Petra Seibold

Individual patient data meta-analysis shows no association between the SNP rs1800469 in TGFB and late radiotherapy toxicity

BACKGROUND AND PURPOSE Reported associations between risk of radiation-induced normal tissue injury and single nucleotide polymorphisms (SNPs) in TGFB1, encoding the pro-fibrotic cytokine transforming growth factor-beta 1 (TGF-β1), remain controversial. To overcome publication bias, the international Radiogenomics Consortium collected and analysed individual patient level data from both published and unpublished studies. MATERIALS AND METHODS TGFB1 SNP rs1800469 c.-1347T>C (previously known as C-509T) genotype, treatment-related data, and clinically-assessed fibrosis (measured at least 2years after therapy) were available in 2782 participants from 11 cohorts. All received adjuvant breast radiotherapy. Associations between late fibrosis or overall toxicity, reported by STAT (Standardised Total Average Toxicity) score, and rs1800469 genotype were assessed. RESULTS No statistically significant associations between either fibrosis or overall toxicity and rs1800469 genotype were observed with univariate or multivariate regression analysis. The multivariate odds ratio (OR), obtained from meta-analysis, for an increase in late fibrosis grade with each additional rare allele of rs1800469 was 0.98 (95% Confidence Interval (CI) 0.85-1.11). This CI is sufficiently narrow to rule out any clinically relevant effect on toxicity risk in carriers vs. non-carriers with a high probability. CONCLUSION This meta-analysis has not confirmed previous reports of association between fibrosis or overall toxicity and rs1800469 genotype in breast cancer patients. It has demonstrated successful collaboration within the Radiogenomics Consortium.

A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy

Background:Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results.Methods:We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer.Results:Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52–3.98).Conclusion:We have identified that alleles of the class III major histocompatibility complex region associate with overall radiotherapy toxicity in breast cancer patients by using internal replication through a staged design. This is the first well-replicated report of a genetic predictor for radiotherapy reactions.

Dietary patterns and survival in German postmenopausal breast cancer survivors

Background:Research on the association between dietary patterns and breast cancer survival is very limited.Methods:A prospective follow-up study was conducted in Germany, including 2522 postmenopausal breast cancer patients diagnosed in 2001–2005 with available food frequency questionnaire data. Vital status, causes of death, and recurrences were verified through the end of 2009. Principle component factor analysis was used to identify pre-diagnostic dietary patterns. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards models.Results:Two major dietary patterns were identified: ‘healthy’ (high intakes of vegetables, fruits, vegetable oil, sauces/condiments, and soups/bouillons) and ‘unhealthy’ (high intakes of red meat, processed meat, and deep-frying fat). Increasing consumption of an ‘unhealthy’ dietary pattern was associated with an increased risk of non-breast cancer mortality (highest vs lowest quartile: HR, 3.69; 95% CI, 1.66–8.17; P-trend <0.001). No associations with breast cancer-specific mortality and breast cancer recurrence were found. The ‘healthy’ dietary pattern was inversely associated with overall mortality (HR, 0.74; 95% CI, 0.47–1.15; P-trend=0.02) and breast cancer recurrence (HR, 0.71; 95% CI, 0.48–1.06; P-trend=0.02) in stage I–IIIa patients only.Conclusion:Increasing intake of an ‘unhealthy’ pre-diagnostic dietary pattern may increase the risk of non-breast cancer mortality, whereas increasing intake of a ‘healthy’ pattern may reduce the risk of overall mortality and breast cancer recurrence.

Coffee consumption modifies risk of estrogen-receptor negative breast cancer

IntroductionBreast cancer is a complex disease and may be sub-divided into hormone-responsive (estrogen receptor (ER) positive) and non-hormone-responsive subtypes (ER-negative). Some evidence suggests that heterogeneity exists in the associations between coffee consumption and breast cancer risk, according to different estrogen receptor subtypes. We assessed the association between coffee consumption and postmenopausal breast cancer risk in a large population-based study (2,818 cases and 3,111 controls), overall, and stratified by ER tumour subtypes.MethodsOdds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated using the multivariate logistic regression models fitted to examine breast cancer risk in a stratified case-control analysis. Heterogeneity among ER subtypes was evaluated in a case-only analysis, by fitting binary logistic regression models, treating ER status as a dependent variable, with coffee consumption included as a covariate.ResultsIn the Swedish study, coffee consumption was associated with a modest decrease in overall breast cancer risk in the age-adjusted model (OR> 5 cups/day compared to OR≤ 1 cup/day: 0.80, 95% CI: 0.64, 0.99, P trend = 0.028). In the stratified case-control analyses, a significant reduction in the risk of ER-negative breast cancer was observed in heavy coffee drinkers (OR> 5 cups/day compared to OR≤ 1 cup/day : 0.43, 95% CI: 0.25, 0.72, P trend = 0.0003) in a multivariate-adjusted model. The breast cancer risk reduction associated with higher coffee consumption was significantly higher for ER-negative compared to ER-positive tumours (P heterogeneity (age-adjusted) = 0.004).ConclusionsA high daily intake of coffee was found to be associated with a statistically significant decrease in ER-negative breast cancer among postmenopausal women.

Determinants of long-term fatigue in breast cancer survivors: results of a prospective patient cohort study

Fatigue is among the most distressing symptoms across the breast cancer continuum. However, little is known about the factors contributing to long‐term persisting fatigue. Therefore, we explored determinants of long‐term physical, affective, and cognitive fatigue in a prospective cohort of breast cancer patients.

Association of pre-diagnosis physical activity with recurrence and mortality among women with breast cancer

Evidence is emerging that physical activity (PA) may improve overall survival after breast cancer diagnosis. However, the effect of PA on breast cancer recurrence and on cause‐specific mortality is less investigated. We assessed the association of pre‐diagnosis PA with recurrence, overall and cause‐specific survival in a prospective cohort study in Germany including 3,393 non‐metastatic breast cancer patients aged 50–74 years. Cox proportional hazards models were calculated adjusted for relevant prognostic factors. During a median follow‐up of 5.6 years, 367 patients deceased. Overall mortality was significantly inversely associated with pre‐diagnosis recreational PA. However, this effect was mainly attributed to deaths due to causes other than breast cancer. Multiple fractional polynomial analyses yielded a nonlinear association with markedly increased non‐breast cancer mortality for women who did not engage in any sports or cycling in the years before the breast cancer diagnosis with a hazard ratio (HR, none vs. any) of 1.71, 95% confidence interval (1.16, 2.52). There were no further risk reductions with increasing activity levels. The association with breast cancer‐specific mortality showed a similar dose‐response but was far less pronounced with HR (none vs. any) = 1.22 (0.91, 1.64). In contrast, regarding cancer recurrence the dose‐response was linear. However, this association was restricted to estrogen/progesterone receptor‐negative (ER−/PR−) cases (pinteraction = 0.033) with HR (highest vs. no recreational PA) = 0.53 (0.24, 1.16), ptrend = 0.0045. Thus, breast cancer patients with a physically inactive lifestyle pre‐diagnosis may decease prematurely irrespective of their cancer prognosis. Higher levels of exercise may reduce the risk of recurrence of ER−/PR− breast tumors.

Mortality and recurrence risk in relation to the use of lipid-lowering drugs in a prospective breast cancer patient cohort.

Lipid-lowering drugs are used for the prevention of cardiovascular diseases. Statins are the most commonly used lipid-lowering drugs. Evidence from preclinical and observational studies suggests that statins might improve the prognosis of breast cancer patients. We analyzed data from the German MARIEplus study, a large prospective population-based cohort of patients aged 50 and older, who were diagnosed with breast cancer between 2001 and 2005. For overall mortality, breast-cancer specific mortality, and non-breast-cancer mortality, we included 3189 patients with invasive breast cancer stage I–IV, and for recurrence risk 3024 patients with breast cancer stage I–III. We used Cox proportional hazards models to assess the association with self-reported lipid-lowering drug use at recruitment. We stratified by study region, tumor grade, and estrogen/progesterone receptor status, and adjusted for age, tumor size, nodal status, metastases (stage I–IV only), menopausal hormone treatment, mode of detection, radiotherapy, and smoking. Mortality analyses were additionally adjusted for cardiovascular disease, diabetes mellitus and body-mass index. During a median follow-up of 5.3 years, 404 of 3189 stage I–IV patients died, and 286 deaths were attributed to breast cancer. Self-reported use of lipid-lowering drugs was non-significantly associated with increased non-breast cancer mortality (Hazard ratio (HR) 1.49, 95% confidence interval (CI) 0.88–2.52) and increased overall mortality (HR 1.21, 95% CI 0.87–1.69) whereas no association with breast cancer-specific mortality was found (HR 1.04, 0.67–1.60). Restricted to stage I–III breast cancer patients, 387 recurrences occurred during a median follow-up of 5.4 years. We found lipid-lowering drug use to be non-significantly associated with a reduced risk of recurrence (HR 0.83, 95% CI 0.54–1.24) and of breast cancer-specific mortality (HR 0.89, 95% CI 0.52–1.49). Although compatible with previous findings of an improved prognosis associated with statin use, our results do not provide clear supportive evidence for an association with lipid-lowering drug use due to imprecise estimates.

Enterolactone concentrations and prognosis after postmenopausal breast cancer: Assessment of effect modification and meta‐analysis

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.

Polymorphisms in oxidative stress‐related genes and postmenopausal breast cancer risk

Breast cancer is the most frequent cancer type among women in western countries. In addition to established risk factors like hormone replacement therapy, oxidative stress may play a role in carcinogenesis through an unbalanced generation of reactive oxygen species that leads to genetic instability. The aim of this study is to assess the influence of common single nucleotide polymorphisms (SNPs) in candidate genes related to oxidative stress on postmenopausal breast cancer risk. We genotyped 109 polymorphisms (mainly tagging SNPs) in 22 candidate genes in 1,639 postmenopausal breast cancer cases and 1,967 controls (set 1) from the German population‐based case‐control study “MARIE”. SNPs showing association in set 1 were tested in further 863 cases and 2,863 controls from MARIE (set 2) using a joint analysis strategy. Six polymorphisms evaluated in the combined set showed significantly modified breast cancer risk per allele in the joint analysis, including SNPs in CYBA (encoding a subunit of the NADPH oxidase: rs3794624), MT2A (metallothionein 2A: rs1580833), TXN (thioredoxin: rs2301241), and in TXN2 (thioredoxin 2: rs2267337, rs2281082, rs4821494). Associations with the CYBA rs3794624 (OR per allele: 0.93, 95% CI 0.87–0.99) and TXN rs2301241 variants (OR per allele: 1.05, 95% CI 1.00–1.10) were confirmed in the summary risk estimate analysis using up to three additional studies. We found some evidence for association of polymorphisms in genes of the thioredoxin system, CYBA, and MT2A with postmenopausal breast cancer risk. Summary evidence including independent datasets indicated moderate effects in CYBA and TXN that warrant confirmation in large independent studies.

Intrinsic breast cancer subtypes defined by estrogen receptor signalling—prognostic relevance of progesterone receptor loss

The majority of luminal type breast carcinomas are slowly growing tumors with an overall favorable prognosis. However, a proportion of cases (luminal B tumors) are characterized by coactivation of growth factor receptors or non-canonical ER signaling and a poorer clinical outcome. The aim of our study was to evaluate whether the expression of proteins that are part of the ER signaling network may be used to distinguish low-risk from high-risk luminal tumors. Unsupervised hierarchical clustering of a set of proteins either involved in estrogen receptor signaling or associated with resistance to endocrine therapy was performed in a series of 443 postmenopausal breast carcinomas. Using this approach, we were able to reproduce the established classification with two distinct groups of luminal (estrogen receptor positive) tumors, one group of HER2-associated tumors and a group of triple-negative tumors. However, neither proliferation nor the expression of one or more of the ER-co-factors or resistance-associated factors, but PR-expression was identified as the most important stratifier distinguishing between the two luminal groups. In fact, not only the four identified clusters were shown to be significantly associated with patient outcome, PR-expression alone or in combination with Ki–67-stains stratified ER-positive tumors into a low-risk and a high-risk group. Our data indicate that defining luminal B tumors by the presence of high-risk criteria (loss of PR-expression or increased proliferation) provides a robust and highly significant stratification of ER-positive breast carcinomas into luminal A and B.