Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers

Early age at first birth and multiparity have been associated with a decrease in the risk of breast cancer in women in the general population. We examined whether this relationship is also present in women at high risk of breast cancer due to the presence of a mutation in either of the 2 breast cancer susceptibility genes, BRCA1 or BRCA2. We performed a matched case-control study of 1,260 pairs of women with known BRCA1 or BRCA2 mutations, recruited from North America, Europe and Israel. Women who had been diagnosed with breast cancer were matched with unaffected control subjects for year of birth, country of residence, and mutation (BRCA1 or BRCA2). Study subjects completed a questionnaire detailing their reproductive histories. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by conditional logistic regression. Among BRCA1 carriers, parity per se was not associated with the risk of breast cancer (OR for parous vs. nulliparous = 0.94; 95% CI = 0.75-1.19; p = 0.62). However, women with a BRCA1 mutation and 4 or more children had a 38% decrease in breast cancer risk compared to nulliparous women (OR = 0.62; 95% CI = 0.41-0.94). In contrast, among BRCA2 carriers, increasing parity was associated with an increased risk of breast cancer; women with 2 or more children were at approximately 1.5 times the risk of breast cancer as nulliparous women (OR = 1.53; 95% CI = 1.01-2.32; p = 0.05). Among women with BRCA2 mutations and who were younger than age 50, the (adjusted) risk of breast cancer increased by 17% with each additional birth (OR = 1.17; 95% CI = 1.01-1.36; p = 0.03). There was no significant increase in the risk of breast cancer among BRCA2 carriers older than 50 (OR for each additional birth = 0.97; 95% CI = 0.58-1.53; p = 0.92). In the 2-year period following a birth, the risk of breast cancer in a BRCA2 carrier was increased by 70% compared to nulliparous controls (OR = 1.70; 95% CI = 0.97-3.0). There was a much smaller increase in breast cancer risk among BRCA2 carriers whose last birth was 5 or more years in the past (OR = 1.24; 95% CI = 0.79-1.95). A modest reduction in risk of breast cancer was observed among BRCA1 carriers with 4 or more births. Among BRCA2 carriers, increasing parity was associated with a significant increase in the risk of breast cancer before age 50 and this increase was greatest in the 2-year period following a pregnancy.     

Impact of menstrual and reproductive factors on breast cancer risk in Japan: results of the JACC study

The incidence of breast cancer among Japanese women, a traditionally low-risk population, has increased substantially. To evaluate the association of reproductive factors with breast cancer risk, we examined 38,159 Japanese women, aged 40-79 years, who responded to a questionnaire on reproductive and other lifestyle factors from 1988 to 1990 in the Japan Collaborative Cohort Study. During an average 7.6 years of follow-up, we documented 151 incidents of breast cancers. Cox proportional hazards modeling was employed to estimate relative risks (RR) and 95% confidence intervals (CI). There was a significant decline in the risk of breast cancer with increasing parity among parous women (trend P=0.01). Women with four or more parities had a 69% lower risk than uniparous women, a reduced risk was also evident among menopausal women. Breast cancer risk tended to rise with increasing age at first delivery (trend P=0.05), the association being very apparent among menopausal women (trend P=0.02). Compared to the women who had their first delivery before age 25, those who delayed this event until after age 34 had an RR of 2.12 (95% CI: 0.72-6.21) and 3.33 (1.07-10.3) among the overall subjects and the menopausal, respectively. There was no apparent association of breast cancer risk with age at menarche or menopause. Our study concerning reproductive risk factors suggests that breast cancer in Japan is similar to that in Western countries, and that reproductive factors, particularly the number of parity and age at first delivery, might be important in the etiology of breast cancer among Japanese women.     

Analysis of menstrual, reproductive, and life-style factors for breast cancer risk in Turkish women: a case-control study

The aim of this study was to investigate the association between menstrual, reproductive, and life-style factors and breast cancer in Turkish women. In a hospital-based case-control study in Ankara, 622 patients with histologically confirmed breast cancer were compared with 622 age-matched controls, admitted to the same hospital for acute and non-neoplastic diseases. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) related to risk factors. Overall, menopausal status and age at menopause were found to be significantly associated with breast cancer. Having a full-term pregnancy and early age at first birth were associated with decreased breast cancer risk (OR = 0.45, 95% CI = 0.30-0.66; OR = 0.34, 95% CI = 0.22-0.53, respectively). Postmenopausal women with lactation longer than 48 mo had reduced risk of breast cancer (OR = 0.36, 95% CI = 0.14-0.93). In conclusion, decreased parity, late age at first birth, early menopause, and shorter duration of lactation were the most important determinants of breast cancer risk in Turkish women.     

Specific fatty acid intake and the risk of pancreatic cancer in Canada

The possible association of specific fatty acid (FA) intake and pancreatic cancer risk was investigated in a population-based case-control study of 462 histologically confirmed cases and 4721 frequency-matched controls in eight Canadian provinces between 1994 and 1997. Dietary intake was assessed by means of a self-administered food frequency questionnaire. Unconditional logistic regression was used to assess associations between dietary FAs and pancreatic cancer risk. After adjustment for age, province, body mass index, smoking, educational attainment, fat and total energy intake, statistically significant inverse associations were observed between pancreatic cancer risk and palmitate (odds ratios (ORs)=0.73; 95% confidence intervals (CIs) 0.56-0.96; P-trend=0.02), stearate (OR=0.70; 95% CI 0.51-0.94; P-trend=0.04), oleate (OR=0.75; 95% CI 0.55-1.02; P-trend=0.04), saturated FAs (OR=0.67; 95% CI 0.50-0.91; P-trend=0.01), and monounsaturated FAs (OR=0.72; 95% CI 0.53-0.98; P-trend=0.02), when comparing the highest quartile of intake to the lowest. Significant interactions were detected between body mass index and both saturated and monounsaturated FAs, with a markedly reduced risk associated with intake of stearate (OR=0.36; 95% CI 0.18-0.70; P-trend=0.001), oleate (OR=0.36; 95% CI 0.19-0.72; P-trend=0.002), saturated FAs (OR=0.35; 95% CI 0.18-0.67; P-trend=0.002), and monounsaturated FAs (OR=0.32; 95% CI 0.16-0.63; P-trend<0.0001) among subjects who are obese. The results suggest that substituting polyunsaturated FAs with saturated or monounsaturated FAs may reduce pancreatic cancer risk, independently of total energy intake, particularly among obese subjects.     

Analysis of menstrual, reproductive, and life-style factors for breast cancer risk in Turkish women

The aim of this study was to investigate the association between menstrual, reproductive, and life-style factors and breast cancer in Turkish women. In a hospital-based case-control study in Ankara, 622 patients with histologically confirmed breast cancer were compared with 622 age-matched controls, admitted to the same hospital for acute and non-neoplastic diseases. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) related to risk factors. Overall, menopausal status and age at menopause were found to be significantly associated with breast cancer. Having a full-term pregnancy and early age at first birth were associated with decreased breast cancer risk (OR=0.45, 95% CI=0.30–0.66; OR=0.34, 95% CI=0.22–0.53, respectively). Postmenopausal women with lactation longer than 48 mo had reduced risk of breast cancer (OR=0.36, 95% CI=0.14–0.93). In conclusion, decreased parity, late age at first birth, early menopause, and shorter duration of lactation were the most important determinants of breast cancer risk in Turkish women.     

Differences in breast cancer risk factors by tumor marker subtypes among premenopausal Vietnamese and Chinese women.

We evaluated associations between reproductive and lifestyle risk factors with breast cancer tumor marker status in a case-control study. Cases were premenopausal women living in Vietnam and China who were eligible for a clinical trial of oophorectomy and tamoxifen as treatment for breast cancer (n = 682). Controls were nonrelative hospital visitors, matched on age to the cases (n = 649). Immunohistochemical analysis was used to identify the presence of estrogen receptor (ER) and progesterone receptor and the overexpression of HER-2/neu oncogene. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression, adjusted for known confounders. Overall, 280 (61%) tumor samples were ER positive and 176 (38%) were ER negative. HER-2/neu overexpression was detected in 161 (35%) samples, whereas 286 (26%) samples were HER-2/neu negative. We observed an inverse trend between increasing parity and decreasing breast cancer risk (P = 0.002). Women ages > or =25 years at first birth had increased breast cancer risk compared with women ages <25 years at first birth (OR, 1.53; 95% CI, 1.20-1.95). Women who consumed alcohol had increased risk of breast cancer compared with women who did not (OR,1.85; 95% CI, 1.32-2.61). Compared with controls, OR estimates for breast cancer by parity and age at first birth were significantly associated with ER and/or HER-2/neu tumor status by Wald test (P < 0.05). Family history, age at menarche, cumulative lactation, body mass index, and education were not significantly related to breast cancer risk. Our findings support the hypothesis that some breast cancer risk factors differ by ER and HER-2/neu tumor marker subtypes.     

Reproductive factors and risk of premenopausal breast cancer by age at diagnosis: Are there differences before and after age 40?

We examined the relationship between reproductive factors and risk of premenopausal breast cancer among women less than age 40 compared with older premenopausal women. We documented 374 incident cases of breast cancer diagnosed before age 40, and 2,533 cases diagnosed at age 40 and older among premenopausal women in the Nurses’ Health Study cohorts. Biennial questionnaires were used to determine age at menarche, age at first birth, parity, breastfeeding, and other reproductive factors. Multivariate relative risks (RR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models within age at diagnosis groups. Tumors in younger women were significantly more likely to be higher grade, larger size, and hormone receptor negative than were tumors in older premenopausal women (p < 0.0001). There was no significant heterogeneity according to age in associations between reproductive factors and risk of premenopausal breast cancer. First birth at age 30 or older increased breast cancer risk in both age groups (age <40: RR 1.10, 95 % CI 0.80–1.50; age ≥40: RR 1.16, 95 % CI 1.02–1.32; p-heterogeneity = 0.44). Risk of premenopausal breast cancer decreased with each additional year of age at menarche in both age groups (age <40: RR 0.93, 95 % CI 0.87–0.99; p trend = 0.02; age ≥40: RR 0.94, 95 % CI 0.91–0.97; p trend = <0.0001). Among premenopausal parous women, breastfeeding was protective regardless of age at diagnosis (age <40: RR 0.84, 95 % CI 0.57–1.22; age ≥40: RR 0.85, 95 % CI 0.72–0.99; p-heterogeneity = 0.79). In the largest prospective examination of reproductive risk factors and risk of breast cancer before and after age 40, we found that younger women were more likely to develop tumors with less favorable prognostic characteristics. However, associations between reproductive factors and risk of breast cancer were similar regardless of age at diagnosis of premenopausal breast cancer.     

Effects of Menstrual and Reproductive Factors on the Risk of Breast Cancer: Meta-analysis of the Case-Control Studies in Japan

To elucidate the magnitude of the effect of menstrual and reproductive factors on breast cancer occurrence among Japanese women, we reviewed eight case-control studies previously conducted in Japan and used a quantitative method (meta-analysis) to summarize the data. While individual studies have different methods and populations, the estimated odds ratios (ORs) in the studies were statistically homogeneous for all study variables. It was confirmed that early age at menarche, late age at first birth, and premenopausal status are significantly associated with risk of breast cancer; an estimated combined OR of 0.68 (95% confidence interval (CI): 0.59-0.77) was obtained for women with onset of menstruation after age 16 compared to those before age 14. Nulliparous women had higher risk than women with first birth before age 25 (OR=1.56 95%, CI: 1.27-1.91). The OR for women with first birth after age 35 was 2.26 (95% CI: 1.85-2.77) compared to women at first birth before age 25. Premenopausal women had a higher risk than women with menopause before age 50 (OR=2.21, 95% CI: 1.53-3.20). We also found a significant protective effect of high parity after controlling for age at first birth and the other menstrual factors. The OR estimate for 3 or more births compared to nulliparity was 0.68 (95% CI: 0.54-0.86). The meta-analysis provided quantitative estimates of breast cancer risk among Japanese women with improved precision.     

The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer

The A2 allele of CYP17 has been associated with polycystic ovarian syndrome, elevated levels of certain steroid hormones in premenopausal women, and increased breast cancer risk. We prospectively assessed the association between the A2 allele of CYP17 and breast cancer risk in a case-control study nested within the Nurses' Health Study cohort. We also evaluated associations between this CYP17 genotype and plasma steroid hormone levels among postmenopausal controls not using hormone replacement to assess the biological significance of this genetic variant. Women with the A2 allele were not at an increased risk of incident breast cancer [OR (odds ratio), 0.85; 95% CI (confidence interval), 0.65-1.12] or advanced breast cancer (OR, 0.84; 95% CI, 0.54-1.32). We did observe evidence that the inverse association of late age at menarche with breast cancer may be modified by the CYP17 A2 allele. The protective effect of later age at menarche was only observed among women without the A2 allele (A1/A1 genotype: for age at menarche > or =13 versus <13; OR, 0.57; 95% CI, 0.36-0.90; A1/A2 and A2/A2 genotypes: OR, 1.05; 95% CI, 0.76-1.45; P for interaction = 0.07). Among controls, we found women with the A2/A2 genotype to have elevated levels of estrone (+14.3%, P = 0.01), estradiol (+13.8%, P = 0.08), testosterone (+8.6%, P = 0.34), androstenedione (+17.1%, P = 0.06), dehydroepiandrosterone (+14.4%, P = 0.02), and dehydroepiandrosterone sulfate (+7.2%, P = 0.26) compared with women with the A1/A1 genotype. These data suggest that the A2 allele of CYP17 modifies endogenous hormone levels, but is not a strong independent risk factor for breast cancer.     

Is birth history the key to highly educated women's higher breast cancer mortality? A follow‐up study of 500,000 women aged 35–54

A positive relationship has been found between high levels of education and breast cancer mortality. The aim of our study is to determine if the educational gradient in breast cancer mortality persists after adjustment for reproductive history. Register data including the total adult population in Norway were used. A total of 512,353 Norwegian women 35-54 years of age at the Norwegian Census in 1990 were followed with respect to breast cancer deaths until December 31, 2001. The analysis included 2,052 breast cancer deaths in 5.6 million person years. Educational differences in breast cancer mortality were analysed using Cox regression. The age adjusted relative risk of dying from breast cancer for women with >12 years of education compared to women with <10 years was 1.25 (95% confidence limits [CI] = 1.10-1.41). Adjustment for age at first birth with nulliparous as reference category reduced this difference to 1.08 (95% CI = 0.95-1.23). For parous women, age at first birth explained all the educational difference in breast cancer mortality. Among nulliparous women there was a larger positive educational gradient in breast cancer mortality than among parous women (relative risk [RR] = 1.57, 95% CI = 1.15-2.13), indicating that there were differences in other confounders than birth history among the childless.     

Plasma prolactin concentrations and risk of postmenopausal breast cancer

Prolactin is important in human breast development, and substantial laboratory and in vitro data suggest a role in mammary carcinogenesis. Therefore, we conducted a prospective case-control study nested within the Nurses' Health Study cohort to examine, in detail, the association between plasma prolactin concentrations and postmenopausal breast cancer by cancer invasiveness, estrogen receptor/progesterone receptor status, and other subject characteristics, including postmenopausal hormone use. Blood samples were collected from 1989 to 1990 and prolactin was measured by microparticle enzyme immunoassay. The analysis included 851 cases of postmenopausal breast cancer diagnosed after blood collection and before June 2000, in which there were one or two controls (n=1,275) matched on age, postmenopausal hormone use, fasting status, and time of day and month of blood collection. Prolactin was associated with a modestly increased risk of postmenopausal breast cancer [relative risk, top versus bottom quartile, 1.34; 95% confidence interval (CI), 1.02-1.76; P-trend = 0.01]. The association differed by estrogen receptor/progesterone receptor status (P-heterogeneity=0.03). The relative risk was 1.78 (95% CI, 1.28, 2.50; P-trend < 0.001) for estrogen receptor+/progesterone receptor+, 0.76 (95% CI, 0.43, 1.32; P-trend=0.28) for estrogen receptor-/progesterone receptor-, and 1.94 (95% CI, 0.99, 3.78; P-trend=0.12) for estrogen receptor+/progesterone receptor- breast cancers. Associations generally were similar for ductal and lobular carcinomas (P-heterogeneity=0.43) and by tumor size (P-heterogeneity=0.24). Among estrogen receptor+/progesterone receptor+ cancers, the association did not significantly differ by postmenopausal hormone use, years between blood draw and diagnosis, or after adjustment for estradiol (relative risk, 1.93; 95% CI, 1.16, 3.22; P-trend=0.01). Our prospective data suggest that plasma prolactin concentrations are associated with an increased risk of postmenopausal breast cancer, particularly for estrogen receptor+/progesterone receptor+ cancers, and independently of estradiol.     

Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers

Women with a BRCA1 or BRCA2 mutation have an elevated risk of breast cancer and of contralateral breast cancer. In this study, we estimate the risk of non-synchronous ipsilateral breast cancer after a diagnosis of breast cancer in BRCA carriers and evaluate the effects of various treatments on this risk. Patients were 396 women with stage I or stage II breast cancer with an intact ipsilateral breast and for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until the first of ipsilateral mastectomy, ipsilateral breast cancer, death or last follow-up. The 5-year actuarial risk of ipsilateral breast cancer was 5.8% (95% CI 3.2-8.4%) and the 10-year risk was 12.9% (95% CI 8.7-17.1%). Subjects who received chemotherapy had a significantly lower risk of ipsilateral breast cancer compared to those who did not receive chemotherapy (RR 0.45; 95% CI 0.24-0.84; P = 0.01). Radiotherapy was associated with a reduced risk of ipsilateral breast cancer (RR 0.28; 95% CI 0.12-0.63; P = 0.002). Oophorectomy was associated with a significant reduction in the risk of ipsilateral breast cancer (RR 0.33; 95% CI; 0.13-0.81; P = 0.02). On average, following a diagnosis of breast cancer, the annual risk of ipsilateral breast cancer risk in BRCA mutation carriers is 1.2% per year. For women treated with chemotherapy, radiation therapy or oophorectomy the risk is low, compared to women who did not receive any of these treatments.     

Myocardial infarction risk and tamoxifen therapy for breast cancer

Tamoxifen prevents recurrence after breast cancer and breast cancer among high-risk women, and may prevent myocardial infarction (MI). To assess the impact of tamoxifen on MI risk, we conducted a case-control study of first MI after breast cancer nested among women diagnosed with breast cancer, while enrolled in a health maintenance organisation from 1980 to 2000. We obtained information on breast cancer treatment and MI risk factors through medical record reviews and interviews. Data were analysed using conditional logistic regression. Of 11,045 women with breast cancer, 134 met MI criteria and were matched to two MI-free control subjects on year of birth and breast cancer diagnosis. After adjusting for smoking, hypertension and diabetes, tamoxifen was unassociated with MI (odds ratio (OR)=1.2, 95% confidence interval (CI)=0.7-1.9). Duration, cumulative dose and recency of use were not associated with MI. Radiation therapy was associated with MI (OR=2.0, 95% CI=1.1-3.5), an association that varied slightly but not statistically significantly by tamoxifen use (radiation with tamoxifen, OR=2.0, 95% CI=0.9-4.4; radiation without tamoxifen, OR=2.9, 95% CI=1.2-7.5). Tamoxifen treatment for breast cancer does not appear to increase or decrease MI risk, although radiation therapy appears to increase MI risk.     

The relation of reproductive factors to mortality from breast cancer.

Young women with breast cancer have been reported to have an increased risk of dying from their disease if they have given birth in <2 years before diagnosis. The prognostic factors associated with the tumors of these women have not been thoroughly studied. We examined the tumors of the women who had a recent birth and compared the tumor characteristics with those of women who were nulliparous or had given birth > or =5 years before diagnosis. A follow-up study was conducted of 1174 women <45 years old whose invasive ductal breast cancer was diagnosed from January 1983 to December 1992 in three counties of western Washington. These women had participated previously in a population-based, case-control study. Mean follow-up time was 105.4 months. Histological slides were collected for 79.1% of the tumors and reviewed by the study pathologist. Using immunoperoxidase assays, tumor tissue was tested for prognostic markers for 70.4% of the tumors from the women. Cox proportional hazards models were used to estimate the relative risk of dying from breast cancer associated with reproductive events. Logistic regression was used to obtain estimates of the association between various reproductive factors and tumor characteristics. At the end of follow-up, 48.2% of the women (n = 83) whose last birth occurred in < 2 years of diagnosis had died, compared with 23.3% of nulliparous women (n = 189) and 24.4% of the women (n = 661) whose last birth was > or =5 years before diagnosis. The tumors of the women with a recent birth (<2 years before diagnosis) were more likely to be progesterone receptor negative, odds ratio (OR) = 2.2, 95% confidence interval (CI) = 1.2-3.9, to be p53 positive, OR = 2.6, 95% CI = 1.5-4.7, to be of high histological grade, OR = 5.9, 95% CI = 1.7-20.1, to have high mitotic count, OR = 2.2, 95% CI = 1.4-4.4, to be node positive, OR = 2.1, 95% CI = 1.3-3.5, to have a high S phase fraction, OR = 2.3, 95% CI = 1.1-4.8, and to have a high American Joint Committee on Cancer stage (III+), OR = 2.8, 95% CI 1.3-5.8, compared with the tumors of nulliparous women. After adjusting for tumor characteristics and treatment, the risk of mortality associated with a birth in < 2 years of diagnosis of breast cancer remained an independent predictor of mortality, hazard radio (HR) = 2.7, 95% CI = 1.6-4.3. Our study provides evidence that reproductive factors influence the biological behavior of breast cancer in young women and prognosis. Clinicians need to be aware that women who have delivered a child in < 2 years before diagnosis are at increased risk of having tumors with especially adverse prognostic profiles and have a poorer survival rate than women who are nulliparous or whose last birth was some years in the past.     

Menstrual and reproductive factors in relation to ovarian cancer risk

We assessed menstrual and reproductive factors in relation to ovarian cancer risk in a large, population-based, case-control study. 563 cases in Massachusetts and New Hampshire were ascertained from hospitals and statewide tumour registries; control women (n = 523) were selected through random digit dialing and matched to case women by age and telephone sampling unit. We used multivariate logistic regression to evaluate factors in relation to risk of ovarian cancer and the major tumour histologic subtypes. Ovarian cancer risk was reduced among parous women, relative to nulliparous women (OR = 0.4; 95% CI = 0.3-0.6). Among parous women, higher parity (P = 0.0006), increased age at first (P = 0.03) or last (P = 0.05) birth, and time since last birth (P = 0.04) were associated with reduced risk. Early pregnancy losses, abortions, and stillbirths were unrelated to risk, but preterm, term, and twin births were protective. Risk was lower among women who had breast-fed, relative to those who had not (OR = 0.7; 95% CI = 0.5-1.0), but the average duration of breast-feeding per child was unrelated to risk (P for trend = 0.21). Age at menarche and age at menopause were unrelated to risk overall, although increasing menarcheal age was protective among premenopausal women (P = 0.02). Menstrual cycle characteristics and symptoms were generally unrelated to risk, although cycle-related insomnia was associated with decreased risk (OR = 0.5; 95% CI = 0.3-0.8). We found no association between the type of sanitary product used during menstruation and ovarian cancer risk. In analyses by histologic subtype, reproductive and menstrual factors had most effect on risk of endometrioid/clear cell tumours, and least influential with regard to risk of mucinous tumours. Overall, our findings offer some support to current hypotheses of ovarian pathogenesis, and show aetiologic differences among the tumour subtypes.     

Reproductive history in relation to breast cancer risk among Hispanic and non-Hispanic white women

Objective To evaluate reproductive history risk factors in breast cancer among Hispanic (HISP) women in the U.S. southwest, a population with approximately 33% lower breast cancer incidence than non-Hispanic whites (NHW). Methods Population-based case–control study of HISP (796 cases, 919 controls) and NHW (1,525 cases, 1,596 controls) women. Results 19.3% of HISP women reported five or more births and had a reduced risk of breast cancer, adjusted odds ratio (OR) 0.70 (95% confidence interval (CI): 0.50, 0.98) compared to those with one or two births. Breast cancer risk for HISP increased with older age at first birth, p trend = 0.008. Parity and age at first birth associations were specific to ER positive tumors. HISP women who had given birth within five years had higher breast cancer risk than women with 16–25 years since a birth, OR 2.62 (95% CI: 1.44, 4.78); the trend with years since last birth was stronger than for NHWs, p interaction = 0.05. Conclusions Reproductive history influences on breast cancer risk among HISP were similar to associations reported for NHWs. Differences in the prevalence of reproductive risk factors would explain an estimated 6.6% lower breast cancer incidence for HISP compared to NHWs.     

Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers

INTRODUCTION: Breastfeeding has been inversely related to breast cancer risk in the general population. Clarifying the role of breastfeeding among women with a BRCA1 or BRCA2 mutation may be helpful for risk assessment and for recommendations regarding prevention. We present an updated analysis of breastfeeding and risk of breast cancer using a large matched sample of BRCA mutation carriers. METHODS: We conducted a case-control study of 1,665 pairs of women with a deleterious mutation in either BRCA1 (n = 1,243 pairs) or BRCA2 (n = 422 pairs). Breast cancer cases and unaffected controls were matched on year of birth, mutation status, country of residence and parity. Information about reproductive factors, including breastfeeding for each live birth, was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the association between ever having breastfed, as well as total duration of breastfeeding, and the risk of breast cancer. RESULTS: Among BRCA1 mutation carriers, breastfeeding for at least one year was associated with a 32% reduction in risk (OR = 0.68; 95% CI 0.52 to 0.91; P = 0.008); breastfeeding for two or more years conferred a greater reduction in risk (OR = 0.51; 95% CI 0.35 to 0.74). Among BRCA2 mutation carriers, there was no significant association between breastfeeding for at least one year and breast cancer risk (OR = 0.83; 95% CI 0.53 to 1.31; P = 0.43). CONCLUSIONS: These data extend our previous findings that breastfeeding protects against BRCA1-, but not BRCA2-associated breast cancer. BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk.     

HSD17B1 and CYP17 polymorphisms and breast cancer risk among Chinese women in Singapore

Reasons for the recent trend of increasing breast cancer incidence among Chinese and other Asian women are not well understood. Endogenous estrogen levels are strongly associated with breast cancer risk and its determinants include both genetic and lifestyle factors. We conducted a nested case-control study to investigate, within the Singapore Chinese Health Study Cohort, the relationships between polymorphisms in 2 genes involved in estrogen metabolism, CYP17 and HSD17B1, and the risk of breast cancer. For this analysis, 188 incident breast cancer cases and 671 female cohort control subjects were compared. When the HSD17B1 A allele was considered as the "putative high-risk" allele, there was a modest increased risk (adjusted relative risk, RR=1.37, 95% CI=0.90-2.07 for HSD17B1 AA vs. other); this association was statistically significant in analysis restricted to postmenopausal women (RR=1.86, 95% CI=1.14-3.03). There was no significant association between the CYP17 MspAI polymorphism and risk in all subjects (RR=1.06, 95% CI=0.65-1.74 for CYP17 A2A2 vs. CYP17 A1A1) or in postmenopausal women only. When we evaluated breast cancer risk in relation to the joint stratification of CYP17 and HSD17B1 genotypes and according to the combined number of putative high-risk alleles (range, 0-4), we observed an elevated joint effect of the CYP17 and HSD17B1 genes on risk. Women who possessed all 4 putative high-risk alleles of both genes (CYP17 A2A2 and HSD17B1 AA) vs. less displayed a nearly 2-fold increased risk (RR=1.83, 95% CI=0.97-3.44); this finding was statistically significant in postmenopausal women (RR=2.31, 95% CI=1.07-4.98). Risk of breast cancer was similar among women possessing the other genotypes (i.e., less than 4 putative high-risk alleles in the joint CYP17/HSD17B1 genotypes). In addition, the significant increased risk of breast cancer associated with nulliparity or late age at first live birth (age 31 years or older) was largely limited to women with the high-risk CYP17 A1A2/A2A2 or HSD17B1 AA genotypes (RR=2.41, 95% CI=1.56-3.72; RR=4.39, 95% CI=1.71-11.30, respectively). The latter gene-parity effects were especially pronounced in postmenopausal women.     

Obstetric history and mammographic density: a population-based cross-sectional study in Spain (DDM-Spain)

High mammographic density (MD) is used as a phenotype risk marker for developing breast cancer. During pregnancy and lactation the breast attains full development, with a cellular-proliferation followed by a lobular-differentiation stage. This study investigates the influence of obstetric factors on MD among pre- and post-menopausal women. We enrolled 3,574 women aged 45-68 years who were participating in breast cancer screening programmes in seven screening centers. To measure MD, blind anonymous readings were taken by an experienced radiologist, using craniocaudal mammography and Boyd's semiquantitative scale. Demographic and reproductive data were directly surveyed by purpose-trained staff at the date of screening. The association between MD and obstetric variables was quantified by ordinal logistic regression, with screening centre introduced as a random effect term. We adjusted for age, number of children and body mass index, and stratified by menopausal status. Parity was inversely associated with density, the probability of having high MD decreased by 16% for each new birth (P value < 0.001). Among parous women, a positive association was detected with duration of lactation [>9 months: odds ratio (OR) = 1.33; 95% confidence interval (CI) = 1.02-1.72] and weight of first child (>3,500 g: OR = 1.32; 95% CI = 1.12-1.54). Age at first birth showed a different effect in pre- and post-menopausal women (P value for interaction = 0.030). No association was found among pre-menopausal women. However, in post-menopausal women the probability of having high MD increased in women who had their first child after the age of 30 (OR = 1.53; 95% CI = 1.17-2.00). A higher risk associated with birth of twins was also mainly observed in post-menopausal women (OR = 2.02; 95% CI = 1.18-3.46). Our study shows a greater prevalence of high MD in mothers of advanced age at first birth, those who had twins, those who have breastfed for longer periods, and mothers whose first child had an elevated birth weight. These results suggest the influence of hormones and growth factors over the proliferative activity of the mammary gland.     

Risk of breast cancer following fertility treatment—A registry based cohort study of parous women in Norway

Despite increasing numbers of women availing themselves of assisted reproductive technology (ART), effects on cancer risk remain unresolved. Given hormonal exposures, breast cancer risk is of particular concern. The aim of this study is to investigate breast cancer risk amongst women giving birth following ART as compared to that amongst women who gave birth without ART. Data on all women who gave birth in Norway with or without ART, between 1984 and 2010 were obtained from the Medical Birth Registry of Norway (MBRN). 808,834 women eligible for study were linked to the Cancer Registry of Norway. Cox proportional models computed hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer between the two groups, adjusting for age, parity, age at first birth, calendar period and region of residence. In total, 8,037 women were diagnosed with breast cancer during the study period, 138 ART women and 7,899 unexposed. Total follow‐up time was 12,401,121 person‐years (median 16.0); median age at entry was 32.5 years (range18.6–49.9) for ART women and 26.3 (range 10.5–54.6) for unexposed. Women exposed to ART had an elevated risk of breast cancer (adjusted HR 1.20, 95% CI 1.01–1.42). Subgroup analyses gave an HR of 1.30 (95% CI 1.07–1.57) for women treated with IVF and 1.35 (95 % CI 1.07–1.71) for women with follow‐up >10 years, compared with controls. Our findings of increased risk in the study population warrant continued monitoring of women treated with ART as this population advances into more typical cancer age ranges.