Affiliations of authors: Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden (HJ, HO); Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland (JL); Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE (HTL); Epidemiology Research Unit, Research Centre, Centre Hospitalier de l'Universitaire Montréal, CHUM Hôtel Dieu, Département de Nutrition, Faculté du Médicine, Québec, Canada (PG); Epidemiology Division, Center for Cancer Genetics Research & Prevention, College of Medicine, University of California, Irvine (SN); Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC (CI); Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia (BLW); British Columbia Cancer Agency, Vancouver, British Columbia, Canada (DH); Familial Ovarian Cancer Clinic, Princess Margaret Hospital, Toronto, Ontario, Canada (BR); Departments of Medicine, Human Genetics, and Oncology, McGill University, Montréal, Québec, Canada (WDF); The Suzanne Levy Gertner Oncogenetics Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel (EF); The Institute of Genetics, Rambat Medical Center, Haifa, Israel (RGB); London Regional Cancer Center, London, Ontario, Canada (PA); Division of Basic Science and Population Science, Fox Chase Cancer Center, Philadelphia, PA (MD); Department of Adult Oncology, Dana-Farber Cancer Center, Boston, MA (JG); Centre for Research in Women's Health, Women's College Hospital, University of Toronto, Canada (PS, SAN)
Correspondence to: Steven A. Narod, MD, FRCPC, Centre for Research in Women's Health, 790 Bay St., 7th Floor, Toronto, ON, Canada M5G 1N8 (e-mail: steven.narod{at}sw.ca)
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ABSTRACT |
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INTRODUCTION |
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To date, no large studies have examined the relationship between breast-feeding and breast cancer risk among women who carry deleterious mutations in the BRCA1 or BRCA2 gene. To establish whether there is an association between breast-feeding and the risk of breast cancer among women who carry a deleterious mutation in either the BRCA1 or BRCA2 gene, we performed a matched casecontrol study.
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METHODS |
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Eligible subjects were drawn from a database of women who carried a deleterious mutation in either the BRCA1 or the BRCA2 gene. These women have been assessed for genetic risk at 53 centers located throughout North America, Europe, and Israel. All study subjects provided written informed consent for genetic testing. The study was approved by the ethics committees of all participating centers.
For most women, genetic testing was offered initially to those who were affected by either breast or ovarian cancer. Subsequently, testing was offered to their relatives. After a mutation in either the BRCA1 or BRCA2 gene was found in a proband or in her relative, genetic testing was offered to other at-risk women in the family. However, for less than 10% of the study subjects, an affected woman in a family was not available for genetic testing, and an unaffected woman was the first in the family to receive genetic testing.
Mutations in BRCA1 or BRCA2 genes were detected by using several techniques, but all nucleotide sequences were confirmed with direct sequencing of DNA. A woman was eligible for the present study after molecular analysis established that she was a carrier of a known deleterious BRCA1 or BRCA2 mutation.
Case and Control Subjects
Data were collected on breast-feeding for 1927 women with invasive breast cancer who carried a BRCA1 or BRCA2 mutation (case subjects) and for 2032 women without invasive breast cancer who carried such a mutation (potential control subjects). Case subjects were excluded if they had been diagnosed with ovarian cancer (n = 200), had undergone bilateral oophorectomy prior to diagnosis (n = 188), had incomplete data on pregnancies (n = 48) or on oral contraceptive use (n = 18), leaving 1473 eligible case subjects. Case and control subjects were matched on year of birth (±2 years), country of residence, and gene with the mutation (BRCA1 or BRCA2). Control subjects were excluded if they had been diagnosed with ovarian cancer (n = 403), had undergone prophylactic oophorectomy before the age of the case subject at diagnosis (n = 107), or data were missing on pregnancies (n = 20) or on oral contraceptive use (n = 19). Control subjects were eligible for matching if they were cancer-free and had not had a prophylactic mastectomy before the age of the case subject at diagnosis of breast cancer. In total, 965 matched pairs were generated: 685 casecontrol pairs who carried BRCA1 mutations and 280 casecontrol pairs who carried BRCA2 mutations. The only variables considered in assessing exposures were pregnancies, breast-feeding, and oral contraceptive use before the age of diagnosis in the matched case subject. The mean year of diagnosis of the case subjects was 39 years (range = 1871 years). On average, the time between diagnosis of breast cancer in the case subject and the completion of the study questionnaire was 8.2 years.
In a second analysis, we excluded nulliparous women and matched case and control subjects on parity. Women who had experienced a stillbirth or reported an early infant death were also excluded because they would have had no opportunity to breast-feed the child. After matching for parity, the analysis included 481 casecontrol pairs who carried BRCA1 mutations and 172 casecontrol pairs who carried BRCA2 mutations.
Breast-feeding Information
The total months of breast-feeding for each pregnancy was reported. For women who gave an approximate length of breast-feeding (e.g., 35 months), the midpoint of duration was used. The year of breast cancer diagnosis and years of all pregnancies were recorded; however, if both occurred during the same calendar year, it was not possible to establish the sequence of breast cancer and pregnancy. Therefore, we included only live births that occurred at least one calendar year before a diagnosis of breast cancer. Twin births were considered to be one birth with respect to breast-feeding. Exposure information on control subjects (e.g., breast-feeding, parity) was restricted to the period before the date of a diagnosis of breast cancer in the matched case subject.
Data and Statistical Analysis
Breast-feeding histories were compared between matched case and control subjects. The paired Student's t test was used for comparing continuous variables among case and control subjects. Conditional logistic regression was used to estimate odds ratios (ORs) in the univariate and multivariate analyses. In the first analysis, parity and oral contraceptive use were used as covariate variables. Because of the strong association between parity and breast-feeding, we performed a second analysis that excluded all nulliparous women, in which we generated a new set of casecontrol pairs that were matched for parity. All analyses were adjusted for oral contraceptive use. All P values were two-tailed. Statistics were generated using the SAS statistical package, version 8.2 (SAS Institute, Cary, NC).
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RESULTS |
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Because there was a strong relationship between parity and breast-feeding, the data were also analyzed after excluding nulliparous women and matching case and control subjects for parity. The result of this matched analysis was essentially the same as that in which we did not match for parity. Women with a deleterious BRCA1 mutation who had breast-fed their children for more than 1 year were statistically significantly less likely to have breast cancer than those who had not breast-fed their children (OR = 0.53, 95% CI = 0.36 to 0.77; P<.001). Women with a deleterious BRCA2 mutation who breast-fed for more than 1 year had a statistically nonsignificantly reduced risk of breast cancer than women who breast-fed for less than 1 year (OR = 0.67, 95% CI = 0.34 to 1.26; P = .25).
Breast-feeding practices differed between subjects from different countries (Table 3). In all countries, with the exception of Israel, case subjects carrying deleterious BRCA1 mutations reported a shorter mean duration of breast-feeding than control subjects. Among women from all countries, a consistent reduced risk of breast cancer was associated with breast-feeding for 1 year or more (Table 4), but the association was statistically significant only for women from the United States.
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DISCUSSION |
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In the present study, the reasons for not starting breast-feeding or for stopping breast-feeding were not recorded. It is possible that breast-feeding is not associated with a reduced risk of breast cancer but that women with BRCA1 mutations who have difficulty in breast-feeding are at greater risk for breast cancer than carriers who have no trouble breast-feeding. We previously reported that a high proportion of women who carry a BRCA1 mutation cited poor milk production as the main reason for weaning their infants compared with female relatives who do not carry a BRCA1 mutation (10). One study of women with nonhereditary breast cancer found that the risk of breast cancer was increased among women who tried to breast-feed but could not (11).
How breast-feeding is associated with a reduced risk of breast cancer is unclear but may be related to changes in mammary gland differentiation or to effects on breast estrogen levels. The mammary gland develops at puberty and undergoes developmental changes with each pregnancy (12,13). During the first part of each pregnancy, the breast epithelium proliferates rapidly, and then the breast tissue undergoes a final differentiation during the final months of the pregnancy. As a result, the parous breast contains a higher percentage of well-differentiated lobules than the nonparous breast (14). Lobuloalveolar differentiation is stimulated by estrogen, progesterone, placental lactogen, placental growth hormone, oxytocin, and prolactin. After delivery, lactation begins as a result of increasing prolactin levels. When prolactin levels decline, postlactational regression occurs and the glands involute (15). Because breast fluid estrogen levels are suppressed for several years after breast-feeding (16), lactation may diminish breast cancer risk by altering the hormonal milieu directly. Breast-feeding may also reduce the risk of breast cancer indirectly by delaying the re-establishment of ovulation (17). Indeed, women who breast-fed exclusively during the first 6 months postpartum have a low (1%5%) rate of ovulation (18), and the number of lifetime ovulations has been linked to breast cancer risk. In support of this association, we observed a small but statistically significant difference in the age of menarche between our case and control subjects (Table 1).
BRCA1 is critical to both appropriate proliferation and differentiation within the mammary gland. In the murine mammary gland, Brca1 expression is increased during puberty and pregnancy, possibly to limit proliferation and to promote differentiation (19). There is also evidence from human cell culture systems that BRCA1 suppresses estrogen-mediated breast cell proliferation (20). BRCA1 is also important in mammary development; mammary tissue from mice with a mammary-specific Brca1 deletion does not develop normally and does not differentiate during pregnancy and lactation (21). Results from other animal models have demonstrated that the susceptibility of the mammary gland to cancer is related to the rate of proliferation of breast epithelial cells and is inversely related to the degree of differentiation (13).
Individuals with low levels of BRCA1 may have increased breast epithelial cell proliferation in response to the increased estrogen exposure of pregnancy. Russo et al. (14,22) reported that breast tissue from parous women with a family history of breast cancer or a BRCA1 mutation does not differentiate normally and resembles breast tissue from nulliparous women.
We used a casecontrol approach to study the relationship between breast-feeding and breast cancer. Because of our large sample size, we were able to assess the effect separately for women who carry deleterious BRCA1 or BRCA2 mutations. We controlled for parity, which is strongly correlated with breast-feeding and is a risk factor for hereditary breast cancer (23), by making two different adjustments. The results were similar regardless of which adjustment for parity was used.
Several possible biases could affect our results. Information on breast-feeding was obtained after childbearing was completed; for case subjects, information was obtained after the diagnosis of breast cancer. If there is differential reporting of breast-feeding by case and control subjects, then recall bias is possible. However, there is no obvious reason why case subjects should be less likely to recall breast-feeding their children than control subjects. Furthermore, study subjects did not know their BRCA mutation status when their children were born, and if recall bias were present, it is not clear why the association should be restricted to BRCA1 carriers.
Our data support the hypothesis that hormonal and reproductive factors modify the risk of breast cancer among women with BRCA1 mutations (24). We found that 1 or more years of breast-feeding in women with deleterious BRCA1 mutations was associated with a reduction in breast cancer risk of 45%an effect that is much greater than that seen in the general population (8). In a large multicenter casecontrol study of patients with breast cancer from 30 countries, breast-feeding for 12 months or more was associated with a reduced risk of breast cancer of 4.3% (8). In our study, we found no association between breast cancer risk and breast-feeding for women with BRCA2 mutations; the difference between women with BRCA1 and BRCA2 mutations may reflect underlying differences in the pathogenesis of cancers associated with the two genes. However, because our sample of women with BRCA2 mutations was small, it is premature to conclude that a modest reduced risk is not present in this subgroup as well.
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NOTES |
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REFERENCES |
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Manuscript received October 20, 2003; revised May 18, 2004; accepted May 27, 2004.
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