Higher lignan exposure has been associated with lower all‐cause mortality (ACM) and breast cancer‐specific mortality (BCSM) for postmenopausal breast cancer patients. However, the biological ...mechanisms underpinning these associations are still unclear. We investigated for the first time whether and to what extent the association between enterolactone (ENL), the major lignan metabolite, and postmenopausal breast cancer prognosis is mediated by inflammatory biomarkers. Circulating concentrations of ENL and inflammatory markers were measured in a population‐based prospective cohort of 1,743 breast cancer patients recruited between 2002 and 2005 and followed‐up until 2009. Hazard ratios (HR) and 95% CIs were estimated using multivariable Cox regression. Mediation analysis was performed to estimate the percentage association between ENL (log2) and ACM, BCSM and distant disease‐free survival (DDFS), which is mediated by C‐reactive protein (CRP) (log2), as the strongest potential mediator, and also interleukin (IL)‐10. Median serum/plasma ENL and CRP concentrations for all patients, including 180 deceased patients, were 23.2 and 17.5 nmol/L, and 3.2 and 6.5 mg/l, respectively. ENL concentrations were significantly inversely associated with ACM, BCSM and DDFS (per doubling of ENL concentrations: HRs 0.93 0.87, 0.99, 0.91 0.84, 0.99 and 0.92 0.87, 0.99), after adjusting for prognostic factors and BMI. Estimated 18, 14 and 12% of the effects of ENL on ACM, BCSM and DDFS, respectively, were mediated through CRP. No mediational effect of IL‐10 was found. We provide first evidence that the proinflammatory marker CRP may partially mediate the association of ENL with postmenopausal breast cancer survival, which supports hormone‐independent mechanisms.
What's new?
Lignans, which are present in oilseeds, whole‐grains, fruits and vegetables, are the major source of phytoestrogens in Western populations. There is growing evidence that lignan exposure improves postmenopausal breast cancer survival. Both hormone‐dependent and ‐independent effects have been postulated as underlying biological mechanisms, but these still have to be fully elucidated. Using data from 1,743 postmenopausal breast cancer patients, here the authors provide first evidence that the protective effects of lignans (measured as the major metabolite enterolactone) on breast cancer survival may be partially mediated by the inflammatory marker C‐reactive protein, which supports the involvement of hormone‐independent mechanisms.
MicroRNAs (miRs) are small, noncoding RNAs that target genes involved in tumor development and progression. In the current study, we investigated the use of circulating miR concentrations as ...biomarkers in the serum of breast cancer patients.
We analyzed serum samples from 120 patients with primary breast cancer after surgery and before chemotherapy (M0, classified into 3 subgroups of 40 patients with progesterone/estrogen-positive, HER2-positive, and triple-negative cancer), 32 patients with overt metastasis (M1), and 40 healthy women. Using quantitative TaqMan MicroRNA PCR, we measured the relative concentrations of 6 circulating microRNAs (miR-10b, -17, -34a, -93, -155, and -373) known to be relevant for tumor development and progression. The data were correlated with clinicopathologic risk factors, with particular reference to HER2 and hormone receptor status of the primary tumor and the presence of metastases.
The relative serum concentrations of circulating miR-34a P = 0.013, area under the curve (AUC) 0.636, miR-93 (P = 0.001, AUC 0.699), and miR-373 (P = 0.0001, AUC 0.879) were significantly different between M0 breast cancer patients and healthy women, whereas miR-17 (P = 0.002, AUC 0.679) and miR-155 (P = 0.0001, AUC 0.781) were differently expressed between M0 and M1 patients. Increased concentrations of miR-373 were associated with negative HER2 status of the primary tumor (P = 0.0001). Deregulated concentrations of miR-17 (P = 0.019) and miR-34a (P = 0.029) were detected in patients with progesterone/estrogen receptor-positive and -negative status, respectively.
Our findings indicate that serum concentrations of deregulated microRNAs may be linked to a particular biology of breast carcinomas favoring progression and metastatic spread.
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.
What's new?
Whether pre‐diagnosis physical activity impacts risk of recurrence and mortality from breast cancer has remained unclear, though such associations could have implications for the interpretation of patient outcome. Here, analysis of data on 3,393 nonmetastatic breast cancer patients reveals an inverse association between pre‐diagnosis physical activity and overall mortality, but primarily for instances of death apparently unrelated to breast cancer, such as non‐breast neoplasms and circulatory events. Higher levels of exercise were linked to a reduced risk of disease recurrence among patients with ER‐/PR‐ breast tumors.
We previously reported that lower post‐diagnostic circulating 25‐hydroxyvitamin D 25(OH)D concentrations were associated with higher risk of overall mortality and distant disease in stage I–IV ...postmenopausal breast cancer survivors. This association was now re‐examined in an extended dataset to investigate potential effect modification by tumor characteristics and lifestyle factors. A prospective cohort study was conducted in Germany including 2,177 incident stage I–IV postmenopausal breast cancer patients aged 50–74 years. Patients were diagnosed between 2001 and 2005 and median follow‐up time was 5.3 years. Cox proportional hazards models were stratified by age at diagnosis, study center and season of blood collection and adjusted for other prognostic factors. A meta‐analysis of studies on circulating 25(OH)D and mortality in breast cancer patients was performed to summarize evidence. Lower concentrations of 25(OH)D were significantly associated with higher risk of overall mortality hazard ratio (HR) lowest vs. highest tertile = 1.86; 95% confidence interval (CI): 1.22, 2.82; p‐trend = 0.002 and distant disease (HR = 1.76; 95% CI: 1.24, 2.49; p‐trend = 0.003) in stage I–IIIa but not in stage IIIb–IV breast cancer patients. No significant interaction by lifestyle factors was observed (all p‐interaction > 0.05). The meta‐analysis yielded significant associations with overall and breast cancer‐specific mortality (lowest vs. highest quantile: HR = 1.52; 95% CI: 1.22, 1.88 and HR = 1.74; 95% CI: 1.23, 2.40, respectively). In conclusion, post‐diagnostic circulating 25(OH)D concentrations were associated with overall mortality and distant disease in stage I–IIIa postmenopausal breast cancer patients. This association was not strongly modified by lifestyle factors.
What's new?
Reduced circulating concentrations of 25‐hydroxyvitamin D may be associated with increased mortality among breast cancer patients. In this study, which examined data on 2,177 postmenopausal women with breast cancer, the association between 25‐hydroxyvitamin D and mortality was found to differ based on tumor characteristics. Lower post‐diagnostic circulating 25‐hydroxyvitamin D concentrations were associated with increased mortality in stage I‐IIIa patients but not in stage IIIb‐IV patients. In contrast, the association between 25‐hydroxyvitamin D and mortality did not strongly differ based on lifestyle factors.
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.
What's new?
Plant‐derived lignans are known to exert anticancer activity in an estrogen‐independent manner, suggesting that they may be of value in the prevention of breast cancer. Here, in a population of 2,182 breast cancer patients, enterolactone, a lignan metabolite, was found to be associated with reduced all‐cause mortality and breast cancer‐specific mortality. The inverse association was restricted to early stage breast cancer and to patients with normal weight. A meta‐analysis of five cohorts yielded consistent evidence that high lignan exposure is linked to lower mortality in breast cancer patients.
Cohort studies of breast cancer (BC) patients, but not of disease‐free women at inclusion, have found menopausal hormone therapy (MHT) to be associated with decreased BC specific mortality (BCM). ...Here, the German population‐based MARIEplus BC cohort was analyzed to further elucidate associations of prediagnostic MHT with BCM (and modification by tumor characteristics), recurrence, and secondarily with other cause and overall mortality. Enrolled 2002–2005, incident invasive BC cases (N = 3,321) were followed up for a median of 6.1 years. Cox proportional hazards models adjusted for tumor characteristics, mammography and lifestyle were applied. Compared with never users of MHT, current users at date of diagnosis had significantly lower BCM (Hazard ratio (HR) 0.72, 95% CI 0.53–0.97) and risk of recurrence (HR 0.61, 95% CI 0.46–0.82). The MHT related reduced BCM was confined to patients with low grade tumors (HR 0.44, 95% CI 0.28–0.70; phet = 0.01) and not modified by estrogen receptor or nodal status. BCM decreased with MHT duration in current and increased in past users (phet = 0.015). Mortality due to causes other than BC and overall mortality were also reduced in current MHT users (HR 0.51, 95% CI 0.32–0.81, HR 0.66, 95% CI 0.52–0.86, respectively). Favorable tumor characteristics and mammographic surveillance could not fully explain associations of current MHT use with BCM and recurrence risk. Thus, the study contributes to the evidence that prediagnostic MHT does not have a negative impact on prognosis after BC. The restriction of a reduced BCM to low grade tumors should be confirmed in independent studies.
What's New?
Despite numerous studies, the impact of menopausal hormone therapy (MHT) on survival after breast cancer diagnosis remains ambiguous. Here, analyses performed on a German population‐based cohort consisting of more than 3,300 patients reveal significant inverse associations between MHT use at diagnosis and breast cancer‐specific mortality (BCM), recurrence risk, and other‐cause mortality. Among current MHT users, BCM was found to decrease with duration of therapy. The reduction in BCM, however, was confined to patients with only low‐grade tumors, a novel finding that warrants further inquiry.
Lignans are a group of estrogenic compounds present in plants. Several epidemiological studies proposed that lignans may protect against breast cancer by exerting anticarcinogenic activity. Levels of ...enterolactone were determined in serum samples of 1,250 cases and 2,164 controls from a large population‐based case–control study. We assessed the association between serum enterolactone and postmenopausal breast cancer risk using conditional logistic regression accounting for potential risk and confounding factors. Fractional polynomials were used to determine the function that best fitted the data. Moreover, we assessed heterogeneity by estrogen/progesterone/herceptin (ER/PR/HER2) status of the tumor. Additionally, a meta‐analysis with seven further studies addressing enterolactone concentrations and breast cancer risk was performed. Postmenopausal breast cancer risk decreased with increasing serum enterolactone levels highest compared to lowest quintile: odds ratio = 0.65; 95% confidence interval (CI) 0.52–0.83, ptrend = <0.0001. A significant inverse association for ER+/PR+ as well as ER−/PR− tumors was observed, with a significantly stronger association for ER−/PR− tumors (pheterogeneity = 0.03). The association for ER−/PR− tumors did not differ by expression of HER2 (pheterogeneity = 0.3). The meta‐analysis yielded a significant reduced pooled risk estimate of: 0.66; 95% CI: 0.55–0.77) comparing the highest to the lowest quantiles of enterolactone levels. We found strong evidence for a significant inverse association between serum enterolactone and postmenopausal breast cancer risk, which was stronger for ER−PR− than for ER+PR+ tumors but not differential by further expression of HER2. The overall evidence together with other studies supports an inverse association between higher serum enterolactone levels 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.
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