Androgen receptor genotypes predict response to endocrine treatment in breast cancer patients.

Background:The androgen receptor (AR) is frequently expressed in breast cancers. The AR genotype may affect disease-free survival and response to endocrine therapy.Methods:In all, 634 women undergoing breast cancer surgery between 2002 and 2008 were followed until 30 June 2010. Six haplotype-tagging single-nucleotide polymorphisms in the AR, and the resulting AR diplotypes, were examined in relation to breast cancer patient characteristics, tumour characteristics, disease-free survival, and response to endocrine treatment.Results:Five common AR diplotypes were found. Seventeen rare variants were combined into a composite group. The resulting six AR diplotype groups were clustered into two subgroups, groups A (n=128) and B (n=499), with three diplotypes in each. Patients in group B had larger total breast volume (P=0.024), higher body mass index (BMI) (P=0.050), more axillary lymph node involvement (P(trend)=0.020), and higher histological grade (P(trend)=0.031). There were 59 breast cancer events in the 569 patients with invasive cancers and no preoperative treatment. Patients in group B also had shorter disease-free survival (P=0.037) than patients in group A. Among patients in group B with oestrogen receptor α positive tumours, tamoxifen (TAM) treatment was associated with longer disease-free survival (P=0.008), while treatment with aromatase inhibitors (AIs) was not (P=0.94). Response to endocrine treatment could not be predicted based on BMI, suggesting that the effect of AR diplotypes went beyond that of a higher BMI.Conclusion:A marker for a group of patients who responded to TAM, but not to AIs, was identified. If this finding is confirmed, AR genotyping may provide useful information for selection of endocrine treatment of breast cancer patients.British Journal of Cancer advance online publication, 27 October 2011; doi:10.1038/bjc.2011.441 www.bjcancer.com

Given breast cancer, is fat better than thin? Impact of the estrogen receptor beta gene polymorphisms.

The role of estrogen receptor beta (ERβ) in breast cancer has been investigated since its identification in 1996. Studies based on protein expression have indicated that ERβ is a favorable prognostic marker. Further, ERβ expression is lower in obese breast cancer patients. Fewer studies have focused on the prognostic impact of ERβ polymorphisms. Therefore, we analyzed the associations between four previously identified haplotype tagging single nucleotide polymorphisms (htSNPs), associated haplo- and diplotypes, and breast cancer-free survival according to body constitution. The patient cohort included 634 women from the prospective breast cancer and blood study (BC Blood study, Sweden) with a median follow-up of 4.92 years. Four htSNPs (i.e., rs4986938, rs1256049, rs1256031, rs3020450) in the ESR2 gene and the correlating haplo- and diplotypes were analyzed and correlated to selected patient and tumor characteristics and to disease-free survival, including stratification for BMI. Based on the four htSNPs, seven haplotypes and eight diplotypes were identified. The patient and tumor characteristics were well-balanced across all geno- and haplotypes. Disease-free survival differed according to rs4986938 and rs1256031 (Log-Rank P = 0.045 and P = 0.041, respectively) and the number of haplotype copies of the wildtype CCGC and TCAC (Log-Rank P = 0.027 and P = 0.038, respectively). In the survival analyses stratified for BMI, significant survival differences between alleles were observed among overweight women (rs4986938 and rs1256031 with Log-Rank P = 0.001 and P = 0.001, respectively). The BMI-stratified survival analyses based on haplotypes showed shorter disease-free survival for overweight women with null copies of CCGC (Log-Rank P = 0.001) and for overweight women with any TCAC copy (Log-Rank P < 0.0001). Markedly impaired disease-free survival was found for genotypes in two out of four ESR2 htSNPs and for two haplotypes. ESR2 polymorphisms seem to divide patients into good and poor survivors based on BMI, stressing the need of taking host factors into consideration in the evaluation of prognostic markers

Given breast cancer, does breast size matter? Data from a prospective breast cancer cohort.

PURPOSE: Body mass index (BMI), waist-to-hip ratio (WHR), and tumor characteristics affect disease-free survival. Larger breast size may increase breast cancer risk, but its influence on disease-free survival is unclear. The purpose of this study was to elucidate whether breast size independently influenced disease-free survival in breast cancer patients. METHODS: Body measurements were obtained preoperatively from 772 breast cancer patients in a population-based ongoing cohort from southern Sweden. The research nurse measured breast volumes with plastic cups used by plastic surgeons doing breast reductions. Clinical data were obtained from patient charts and pathology reports. RESULTS: Patients with a BMI ≥ 25 kg/m(2) had larger tumors (p 0.85 had larger tumors (p = 0.013), more advanced histological grade (p = 0.0016), and more axillary nodal involvement (p = 0.012). Patients with right + left breast volume ≥ 850 mL were more likely to have larger tumor sizes (p = 0.018), more advanced histological grade (p = 0.031), and more axillary nodal involvement (p = 0.025). There were 62 breast cancer events during the 7-year follow-up. Breast volume ≥ 850 mL was associated with shorter disease-free survival (p = 0.004) and distant metastasis-free survival (p = 0.001) in patients with estrogen receptor (ER)-positive tumors independent of other anthropometric measurements and age. In patients with ER-positive tumors, breast size was an independent predictor of shorter disease-free (HR 3.64; 95 % CI 1.42-9.35) and distant metastasis-free survival (HR 6.33; 95 %CI 1.36-29.43), adjusted for tumor characteristics, BMI, age, and treatment. CONCLUSION: A simple and cheap anthropometric measurement with standardized tools may help identify a subgroup of patients in need of tailored breast cancer therapy

Quasilocal equilibrium condition for black ring

We use the conservation of the renormalized boundary stress-energy tensor to obtain the equilibrium condition for a general (thin or fat) black ring solution. We also investigate the role of the spatial stress in the thermodynamics of deformation within the quasilocal formalism of Brown and York and discuss the relation with other methods. In particular, we discuss the quantum statistical relation for the unbalanced black ring solution.Comment: v2: refs. added, matches the published versio

Quasilocal formalism and thermodynamics of asymptotically flat black objects

We study the properties of 5-dimensional black objects by using the renormalized boundary stress-tensor for locally asymptotically flat spacetimes. This provides a more refined form of the quasilocal formalism which is useful for a holographic interpretation of asymptotically flat gravity. We apply this technique to examine the thermodynamic properties of black holes, black rings, and black strings. The advantage of using this method is that we can go beyond the `thin ring' approximation and compute the boundary stress tensor for any general (thin or fat) black ring solution. We argue that the boundary stress tensor encodes the necessarily information to distinguish between black objects with different horizon topologies in the bulk. We also study in detail the susy black ring and clarify the relation between the asymptotic charges and the charges defined at the horizon. Furthermore, we obtain the balance condition for `thin' dipole black rings.Comment: v2 clarifications on the advantage of using quasilocal formalism for black rings added, CQG versio

Genetic polymorphisms, IGF-1, and oral contraceptive use in women from high-risk breast cancer families

Breast cancer is the most common cancer among Swedish women, affecting more than 7000 women each year. About 5-10% of all breast cancers are hereditary, with a monogenic inheritance pattern, but only 2-4% are explained by germline mutations in BRCA1 or BRCA2. BRCA1/BRCA2 mutation carriers have a 60-80% risk of developing breast cancer. Further, a large proportion of the breast cancers that are clustered in families are not associated with known disease-causing mutations. Those cases are likely to be explained by different combinations of low-penetrance genetic polymorphisms and exposure to other risk factors such as lifestyle, hormones, and high insulin-like growth factor 1 (IGF-1) levels. Such factors are also likely to influence the penetrance among high-risk women. Knowledge of which combinations of risk factors are important for the identification of women with high risk for early-onset breast cancer would allow more individualized risk assessments. For example, the absence of the common IGF1 19 CA-repeat allele in combination with oral contraceptive (OC) use has been associated with high IGF-1 levels. The aim of this thesis was to study genetic and non-genetic risk factors in women from high-risk breast cancer families. In paper I, the variant allele (A2) of a SNP (rs743572) in the CYP17 gene was associated with short menstrual cycles and early OC use. The A2 allele was also more common among non-mutation carriers from BRCA1/2 mutation families. In paper II, the absence of the common IGF1 19 CA-repeat allele was more common among BRCA1 mutation carriers than among non-carriers from BRCA1 families. This result confirms a previous finding of a smaller study. In paper III, a three-way interaction between homozygous deletions of the GSTM1 and GSTT1 genes and OC use on IGF-1 levels was observed. Women who were lacking one, but not both, genes had the highest IGF-1 levels during OC use compared to OC users with either both genes deleted or both genes intact. In paper IV, rare IGF1 diplotypes were associated with the absence of the common IGF1 19 CA-repeat allele, and they were more common among BRCA1 mutation carriers than other women from high-risk families. Rare diplotypes were also associated with breast cancer risk among all women and with an earlier age at first diagnosis of breast cancer among BRCA1 mutation carriers. In conclusion, associations between genetic polymorphisms and other breast cancer risk factors need to be considered in future studies to understand their importance for breast cancer development and to improve current risk prediction models

IGFBP1 and IGFBP3 polymorphisms predict circulating IGFBP-3 levels among women from high-risk breast cancer families.

The insulin-like growth factor (IGF) pathway has been implicated as risk modifier in premenopausal breast cancer. In this study, associations between single nucleotide polymorphisms (SNPs) and diplotypes in the IGFBP1 and IGFBP3 genes and circulating IGFBP-3 levels, BRCA family status and breast cancer among women from high-risk breast cancer families were investigated. Nine IGFBP1 and IGFBP3 SNPs were genotyped with PCR-based methods in 323 women. Nine IGFBP1 and ten IGFBP3 diplotypes were identified. Plasma IGFBP-3 levels obtained during cycle day 18-23 were available for 231 women, 87 current users of combined oral contraceptives and 144 non-users. IGFBP1 (rs1995051 and rs4988515) and IGFBP3 (rs2471551 and rs2854744) SNPs were associated with circulating IGFBP-3 levels (P < 0.05). IGFBP1 (low) diplotypes were associated with lower IGFBP-3 levels and were more common in BRCA2 families OR 2.05 (95%CI 0.97-4.30). IGFBP3 (high) diplotypes were associated with higher IGFBP-3 levels and were more common in BRCAX families OR 1.68 (95%CI 1.04-2.74). After adjusting the models for BRCA family status, both the BRCA1 and BRCA2 family status (P ≤ 0.006) and the IGFBP1 diplotype GTAC/ACAT (P = 0.004) were associated with lower IGFBP-3 levels. Similarly, both the BRCA1 and BRCA2 family status (P ≤ 0.03) and the IGFBP-3 diplotypes GCA/GCG (P = 0.007) and GCG/CCG (P = 0.002) were significantly associated with lower IGFBP-3 levels, adjusted for age, weight, OC use, and other IGFBP diplotypes. No individual SNP was associated with breast cancer. There were 23 cases of breast cancer and one IGFBP1 diplotype was associated with a decreased risk of breast cancer after age 18 (log rank P=0.05). In conclusion, independent effects from IGFBP1, IGFBP3 diplotypes, and BRCA family status on IGFBP-3 levels were observed. These factors may influence the risk of breast cancer among women from high-risk breast cancer families

Androgen receptor htSNPs in relation to androgen levels and OC use in young women from high-risk breast cancer families.

High testosterone levels have been associated with breast cancer. BRCA1 may function as an androgen receptor (AR) co-regulator. We aimed to examine AR haplotype-tagging single-nucleotide polymorphisms (AR htSNPs) and diplotypes in relation to in vivo androgen levels, combined OC use, CAG and GGC genotypes, and BRCA1/2/X family status in 269 young healthy women from breast cancer high-risk families and 56 additional BRCA1/2 mutation carriers. Testosterone, androstenedione, dehydroepiandrosterone sulfate, and body constitution were measured on cycle days 18-23. Six AR htSNPs and CAG and GGC repeat lengths were genotyped. Most OC users had lower androgen levels than non-users (all Ps<0.0001). Rare variant diplotypes were associated with higher testosterone levels in OC users than in non-users (P(interaction)=0.011). The interaction remained after adjustment for family clustering. Neither individual AR htSNPs nor other diplotypes were significantly associated with androgen levels and did not tag for CAG or GGC genotypes. In the first included woman from each family, the odds of having the most common diplotype was lower in BRCA1 families compared to other families OR 0.41 (95% CI 0.22-0.78). In conclusion, we found few associations between AR htSNPs or diplotypes and androgen levels in women. Diplotypes cannot replace genotyping of microsatellites CAG or GGC. Since testosterone levels are not affected the same way by combined OC use among all women, young women who have higher testosterone levels during combined OC use may belong to the subgroup of women who will not be helped by combined OCs for treatment of androgen-dependent conditions and may be at higher risk for early-onset breast cancer. Whether these women can be identified with AR genotyping needs to be confirmed in an independent cohort

Conformity to the Rule of Law in the EU - the case of the Stability and Growth Pact

This paper provides a presentation of the rule of law in the EU with regard to the Stability and Growth Pact. As there are different jurisprudential conceptions as to define law, the meaning of the rule of law is inexact. The concept is however generally understood to be an antithesis to the rule of men, which implies arbitrariness. The Stability and Growth Pact is a legal instrument, adopted in accordance with the EC Treaty, aiming to assure sound public finances in the EMU Member States by providing for sanctions against countries with excessive budget deficits. In November 2003, the Council of ministers of economy and finance (hereinafter the Ecofin Council) decided not to impose sanctions against France and Germany although they had excessive budget deficits, a decision that was contrary to EC law. In a subsequent ruling by the European Court of Justice in July 2004, the Ecofin Council decisions were annulled. This paper analyses the Ecofin Council's refusal to apply EC law and the subsequent ruling from the European Court of Justice by using two perspectives on the rule of law in the EU. From a public international law perspective, which assumes that the EU consists of essentially sovereign states, the rule of law functions imperfectly in the Union. The reason is that law and state are intimately linked. The authority of law depends on the coercive means to enforce it. In this regard, the question of the authority of law depends on the body that controls the state. In classical legal theory this idea is expressed in terms of sovereignty and coercive powers. Since EU has no real sanction possibilities at its disposal, the authority of EC law is weak. The reason the Ecofin Council refused to apply EC law is because the Stability and Growth Pact is an unfortunate legal instrument. It cannot be expected to work properly between essentially sovereign states, since its application is at the mercy of the very states it purports to control. From a public international law perspective, no criticism can be pointed towards the Member States for not implementing the Pact. Instead, criticism should be pointed towards the European Court of Justice that through its case law and different conception of the rule of law has extended its powers beyond what the Member States intended. The Ecofin Council decisions not to implement the Stability and Growth Pact is in this view explainable and even justifiable. The other perspective this paper presents is a constitutional perspective, which involves a conception of law that is held by the European Court of Justice. This view holds that the EU consists of not fully sovereign Member States and that it has several constitutional features. It assumes a rights-based conception of law that can be traced back to the constitutional theory of John Locke. The law of the constitution is in this view merely an expression and a consequence of natural rights. The function of law is to safeguard and promote these natural rights that exist independently of society. To break the law is, in Lockean terminology, comparable to rebellion. The task of the Court is to interpret a constitution, whose purpose is to uphold rights and not to create them. From this perspective, the Ecofin Council decisions constituted an unacceptable encroachment on EC law. The provisions of the Stability and Growth Pact are specific and clear, and the Ecofin Council decisions concerned mere application of law, as opposed to interpretation. Nevertheless, the Ecofin Council decided contrary to EC law. This situation might be explained by the active role of the Court in developing EC law. The Court might have anticipated this situation by its creative case law through which it has developed the material scope of EC law beyond the intentions of the Member States. Despite this, the judgement of the Court that annulled the Ecofin Council decisions is likely to be followed. The alternative would lead to a constitutional crisis, which is not in the interest of the Member States. Thus in the trial of strength between the Member States and the EU, the Ecofin Council decisions were probably enough a statement of the power of the Member States