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  • 1
    Keywords: EXPRESSION ; IONIZING-RADIATION ; SURVIVAL ; tumor ; DIAGNOSIS ; FOLLOW-UP ; COHORT ; GLUTATHIONE ; METALLOTHIONEIN ; GENOME-WIDE ASSOCIATION
    Abstract: We assessed whether variants in 22 oxidative stress-related genes are associated with mortality of breast cancer patients and whether the associations differ according to radiotherapy. Using a prospective cohort of 1348 postmenopausal breast cancer patients, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for 109 single nucleotide polymorphisms (SNPs) using Cox proportional hazards regression. Validation of results was attempted using two Scandinavian studies. Eleven SNPs in MT2A, NFE2L2, NQO1, PRDX1, and PRDX6 were significantly associated with overall mortality after a median follow-up of 5.7 years. Three SNPs in NQO1 (rs2917667) and in PRDX6 (rs7314, rs4916362) were consistently associated with increased risk of dying across all three study populations (pooled: HRNQO1_rs2917667 1.20, 95% CI 1.00-1.44, p = 0.051; HRPRDX6_rs7314 1.16, 95% CI 1.00-1.35, p = 0.056, HRPRDX6_rs4916362 1.14 95% CI 1.00-1.32, p = 0.062). Potential effect modification by radiotherapy was found for CAT_rs769218. In conclusion, genetic variants in NQO1 and PRDX6 may modify breast cancer prognosis.
    Type of Publication: Journal article published
    PubMed ID: 23489758
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  • 2
    Keywords: COHORT ; RISK ; HEALTH ; POSTMENOPAUSAL WOMEN ; PHYSICAL-ACTIVITY ; METAANALYSIS ; HEART-FAILURE ; AROMATASE INHIBITORS ; TRASTUZUMAB ; ADJUVANT ENDOCRINE THERAPY
    Abstract: PURPOSE: Comorbid conditions have become increasingly relevant for breast cancer care given the large numbers of long-term survivors. Our aim was to identify potential determinants associated with the development of comorbidities after breast cancer. METHODS: Self-reported comorbidities and lifestyle were assessed at recruitment and after a median follow up of 69.4 months from diagnosis in a population-based cohort of breast cancer cases aged 50 to 74 years at diagnosis (MARIEplus study). Tumor and therapy data were extracted from medical records. Determinants potentially associated with incident diagnoses of hypertension, cardiovascular diseases (CVD), and osteoporosis were assessed using multivariable Cox proportional hazard regression models. RESULTS: Follow-up interview was completed by 2,542 women (76.4 % of eligible patients). A diagnosis of hypertension was significantly associated with age, higher education (hazard ratio (HR) 0.54, CI 0.37-0.79), baseline body mass index (BMI; 〉/=30 kg/m(2); HR, 1.90; CI, 1.24-2.90), and trastuzumab medication (HR, 2.16; CI, 1.09-4.33). An increased risk for CVD was associated with age, BMI, and intake of aromatase inhibitors (AI; HR, 1.42; CI, 1.09-1.84). Risk of osteoporosis was also positively associated with AI treatment (HR, 2.15; CI, 1.64-2.82) but inversely associated with a higher BMI (〉/=30 kg/m(2); HR, 0.50; CI, 0.31-0.79). CONCLUSION: In breast cancer survivors, treatment with AI constituted a risk factor for incident CVD and osteoporosis. Besides known risk factors, patients who were treated with trastuzumab may have an increased risk for hypertension. IMPLICATIONS FOR CANCER SURVIVORS: Reducing overweight and regular sport/cycling activities may help to prevent CVD after breast cancer. Patients should be monitored for risk factors and advised on possible cardiac side effects of AI and trastuzumab.
    Type of Publication: Journal article published
    PubMed ID: 24570215
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  • 3
    Keywords: COHORT ; VARIANTS ; WOMEN ; HEIGHT ; METAANALYSIS ; bias ; ESTROGEN ; GENOME-WIDE ASSOCIATION ; PROGESTERONE-RECEPTOR STATUS ; INOSITOL POLYPHOSPHATES
    Abstract: A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (p(int)) 〈1.1 x 10(-3). None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women 170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women 〈160 cm (OR = 0.83, p = 0.039, p(int) = 1.9 x 10(-4)). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 x 10(-4)), and absent in women who had had just one (OR = 0.96, p = 0.19, p(int) = 6.1 x 10(-4)). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 x 10(-5)), but no association was observed in current smokers (OR = 1.07, p = 0.14, p(int) = 3.4 x 10(-4)). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. What's new? The recent discovery of 47 susceptibility loci associated with all or estrogen receptor-negative breast cancer provided new opportunities for genetic risk prediction but it remained unclear how exposure levels of environmental (non-genetic) risk factors influenced the risk assessment. In this gene-environment study, the international team examined interactions between the single nucleotide polymorphisms and 13 established environmental risk factors including parity, height and alcohol consumption. Notably, relative risks of breast cancer associated with the susceptibility loci were not strongly modified by environmental risk factors, a finding that, if confirmed, has important implications for the risk assessment in breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 25227710
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  • 4
    Keywords: COHORT ; FAMILY ; RISK-FACTORS ; VARIANTS ; WOMEN ; METAANALYSIS ; BODY-MASS INDEX ; GENOME-WIDE ASSOCIATION ; HORMONE-THERAPY ; FGFR2 GENE
    Abstract: Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G x E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 x 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 x 10(-05)). Our findings confirm comparable power of the recent methods for detecting G x E interaction and the utility of using G x E interaction analyses to identify new susceptibility loci.
    Type of Publication: Journal article published
    PubMed ID: 24248812
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  • 5
    Keywords: SURVIVAL ; COHORT ; WOMEN ; CONSUMPTION ; phytoestrogens ; enterolignans ; lignan ; SERUM ENTEROLACTONE ; FLAXSEED ; Food sources
    Abstract: We previously reported that high concentrations of enterolactone, a lignan metabolite, are associated with lower mortality in 1,140 breast cancer patients from Germany. Using an extended set of 2,182 patients aged 50-74 years at diagnosis (2001-2005) and prospectively followed up until 2009, we investigated whether the association with mortality differs by lifestyle factors and tumor characteristics. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression. Potential differential effects by tumor characteristics and lifestyle factors were assessed and a meta-analysis of five studies addressing lignan exposure and breast cancer prognosis was performed to summarize evidence. Median enterolactone concentrations were 17.4 (+/-30.5 standard deviation) and 22.9 nmol L(-1) (+/-44.8), respectively, for 269 deceased and 1,913 patients still alive. High enterolactone concentrations were significantly associated with lower all-cause mortality (per 10 nmol L(-1) : HR 0.94, 95% CI 0.90-0.98), breast cancer-specific mortality (HR 0.94, 0.89-0.99), and distant disease-free survival (HR 0.94, 0.90-0.98). Associations were found for stage 0-IIIA but not for stage IIIB-IV disease (phet = 0.01) and were stronger in patients with BMI 〈25 kg m(-2) than those with BMI 〉/=25 (phet = 0.04). In patients with healthy lifestyle (BMI 〈25, nonsmoker, physically active), the inverse association with all-cause mortality was still apparent (HR 0.92, 0.85-0.99). The meta-analysis yielded significant associations both for all-cause (HR 0.57, 0.42-0.78) and breast cancer-specific mortality (HR 0.54, 0.39-0.75). Our findings show that high lignan exposure is associated with reduced mortality in breast cancer patients. The inverse association observed in this study cannot be entirely explained by a healthy lifestyle.
    Type of Publication: Journal article published
    PubMed ID: 24436155
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