Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5 in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10−8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10–6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10−9), and with both ER-positive (OR = 1.09; P = 1.5 × 10−5) and ER-negative (OR = 1.16, P = 2.5 × 10−7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
Evidence is inconsistent regarding whether dietary fat influences sex hormone concentrations. This issue is important for breast cancer survivors since clinical recommendations suggest maintaining low hormone levels primarily via pharmacologic agents. This study examines associations between dietary fat and circulating sex hormones among participants in the HEAL (Health, Eating, Activity and Lifestyle) Study, a cohort of breast cancer survivors (n=511). During a post-diagnosis interview, detailed data were collected on diet, physical activity, lifestyle habits, and medication use (including tamoxifen). Staff measured height and weight and collected fasting bloods. Multivariate linear regression modeled associations of dietary fat with serum sex hormones. Among women using tamoxifen, we observed modest inverse associations of dietary fat with estrone (p< 0.01), estradiol (p< 0.05), testosterone (p< 0.01), free testosterone (p< 0.01), and DHEA (p< 0.01) for higher vs. lower fat intake, but there was no evidence for a trend. Associations were consistent across measures (percent energy from fat, total, saturated and polyunsaturated fat) and modest effect modification was observed between fat intake and tamoxifen in relation to hormones. Among women not using tamoxifen, fat intake was not associated with hormone concentrations. Further work is needed to confirm the findings and to understand the clinical implications of these observations.
Diet; dietary fat; sex steroid hormones; estrogen; testosterone; postmenopausal breast cancer; tamoxifen
Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation and altered levels of adipose derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight and weight change are associated with CBC risk.
Variants in twenty genes (182 single nucleotide polymorphisms) involved in adipose tissue metabolism, energy balance, insulin resistance and inflammation, as well as those identified through genome-wide association studies of BMI and type II diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants (643 cases with CBC and 1,271 controls with unilateral breast cancer) in the population-based Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression.
After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor status did not alter these findings.
Among women with early onset disease who survive a first breast cancer diagnosis there was no association between variation in obesity-related genes and risk of CBC.
Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer.
genetic variation; obesity; weight; weight change; contralateral breast cancer
Epidemiological evidence continues to accumulate on the benefits of physical activity in relation to cancer risk, progression and mortality. Recent studies suggest that sedentary behavior may independently affect cancer risk; they also focus on factors that may explain associations with physical activity, including cancer risk factors and whether associations exist for precancerous lesions. Despite enormous efforts to examine associations between physical activity and cancer, the literature is hindered by inconsistent assessment of physical activity across studies, and incomplete consideration of variation of effects across population subgroups (for example, defined by body size, age or sex) or tumors subgroups (organ location, receptor status, or molecular subtype), and whether other factors explain study results. Clearly, public health recommendations for appropriate changes in activity levels are needed; unfortunately, at this time, we have no exact physical activity prescription to give to the public.
Review; Physical activity; Cancer risk; Cancer survival; Recreational activity; Occupational activity; Exercise; Biological mechanisms; Methodology; Sedentary behavior; Sitting time; Breast cancer; Colon cancer
This study aimed to determine the prevalence of sarcopenia and examine whether sarcopenia was associated with overall and breast-cancer-specific mortality in a cohort of women diagnosed with breast cancer (stages I–IIIA).
A total of 471 breast cancer patients from western Washington State and New Mexico who participated in the prospective Health, Eating, Activity, and Lifestyle Study were included in this study. Appendicular lean mass was measured using dual X-ray absorptiometry scans at study inception, on average, 12 months after diagnosis. Sarcopenia was defined as two standard deviations below the young healthy adult female mean of appendicular lean mass divided by height squared (<5.45 kg/m2). Total and breast-cancer-specific mortality data were obtained from Surveillance Epidemiology and End Results registries. Multivariable Cox proportional hazard models assessed the associations between sarcopenia and mortality.
Median follow-up was 9.2 years; 75 women were classified as sarcopenic, and among 92 deaths, 46 were attributed to breast cancer. In multivariable models that included age, race-ethnicity/study site, treatment type, comorbidities, waist circumference, and total body fat percentage, sarcopenia was independently associated with overall mortality (hazard ratio (HR)=2.86; 95 % CI, 1.67– 4.89). Sarcopenic women had increased risk of breast-cancer-specific mortality, although the association was not statistically significant (HR=1.95, 95 % CI, 0.87–4.35).
Sarcopenia is associated with an increased risk of overall mortality in breast cancer survivors and may be associated with breast-cancer-specific mortality. The development of effective interventions to maintain and/or increase skeletal muscle mass to improve prognosis in breast cancer survivors warrants further study.
Implications for Cancer Survivors
Such interventions may help breast cancer patients live longer.
Sarcopenia; Appendicular lean mass; Mortality; Breast cancer survivor
To investigate the association between physical activity, body mass
index (BMI) and mammographic density in an ethnically-diverse
population-based sample of 522 postmenopausal women diagnosed with stage
0–IIIA breast cancer and enrolled in the Health, Eating, Activity,
and Lifestyle Study.
We collected information on BMI and physical activity during a clinic
visit two to three years after diagnosis. Weight and height were measured in
a standard manner. Using an interview-administered questionnaire,
participants recalled the type, duration, and frequency of physical
activities in the past year. We estimated dense area and percent density as
a continuous measure using a computer-assisted software program from
mammograms imaged approximately one to two years after diagnosis. Analysis
of covariance methods were used to obtain mean density across World Health
Organization BMI categories and physical activity tertiles adjusted for
We observed a statistically significant decline in percent density (p
for trend = .0001), and mammographic dense area (p for trend = 0.0052), with
increasing level of BMI adjusted for potential covariates. We observed a
statistically significant decline in mammographic dense area (p for trend =
.036) with increasing level of sports/recreational physical activity in
women with a BMI ≥ 30 kg/m2. Conversely, in women with a
BMI < 25 kg/m2, we observed a nonstatistically significant
increase in mammographic dense area and percent density with increasing
level of sports/recreational physical activity.
Increasing physical activity among obese postmenopausal breast cancer
survivors may be a reasonable intervention approach to reduce mammographic
breast cancer; body fat; exercise; obesity; weight; breast tissue; breast density
There is growing evidence linking genetic variations to non–Hodgkin lymphoma (NHL) etiology. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 488 candidate gene regions and their relation to risk for NHL and NHL subtypes.
We genotyped 6,679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S. case–control study. Gene-level summary of associations were obtained by computing the minimum P value (“minP test”) on the basis of 10,000 permutations. We used logistic regression to evaluate the association between genotypes and haplotypes with NHL. For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the codominant model for each SNP.
Fourteen gene regions were associated with NHL (P < 0.01). The most significant SNP associated with NHL maps to the SYK gene (rs2991216, P-trend = 0.00005). The three most significant gene regions were on chromosome 6p21.3 (RING1/RXRB; AIF1; BAT4). Accordingly, SNPs in RING1/RXRB (rs2855429), AIF1 (rs2857597), and BAT4 (rs3115667) were associated with NHL (P-trends ≤ 0.0002) and both diffuse large B-cell and follicular lymphomas (P-trends < 0.05).
Our results suggest potential importance for SYK on chromosome 9 with NHL etiology. Our results further implicate 6p21.3 gene variants, supporting the need for full characterization of this chromosomal region in relation to lymphomagenesis.
Gene variants on chromosome 9 may represent a new region of interesting for NHL etiology. The independence of the reported variants in 6p21.3 from implicated variants (TNF/HLA) supports the need to confirm causal variants in this region
Alcohol consumption increases breast cancer risk, but its effect may be modified by hormone therapy (HT) use, such that exposure to both may be synergistic. Because many women stopped taking HT after mid-2002, it is important to quantify risks associated with alcohol consumption in the context of HT cessation, as these risks may be more relevant to cancer prevention efforts today.
Among 40,680 eligible postmenopausal California Teachers Study cohort participants, 660 were diagnosed with invasive breast cancer before 2010. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI).
Increased breast cancer risk associated with alcohol consumption was observed among postmenopausal women who were current HT users (RR=1.60, 95% CI: 1.13–2.26 and RR=2.11, 95% CI: 1.41–3.15 for <20 and ≥20 g/d of alcohol), with risks being similar by HT preparation. Alcohol did not increase risk among women who had stopped using HT within 3 years or 3–4 years before completing the follow-up questionnaire or in the more distant past. Results were similar for ER+ and ER+PR+ tumors; while power was limited, no increase in risk was observed for ER- tumors.
Following the cessation of HT use, alcohol consumption is not significantly associated with breast cancer risk, although a non-significant increased risk was observed among women who never used HT.
Our findings confirm that concurrent exposure to HT and alcohol has a substantial adverse impact on breast cancer risk. However, after HT cessation, this risk is reduced.
breast cancer; alcohol; hormone therapy; cessation; epidemiology
Brief, valid measures of fatigue, a prevalent and distressing cancer symptom, are needed for use in research. This study’s primary aim was to create a shortened version of the revised Piper Fatigue Scale (PFS-R) based on data from a diverse cohort of breast cancer survivors. A secondary aim was to determine whether the PFS captured multiple distinct aspects of fatigue (a multidimensional model) or a single overall fatigue factor (a unidimensional model).
Breast cancer survivors (n=799; stages in situ through IIIa; ages 29–86 yrs) were recruited through 3 SEER registries (New Mexico, Western Washington, and Los Angeles, CA) as part of the Health, Eating, Activity, and Lifestyle (HEAL) study. Fatigue was measured approximately 3 years post-diagnosis using the 22-item PFS-R that has 4 subscales (Behavior, Affect, Sensory, and Cognition). Confirmatory factor analysis was used to compare unidimensional and multidimensional models. Six criteria were used to make item selections to shorten the PFS-R: scale’s content validity, items’ relationship with fatigue, content redundancy, differential item functioning by race and/or education, scale reliability, and literacy demand.
Factor analyses supported the original 4-factor structure. There was also evidence from the bi-factor model for a dominant underlying fatigue factor. Six items tested positive for differential item functioning between African-American and Caucasian survivors. Four additional items either showed poor association, local dependence, or content validity concerns. After removing these 10 items, the reliability of the PFS-12 subscales ranged from 0.87–0.89, compared to 0.90–0.94 prior to item removal.
The newly developed PFS-12 can be used to assess fatigue in African-American and Caucasian breast cancer survivors and reduces response burden without compromising reliability or validity. This is the first study to determine PFS literacy demand and to compare PFS-R responses in African-Americans and Caucasian breast cancer survivors. Further testing in diverse populations is warranted.
fatigue; breast cancer survivors; patient-reported outcomes; Piper Fatigue Scale; psychometrics
Testicular germ cell tumor (TGCT) incidence increased steadily in recent decades, but causes remain elusive. Germ cell function may be influenced by cannabinoids, and two prior epidemiologic studies report that use of marijuana may be associated with non-seminomatous TGCT. Here we evaluate the relationship between TGCTs and exposure to marijuana and other recreational drugs using a population-based case-control study.
163 TGCT cases diagnosed in Los Angeles County from December 1986 to April 1991 were enrolled with 292 controls matched on age, race/ethnicity and neighborhood. Participants were asked about drug use by structured in-person interview. Odds ratios and 95% confidence intervals were estimated using conditional logistic regression, adjusted for history of cryptorchidism; education; religiosity; and reported use of marijuana, cocaine and amyl nitrite.
Compared to never use, ever use of marijuana had two-fold increased risk (OR=1.94, 95%CI: 1.02–3.68) while ever use of cocaine was negatively associated with TGCT (OR=0.54, 95%CI: 0.32–0.91). Stratification on tumor histology revealed a specific association of marijuana use with non-seminoma and mixed histology tumors (OR=2.42, 95%CI: 1.08–5.42).
We observed a specific association of marijuana use with risk of non-seminoma and mixed tumors. This is the first report of a negative association between cocaine use and TGCT risk. Results warrant mechanistic studies of marijuana’s effect on the endocannabinoid system and TGCT risk, and caution that recreational and therapeutic cannabinoids by young men may confer malignant potential to testicular germ cells.
Testicular Germ Cell Tumors; Non-Seminoma; Marijuana; Cannabis; Δ9-Tetrahydrocannabinol (THC); cocaine; amyl nitrite; recreational drug use; tobacco; alcohol
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.