1
2.99
1.01
1.19
0.74
1 0.90
1.42
1
0.83
0.58
1
1.27
2.28
1
HR
(0.73–1.18)
(0.25–1.81) (0.41–3.98)
Referent
(0.68–5.17)
Referent
(1.12–7.98)
(0.84–1.22)
(0.49–2.92)
(0.28–1.96)
Referent (0.37–2.18)
(0.60–3.33)
Referent
(0.60–1.15)
(0.32–1.04)
Referent
(0.85–1.89)
(1.11–4.69)
Referent
95 % CI
8 8
17
7
40
3
8
11
12 14
49
8
31
14
35
16
n
1.09
0.69 1.43
1
1.18
1
1.06
0.85
0.53
0.76
1 0.73
1.09
1
1.25
1.78
1
0.80
1.03
1
HR
(0.86–1.38)
(0.28–1.71) (0.47–4.41)
Referent
(0.48–2.89)
Referent
(0.32–3.51)
(0.68–1.08)
(0.21–1.38)
(0.33–1.76)
Referent (0.34–1.58)
(0.52–2.31)
Referent
(0.93–1.69)
(0.94–3.37)
Referent
(0.52–1.21)
(0.56–1.86)
Referent
95 % CI
Basal-like phenotype
among women with 1–4 children who ever breastfed, adjusted for age, birth cohort, age at first birth and number of births
among women with 1–4 children, adjusted for age, birth cohort, age at first birth and number of births
adjusted for age, birth cohort and age at first birth
adjusted for age and birth cohort
Per 6 month increase
30
1–3 month
Breastfeeding (total duration)d, n = 12,607
Ever (C1 month)
Never
7
32
36
47 51
Breastfeeding (ever versus never)c, n = 13,423
Per birth
64 93
1 2
Number of births among parous womenb, n = 16,625
Parous
Nulliparous
Nulliparous versus parousa, n = 21,062
per 5 year increase
123
\25
Age at first birth (years)a, n = 16,625
per 2 year increase
136
\14
Age at menarche (years)a, n = 20,244
HR
n
95 % CI
n
HR
HER2 subtype
Luminal B (HER2-)
Luminal A
Luminal B (HER2?)
Non-luminal
Luminal
Table 3 Reproductive factors in relation to molecular breast cancer subtypes among 21,532 Norwegian women followed up from 1961 to 2008
8 5
6
0
19
3
5
10
2 8
27
5
14
11
19
12
n
1.06
1.11 0.87
1
–
1
3.85
0.91
1.43
3.50
1 2.40
1.08
1
0.90
0.86
1
0.71
0.68
1
HR
(0.79–1.43)
(0.36–3.42) (0.22–3.49)
Referent
–
Referent
(1.10–13.56)
(0.70–1.20)
(0.27–7.64)
(0.76–16.13)
Referent (0.51–11.35)
(0.41–2.83)
Referent
(0.60–1.35)
(0.39–1.92)
Referent
(0.41–1.21)
(0.33–1.42)
Referent
95 % CI
Five negative phenotype
0.92
0.55
0.06
0.40
0.66
0.50
0.10
0.03
0.38
0.09
p for heterogeneity
886 Cancer Causes Control (2014) 25:881–889
Cancer Causes Control (2014) 25:881–889
0.40–0.70 for C4 births vs. 1 birth). We observed no corresponding associations with the risk for non-luminal breast cancer. For the comparison of nulliparous versus parous women (p for heterogeneity = 0.05), but not for the other associations, there was some statistical evidence that the associations of reproductive factors differed between the risk for luminal and non-luminal tumors (Table 2). We found no association of breastfeeding with the risk for luminal breast cancer. However, breastfeeding was associated with the risk for non-luminal tumors. Thus, among parous women, never having breastfed was associated with an increased risk (HR 2.13, 95 % CI 1.11–4.07), compared to ever having breastfed, and the association of breastfeeding (ever vs. never) was statistically different between non-luminal and luminal tumors (p for heterogeneity = 0.02). Among women who had breastfed, there was no evidence that longer duration of breastfeeding was associated with a further reduction in risk for non-luminal breast cancer. Reproductive factors and the risk for each molecular breast cancer subtype We examined reproductive factors and risk for each of the luminal [Luminal A, Luminal B (HER2-) and Luminal B (HER2?)] and non-luminal (HER2 subtype, BP and 5NP) breast cancer subtypes (Table 3). Early age at menarche, late age at first birth and low parity were associated with a similar increase in breast cancer risk for all tumor subtypes except for HER2 subtype. For HER2 subtype, the results suggested that older age at menarche was associated with increased risk (HR 2.28, 95 % CI 1.11–4.69, comparing menarche at C14 vs. \14 years of age), that late age at first birth was associated with a reduced risk (HR 0.58, 95 % CI 0.32–1.04, comparing first birth at C25 vs.\25 years of age), and that a high number of births was not associated with reduced risk. For age at first birth (p for heterogeneity = 0.03), but not for age at menarche and parity, there was statistical evidence to suggest heterogeneity across subtypes. Among parous women, never having breastfed was associated with increased risk for HER2 (HR 2.99, 95 % CI 1.12–7.98) and 5NP subtypes (HR 3.85, 95 % CI 1.10–13.56), compared to ever having breastfed. For the other breast cancer subtypes, there was no association with breastfeeding, and there was some statistical evidence to suggest heterogeneity across subtypes (p for heterogeneity = 0.06).
Discussion In this population-based cohort of more than 21,000 Norwegian women, we examined reproductive factors and the risk of breast cancer subtypes. We found that young age at
887
menarche, high age at first birth and low parity were associated with increased risk for luminal breast cancer subtypes, but for HER2 subtype of breast cancer (a nonluminal form), we found either no associations, or associations that tended to be in the opposite direction of associations with the luminal subtypes. The BP subtype of nonluminal breast cancer appeared to have a similar reproductive risk factor profile as the luminal subtypes. Breastfeeding was associated with a reduced risk for HER2 subtype and 5NP breast cancer, but was not associated with risk for any other subtype. Strengths of this study include the population-based prospective design with long-term follow-up, the high attendance and the high comparability at baseline between women who participated and women who declined to participate [13]. As the participants were born between 1886 and 1928, few of them have been exposed to menopausal hormone treatment, and they have not been invited to systematic mammography screening, which are factors that most likely influence breast cancer incidence and tumor characteristics at diagnosis in more recent cohorts [19–22]. The original breast cancer diagnoses were revised by two pathologists, and the use of TMA technology enabled standardized conditions for immunohistochemical analyses. Unlike most previous studies, we analyzed the proliferation marker Ki67, yielding a better differentiation between luminal A and B tumors than in some other studies [10]. Also, the analyses of EGFR and CK5 enabled us to separate the BP subtype from the broader subgroup of triple-negative (ER negative, PR negative, HER2 negative) breast cancer [23]. Similar to previous studies, the relatively low number of HER2 subtype, BP and 5NP tumors precluded precise risk estimates for these subtypes and restricted the power to obtain statistical evidence for heterogeneity across subtypes. In this population, some of the cases could not be subtyped, but the distributions of hormone-receptor status, HER2 status and Ki67 among the subtyped cases were quite similar to those observed in other Scandinavian studies [24]. Also, the distribution of reproductive factors did not differ between breast cancer cases that either could, or could not be subtyped, which is reassuring in relation to possible selection bias of cases in the analysis. Due to the observational design of this study, we cannot rule out the possibility of uncontrolled confounding. For example, we had no available information on family history of breast cancer, history of benign breast disease or current alcohol consumption, and baseline measurements of height and weight were not conducted. Reproductive factors have been more strongly associated with risk for luminal than non-luminal breast cancer in other studies, whereas breastfeeding has been associated with a reduced risk for both luminal and non-luminal tumors [3,
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Cancer Causes Control (2014) 25:881–889
25–28]. Associations appear to be similar across subtypes of luminal breast cancer [6, 7, 29], but may differ between subtypes of non-luminal breast cancer [7, 30, 31]. Neither age at first birth nor parity have been associated with the risk of HER2 subtype breast cancer [6, 7, 29], except in one study that reported increased risk among women with a late first birth [8]. In contrast, a high age at first birth and low parity have been associated with a reduced risk for the BP [6, 7] or the triple-negative subtype that includes BP and 5NP tumors [9, 32]. However, other studies have reported no such associations [8, 26, 29, 33], consistent with the similar reproductive risk profile between BP and luminal subtypes in our data. Similar to our results, breastfeeding has been associated with a reduced risk for the HER2 subtype or HER2 gene amplified breast cancer (Luminal B (HER2?) and HER2 subtype) in some [30, 34] but not in other studies [6, 7, 33]. It has been suggested that the combination of multiparity and no breastfeeding may be associated with a particularly high risk for BP [7] and other non-luminal tumors [27, 30], but we could not examine that combination of exposures, because few (8 %) of the parous women in our cohort had never breastfed. The reasons why reproductive risk factors for nonluminal breast cancer subtypes differ between studies are not known, but could be related to different models for classifying the various subtypes or to differences between study populations. Compared to others, our cohort was homogenously Caucasian and not affected by menopausal hormonal treatment or organized mammography screening, and a high proportion of breast cancer cases were diagnosed in old age. The relatively low number of non-luminal breast cancer cases in each study is also likely to contribute to the inconsistencies in results, and meta-analyses of available data may increase our understanding of how reproductive risk factors are related to risk for the nonluminal breast cancer subtypes. In conclusion, this prospective population-based study provides evidence that the associations of reproductive factors with the risk for breast cancer may vary according to breast cancer subtypes. For luminal breast cancers, early menarche, a late first birth and low parity were associated with increased risk. For the HER2 subtype of non-luminal breast cancer, there was either no association, or the associations were in the opposite direction of associations with the luminal subtypes. For HER2 and 5NP subtypes, breastfeeding was associated with a reduced risk. Differences in reproductive risk factor profiles between non-luminal breast cancer subtypes are still poorly understood and warrant further study. Acknowledgments Cancer Society.
This study was funded by The Norwegian
Conflict of interest of interest.
The authors declare that they have no conflict
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