Plasma protein carbonyl levels and breast cancer risk

To study the role of oxidative stress in breast cancer risk, we analysed plasma levels of protein carbonyls in 1050 cases and 1107 controls. We found a statistically significant trend in breast cancer risk in relation to increasing quartiles of plasma protein carbonyl levels (OR = 1.2, 95% CI = 0.9-1.5; OR = 1.5, 95% CI = 1.2-2.0; OR = 1.6, 95% CI = 1.2-2.1, for the 2(nd), 3(rd) and 4(th) quartile relative to the lowest quartile, respectively, P for trend = 0.0001). The increase in risk was similar for younger (<50 years) and older women, more pronounced among women with higher physical activity levels (0.7 hrs/week for 4(th) quartile versus lowest quartile OR = 2.0, 95% CI = 1.4-3.0), higher alcohol consumption (> or = 15 grams/day for 4(th) quartile versus lowest quartile OR = 2.3, 95% CI = 1.1-4.7), and hormone replacement therapy use (HRT, OR = 2.6, 95% CI = 1.6-4.4 for 4(th) quartile versus lowest quartile). The multiplicative interaction terms were statistically significant only for physical activity and HRT. The positive association between plasma protein carbonyl levels and breast cancer risk was also observed when the analysis was restricted to women who had not received chemotherapy or radiation therapy prior to blood collection. Among controls, oxidized protein levels significantly increased with cigarette smoking and higher fruit and vegetable consumption, and decreased with alcohol consumption >30 grams per day. Women with higher levels of plasma protein carbonyl and urinary 15F(2t)-isoprostane had an 80% increase in breast cancer risk (OR = 1.8, 95% CI = 1.2-2.6) compared to women with levels below the median for both markers of oxidative stress. In summary, our results suggest that increased plasma protein carbonyl levels may be associated with breast cancer risk.     

Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer

Background: The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. Methods: We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). Results: Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (OR(per allele)=1.22, 95% CI=1.01-1.47, p(trend)=0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (OR(per allele)=1.20, 95% CI=0.99-1.45, p(trend)=0.06). PGR rs1042838 was also marginally associated with risk (OR(per allele)=1.25, 95% CI=0.96-1.61, p(trend)=0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. Conclusion: Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.     

The XRCC3 Thr241Met polymorphism and breast cancer risk: a case-control study in a Thai population

The X-ray repair cross-complementing group 3 gene (XRCC3) belongs to a family of genes responsible for repairing DNA double-strand breaks caused by normal metabolic processes and exposure to ionizing radiation. Polymorphisms in DNA repair genes may alter an individual's capacity to repair damaged DNA and may lead to genetic instability and contribute to malignant transformation. We examined the role of a polymorphism in the XRCC3 gene (rs861529; codon 241: threonine to methionine change) in determining breast cancer risk in Thai women. The study population consisted of 507 breast cancer cases and 425 healthy women. The polymorphism was analysed by fluorescence-based melting curve analysis. The XRCC3 241Met allele was found to be uncommon in the Thai population (frequency 0.07 among cases and 0.05 among controls). Odds ratios (OR) adjusted for age, body mass index, age at menarche, family history of breast cancer, menopausal status, reproduction parameters, use of contraceptives, tobacco smoking, involuntary tobacco smoking, alcohol drinking, and education were calculated for the entire population as well as for pre- and postmenopausal women. There was a significant association between 241Met carrier status and breast cancer risk (OR 1.58, 95% confidence interval (CI) 1.02-2.44). Among postmenopausal women, a slightly higher OR (1.82, 95% CI 0.95-3.51) was found than among premenopausal women (OR 1.48, 95% CI 0.82-2.69). Our findings suggest that the XRCC3 Thr241Met polymorphism is likely to play a modifying role in the individual susceptibility to breast cancer among Thai women as already shown for women of European ancestry.     

SULT1A1 Arg213His polymorphism, smoked meat, and breast cancer risk: a case-control study and meta-analysis

SULT1A1 is involved in both detoxification of estrogens and bioactivation of carcinogens in smoked meat. SULT1A1 Arg213His polymorphism's effect on breast cancer risk is still unclear. We recruited 400 case-control pairs to investigate the association between SULT1A1 genotypes and breast cancer risk, and the combined effect of SULT1A1 polymorphism and daily intake of smoked meat. Participants were questioned about their dietary habits and other risk factors, and their SULT1A1 genotypes were determined. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated by multivariable unconditional logistic regression. We also performed a meta-analysis of relevant published studies to test these associations. In the case-control study, no significant associations were observed between SULT1A1 polymorphism and breast cancer risk. In the meta-analysis, SULT1A1 His/His genotype slightly increased risk among both overall and postmenopausal women (OR(pooled-overall)=1.12, 95% CI: 1.02-1.24; OR(pooled-post)=1.17, 95% CI: 1.03-1.32). A larger positive association was observed in Asian populations (OR(pooled-Asian)=2.01, 95% CI: 1.24-3.26). In our case-control study, high energy-adjusted daily intake of smoked meat was significantly associated with breast cancer risk in overall, pre- and postmenopausal women (aORs: 2.31-3.13, OR 95% CIs exclude 1). High smoked meat intake interacted positively with the His variant allele (all γ>1). These results correlated with those of the meta-analysis (γ(pooled-overall)=1.27). The SULT1A1 His/His genotype may increase the risk of breast cancer among Asian women, and dietary exposure to heterocyclic amines and polycyclic aromatic hydrocarbons, along with the SULT1A1 His/His variant genotype, may synergistically increase the risk of breast cancer.     

Passive Smoking and Breast Cancer Risk among Non-Smoking Women: A Case-Control Study in China

Background

The role of passive smoking on breast cancer risk was unclear. This study aimed to evaluate the association between passive smoking and breast cancer risk among Chinese women.

Methods/Principal Findings

A hospital-based case-control study, including 877 breast cancer cases and 890 controls, frequency-matched by age and residence, was conducted. A structured questionnaire was used to collect information on passive smoking history through face-to-face interview by trained interviewers. Unconditional logistic regression models were used to estimate the association between passive smoking and breast cancer risk. A positive association between any passive smoking exposure and breast cancer risk was observed. Compared with women who were never exposed to passive smoking, women who were ever exposed had a higher breast cancer risk, with the adjusted odds ratio (OR) and 95% confidence interval (CI) of 1.35 (1.11-1.65). Similar result was found on home passive smoking exposure and breast cancer risk, but not on workplace passive smoking exposure. Women who were ever exposed to tobacco smoke at home had a higher risk of breast cancer compared with never exposed women, with the adjusted OR (95% CI) of 1.30 (1.05-1.61). Home passive smoking exposure showed significant dose-response relationships with breast cancer risk in smoker-years, cigarettes/day and total pack-years (P _trend=0.003, 0.006 and 0.009, respectively). An increased total smoker-years of any passive exposure significantly elevated the risk of breast cancer (P _trend<0.001). Positive associations and dose-response relationships were found among postmenopausal women and all subtypes of estrogen receptor (ER) and progesterone receptor (PR) status of breast cancer.

Conclusions

Passive smoking was associated with an increased risk of breast cancer among non-smoking Chinese women. A stronger positive association with breast cancer risk was seen mainly among postmenopausal women.     

Diabetes,physical activity and breast cancer among Hispanic women

Purpose: We assessed the association between diabetes and breast cancer and whether physical activity modified the effect of diabetes on breast cancer in Hispanic women. Methods: We used data from a case-control study of breast cancer among Hispanic women aged 30–79 conducted between 2003 and 2008 on the Texas–Mexico border. In-person interviews were completed with 190 incident breast cancer cases ascertained through surgeons and oncologists, and 979 controls who were designated as both high-risk (n = 511) and low-risk (N = 468) for breast cancer (with respective response rates of 97%, 83% and 74%). Results: After adjustment for menopausal status and mammography screening, there was no effect of diabetes on breast cancer risk (high-risk control group odds ratio [OR] 1.02, 95% confidence interval [CI] 0.71–1.48; low-risk control group OR 0.87, 0.58–1.30). Women who had a diabetes history and did not exercise were at no risk of breast cancer (OR 0.96, 95% CI 0.63–1.48) or a slightly reduced breast cancer risk (low-risk control group OR 0.72, 95% CI 0.46–1.15) depending on the control group used, while women with diabetes who did exercise had significantly reduced breast cancer risk (OR 0.41, 95% CI 0.21–0.83) regardless of the control group used (high-risk control group p-value for interaction = 0.013, low-risk control group p-value for interaction 0.183). Conclusions: Should other studies confirm our results, physical activity should be explored as a means of reducing breast cancer risk in diabetic women.     

The Role of Adiponectin in Breast Cancer: A Meta-Analysis

Published results suggests that high adiponectin level may decrease the risk of breast cancer. However, available evidence on breast cancer is conflicting. Therefore a meta-analysis was performed to assess the association between blood adiponectin and breast cancer risk. PubMed database, Web of Science, Elsevier Science, Springer Link and bibliographies of retrieved articles were searched for epidemiological studies published up to March 2013. Meta-analysis was performed on the combined effect values (OR) as well as standardized mean difference (SMD) including 17 studies. Fixed or random effect pooled measure was selected on the basis of homogeneity test among studies. The publication bias was assessed by the Egger’s regression asymmetry test and Begg’s rank correlation test with Begg’s funnel plot. Subgroup analyses and sensitivity analysis were also performed. A total of 13 studies involving 3578 breast cancer cases and 4363 controls contributed to the OR analysis. The high adiponectin level did not significantly affect breast cancer risk (OR=0.902, 95% CI=0.773–1.053). After excluding articles that were the key contributors to between-study heterogeneity, the OR of high adiponectin level was associated with decreased breast cancer risk (OR=0.838, 95% CI=0.744–0.943). There was a significantly association between high adiponectin level and postmenopausal breast cancer women (OR=0.752, 95%CI=0.604-0.936); and it was not associated with premenopausal breast cancer women (OR=0.895, 95%CI=0.638-1.256). The result of pooled measure on SMD was that the high adiponectin level was associated with decreased breast cancer risk (SMD= -0.348, 95% CI= -0.533--0.614) after excluding articles which were the key contributors to between-study heterogeneity. Our findings indicate that high adiponectin level might decrease the risk of postmenopausal breast cancer. More randomized clinical trials and observational studies are needed to confirm this association with underlying biological mechanisms in the future.     

Soy isoflavones, CYP1A1, CYP1B1, and COMT polymorphisms, and breast cancer: a case-control study in southwestern China

CYP1A1, CYP1B1, and COMT are key enzymes involved in estrogen metabolism. Soy isoflavones, phytoestrogens found in soy foods, may modify the activity of these enzymes. A case-control study was conducted to assess the associations between soy isoflavone intake and the CYP1A1 Ile462Val, CYP1B1 Val432Leu, and COMT Val158Met polymorphisms and breast cancer, as well as their combined effects on breast cancer. A total of 400 newly diagnosed breast cancer cases and 400 healthy controls were recruited. Participants' daily intake of soy isoflavones (DISI [mg/day]) was calculated and transformed to energy-adjusted DISI by the residual method. Gene sequencing was used to analyze CYP1A1, CYP1B1, and COMT polymorphisms. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated by conditional logistic regression. A strong protective dose-dependent effect of energy-adjusted DISI on breast cancer was found in both pre- and postmenopausal women (P(trend)??1, OR 95% CIs exclude 1). In premenopausal women, only carrying CYP1B1 Leu/Leu was associated with breast cancer risk (aOR?=?2.05, 95% CI: 1.11-3.79). Carrying CYP1A1 Val/Val was related to breast cancer risk only among all women. A stratified analysis was performed at two levels of energy-adjusted DISI, with wildtype homozygous genotypes and low energy-adjusted DISI as the reference. In the high energy-adjusted DISI subgroup, carrying the CYP1B1 Leu/Leu genotype did not affect breast cancer risk in either all women or in the menopausal subgroups, compared with the reference. Overall, in Han Chinese women, carrying CYP1A1 Val/Val and COMT Met/Met appears to be associated with breast cancer risk, especially in postmenopausal women. CYP1B1 susceptible genotypes (Val/Leu or Leu/Leu) also contribute to increased breast cancer risk, regardless of menopausal status, but high soy isoflavone intake may reduce this risk.     

Association between SHBG Asp327Asn (rs6259) polymorphism and breast cancer risk: a meta-analysis of 10,454 cases and 13,111 controls

Sex hormone-binding globulin (SHBG) is a plasma glycoprotein that plays an important role in breast cancer pathophysiology and risk definition, since it regulates the bioavailable fraction of circulating estradiol. Epidemiological studies have evaluated the association between SHBG Asp327Asn polymorphism and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 10 studies were identified for the meta-analysis, including 10,454 cases and 13,111 controls for SHBG Asp327Asn polymorphism. When all studies were pooled into the meta-analysis, there was no evidence for significant association between SHBG Asp327Asn polymorphism and breast cancer risk (for Asn/Asn vs. Asp/Asp: OR = 1.20, 95 % CI = 0.94-1.55; for Asp/Asn vs. Asp/Asp: OR = 0.94, 95 % CI = 0.87-1.01; for dominant model: OR = 0.95, 95 % CI = 0.90-1.02; for recessive model: OR = 1.22, 95 % CI = 0.95-1.57). In the subgroup analyses by ethnicity, menopausal status, and source of controls, no significant associations were found in all genetic models. Interestingly, further analyses stratified by menopausal status in different ethnicities revealed that this polymorphism might provide protective effects against breast cancer risk in postmenopausal Asian women (for dominant model: OR = 0.83, 95 % CI = 0.70-0.97). Sensitivity analyses were performed by sequential removal of individual studies and cumulative statistics have showed combined ORs were not materially altered by any individual study under all comparisons. In summary, this meta-analysis suggests that SHBG Asp327Asn polymorphism is not associated with breast cancer risk overall, while it might be an important genetic susceptibility factor in postmenopausal Asian women for developing breast cancer. Larger and well-designed studies are warranted to confirm our findings in the future.     

The XRCC3 Thr241Met polymorphism and breast cancer risk: a case–control study in a Thai population

The X-ray repair cross-complementing group 3 gene (XRCC3) belongs to a family of genes responsible for repairing DNA double-strand breaks caused by normal metabolic processes and exposure to ionizing radiation. Polymorphisms in DNA repair genes may alter an individual's capacity to repair damaged DNA and may lead to genetic instability and contribute to malignant transformation. We examined the role of a polymorphism in the XRCC3 gene (rs861529; codon 241: threonine to methionine change) in determining breast cancer risk in Thai women. The study population consisted of 507 breast cancer cases and 425 healthy women. The polymorphism was analysed by fluorescence-based melting curve analysis. The XRCC3 241Met allele was found to be uncommon in the Thai population (frequency 0.07 among cases and 0.05 among controls). Odds ratios (OR) adjusted for age, body mass index, age at menarche, family history of breast cancer, menopausal status, reproduction parameters, use of contraceptives, tobacco smoking, involuntary tobacco smoking, alcohol drinking, and education were calculated for the entire population as well as for pre- and postmenopausal women. There was a significant association between 241Met carrier status and breast cancer risk (OR 1.58, 95% confidence interval (CI) 1.02–2.44). Among postmenopausal women, a slightly higher OR (1.82, 95% CI 0.95–3.51) was found than among premenopausal women (OR 1.48, 95% CI 0.82–2.69). Our findings suggest that the XRCC3 Thr241Met polymorphism is likely to play a modifying role in the individual susceptibility to breast cancer among Thai women as already shown for women of European ancestry.     

Genetic polymorphism of glutathione S-transferase P1 and breast cancer risk

To evaluate the potential association between the GSTP1 genotype and the development of breast cancer, a hospital based case-control study was conducted on Korean women. The study population consisted of 171 histologically confirmed incident breast cancer cases and 171 age-matched controls with no present or previous history of cancer. PCR-RFLP was used for the GSTP1 genotyping and statistical evaluations were performed using an unconditional logistic regression model. Postmenopausal women with the GSTP1 Val allele were found to have a reduced risk of breast cancer (OR = 0.3, 95 % CI = 0.10-0.74). A significant interaction was observed between the GSTP1 genotype and alcohol consumption (p for interaction = 0.01); compared with never-drinking women with Ile/Ile genotype, ever-drinking women with the GSTP1 Val allele had almost a three-fold risk of breast cancer (OR = 2.9, 95 % CI = 1.05-7.85), whereas never-drinking women with Val allele had half this risk (OR = 0.5, 95 % CI = 0.27-0.93). Our findings suggest that the GSTP1 polymorphism influences individual susceptibility to breast cancer in the Korean women and this effect may be modified by alcohol consumption.     

DNA methylation and breast tumor clinicopathological features: The Western New York Exposures and Breast Cancer (WEB) study

We evaluated the association between methylation of 9 genes, SCGB3A1, GSTP1, RARB, SYK, FHIT, CDKN2A, CCND2, BRCA1, and SFN in tumor samples from 720 breast cancer cases with clinicopathological features of the tumors and survival. Logistic regression was used to estimate odds ratios (OR) of methylation and Cox proportional hazards models to estimate hazard ratios (HR) between methylation and breast cancer related mortality. Estrogen receptor (ER) and progesterone receptor (PR) positivity were associated with increased SCGB3A1 methylation among pre- and post-menopausal cases. Among premenopausal women, compared with Stage 0 cases, cases of invasive cancer were more likely to have increased methylation of RARB (Stage I OR = 4.7, 95% CI: 1.1–19.0; Stage IIA/IIB OR = 9.7, 95% CI: 2.4–39.9; Stage III/IV OR = 5.6, 95% CI: 1.1–29.4) and lower methylation of FHIT (Stage I OR = 0.2, 95% CI: 0.1–0.9; Stage IIA/IIB OR = 0.2, 95% CI: 0.1–0.8; Stage III/IV OR = 0.6, 95% CI: 0.1–3.4). Among postmenopausal women, methylation of SYK was associated with increased tumor size (OR = 1.7, 95% CI: 1.0–2.7) and higher nuclear grade (OR = 2.0, 95% CI 1.2–3.6). Associations between methylation and breast cancer related mortality were observed among pre- but not post-menopausal women. Methylation of SCGB3A1 was associated with reduced risk of death from breast cancer (HR = 0.41, 95% CI: 0.17–0.99) as was BRCA1 (HR = 0.41, 95% CI: 0.16–0.97). CCND2 methylation was associated with increased risk of breast cancer mortality (HR = 3.4, 95% CI: 1.1–10.5). We observed differences in methylation associated with tumor characteristics; methylation of these genes was also associated with breast cancer survival among premenopausal cases. Understanding of the associations of DNA methylation with other clinicopathological features may have implications for prevention and treatment.     

Breast cancer risk and the interaction between adolescent body size and weight gain in later life: A case-control study

BackgroundWhile the breast cancer risk associated with increasing adult BMI in postmenopausal women can be explained by increases in concentrations of endogenous estrogens the biologic mechanisms behind the inverse association between adolescent BMI and breast cancer risk are still a subject of controversial debate.MethodsWe investigated the association of breast cancer with body size and changes in body size across life time estimated by age-specific BMI Z scores and changes in BMI Z scores from teenage years to middle age in an age-matched population-based case-control study of 2994 Australian women. Logistic regression adjusted for the matching factor age and further potential confounders was used.ResultsAdolescent body leanness in postmenopausal women and excess adult weight gain in all study participants were associated with an increased breast cancer risk with an odds ratio [95% confidence interval] of 1.29 [1.08,1.54] and 1.31 [1.09,1.59], respectively. Interaction analyses restricted to postmenopausal women revealed an increased risk of breast cancer in those who were lean during adolescence and gained excess weight during adulthood (odds ratio [95% confidence interval]: 1.52 [1.19,1.95]) but not in women who were lean during adolescence and did not gain excess weight during adulthood (1.20 [0.97,1.48]) and not in women who were not lean during adolescence and but gained excess weight during adulthood (1.10 [0.95,1.27]) compared to postmenopausal women who were neither lean during adolescence nor gained excess weight.ConclusionIn postmenopausal women adolescent leanness was only associated with increased breast cancer risk when excess weight was gained during adulthood.     

Smoking (active and passive), N-acetyltransferase 2, and risk of breast cancer

Background: The relationship between smoking and breast cancer remains controversial. The study aim was to assess the relationship of passive and active smoking to breast cancer risk by N-acetyltransferase 2 (NAT2) phenotype, using a comprehensive assessment of both passive and active smoking. Methods: We undertook a population-based case–control study in Northeastern Ontario, Canada of 347 women diagnosed (2002–2004) with breast cancer and 775 population-based controls. The mailed study package included a questionnaire requesting information about established breast cancer risk factors, passive and active smoking, and a buccal swab for genetic analyses. Results: Among never-active smokers, a long duration of passive smoking was associated with an increased risk of breast cancer (odds ratio (OR) 1.86 (95% confidence interval (95% CI) 1.01–3.44) (test for trend (p = 0.07)); that risk was more elevated for NAT2 slow acetylators (OR 2.76, 95% CI 1.16–6.59) (and highest in extremely slow acetylators), but not elevated for NAT2 fast acetylators (OR 1.17, 95% CI 0.42–3.23). Among active smokers more than 20 pack-years of smoking was associated with an OR of 1.34 (95% CI 0.92-1.96); more elevated among NAT2 fast acetylators OR 1.93 (95% CI 1.01–3.69) but not elevated among NAT2 slow acetylators. Women who were NAT2 fast acetylators in the highest quartile for duration of active smoking had an OR of 2.74 (95% CI 1.42–5.27), with a significant test of trend (p = 0.005). Conclusions: These findings suggest that passive and active smoking may be related to breast cancer, and the effect may be differentially modified by NAT2 phenotype. Further research into the genetic modification of a breast cancer–smoking relationship may help to reconcile earlier discrepant findings.     

Glutathione S-transferase T1 polymorphism is associated with breast cancer susceptibility

The association between present/null polymorphism of glutathione S-transferase T1 (GSTT1) and breast cancer risk are still inconclusive. We performed a meta-analysis to derive a more precise estimation of the relationship. A total of 48 studies including 17,254 cases and 21,163 controls were involved in this meta-analysis. When all studies were pooled into the meta-analysis, significantly elevated breast cancer risk was associated with null genotype (OR = 1.138, 95% CI = 1.051–1.232). When stratified by ethnicity, significantly increased risks were found for Caucasians (OR = 1.185, 95% CI = 1.075–1.306), but no statistically significantly increased risks were found in Asians (OR = 1.017, 95% CI = 0.846–1.223) and Africans (OR = 1.160, 95% CI = 0.815–1.650). In the subgroup analysis by controls source, statistically significantly elevated risks were both found in population-based studies (OR = 1.123, 95% CI = 1.014–1.243) and hospital-based studies (OR = 1.181, 95% CI = 1.056–1.321). When stratified by menopausal status, no statistically significantly increased risks were found in premenopausal women (OR = 1.115, 95% CI = 0.925–1.345) and postmenopausal women (OR = 1.077, 95% CI = 0.992–1.169). In summary, this meta-analysis suggests that the GSTT1 null genotype is a risk allele for breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.     

Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan

The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution that genetic factors make to these high rates, we have conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from two major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7% (95% confidence interval [CI] 4.1%-9.4%), and that among case subjects with ovarian cancer was 15.8% (95% CI 9.2%-22.4%). Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. The majority of detected mutations are unique to Pakistan. Five BRCA1 mutations (2080insA, 3889delAG, 4184del4, 4284delAG, and IVS14-1A-->G) and one BRCA2 mutation (3337C-->T) were found in multiple case subjects and represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 is comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1-mutation-positive case subjects was 48% and was 37% for first-degree relatives of the BRCA2-mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio [OR] 2.1; 95% CI 1.4-3.3; P=.001). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age <40 years) (OR=2.7; 95% CI 1.5-4.9; P=.0008) and case subjects with ovarian cancer (OR=2.4; 95% CI 1.4-4.2; P=.002). These results suggest that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan.     

Lower Breast Cancer Risk among Women following the World Cancer Research Fund and American Institute for Cancer Research Lifestyle Recommendations: EpiGEICAM Case-Control Study

BackgroundAccording to the “World Cancer Research Fund” and the “American Institute of Cancer Research” (WCRF/AICR) one in four cancer cases could be prevented through a healthy diet, weight control and physical activity.ObjectiveTo explore the association between the WCRF/AICR recommendations and risk of breast cancer.MethodsDuring the period 2006 to 2011 we recruited 973 incident cases of breast cancer and 973 controls from 17 Spanish Regions. We constructed a score based on 9 of the WCRF/AICR recommendations for cancer prevention:: 1)Maintain adequate body weight; 2)Be physically active; 3)Limit the intake of high density foods; 4)Eat mostly plant foods; 5)Limit the intake of animal foods; 6)Limit alcohol intake; 7)Limit salt and salt preserved food intake; 8)Meet nutritional needs through diet; S1)Breastfeed infants exclusively up to 6 months. We explored its association with BC by menopausal status and by intrinsic tumor subtypes (ER+/PR+ & HER2-; HER2+; ER&PR-&HER2-) using conditional and multinomial logistic models respectively.ResultsOur results point to a linear association between the degree of noncompliance and breast cancer risk. Taking women who met 6 or more recommendations as reference, those meeting less than 3 showed a three-fold excess risk (OR=2.98(CI95%:1.59-5.59)), especially for postmenopausal women (OR=3.60(CI95%:1.24;10.47)) and ER+/PR+&HER2- (OR=3.60(CI95%:1.84;7.05)) and HER2+ (OR=4.23(CI95%:1.66;10.78)) tumors. Noncompliance of recommendations regarding the consumption of foods and drinks that promote weight gain in premenopausal women (OR=2.24(CI95%:1.18;4.28); p for interaction=0.014) and triple negative tumors (OR=2.93(CI95%:1.12-7.63)); the intake of plant foods in postmenopausal women (OR=2.35(CI95%:1.24;4.44)) and triple negative tumors (OR=3.48(CI95%:1.46-8.31)); and the alcohol consumption in ER+/PR+&HER2- tumors (OR=1.52 (CI95%:1.06-2.19)) showed the strongest associations.ConclusionBreast cancer prevention might be possible by following the “World Cancer Research Fund” and the “American Institute of Cancer Research” recommendations, even in settings like Spain, where a high percentage of women already comply with many of them.     

Serum Lipids and Breast Cancer Risk: A Meta-Analysis of Prospective Cohort Studies

Purpose

Epidemiologic studies exploring causal associations between serum lipids and breast cancer risk have reported contradictory results. We conducted a meta-analysis of prospective cohort studies to evaluate these associations.

Methods

Relevant studies were identified by searching PubMed and EMBASE through April 2015. We included prospective cohort studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of specific lipid components (i.e., total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides [TG]) with breast cancer risk. Either a fixed- or a random-effects model was used to calculate pooled RRs.

Results

Fifteen prospective cohort studies involving 1,189,635 participants and 23,369 breast cancer cases were included in the meta-analysis. The pooled RRs of breast cancer for the highest versus lowest categories were 0.96 (95% CI: 0.86–1.07) for TC, 0.92 (95% CI: 0.73–1.16) for HDL-C, 0.90 (95% CI: 0.77–1.06) for LDL-C, and 0.93 (95% CI: 0.86–1.00) for TG. Notably, for HDL-C, a significant reduction of breast cancer risk was observed among postmenopausal women (RR = 0.77, 95% CI: 0.64–0.93) but not among premenopausal women. Similar trends of the associations were observed in the dose-response analysis.

Conclusions

Our findings suggest that serum levels of TG but not TC and LDL-C may be inversely associated with breast cancer risk. Serum HDL-C may also protect against breast carcinogenesis among postmenopausal women.     

Maternal Obesity and Breast‐feeding Practices Among White and Black Women

Despite the increase in obesity among women of reproductive ages, few studies have considered maternal obesity as a risk factor for breast‐feeding success. We tested the hypothesis that women who are obese (BMI = 30–34.9) and very obese (BMI ≥35) before pregnancy are less likely to initiate and maintain breast‐feeding than are their normal‐weight counterparts (BMI = 18.5–24.9) among white and black women. Data from 2000 to 2005 South Carolina Pregnancy Risk Assessment Monitoring System (PRAMS) were used. The overall response rate was 71.0%; there were 3,517 white and 2,846 black respondents. Black women were less likely to initiate breast‐feeding and breast‐fed their babies for a shorter duration than white women. Compared to normal‐weight white women, very obese white women were less likely to initiate breast‐feeding (odds ratio: 0.63; 95% confidence interval (CI) = 0.42, 0.94) and more likely to discontinue breast‐feeding within the first 6 months (hazard ratio (HR) = 1.89; 95% CI: 1.39, 2.58). Among black women, prepregnancy BMI was neither associated with breast‐feeding initiation nor with breast‐feeding continuation within the first 6 months. Because very obese white women are less likely to initiate or continue breast‐feeding than other white women, health professionals should be aware that very obese white women need additional breast‐feeding support. Lower rates of breast‐feeding among black women suggest that they should continue to be the focus of the programs and policies aimed at breast‐feeding promotion in the United States.     

Development of Overweight Associated with Childbearing Depends on Smoking Habit: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Objective: To prospectively evaluate whether childbearing leads to development of overweight in women and to evaluate the role of other known risk factors. Research Methods and Procedures: A prospective, multicenter observational study, the Coronary Artery Risk Development in Young Adults (CARDIA) Study from 1986 to 1996, examined subjects at baseline and in follow‐up years 2, 5, 7, and 10. Included were 998 (328 black and 670 white) nulliparous women, age 18‐30 years, who were not overweight at baseline. Relative odds for incident overweight (BMI ≥ 25 kg/m²) associated with parity change (0, 1, or 2+) and risk factors were estimated using discrete‐time survival models adjusted for baseline and time‐dependent covariates. Results: Parity change‐association with development of overweight depended on smoking habit (interaction, p < 0.001). In multivariate adjusted models, 1 and 2+ births vs. 0, respectively, were associated with increased risk for development of overweight among never smokers [odds ratio (OR) = 2.66; 95% confidence interval (CI): 1.80, 3.93, and 2.10, 95% CI: 1.24, 3.56] and decreased risk among current smokers (OR = 0.41; 95% CI: 0.17, 0.96, and 0.36, 95% CI: 0.08, 1.65). Risk was increased for black vs. white race (OR = 3.49; 95% CI: 2.59, 4.69), frequent weight cycling (OR = 1.45; 95% CI: 1.03, 2.04), and high school education or less (OR = 2.21; 95% CI: 1.50, 3.26) and was decreased for highest physical activity quartile (OR = 0.62; 95% CI: 0.43, 0.90). Discussion: Childbearing contributes to development of overweight in nonsmokers but not in smokers, where development of overweight is less likely in women who bear children. Race, education, and behaviors are important factors in development of overweight in young women.