Genetic epidemiology of bilateral breast cancer: a linkage analysis using the affected-pedigree-member method

We used the affected-pedigree-member (APM) method to conduct linkage analyses on 19 pedigrees in which the probands had premenopausal bilateral breast cancer. This method analyzes all affected pairs of relatives, as opposed to siblings only, and incorporates into the analyses information on the frequency of marker alleles. Fourteen codominant marker systems were evaluated in two separate analyses. In the first, only premenopausal cases of breast cancer were coded as affected because we assumed that postmenopausal cases were due to a different etiology. In the second analysis, all cases of breast cancer were coded as affected, irrespective of menopausal status. In the premenopausal-cases-only analysis, we observed evidence suggestive of nonindependent segregation for C3 and ESD. In the all-cases analysis, we observed much weaker evidence for C3 and ESD and noted a suggestion of nonindependent segregation for AMY2 and PGM1.     

Body fat distribution and obesity in pre- and postmenopausal breast cancer

BACKGROUND: Excessive body weight is known to increase the risk of postmenopausal, but not premenopausal breast cancer. Some studies have suggested that being overweight is protective against premenopausal breast cancer, but the evidence is not compelling. Much less is known about the role of body fat distribution in either pre- or postmenopausal breast cancer. METHODS: Breast cancer risk was examined in relation to body weight, height, Quetelet index (kg/m2), and waist/hip ratio (WHR) in the New York University Women's Health Study, a prospective cohort study. Cases were 109 premenopausal and 150 postmenopausal women diagnosed with breast cancer between 1985 and 1994. Non-cases were 8,157 cohort members free of breast cancer. RESULTS: Among premenopausal women, there was an increasing risk of breast cancer with increasing WHR. The relative risk (RR) of breast cancer increased to 1.72 (95% confidence interval [CI]: 1.0-3.1) in the upper quartile of WHR. The association was limited to subjects who had elevated Quetelet index, but not among those with lower weight. Overall, Quetelet index itself was not related to breast cancer risk in the premenopausal group, but there was a protective association among those ranking below the median WHR. In postmenopausal women, the RR for breast cancer increased to 2.36 (95% CI: 1.4-3.9) in the upper quartile of Quetelet index, but there was no association with WHR. Height was not associated with breast cancer in this study. CONCLUSIONS: The study confirms that excessive body weight increases breast cancer risk in postmenopausal women. On the contrary, in premenopausal women, excessive body weight may be protective among women who have a lower-body type of fat accumulation (low WHR). An upper-body fat accumulation (high WHR) is a predictor of breast cancer risk in premenopausal women, and this effect is especially pronounced among subjects who are overweight.     

Relation between insulin resistance and breast cancer among Chilean women

PURPOSE: In Chile, diabetes and breast cancer are important public health problems. The association between insulin resistance and breast cancer, however, remains largely unexplored. METHODS: We conducted a case-control study to assess the relationship of insulin resistance (IR) and breast cancer in Chilean premenopausal and postmenopausal women. We compared 170 women, 33 to 86 years old, with incident breast cancer and 170 normal mammography controls, matched by 5-year age interval. Plasmatic insulin and glucose were measured and IR was calculated by the homeostasis model assessment method. Anthropometric measurements and sociodemographic and behavioral data were also collected. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by multivariable conditional logistic regression. RESULTS: IR was independently associated with breast cancer in postmenopausal women (OR = 2.70, 95%CI = 1.10-6.63), but not in premenopausal women (OR = 0.84, 95%CI = 0.20-3.52). Obesity was not associated with breast cancer at any age (OR = 0.68, 95%CI = 0.39-1.20). CONCLUSION: In this sample, IR increased the risk of breast cancer among postmenopausal women.     

Pre- and postmenopausal breast cancer

It has been postulated that breast cancer is not a single disease, and that the risk factors occurring in premenopausal women are different from those occurring in postmenopausal women. This case-control study of pre- and postmenopausal breast cancer was designed to investigate a variety of variables including age of menarche, parity, age at first full-term birth, breast feeding patterns, age at menopause, and history of oral contraceptive use. The study compared 60 breast cancer cases and 125 matched controls from the same breast cancer screening population. Cases and controls were matched for race, age, place of birth, marital status, education, and annual family income. More cases than controls used oral contraceptives; the differences were statistically significant. The risk ratio estimates were 2.9 (confidence intervals 1.19-7.15). The mean duration of oral contraceptive use was more than two times longer among premenopausal breast cancer cases than controls and five times longer among postmenopausal cases than the controls. The breast cancer cases had significantly more relatives with a history of other cancers than the control group (risk ratio estimate 2.3, P < 0.03). No association was found between height and breast cancer; however, cases were found to be significantly heavier than controls. No differences were found in reproductive variables between breast cancer patients and their matched controls. In addition, a subdivision of breast cancer cases into pre- and postmenopausal groups did not reveal any clear differences in reproductive variables that would support the hypothesis that different specific risk factors are operating during pre- and postmenopausal periods.     

A possible dual effect of cigarette smoking on the risk of postmenopausal breast cancer

Smoking seems modestly associated with breast cancer, but the potential dual effect of smoking (with opposing properties: carcinogenic vs anti-estrogenic) is understudied. The relationship between smoking before and after menopause and risk of postmenopausal breast cancer was investigated in the Netherlands Cohort Study (NLCS). In the NLCS, 62,573 women aged 55–69 years provided information on smoking, dietary and other lifestyle habits in 1986. Follow-up for cancer incidence until 2007 (20.3 years) consisted of record linkages with the Netherlands Cancer Registry and the Dutch Pathology Registry PALGA. Multivariate case-cohort analyses were based on 2526 incident breast cancer cases and 1816 subcohort members with complete data on smoking. When smoking during pre- and postmenopausal periods was mutually adjusted for, breast cancer risk was significantly positively associated with premenopausal smoking pack-years, but inversely associated with postmenopausal smoking pack-years, both in a dose-dependent manner. In continuous analyses, the hazard ratios (95% CI) were 1.35 (1.10–1.65), and 0.47 (0.28–0.80) per increment of 20 premenopausal, and postmenopausal pack-years, respectively. The interaction between pre- and postmenopausal pack-years in relation to breast cancer risk was significant (P < 0.001). This study highlights the importance of distinguishing and adjusting for smoking in different life periods, and suggests dual effects of smoking on postmenopausal breast cancer risk.     

Lactation in relation to postmenopausal breast cancer.

A modest inverse association between lactation and breast cancer risk has most consistently been observed in premenopausal women, and certain breastfeeding patterns, such as prolonged duration and early age at first lactation, may be important determinants of risk. However, these associations have not generally been observed in relation to postmenopausal breast cancer. As part of a multicenter population-based case-control study, the authors examined postmenopausal breast cancer risk according to breastfeeding characteristics. Breast cancer patients aged 50-79 years were identified from statewide tumor registries in Massachusetts, New Hampshire, and Wisconsin from July 1992 through July 1995. Similarly aged control women were randomly selected from population lists. Information regarding lactation history and breast cancer risk factors was obtained through telephone interviews. This analysis included only data on parous postmenopausal women (3,633 cases and 3,790 controls). After adjustment for age, parity, age at first birth, and other breast cancer risk factors, breastfeeding for at least 2 weeks was associated with a slightly reduced risk of breast cancer in comparison with women who had never lactated (relative risk = 0.87, 95% confidence interval 0.78-0.96). There was only a modest suggestion that increasing cumulative duration of lactation was inversely associated with breast cancer risk; the relative risk for women who had breastfed for > or =24 months was 0.73 (95% confidence interval 0.56-0.94) (p-trend for duration = 0.10). Age at first lactation was not consistently associated with risk. Modest inverse associations appeared to persist even up to 50 years since first lactation. Use of hormones to suppress lactation was not associated with postmenopausal breast cancer, nor was inability to breastfeed related to risk. These results suggest that lactation may have a slight and perhaps long-lasting protective effect on postmenopausal breast cancer risk.     

Association of polymorphism in MDM-2 and p53 genes with breast cancer risk in Indian women

PURPOSE: Single nucleotide polymorphism (SNP) at position -309 (T309G) in MDM-2 promoter induces tumor formation in the individuals possessing inherited p53 mutations. The present study was undertaken to investigate the association of MDM-2 SNP309, p53 Arg72Pro, and p53 intron-6 G/A polymorphism with total, premenopausal, and postmenopausal breast cancer risks in Indian women. METHODS: Genotyping of MDM-2 SNP309, p53 Arg72Pro, and p53 intron-6 G/A in 104 patients and 105 controls was performed either by ARMS-PCR or by polymerase chain reaction and direct sequencing. RESULTS: The p53 Arg72Pro heterozygous variant and in combination with its homozygous variant exhibited a significant protective association with total (odds ratio [95% confidence interval]: 0.42 [0.22-0.81] and 0.46 [0.25-0.85], p value; 0.007 and 0.012) and postmenopausal breast cancer risk (odds ratio [95% confidence interval]: 0.25 [0.07-0.73] and 0.27 [0.08-0.77], p value; 0.009 and 0.013]. Neither combined nor homozygous/heterozygous MDM-2 SNP309G was associated with total, premenopausal, or postmenopausal breast cancer risk; however, MDM-2 SNP309G, along with p53 Arg72Pro heterozygous variant, showed a significant protective association with premenopausal breast cancer risk (odds ratio [95% confidence interval]: 0.18 [0.02-1.20], p value; 0.041 for homozygous + heterozygous MDM-2 SNP309G). CONCLUSIONS: The results indicate protective associations of p53 Arg72Pro heterozygous variant with postmenopausal and MDM-2 SNP309G along with p53 Arg72Pro heterozygous variant with premenopausal breast cancer risk.     

Body size across the life course, mammographic density, and risk of breast cancer

Adult body mass index (BMI) is inversely associated with premenopausal breast cancer risk, and childhood and adolescent body size is inversely associated with breast cancer risk in pre- and postmenopausal women. Breast density is inversely related to body size and may play a role in the association of body size with breast cancer risk. The authors conducted a nested case-control study including 1,528 cases and 2,844 controls from the Nurses' Health Study (1989-2004) and Nurses' Health Study II (1996-2003). Prior to breast cancer diagnosis, participants reported their body fatness during childhood and adolescence, BMI at age 18 years, and current BMI. Mammographic density was measured by using a computer-assisted thresholding method. The inverse association between adult BMI and premenopausal breast cancer (for BMI ≥30 vs. BMI 20-22.4, odds ratio = 0.64, 95% confidence interval: 0.38, 1.06) (P(trend) = 0.36) became positive after adjustment for mammographic density (odds ratio = 1.28, 95% confidence interval: 0.72, 2.30) (P(trend) = 0.07). Conversely, the inverse association between childhood and adolescent body size and breast cancer risk remained after adjustment for mammographic density. The inverse association between adult BMI and premenopausal breast cancer risk may be partially due to negative confounding by mammographic density. Conversely, mammographic density does not appear to explain the inverse association between childhood and adolescent body fatness and breast cancer risk.     

Physical activity and breast cancer: a systematic review

BACKGROUND: Many epidemiologic studies have found an association between physical activity and breast cancer risk, although this has not been a consistent finding. METHODS: Studies were identified through a systematic review of literature available on PubMed through February 2006. We included all cohort and case-control studies that assessed total or leisure time activities in relation to occurrence or mortality of breast cancer. The fully adjusted risk estimates and 95% confidence intervals for the highest versus lowest level of activity were documented for each study as well as evidence for a dose-response relationship. Methodologic quality was also assessed. Due to statistical and methodologic heterogeneity among studies, we did not carry out statistical pooling. To draw conclusions, we performed a best-evidence synthesis taking study quality into account. RESULTS: Nineteen cohort studies and 29 case-control studies were evaluated. There was strong evidence for an inverse association between physical activity and postmenopausal breast cancer with risk reductions ranging from 20% to 80%. For premenopausal breast cancer, however, the evidence was much weaker. For pre- and postmenopausal breast cancer combined, physical activity was associated with a modest (15-20%) decreased risk. Evidence for a dose-response relationship was observed in approximately half of the higher-quality studies that reported a decreased risk. A trend analysis indicated a 6% (95% confidence interval = 3% to 8%) decrease in breast cancer risk for each additional hour of physical activity per week assuming that the level of activity would be sustained. CONCLUSIONS: There is evidence for an inverse association between physical activity and breast cancer risk. The evidence is stronger for postmenopausal breast cancer than for premenopausal breast cancer.     

Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk

The association between anthropometric indices and the risk of breast cancer was analyzed using pooled data from seven prospective cohort studies. Together, these cohorts comprise 337,819 women and 4,385 incident invasive breast cancer cases. In multivariate analyses controlling for reproductive, dietary, and other risk factors, the pooled relative risk (RR) of breast cancer per height increment of 5 cm was 1.02 (95% confidence interval (CI): 0.96, 1.10) in premenopausal women and 1.07 (95% CI: 1.03, 1.12) in postmenopausal women. Body mass index (BMI) showed significant inverse and positive associations with breast cancer among pre- and postmenopausal women, respectively; these associations were nonlinear. Compared with premenopausal women with a BMI of less than 21 kg/m2, women with a BMI exceeding 31 kg/m2 had an RR of 0.54 (95% CI: 0.34, 0.85). In postmenopausal women, the RRs did not increase further when BMI exceeded 28 kg/m2; the RR for these women was 1.26 (95% CI: 1.09, 1.46). The authors found little evidence for interaction with other breast cancer risk factors. Their data indicate that height is an independent risk factor for postmenopausal breast cancer; in premenopausal women, this relation is less clear. The association between BMI and breast cancer varies by menopausal status. Weight control may reduce the risk among postmenopausal women.     

Cigarette smoking and breast cancer: case-control studies of prevalent and incident cancer in the Canadian National Breast Screening Study

Two case-control studies of Canadian women aged 40-59 years are reported investigating the relation of cigarette smoking with initial visit (prevalent) and subsequent visit (incident) breast cancer detection, respectively, within the Canadian National Breast Screening Study. The analysis of prevalent breast cancer (1982-1985), which involved 254 cases and 762 controls, showed no evidence of an elevated risk for women with a history of cigarette smoking, with odds ratios of 0.9 (95% confidence interval (Cl) 0.6-1.5) and 1.2 (95% Cl 0.8-1.8) in premenopausal and postmenopausal subjects, respectively. Similarly, in the incident breast cancer analysis (1981-1987) based on 317 cases and 951 controls, women with a history of cigarette smoking had odds ratios of 1.2 (95% Cl 0.8-2.0) and 1.2 (95% Cl 0.9-1.7) in the premenopausal and postmenopausal categories, respectively. No evidence of dose response or of elevated risk in ex-smokers or current smokers was found in either study. These results persisted despite adjustment for several important variables. The present data demonstrate no association between smoking and prevalent or incident breast cancer in either menopausal category, contradicting the authors' previous finding of a positive association with premenopausal prevalent disease earlier in this screening study. The relation of smoking and breast cancer remains controversial. Further study is required to determine whether an association truly does not exist or whether smoking might have both protective and harmful effects that are mediated through different pathways, thus accounting for the paradoxical findings in the literature to date.     

武汉地区女性乳腺癌危险因素的病例对照研究

目的 探讨武汉地区女性乳腺癌的危险因素及其变化情况。方法 以病例对照研究方法,对经病理确诊的213例乳腺癌患者及430例匹配对照进行危险因素的条件logistic回归分析。结果 单因素分析显示:文化程度、乳腺良性肿瘤、初潮年龄、绝经年龄、肉类摄入量、油炸烧烤食物摄入、豆类食品摄入、水果摄入、哺乳时间。体重指数、10～19岁胸透次数、精神心理因素等28项因素与乳腺癌的危险性有关。联合多因素及分组多因素条件1ogistic回归分析显示:文化程度高、精神创伤、乳腺良性肿瘤史、绝经晚、行经年数和初产前行经年数长、体重指数高、常食油炸烧烤和烟熏腊制食物为乳腺癌的危险因素;初潮晚、哺乳时间长、豆类或水果摄入量高、常饮茶为保护因素。绝经前与绝经后的危险因素种类及效应强度有一定差别。经多因素分析,绝经前主要相关因素为乳腺良性肿瘤、初潮年龄、豆类摄入量;绝经后主要与绝经年龄、体重指数、腰臀比和水果摄入量有关。另外,精神创伤及哺乳时间为绝经前后共同的危险因素和保护因素。结论 武汉地区女性乳腺癌危险因素中,饮食习惯和内源性雌激素暴露等相关因素起着重要作用。     

Estrogen metabolism and breast cancer

BACKGROUND: Specific pathways involved in estrogen metabolism may play a role in the etiology of breast cancer. We used data from a large population-based case-control study to assess the association of the urinary estrogen metabolites 2-hydroxyestrone (2-OHE1), 16alpha-hydroxyestrone (16-OHE1), and their ratio (2/16) with both invasive and in situ breast cancer. METHODS: Study participants from the Long Island Breast Cancer Study Project provided a spot urine specimen and completed a comprehensive interviewer-administered questionnaire. Women who used exogenous hormones or who took tamoxifen in the 6 months before urine collection were excluded from the analysis, leaving 269 invasive cases, 158 in situ cases, and 326 controls. Unconditional logistic regression was used to obtain adjusted odds ratios (ORs) for invasive and in situ breast cancer, separately, in relation to tertiles of the individual metabolites (standardized for creatinine) and the 2/16 ratio, stratified by menopausal status. RESULTS: The OR for invasive breast cancer was inversely associated with the 2/16 ratio among premenopausal women (OR = 0.50 for extreme tertiles; 95% confidence interval = 0.25-1.01). ORs ranged from 0.32 to 0.60 when women were stratified by whether cases had received chemotherapy within 6 months before urine collection and by estrogen receptor status. In postmenopausal women, there was a slight reduction in the odds ratio for invasive cancer with high levels of the 2/16 ratio (OR = 0.78; 95% confidence interval = 0.46-1.33). Neither the individual metabolites nor the ratio were associated with in situ breast cancer. CONCLUSION: These data provide support for the hypothesis that the 2/16 ratio is associated with reduced breast cancer risk. The most consistent associations were observed with invasive cancer in premenopausal women.     

体重指数对绝经前后Luminal型乳腺癌预后的 影响分析

摘要:目的　探讨体重指数（BMI）对绝经前后Luminal型乳腺癌预后的影响。方法　回顾性收集四川省肿瘤医院2005-2010年收治的298例女性原发Luminal型乳腺癌病例资料并进行随访,中位随访时间为39个月。将病例根据绝经状态分层,采用COX比例风险模型分析不同BMI（BMI＜23.0 kg/m2和BMI≥23.0 kg/m2）对乳腺癌病例无病生存期（DFS）的影响。结果　绝经前和绝经后Luminal型乳腺癌患者的平均BMI分别为（22.77±2.67）kg/m2和（24.47±3.63）kg/m2,差异有统计学意义（P＜0.001）,BMI＜23.0 kg/m2和BMI≥23.0 kg/m2的绝经前Luminal型乳腺癌患者的5年无病生存率分别为78.9%和60.7%（P＝0.036）,BMI≥23 kg/m2可显著增加绝经前Luminal型乳腺癌复发转移的风险（调整HR＝2.451,95%CI:1.100～5.459）,BMI对绝经后Luminal型乳腺癌DFS的影响无统计学意义。结论　高BMI是影响绝经前Luminal型乳腺癌预后的不良因素。     

Inclusion of risk factor covariates in a segregation analysis of a population-based sample of 426 breast cancer families

Although many segregation analyses of breast cancer have been published, few have included risk factor covariates. Maximum likelihood segregation analyses examining age-at-onset (model 1) and susceptibility (model 2) models of breast cancer were performed on 426 four-generation families originally ascertained between 1944 and 1952 through a breast cancer proband. Cancer status and risk factor data were collected through interviews of participants or surrogates. When segregation analyses were performed on 10,791 women, without estimation of any covariates, all hypotheses under both models were rejected. Model 1, which required estimation of fewer parameters than model 2, provided a better fit to the data according to Akaike's Information Criterion. Further segregation analyses were performed under model 1 on a subset of women with complete data on education, age at first birth (nulliparous women included), and alcohol use, covariates that were found to significantly (P<0.05) improve the fit over the addition of exam age alone in logistic regression models. All three covariates improved the fit of the models, as did year of birth, but at all stages of model building, all of the hypotheses were still rejected. After the allele frequency was fixed at 0.0033, a subset of families appeared to fit a dominant model. Using this model, risk estimates were calculated based on inferred genotype, age, and covariate values. The penetrance was estimated to be 0.15, much lower than previous estimates based on families ascertained through breast cancer probands with early onset. Moreover, the estimates of penetrance were not greatly influenced by incorporation of the measured risk factors.     

The relationship between obesity and breast cancer risk and mortality

Obesity is an established risk factor for postmenopausal, but not premenopausal, development of breast cancer. Evidence for a positive association between obesity and breast cancer mortality is mounting. Avoiding adult weight gain and maintaining a healthy body weight may contribute importantly to decreasing breast cancer risk and mortality, especially in postmenopausal women.     

Inverse association between dietary and serum conjugated linoleic acid and risk of breast cancer in postmenopausal women

Conjugated linoleic acid (CLA) is anticarcinogenic in experimental animal studies. We studied dietary and serum CLA in Finnish patients with breast cancer in 1992-1995. Participants were consecutive women with breast cancer (68 premenopausal and 127 postmenopausal) and population-based control women (75 premenopausal and 133 postmenopausal), matched for age and area of residence. Diet was assessed by a validated food frequency questionnaire and the fatty acid composition of serum by gas-liquid chromatography. In postmenopausal women, dietary CLA, serum CLA, myristic acid, and trans-vaccenic acid were significantly lower in cases than in controls. The odds ratio for breast cancer in the highest quintile vs. the lowest was 0.4 [95% confidence interval (CI) = 0.2-0.9]for CLA, 0.3 (95% CI = 0.1-0.7) for myristic acid, and 0.3 (95% CI = 0.1-0.7) for trans-vaccenic acid in serum. The odds ratios remained similar after adjustment for known risk factors of breast cancer. A diet composed of CLA-rich foods, particularly cheese, may protect against breast cancer in postmenopausal women, but it is impossible to assess the independent effects of CLA in this study. The findings may be of relevance for food production, inasmuch as it is possible to increase CLA and its precursor trans-vaccenic acid in foods by modifying the feeding of ruminants.     

Relationship of mammographic parenchymal patterns with breast cancer risk factors and risk of breast cancer in a prospective study

A prospective study has been conducted on 4954 female volunteers from the Island of Guernsey between 1977 and 1985 to examine risk factors for breast cancer and their relationship to mammographic parenchymal patterns as assessed by Wolfe's method of grading. Up to September 1988, 69 women had developed breast cancer, 11 of whom were prevalent cases being diagnosed within six months of mammography. The remaining incident cases were diagnosed six to 126 months (median 65 months) after entry to the study. Univariate analysis showed that the distribution of Wolfe grades in the population was significantly associated with menopausal status, age, parity, adiposity, age at menarche, age at first childbirth and use of oral contraception, but not with a family history of breast cancer. Multivariate analysis of the data for these variables from either pre- and/or post-menopausal women indicated that age, parity and adiposity were significantly related to Wolfe grade pattern. Age had an opposite effect in pre- compared with postmenopausal women thus the probability of either a P2 or DY pattern increased with increasing age in premenopausal but decreased in postmenopausal women so that incidence peaked around the menopause. Other variables did not achieve significance in the multivariate analysis. Odds ratios (ORs) were calculated for women with P2 or DY patterns using those with N1 or P1 grades as the reference group. The ORs were determined at two censoring times; one at five years and the other to include the most recent follow-up of this cohort. The ORs were adjusted for years of follow-up, age and adiposity and in postmenopausal women adjustment was also made for age at menarche.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic analysis of human breast cancer: implications for family study designs

Genetic analysis of human breast cancer, as with many common diseases, raises several problems including sampling strategies, genetic heterogeneity, and gene-environment interactions. A reanalysis of 200 Danish breast cancer pedigrees, under the unified mixed model, was conducted to investigate more specifically these three points. We found that use of different sampling schemes leads to similar conclusions: familial transmission of breast cancer in this whole Danish sample cannot be accounted for by the Mendelian segregation of a dominant gene. Homogeneity tests, based on an a priori subdivision of the sample, were all nonsignificant under a given genetic model. However, it was possible to isolate a particular subgroup of pedigrees displaying only breast cancer, which was compatible with the segregation of a dominant gene. We have also shown that correct specification of a liability indicator according to epidemiological factors is of major importance to detect a major effect under the mixed model. Our results emphasize the need to design family studies including various types of information in the probands and family members to permit some progress in the understanding of complex diseases.