Ages at menarche and first birth are established risk factors for breast cancer. The interval between these ages may also affect risk, since the breast is more susceptible to carcinogenic insults during this period than during the parous period. However, few investigators have studied this relation. Using logistic regression, the authors evaluated associations between the timing of reproductive events and breast cancer risk among 4,013 cases and 4,069 controls enrolled in a multicenter, population-based US case-control study of White and African-American women (1994–1998). For White, parous premenopausal and postmenopausal women, those who had an interval of ≥16 years between the ages of menarche and first birth had 1.5-fold (95% confidence interval (CI): 1.0, 2.2) and 1.4-fold (95% CI: 1.1, 1.8) increased risks of breast cancer, respectively, in comparison with those who had ≤5 years between these ages. Adjusting for age at first birth altered these risk estimates somewhat, to odds ratios of 1.5 (95% CI: 0.8, 2.9) and 1.0 (95% CI: 0.6, 1.5), respectively. These associations were stronger for lobular and hormone-receptor-positive tumors but were absent among premenopausal African-American women. The authors conclude that the interval between age at menarche and age at first birth is associated with the risk of hormonally sensitive types of breast cancer, particularly among White women.
breast neoplasms; histology; menarche; menopause; pregnancy; premenopause; receptors, estrogen; receptors, progesterone
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.
Oral contraceptives; Breast cancer; Hormones; Epidemiology; Case–control studies
We investigated the impact of breast cancer molecular subtypes and treatment on survival in a cohort of medically insured women followed for over twenty years.
We examined 934 female members of an integrated health care delivery system newly diagnosed with invasive breast cancer between 1988 and 1995 and followed them through 2008. Tumors were classified into four molecular subtypes based on their expression profile: luminal A; luminal B; basal-like; and HER2-enriched. We followed women from the surgery date to death, health plan disenrollment, or study’s end. Hazard rate ratios (HR) and 95% confidence intervals (CI) were fit using Cox proportional hazards models adjusting for cancer treatments and tumor characteristics.
A total of 223 (23.9%) women died due to breast cancer during the 21-year study period. Compared to women with luminal A tumors, women with HER2-enriched (HR 2.56, 95% CI 1.53–4.29) and luminal B tumors (HR 1.96, 95% CI: 1.08–3.54) had roughly a two-fold increased adjusted risk of breast cancer mortality. In addition, the survival curves suggest that risk of late mortality persists in women with luminal A tumors.
Among women with healthcare coverage, molecular subtypes were important predictors of breast cancer mortality. Women with HER2-enriched tumors and luminal B subtypes had the poorest survival despite adjusting for important covariates.
In a cohort followed over 20 years, women with HER2 enriched tumors had worse survival, but interestingly, the survival curve for women with luminal A tumors continued to steadily decline after 10 years of follow-up.
breast cancer; biologic subtypes; cancer treatment; survival; cohort
We investigated the extent to which estrogen receptor (ER) and progesterone receptor (PR) status results from a centralized pathology laboratory agree with ER and PR results from community pathology laboratories reported to two Surveillance, Epidemiology and End Results (SEER) registries (Los Angeles County and Detroit) and whether statistical estimates for the association between reproductive factors and breast cancer receptor subtypes differ by the source of data. The agreement between the centralized laboratory and SEER registry classifications was substantial for ER (κ = 0.70) and nearly so for PR status (κ = 0.60). Among the four subtypes defined by joint ER and PR status, the agreement between the two sources was substantial for the two major breast cancer subtypes (ER−/PR−, κ = 0.69; ER+/PR+, κ = 0.62) and poor for the two rarer subtypes (ER+/PR−, κ = 0.30; ER−/PR+, κ = 0.05). Estimates for the association between reproductive factors (number of full-term pregnancies, age at first full-term pregnancy, and duration of breastfeeding) and the two major subtypes (ER+/PR+ and ER−/PR−) differed minimally between the two sources of data. For example, parous women with at least four full-term pregnancies had 40% lower risk for ER+/PR+ breast cancer than women who had never been pregnant [centralized laboratory, odds ratio, 0.60 (95% confidence interval, 0.39–0.92); SEER, odds ratio, 0.57 (95% confidence interval, 0.38–0.85)]; no association was observed for ER−/PR− breast cancer (both Ptrend > 0.30). Our results suggest that conclusions based on SEER registry data are reasonably reliable for ER+/PR+ and ER−/PR− subtypes.
To quantify the risk of second primary breast cancer in the contralateral breast (CB) following radiation therapy (RT) for first breast cancer.
Methods and Materials
The study population included participants in the Women’s Environmental, Cancer, and Radiation Epidemiology (WECARE) study: 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls (women with unilateral breast cancer) counter-matched on radiation treatment. Participants were < 55 years of age at first breast cancer. Absorbed doses to quadrants of the CB were estimated. Rate ratios (RR) and 95% confidence intervals were calculated using multivariable-adjusted conditional logistic regression models.
Across all patients, the mean radiation dose to the specific quadrant of the CB tumor was 1.1 Gy. Women < 40 years of age who received > 1.0 Gy of absorbed dose to the specific quadrant of the CB had a 2.5-fold greater risk for CB cancer than unexposed women (RR=2.5, 95% CI= 1.4 – 4.5). No excess risk was observed in women >40 years of age. Women < 40 years of age with followup periods > 5 years had a RR of 3.0 (95% CI=1.1–8.1), and the dose response was significant (excess RR per Gy of 1.0, 95% CI=0.1–3.0).
Women < 40 years of age who received a radiation dose > 1.0 Gy to the CB had an elevated, long-term risk of developing a second primary CB cancer. The risk is inversely related to age at exposure and is dose dependent.
Contralateral breast; Radiation risk; Secondary breast cancer
Lifetime physical activity (PA) is associated with decreased breast cancer (BC) risk; reports suggest that PA during adolescence contributes strongly to this relationship. PA lowers production of sex hormones, specifically estradiol, or decreases insulin resistance (IR), thereby lowering risk. Overweight Latina adolescents are insulin resistant and exhibit low levels of PA, potentially increasing their future BC risk.
37 obese Latina adolescents (15.7 ±1.1 yrs) provided measures of PA using accelerometry; plasma follicular phase estradiol, sex-hormone binding globulin, total and free testosterone, dehydroepiandrosterone-sulfate (DHEAS); IR using HOMA-IR; body composition via DEXA. Partial correlations and stepwise linear regressions assessed cross-sectional relationships between sex hormones, IR and PA. Body composition, and age were included a priori as covariates.
Estradiol was negatively associated with accelerometer counts per minute (CPM) (r= −0.4; p=0.02), percent time spent in moderate PA (%MPA) (r= −0.5; p=0.006), and percent time in moderate or vigorous PA (%MVPA) (r= −0.5; p=0.007). DHEAS was positively associated with CPM (r=0.4, p=0.009), %MPA (r=0.3, p=0.04), and %MVPA (r=0.3, p=0.04). Other sex hormones and IR were not associated with PA measures.
This study is the first to show that higher habitual PA was inversely associated with estradiol in obese adolescents.
Accelerometer; insulin resistance; sex hormones; breast cancer
Sedentary time is a rapidly emerging independent risk factor for mortality in the general population, but its prognostic effect among cancer survivors is unknown. In a multiethnic, prospective cohort of breast cancer survivors, we hypothesized that television watching time would be independently associated with an increased risk of death from any cause.
The Health, Eating, Activity and Lifestyle (HEAL) Study cohort included 687 women diagnosed with local or regional breast cancer. On average 30 (± 4) months postdiagnosis, , women completed self-report assessments on time spent sitting watching television/videos in a typical day in the previous year. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for death from any cause (n=89) during the 7 years of follow-up.
Television time (top tertile vs. bottom tertile) was positively related to risk of death (HR: 1.94, 95% CI: 1.02, 3.66, ptrend=0.024) but the association was attenuated and not statistically significant after adjustment for aerobic moderate-vigorous intensity physical activity (HR: 1.70, 95% CI: 0.89, 3.22, ptrend=0.14) and all covariates (HR: 1.39, 95% CI: 0.69, 2.82, ptrend=0.48).
In this first published investigation on this topic, we did not observe a statistically significant multivariate-adjusted association between television watching time and risk of death among women diagnosed with breast cancer.
Implications for Cancer Survivors
These results begin an evidence base on this topic that can be built upon to inform lifestyle recommendations for this expanding, aging population.
Sedentary behavior; Exercise; Breast Neoplasm; Mortality; Physical activity
Diabetes has been consistently associated with an increased risk of liver, pancreas and endometrial cancer and has been implicated as a risk factor for esophageal and gastric cancers, although this association has been less well studied. We sought to determine the role of diabetes in the etiology of esophageal, gastric cardia and distal gastric adenocarcinomas. This analysis included patients with esophageal adenocarcinoma (n=209), gastric cardia adenocarcinoma (n=257) and distal gastric adenocarcinoma (n=382), and 1,309 control participants from a population-based case-control study conducted in Los Angeles County. The study included non-Hispanic whites, African Americans, Hispanics and Asian Americans. The association of diabetes with the three tumor types was estimated using polytomous logistic regression. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated. Nine percent of control participants and 13% of the case patients reported a history of diabetes. After adjustment for age, gender, race, birthplace, education, cigarette smoking status and body mass index, diabetes was associated with an increased risk of esophageal adenocarcinoma (OR, 1.48; 95% CI, 0.94–2.32; P=0.089) and distal gastric adenocarcinoma (OR, 1.47; 95% CI, 1.01–2.15; P=0.045), but was not associated with risk of gastric cardia adenocarcinoma (OR, 0.96; 95% CI, 0.59–1.55; P=0.87). However, the association between diabetes and risk of DGA was statistically significant only among patients for whom we interviewed their next-of-kin. This study further investigated the association between diabetes and adenocarcinomas of the esophagus and distal stomach.
diabetes; esophageal adenocarcinoma; gastric adenocarcinoma; case-control study; polychotomous logistic regression
Here we assessed associations between null mutations in glutathione-S-transferase (GST)T1 and GSTM1 genes, and the rs1695 polymorphism in GSTP1 (Ile105Val), and risk of breast cancer-specific (n=45) and all-cause (n=99) mortality in a multiethnic, prospective cohort of 533 women diagnosed with stage I-IIIA breast cancer in 1995–1999, enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study.
We measured the presence of the null mutation in GSTT1 and GSTM1, and the rs1695 polymorphism in GSTP1 by polymerase chain reaction. We assessed associations between breast-cancer specific and all-cause mortality using Cox proportional hazards models.
Participants with ER-negative tumors were more likely to be GSTT1 null (χ2=4.52; P=0.03), and African American women were more likely to be GSTM1 null (χ2=34.36; P<0.0001). Neither GSTM1 nor GSTT1 null mutations were associated with breast cancer-specific or all-cause mortality. In a model adjusted for body mass index, race/ethnicity, tumor stage and treatment received at diagnosis, the variant Val allele of rs1695 was associated with increased risk of all-cause (HR=1.81, 95% CI 1.16-2.82, P=0.008), but not breast cancer-specific mortality. The GSTT1 null mutation was associated with significantly higher levels of C-reactive protein.
GSTM1 and GSTT1 null genotypes had no effect on outcome; however the variant allele of rs1695 appears to confer increased risk for all-cause mortality in breast-cancer survivors.
Given the limited sample size of most studies examining associations between GST polymorphisms with breast cancer survival, and the lack of women undergoing more contemporary treatment protocols (treated prior to 1999), it may be helpful to re-examine this issue among larger samples of women diagnosed after the late 1990s, who all received some form of chemotherapy or radiotherapy.
Glutathione-S-transferases; GSTT1; GSTM1; GSTP1; Polymorphisms; Breast cancer survival; Mortality
Germline mutations in the PALB2 gene are associated with an increased risk of developing breast but little is known about the frequencies of rare variants in PALB2 and the nature of the variants that influence risk. We selected participants recruited to the Women’s Environment, Cancer, and Radiation Epidemiology (WECARE) Study and screened lymphocyte DNA from cases with contralateral breast cancer (n = 559) and matched controls with unilateral breast cancer (n = 565) for PALB2 mutations. Five pathogenic PALB2 mutations were identified among the cases (0.9%) versus none among the controls (p=0.04). The first degree female relatives of these five carriers demonstrated significantly higher incidence of breast cancer than relatives of non-carrier cases, indicating that pathogenic PALB2 mutations confer an estimated 5.3 fold increase in risk (95% CI: 1.8–13.2). The frequency of rare (<1% MAF) missense mutations was similar in both groups (23 versus 21). Our findings confirm in a population-based study setting of women with breast cancer the strong risk associated with truncating mutations in PALB2 that has been reported in family studies. Conversely, there is no evidence from this study that rare PALB2 missense mutations strongly influence breast cancer risk.
PALB2; breast cancer; case-control; contralateral
Fruit and vegetable intake may protect against pancreatic cancer, since fruits and vegetables are rich in potentially cancer-preventive nutrients. Most case-control studies have found inverse associations between fruit and vegetable intake and pancreatic cancer risk, although bias due to reporting error cannot be ruled out. In most prospective studies, inverse associations have been weaker and imprecise because of small numbers of cases. The authors examined fruit and vegetable intake in relation to pancreatic cancer risk in a pooled analysis of 14 prospective studies from North America, Europe, and Australia (study periods between 1980 and 2005). Relative risks and 2-sided 95% confidence intervals were estimated separately for the 14 studies using the Cox proportional hazards model and were then pooled using a random-effects model. Of 862,584 men and women followed for 7−20 years, 2,212 developed pancreatic cancer. The pooled multivariate relative risks of pancreatic cancer per 100-g/day increase in intake were 1.01 (95% confidence interval (CI): 0.99, 1.03) for total fruits and vegetables, 1.01 (95% CI: 0.99, 1.03) for total fruits, and 1.02 (95% CI: 0.99, 1.06) for total vegetables. Associations were similar for men and women separately and across studies. These results suggest that fruit and vegetable intake during adulthood is not associated with a reduced pancreatic cancer risk.
diet; fruit; pancreatic neoplasms; prospective studies; vegetables
Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (Ptrend < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.
endometrial neoplasms; parity; reproductive history
To evaluate how the association between body size and breast cancer risk varies by tumor receptor subtype, host factors and other exposures among women in the California Teacher Study cohort.
Among 52,642 postmenopausal women, 2,321 developed invasive breast cancer with known estrogen- and progesterone-receptor status (1,652 ER+PR+, 338 ER+PR−, 312 ER−PR−) between 1995 and 2007. In a subset of 35,529 with waist circumference data, 1,377 developed invasive breast cancer with known ERPR status (991 ER+PR+, 208 ER+PR−, 169 ER−PR−) between 1997 and 2007. Multivariate Cox regression was performed to estimate relative risks (RR) and 95% confidence intervals (CI).
Obesity, adult weight gain of ≥40 pounds, greater abdominal adiposity and greater height increased risk of ER+PR+ breast cancer. The increased risk associated with postmenopausal obesity was limited to those who did not use hormone therapy (HT) at cohort entry (RR=1.37, 95% CI: 1.05–1.78 for BMI ≥30 vs. <25 kg/m2; P-interaction=0.14) and those who were not overweight or obese at age 18 (P-interaction=0.06). The increased risk associated with greater abdominal adiposity was limited to those who were not also overweight or obese (P-interaction=0.01). Neither obesity, abdominal adiposity nor height were associated with the risk of ER−PR− tumors.
The effects of body size on postmenopausal breast cancer risk differed by hormone receptor subtype, and among women with ER+PR+ tumors, by HT use and early adult body size.
breast cancer; obesity; hormone receptor status; abdominal adiposity; hormone therapy
African American (AA) women have a higher mortality from breast cancer (BC) compared to European American (EA) women. This may be due to the higher proportion of AA women with tumors that are diagnosed at more advanced stages and are characterized as being estrogen receptor negative (ER-)/ progesterone receptor negative (PR-). Our study sought to determine whether self-reported race and percent African ancestry were associated with BC tumor characteristics.
In a multi-center, population-based case-control study of BC, we determined percent African ancestry using ancestry informative markers (AIM) among women self-reporting race as AA or Black.
BC tumor characteristics were associated with self-reported race (including a 30% reduction in ER+/PR+ tumors [95% confidence interval [CI]: 0.6-0.9] and a 1.5-fold increased risk of high grade [95% CI: 1.2-1.9] for AA women compared to EA women). AIMs among AA women were not associated with BC tumor characteristics (AA women with ≥ 95% versus < 80% African ancestry, odds ratio [OR]=1.0 for ER+/PR+ [95% CI: 0.6-1.8] and OR=0.9 for high-grade tumors [95% CI: 0.6-1.4]). Similar findings were observed for BC stage.
While BC subtypes were associated with self-reported race, BC subtypes were not associated with percent African ancestry.
These study results suggest that subtle differences in percent African ancestry are less important than the overall presence of African ancestry in relation to BC tumor characteristics.
Women who receive chemotherapy for a first primary breast cancer have been observed to have a reduced risk of contralateral breast cancer (CBC), however, whether the genetic profile of a patient modifies this protective effect is currently not understood. The purpose of this study is to investigate the impact of germline genetic variation in genes coding for drug metabolizing enzymes, transporters, and targets on the association between chemotherapy and risk of CBC.
From the population-based Women’s Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 636 Caucasian women with CBC (cases) and 1,224 women with unilateral breast cancer (controls). The association between common chemotherapeutic regimens, CMF and FAC/FEC, and risk of CBC stratified by genotype of 180 single nucleotide polymorphisms in 14 genes selected for their known involvement in metabolism, action, and transport of breast cancer chemotherapeutic agents, were determined using conditional logistic regression.
CMF (RR = 0.5, 95 % CI 0.4, 0.7) and FAC/FEC (RR = 0.7, 95 % CI 0.4, 1.0) are associated with lower CBC risk relative to no chemotherapy in multivariable-adjusted models. Here we show that genotype of selected genes involved in the metabolism and uptake of these therapeutic agents does not significantly alter the protective effect of either CMF or FAC/FEC on risk of CBC.
The results of this study show that germline genetic variation in selected gene does not significantly alter the protective effect of CMF, FAC, and FEC on risk of CBC.
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-013-0237-6) contains supplementary material, which is available to authorized users.
Genetic variation; Chemotherapy; CMF; Contralateral breast cancer
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; phet = 0.003) and within CYP17A1 (rs743572; phet = 0.009) in which never users of HT were at a decreased risk of breast cancer, while 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.
Breast cancer; Genetic variation; Racial disparities; Gene–environment interactions; Hormone therapy
Evidence suggests that inflammation may drive fatigue in cancer survivors. Research in healthy populations has shown reduced inflammation with higher dietary intake of ω-3 polyunsaturated fatty acids (PUFAs), which could potentially reduce fatigue. This study investigated fatigue, inflammation, and intake of ω-3 and ω-6 PUFAs among breast cancer survivors.
Six hundred thirty-three survivors (mean age, 56 years; stage I to IIIA) participating in the Health, Eating, Activity, and Lifestyle Study completed a food frequency/dietary supplement questionnaire and provided a blood sample assayed for C-reactive protein (CRP) and serum amyloid A (30 months after diagnosis) and completed the Piper Fatigue Scale and Short Form-36 (SF-36) vitality scale (39 months after diagnosis). Analysis of covariance and logistic regression models tested relationships between inflammation and fatigue, inflammation and ω-3 and ω-6 PUFA intake, and PUFA intake and fatigue, controlling for three incremental levels of confounders. Fatigue was analyzed continuously (Piper scales) and dichotomously (SF-36 vitality ≤ 50).
Behavioral (P = .003) and sensory (P = .001) fatigue scale scores were higher by increasing CRP tertile; relationships were attenuated after adjustment for medication use and comorbidity. Survivors with high CRP had 1.8 times greater odds of fatigue after full adjustment (P < .05). Higher intake of ω-6 relative to ω-3 PUFAs was associated with greater CRP (P = .01 after full adjustment) and greater odds of fatigue (odds ratio, 2.6 for the highest v lowest intake; P < .05).
Results link higher intake of ω-3 PUFAs, decreased inflammation, and decreased physical aspects of fatigue. Future studies should test whether ω-3 supplementation may reduce fatigue among significantly fatigued breast cancer survivors.
We investigated whether variants in sex steroid hormone metabolism genes modify the effect of hormone therapy (HT) on endometrial cancer risk in postmenopausal non-Hispanic white women. A nested-case control study was conducted within the California Teachers Study (CTS). We genotyped htSNPs in six genes involved in the hormone metabolism in 286 endometrial cancer cases and 488 controls. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each haplotype using unconditional logistic regression, adjusting for age. The strongest interaction was observed between duration of estrogen therapy (ET) use and haplotype 1A in CYP11A1 (Pinteraction=0.0027; Pinteraction=0.027 after correcting for multiple testing within each gene). The OR for endometrial cancer per copy of haplotype 1A was 2.00 (95%CI: 1.05-3.96) for long-term ET users and 0.90 (95% CI: 0.69-1.18) for never users. The most significant interaction with estrogen-progestin therapy (EPT) was found for two haplotypes on CYP19A1 and EPT use (haplotype 4A, Pinteraction=0.024 and haplotype 3B, Pinteraction=0.043. However, neither this interaction, nor the ET or EPT interactions for any other genes, was statistically significant after correction for multiple testing. Variations in CYP11A1 may modify the effect of ET use on risk of postmenopausal endometrial cancer; however, larger studies are needed to explore these findings further.
menopausal hormone therapy; genetic polymorphism; hormone metabolism gene; endometrial cancer
We considered interactions between physical activity and body mass index (BMI) and neighborhood factors.
We used recursive partitioning to identify predictors of low recreational physical activity (<2.5 hours/week) and overweight and obesity (BMI≥25.0 kg/m2) among 118 315 women in the California Teachers Study. Neighborhood characteristics were based on 2000 US Census data and Reference US business listings.
Low physical activity and being overweight or obese were associated with individual sociodemographic characteristics, including race/ethnicity and age. Among White women aged 36 to 75 years, living in neighborhoods with more household crowding was associated with a higher probability of low physical activity (54% vs 45% to 51%). In less crowded neighborhoods where more people worked outside the home, the existence of fewer neighborhood amenities was associated with a higher probability of low physical activity (51% vs 46%). Among non–African American middle-aged women, living in neighborhoods with a lower socioeconomic status was associated with a higher probability of being overweight or obese (46% to 59% vs 38% in high–socioeconomic status neighborhoods).
Associations between physical activity, overweight and obesity, and the built environment varied by sociodemographic characteristics in this educated population.
Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10−6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10−4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10−5), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
Breast cancer involves combined effects of numerous genetic, environmental, and behavioral risk factors that are unique to each individual. High risk genes, such as BRCA1 and BRCA2, account for only a small proportion of disease occurrence. Recent genome-wide research has identified more than 20 common genetic variants, which individually alter breast cancer risk very moderately. We undertook an international collaborative study to determine whether the effect of these genetic variants vary with environmental factors, such as parity, body mass index (BMI), height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity, which are known to affect risk of developing breast cancer. Using pooled data from 24 studies of the Breast Cancer Association Consortium (BCAC), we provide first convincing evidence that the breast cancer risk associated with a genetic variant in LSP1 differs with the number of births and that the risk associated with a CASP8 variant is altered by high alcohol consumption. The effect of an additional genetic variant might also be modified by reproductive factors. This knowledge will stimulate new research towards a better understanding of breast cancer development.
Tamoxifen has been shown to greatly reduce risk of recurrence and contralateral breast cancer (CBC). Still, second primary contralateral breast cancer is the most common malignancy to follow a first primary breast cancer. Genetic variants in CYP2D6 and other drug-metabolizing enzymes that alter the metabolism of tamoxifen may be associated with CBC risk in women who receive the drug. This is the first study to investigate the impact of this variation on risk of CBC in women who receive tamoxifen. From the population-based Women’s Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 624 Caucasian women with CBC (cases) and 1,199 women with unilateral breast cancer (controls) with complete information on tumor characteristics and treatment. Conditional logistic regression was used to assess the risk of CBC associated with 112 single nucleotide polymorphisms (SNPs) in 8 genes involved in the metabolism of tamoxifen among tamoxifen users and non-users. After adjustment for multiple testing, no significant association was observed between any of the genotyped variants and CBC risk in either tamoxifen users or non-users. These results suggest that when using a tagSNP approach, common variants in selected genes involved in the metabolism of tamoxifen are not associated with risk of CBC among women treated with the drug.
Contralateral breast cancer; tamoxifen; single nucleotide polymorphisms
Background & Aims
Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) has been reported to reduce risks for esophageal adenocarcinoma (EAC) and esophagogastric junctional adenocarcinoma (EGJA). However, individual studies have been too small to accurately assess the effects of medication type, frequency, or duration of use. We performed a pooled analysis to investigate these associations.
We performed a pooled analysis of 6 population-based studies within the Barrett's and Esophageal Adenocarcinoma Consortium to evaluate the association between NSAID use and the risk of EAC and EGJA, using uniform exposure definitions. We collected information from 6 studies (5 case-control and 1 cohort), with a total of 1226 EAC and 1140 EGJA cases, on aspirin and/or NSAID use. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate adjusted logistic regression models and then pooled using a random effects meta-analysis model.
Compared to non-users, individuals who have used NSAIDs had a statistically significant, reduced risk of EAC (OR=0.68; 95% CI, 0.56–0.82); they also appeared to have a reduced risk of EGJA (OR=0.84; 95% CI, 0.68–1.03). Similar reductions in risk were observed among individuals who took aspirin or non-aspirin NSAIDs. The highest levels of frequency (≥daily) and duration (≥10 years) of NSAID use were associated with an approximately 40% reduction in risk for EAC: OR=0.56 (95% CI, 0.43–0.73; P-trend, <.001) and OR=0.63 (95% CI, 0.45–0.90; P-trend, 0.04), respectively.
Although reverse causation could, in part, explain the inverse association observed between NSAID use and EAC risk, pooled analysis indicates a role for NSAIDs in prevention of adenocarcinomas of the esophagus and esophagogastric junction.
BEACON; Esophageal Neoplasm; Stomach Cancer; Anti-Inflammatory Agent
Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.
Coffee has been hypothesized to have pro- and anti-carcinogenic properties, while tea may contain anti-carcinogenic compounds. Studies assessing coffee intake and pancreatic cancer risk have yielded mixed results, while findings for tea intake have mostly been null. Sugar-sweetened carbonated soft drink (abbreviated as SSB) intake has been associated with higher circulating levels of insulin, which may promote carcinogenesis. Few prospective studies have examined SSB intake and pancreatic cancer risk; results have been heterogeneous.
In this pooled analysis from 14 prospective cohort studies, 2,185 incident pancreatic cancer cases were identified among 853,894 individuals during follow-up. Multivariate (MV) study-specific relative risks (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models and then pooled using a random effects model.
No statistically significant associations were observed between pancreatic cancer risk and intake of coffee (MVRR=1.10, 95% CI=0.81-1.48 comparing ≥900 to <0g/day; 237g≈8oz), tea (MVRR=0.96, 95% CI=0.78-1.16 comparing ≥400 to 0g/day; 237g≈8oz) or SSB (MVRR=1.19, 95% CI=0.98-1.46 comparing ≥250 to 0g/day; 355g≈12oz) (p-value, test for between-studies heterogeneity >0.05). These associations were consistent across levels of sex, smoking status and body mass index. When modeled as a continuous variable, a positive association was evident for SSB (MVRR=1.06, 95% CI=1.02-1.12).
CONCLUSION AND IMPACT
Overall, no associations were observed for intakes of coffee or tea during adulthood and pancreatic cancer risk. Although we were only able to examine modest intake of SSB, there was a suggestive, modest positive association for risk of pancreatic cancer for intakes of SSB.
Pancreatic Cancer; Beverages; Pooled Analysis