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Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Women's Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case–control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER + PR + tumours (P for trend=0.0001 and 0.01, respectively), but not of ER − PR − tumours (P for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend=0.0002) and receptor-negative tumours (P=0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin.

Background: Evidence suggests that recent oral contraceptive (OC) use is associated with a small increased breast cancer risk; yet risks associated with contemporary OC preparations and by molecular subtype are not well characterized. Methods: We conducted a population-based case–control study of invasive breast cancer among women ages 20 to 44 residing in the Seattle–Puget Sound area from 2004 to 2010 (985 cases and 882 controls). We collected information on contraceptive use and participant characteristics via an in-person interview. Multivariable-adjusted logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Results: Lifetime duration of OC use for ≥15 years was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.1–2.2). Current OC use (within 1 year of reference date) for ≥5 years was associated with an increased risk (OR, 1.6; 95% CI, 1.1–2.5) and there were no statistically significant differences in risk by OC preparation. Risk magnitudes were generally greater among women ages 20 to 39, and for estrogen receptor–negative (ER−) and triple-negative breast cancer (current use for ≥5 years among ages 20–39: ER− OR, 3.5; 95% CI, 1.3–9.0; triple-negative OR, 3.7; 95% CI, 1.2–11.8), although differences between groups were not statistically significant. Conclusions: Long-term use of contemporary OCs and current use for ≥5 years was associated with an increased breast cancer risk among women ages 20 to 44. Risk may be greater among younger women and for ER− and triple-negative breast cancer, but these findings require confirmation. Impact: Continued surveillance and pooled analyses of OC use and breast cancer risk by molecular subtype are needed as OC preparations evolve. Cancer Epidemiol Biomarkers Prev; 23(5); 755–64. ©2014 AACR.

Breast cancer survivors have a 60 % higher risk of developing a second primary asynchronous contralateral breast cancer (CBC) compared to women's risk of developing a first primary breast cancer (FBC). However, little is known about how expression of tumor markers in first breast cancers influences CBC risk. We conducted a population-based nested case-control study among women 20-74 years of age diagnosed with a first breast cancer between 1996 and 2008 in western Washington State to evaluate the association between their tumor's estrogen receptor (ER), progesterone receptor (PR) and HER2-neu (HER2) expression, and risk of CBC. The study included 482 cases diagnosed with both a FBC and a CBC and 1,506 control women diagnosed only once with breast cancer identified through our local Surveillance, Epidemiology and End Results (SEER) cancer registry. Compared to the women whose FBC was ER+/PR+, those with ER-/PR- first tumors had a 1.6-fold (95 % confidence interval (CI): 1.2-2.3) increased risk of developing a CBC. When evaluated by joint ER/PR/HER2 status, compared to women with ER+/HER2- first cancers, those with HER2-overexpressing (ER-/HER2+) and triple-negative disease (ER-/PR-/HER2-) had 2.0-fold (95 % CI: 1.1-3.8) and 1.4-fold (95 % CI: 0.9-2.3) elevated risks of developing CBC, respectively. Beyond the known higher risks of mortality among patients diagnosed with more aggressive BC subtypes, here, we observe that they may also have increased risks of developing CBC.

Racial differences in breast cancer risk, including the risks of hormone receptor subtypes of breast cancer, have been previously reported. We evaluated whether variation in genes related to estrogen metabolism (COMT, CYP1A1, CYP1B1, CYP17A1, CYP19A1, ESR1, GSTM1, GSTP1, GSTT1, HSD17B1, SULT1A1, and UGT1A1) contributes to breast cancer risk and/or racial differences in risk within the CARE study, a multi-centered, population-based case-control study of breast cancer. Genetic variation was assessed as single nucleotide polymorphisms (SNPs), haplotypes, and SNP-hormone therapy (HT) interactions within a subset of 1,644 cases and 1,451 controls, including 949 Black women (493 cases and 456 controls), sampled from the CARE study population. No appreciable associations with breast cancer risk were detected for single SNPs or haplotypes in women overall. We detected SNP-HT interactions in women overall within CYP1B1 (rs1800440; p (het) = 0.003) and within CYP17A1 (rs743572; p (het) = 0.009) in which never users of HT were at a decreased risk of breast cancer, while ever users were at a non-significant increased risk. When investigated among racial groups, we detected evidence of an SNP-HT interaction with CYP1B1 in White women (p value = 0.02) and with CYP17A1 in Black women (p value = 0.04). This analysis suggests that HT use may modify the effect of variation in estrogen-related genes on breast cancer risk, which may affect Black and White women to a different extent.

While evidence on the association between oral contraceptive (OC) use and breast cancer generally suggests little or no increased risk, the question of whether breast cancer risk varies by OC formulation remains controversial. Few studies have examined this issue because large samples and extensive OC histories are required.We used data from a multicenter, population-based, case-control investigation. Women aged 35-64 years were interviewed. To explore the association between OC formulation and breast cancer risk, we used conditional logistic regression to derive adjusted odds ratios, and we used likelihood ratio tests for heterogeneity to assess whether breast cancer risk varied by OC formulation. Key OC exposure variables were ever use, current or former use, duration of use and time since last use. To strengthen inferences about specific formulations, we restricted most analyses to the 2282 women with breast cancer and the 2424 women without breast cancer who reported no OC use or exclusive use of one OC.Thirty-eight formulations were reported by the 2674 women who used one OC; most OC formulations were used by only a few women. We conducted multivariable analyses on the 10 formulations that were each used by at least 50 women and conducted supplemental analyses on selected formulations of interest based on recent research. Breast cancer risk did not vary significantly by OC formulation, and no formulation was associated with a significantly increased breast cancer risk.These results add to the small body of literature on the relationship between OC formulation and breast cancer. Our data are reassuring in that, among women 35-64 years of age, we found no evidence that specific OC formulations increase breast cancer risk.

Combined estrogen-progesterone therapy (EPT) is a well-established risk factor for breast cancer (1–5). Multiple observational studies document 1.6- to 3.0-fold elevated risks of breast cancer associated with current, long-term use of EPT (4, 6–11). In the Women's Health Initiative randomized trial, investigators observed a 1.3-fold (95% confidence interval (CI): 1.00, 1.59) increased risk of breast cancer associated with EPT use after a mean follow-up period of 5.2 years (2, 12). In contrast, use of unopposed estrogen therapy was not related to breast cancer risk in the Women's Health Initiative trial, which is consistent with several recent observational studies (6, 9, 13–15). The mechanisms by which EPT, particularly progestogen, influences the risk of breast cancer remain unclear. With progesterone appearing to exhibit both anticarcinogenic and procarcinogenic qualities in the female body (16–21), there is a potential for mechanisms involved in this duality to be involved in breast carcinogenesis. First, the progesterone receptor (PGR) gene codes for 2 PGR isoforms, PGR-A and PGR-B, which have opposing transcriptional targets (17). Additionally, several enzymes involved in the prereceptor metabolism of progesterone, including the enzymes steroid 5-α reductase (SRD5A) and aldo-keto reductase 1C (AKR1C), metabolize progesterone into the 5α-pregnanes and 4-pregnenes, respectively (16). These metabolites have opposing effects within breast tissue: The 5α-pregnanes have been observed to increase cellular proliferation and detachment, while the 4-pregnenes are associated with weak activation of PGR (16, 22–24). Lastly, the cytochrome P-450 3A4 (CYP3A4) enzyme is included in this pathway because the vast majority of EPT used in the United States contains a synthetic progestogen, medroxyprogesterone acetate, which is predominantly metabolized in the liver by the CYP3A4 enzyme (25, 26). Thus, single nucleotide polymorphisms (SNPs) in the AKR1C1, AKR1C2, AKR1C3, CYP3A4, PGR, SRD5A1, and SRD5A2 genes could influence progesterone's regulation and carcinogenic potential. On the basis of evidence accumulated to date, we hypothesized that the presence of 1 or more specific alleles in polymorphic genes that regulate PGR or lie within the progestogen metabolism pathway influence the risk of developing breast cancer and, more specifically, interact with EPT to affect breast cancer risk.

CXCL12 provides a chemotactic signal-directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population-based case-control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56-0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5'-flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56-0.93; recessive model OR = 0.35, 95% CI: 0.12-0.97; and log-additive model OR = 0.72, 95% CI: 0.57-0.90). A stepwise procedure identified rs17885289, rs266085 and 3'-untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3'-UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population-based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk.

Purpose An outcome of considerable concern among breast cancer survivors is the development of second primary breast cancer. However, evidence regarding how potentially modifiable lifestyle factors modulate second breast cancer risk is limited. We evaluated the relationships between obesity, alcohol consumption, and smoking on risk of second primary invasive contralateral breast cancer among breast cancer survivors. Methods Utilizing a population-based nested case-control study design, we enrolled 365 patients diagnosed with an estrogen receptor–positive (ER+) first primary invasive breast cancer and a second primary contralateral invasive breast cancer, and 726 matched controls diagnosed with only an ER+ first primary invasive breast cancer. Obesity, alcohol use, and smoking data were ascertained from medical record reviews and participant interviews. Using conditional logistic regression we evaluated associations between these three exposures and second primary contralateral breast cancer risk. Results Obesity, consumption of ≥ 7 alcoholic beverages per week, and current smoking were all positively related to risk of contralateral breast cancer (odds ratio [OR], 1.4; 95% CI, 1.0 to 2.1; OR, 1.9; 95% CI, 1.1 to 3.2; and OR, 2.2; 95% CI, 1.2 to 4.0, respectively). Compared with women who consumed fewer than seven alcoholic beverages per week and were never or former smokers, women who consumed ≥ 7 drinks per week and were current smokers had a 7.2-fold (95% CI, 1.9 to 26.5) elevated risk of contralateral breast cancer. Conclusion Our population-based study adds to the limited available literature and suggests that obesity, smoking, and alcohol consumption influence contralateral breast cancer risk, affording breast cancer survivors three means of potentially reducing this risk.

Compared with the breast cancer risk women in the general population have, breast cancer survivors have a substantially higher risk of developing a second primary contralateral breast cancer. Adjuvant hormonal therapy reduces this risk, but preliminary data indicate that it may also increase risk of hormone receptor–negative contralateral tumors. We conducted a population-based nested case-control study including 367 women diagnosed with both first primary estrogen receptor (ER)–positive invasive breast cancer and second primary contralateral breast cancer and 728 matched control women diagnosed only with a first breast cancer. Data on adjuvant hormonal therapy, other treatments, and breast cancer risk factors were ascertained through telephone interviews and medical record abstractions. Two-sided statistical tests using conditional logistic regression were conducted to quantify associations between adjuvant hormonal therapy and risk of hormone receptor–specific subtypes of contralateral breast cancer (n = 303 ER+ and n = 52 ER− cases). Compared with women not treated with hormonal therapy, users of adjuvant tamoxifen for ≥5 years had a reduced risk of ER+ contralateral breast cancer [odds ratio, 0.4; 95% confidence interval (CI), 0.3–0.7], but a 4.4-fold (95% CI, 1.03–19.0) increased risk of ER− contralateral breast cancer. Tamoxifen use for

We analyzed the Washington State births in 1980-1986 to Southeast Asian parents whose birth place was coded as being outside of the US. The mean birthweight increased from 3188 grams in 1980-81 to 3283 grams in 1986, an annual increment of about 18 grams (95% CI = 11, 25 grams). The prevalence of low birthweight (less than 2500 grams) decreased from 7.2 percent in 1980-81 to 5.4 percent in 1986, an annual reduction of 6.4 percent (95% CI = 1.3, 11.2 percent). In an analysis of information ascertained from the birth certificate, the change of paternal occupational status (from student to employed) was associated with 27 percent of the reduction in the prevalence of low birthweight, independent of maternal age, infant sex, and prior gravidity. A similar temporal change of birthweight during the same period of time was not observed among infants of US-born Asian mothers. Among the women who had two consecutive births from 1984 to 1986, the improvement of birthweight for the second birth compared to the first birth was much greater in infants born to the Southeast Asian mothers than that to White mothers. Our study suggests that living in the United States after immigration from their native countries has had a positive impact on the birthweight of infants born to Southeast Asian immigrants.

Introduction The involvement of vitamin D receptor (VDR), which is a key mediator in the vitamin D pathway, in breast cancer etiology has long been of interest. Methods We examined the association between polymorphisms in the 3' end of the VDR gene, specifically BsmI and Poly(A), and breast cancer risk within a large, population-based, case-control study of breast cancer. Cases (n = 1,631) were Caucasian and African-American women, aged 35 to 64 years, who were diagnosed with incident, invasive breast cancer between July 1994 and April 1998. Control individuals (n = 1,435) were women without breast cancer ascertained through random digit dialing. Results Accounting for age, study site, and sampling weights, we observed a significantly increased risk for breast cancer among Caucasian, postmenopausal carriers of the bb genotype of BsmI (odds ratio = 1.53, 95% confidence interval = 1.04 to 2.27). However, no associations with the bb genotype were observed in African-American women. Overall, there were no significant associations between the Poly(A) genotype and breast cancer risk in either racial group. Smoking status (ever/never) modified the association between both the BsmI and Poly(A) genotypes and breast cancer risk. The respective associations between these genotypes and breast cancer risk did not significantly vary by oral contraceptive use, hormone replacement therapy, or body mass index. Conclusion Our results provide additional support for an increased risk for breast cancer in postmenopausal Caucasian women with the BsmI bb genotype and shed light on possible differential effects by menopausal status and race.

To examine the relation of regular vigorous exercise to ovulatory infertility, we interviewed 346 infertile women, in whom there was evidence of ovulatory failure, regarding their exercise patterns during the year preceding their unsuccessful effort to conceive. Their responses were compared with similar exercise histories in women who had successfully conceived at the time the infertile women started trying to become pregnant. Vigorous exercise for an hour or more per day was reported more commonly in nulligravid cases (n = 187) than by their primiparous controls. The difference was particularly great in the subgroup of cases without additional evidence of tubal dysfunction (relative risk = 6.2, 90% confidence interval = 1.0 - 39.8). This association was not seen among infertile women who had previously been pregnant. Vigorous exercise for an average of less than one hour per day was not associated with either primary or secondary infertility.

Response levels obtained from two methods of patient contact to obtain subject consent for participation in epidemiologic studies were compared. When a signed, return card was required prior to further contact, 70 to 83 per cent of patients consented to participate, compared with consistently higher levels (89 to 93 per cent) obtained with telephone contact. These data suggest that the likelihood of obtaining the high response level required in epidemiologic studies is increased by methods that do not rely on a return card.

Introduction The cell-cycle checkpoint kinase (CHEK)2 protein truncating mutation 1100delC has been associated with increased risk for breast or prostate cancer. Multiple studies have found an elevated frequency of the 1100delC variant in specific stratifications of breast cancer patients with a family history of the disease, including BRCA1/BRCA2 negative families and families with a history of bilateral disease or male breast cancer. However, the 1100delC mutation has only been investigated in a few population-based studies and none from North America. Methods We report here on the frequency of three CHEK2 variants that alter protein function – 1100delC, R145W, and I175T – in 506 cases and 459 controls from a population based, case–control study of breast cancer conducted in young women from western Washington. Results There was a suggestive enrichment in the 1100delC variant in the cases (1.2%) as compared with the controls (0.4%), but this was based on small numbers of carriers and the differences were not statistically significant. The 1100delC variant was more frequent in cases with a first-degree family history of breast cancer (4.3%; P = 0.02) and slightly enriched in cases with a family history of ovarian cancer (4.4%; P = 0.09). Conclusion The CHEK2 variants are rare in the western Washington population and, based on accumulated evidence across studies, are unlikely to be major breast cancer susceptibility genes. Thus, screening for the 1100delC variant may have limited usefulness in breast cancer prevention programs in the USA.