Relationship of body mass index with aromatisation and plasma and tissue oestrogen levels in postmenopausal breast cancer patients treated with aromatase inhibitors

Background: Recent data have raised concern about the clinical efficacy of aromatase inhibitors in overweight and/or obese breast cancer patients. We report in vivo aromatase inhibition and plasma and tissue oestrogen levels in relation to body mass index (BMI) status among breast cancer patients treated with different aromatase inhibitors. Methods: We compared data on in vivo aromatase inhibition (64 patients) as well as plasma and tissue oestrogen levels from patients participating in our studies to BMI values. Results: We found a weak positive correlation between pretreatment aromatisation level and BMI (n = 64; R = 0.236; p = 0.060) but no correlation between on-treatment aromatisation levels or percentage aromatase inhibition and BMI within patient subgroups treated with any of a panel of aromatase inhibitors. Pre-treatment levels of plasma estradiol (p < 0.001), estrone (p = 0.001) and estrone sulphate (p = 0.002) correlated to BMI. While on-treatment levels of plasma estrane sulphate correlated to BMI in patients on letrozole (R = 0.601; p = 0.001; n = 25 for all) or anastrozole (n = 12; R = 0.611; p = 0.035) therapy, letrozole suppressed plasma estrone sulphate more than anastrozole independent of BMI. No correlation between on-treatment tumour oestrogen levels and BMI was recorded. Conclusions: Our unique data do not support a lack of effective aromatase inhibition in overweight patients or therefore a need for alternative therapy. The higher levels of estrogens in overweight postmenopausal breast cancer patients before and during aromatase inhibition may be due to effects of BMI on oestrogen metabolism rather than aromatisation.publishedVersio

Relationship of body mass index with aromatisation and plasma and tissue oestrogen levels in postmenopausal breast cancer patients treated with aromatase inhibitors

Background: Recent data have raised concern about the clinical efficacy of aromatase inhibitors in overweight and/or obese breast cancer patients. We report in vivo aromatase inhibition and plasma and tissue oestrogen levels in relation to body mass index (BMI) status among breast cancer patients treated with different aromatase inhibitors. Methods: We compared data on in vivo aromatase inhibition (64 patients) as well as plasma and tissue oestrogen levels from patients participating in our studies to BMI values. Results: We found a weak positive correlation between pretreatment aromatisation level and BMI (n = 64; R = 0.236; p = 0.060) but no correlation between on-treatment aromatisation levels or percentage aromatase inhibition and BMI within patient subgroups treated with any of a panel of aromatase inhibitors. Pre-treatment levels of plasma estradiol (p < 0.001), estrone (p = 0.001) and estrone sulphate (p = 0.002) correlated to BMI. While on-treatment levels of plasma estrane sulphate correlated to BMI in patients on letrozole (R = 0.601; p = 0.001; n = 25 for all) or anastrozole (n = 12; R = 0.611; p = 0.035) therapy, letrozole suppressed plasma estrone sulphate more than anastrozole independent of BMI. No correlation between on-treatment tumour oestrogen levels and BMI was recorded. Conclusions: Our unique data do not support a lack of effective aromatase inhibition in overweight patients or therefore a need for alternative therapy. The higher levels of estrogens in overweight postmenopausal breast cancer patients before and during aromatase inhibition may be due to effects of BMI on oestrogen metabolism rather than aromatisation

The novel microRNAs hsa-miR-nov7 and hsamiR- nov3 are over-expressed in locally advanced breast cancer

miRNAs are an important class of small non-coding RNAs, which play a versatile role in gene regulation at the post-transcriptional level. Expression of miRNAs is often deregulated in human cancers. We analyzed small RNA massive parallel sequencing data from 50 locally advanced breast cancers aiming to identify novel breast cancer related miRNAs. We successfully predicted 10 novel miRNAs, out of which 2 (hsa-miR-nov3 and hsa-miR-nov7) were recurrent. Applying high sensitivity qPCR, we detected these two microRNAs in 206 and 214 out of 223 patients in the study from which the initial cohort of 50 samples were drawn. We found hsa-miR-nov3 and hsa-miR-nov7 both to be overexpressed in tumor versus normal breast tissue in a separate set of 13 patients (p = 0.009 and p = 0.016, respectively) from whom both tumor tissue and normal tissue were available. We observed hsa-miR-nov3 to be expressed at higher levels in ER-positive compared to ER-negative tumors (p = 0.037). Further stratifications revealed particularly low levels in the her2-like and basal-like cancers compared to other subtypes (p = 0.009 and 0.040, respectively). We predicted target genes for the 2 microRNAs and identified inversely correlated genes in mRNA expression array data available from 203 out of the 223 patients. Applying the KEGG and GO annotations to target genes revealed pathways essential to cell development, communication and homeostasis. Although a weak association between high expression levels of hsa-miR-nov7 and poor survival was observed, this did not reach statistical significance. hsa-miR-nov3 expression levels had no impact on patient survival.publishedVersio

Polymorphisms in the TP53-MDM2-MDM4-axis in patients with rheumatoid arthritis

Background In addition to being a tumour suppressor, TP53 is a suppressor of inflammation, and dysfunction of this gene has been related to autoimmune diseases. Patients with autoimmunity, such as rheumatoid arthritis (RA) have an increased risk of certain cancers, like lymphomas, indicating that some underlying mechanisms may modulate risk of both cancers and autoimmunity. Methods We genotyped 5 common genetic variants in TP53 and its main regulators MDM2 and MDM4 in a sample of 942 RA patients and 3,747 healthy controls, and mined previously published GWAS-data, to assess the potential impact of these variants on risk of RA. Results For the TP53 Arg72Pro polymorphism (rs1042522), MDM4 SNP34091 (rs4245739) and MDM2 SNP285C (rs117039649), we found no association to risk of RA. For MDM2 SNP309 (rs2279744), the minor G-allele was associated with a reduced risk of RA (OR: 0.87; CI: 0.79–0.97). This association was also seen in genotype models (OR: 0.86; CI: 0.74–0.99 and OR: 0.79; CI 0.63–0.99; dominant and recessive model, respectively), but was not validated in a large GWAS data set. For MDM2 del1518 (rs3730485), the minor del-allele was associated with an increased risk of RA in the dominant model (OR: 1.18; CI: 1.02–1.38). Stratifying RA cases and controls into phylogenetic subgroups according to the combined genotypes of all three MDM2 polymorphism, we found individuals with the del158-285–309 genotype del/ins-G/G-T/T to have an increased risk of RA as compared to those with the ins/ins-G/G-G/G genotype (OR: 1.56; CI: 1.18–2.06) indicating opposite effects of the del1518 del-allele and the SNP309 G-allele. Conclusion We find a potential association between the MDM2 del1518 variant and RA, and indications that combinatorial genotypes and haplotypes in the MDM2 locus may be related to RA.publishedVersio

APOBEC3A/B deletion polymorphism and cancer risk.

Activity of the apolipoprotein B mRNA editing enzyme, catalytic-polypeptide-like (APOBEC) enzymes has been linked to specific mutational processes in human cancer genomes. A germline APOBEC3A/B deletion polymorphism is associated with APOBEC-dependent mutational signatures, and the deletion allele has been reported to confer an elevated risk of some cancers in Asian populations, while the results in European populations, so far, have been conflicting. We genotyped the APOBEC3A/B deletion polymorphism in a large population-based sample consisting of 11 106 Caucasian (Norwegian) individuals, including 7279 incident cancer cases (1769 breast, 1360 lung, 1585 colon, and 2565 prostate cancer) and a control group of 3827 matched individuals without cancer (1918 females and 1909 males) from the same population. Overall, the APOBEC3A/B deletion polymorphism was not associated with risk of any of the four cancer types. However, in subgroup analyses stratified by age, we found that the deletion allele was associated with increased risk for lung cancer among individuals <50 years of age (OR 2.17, CI 1.19-3.97), and that the association was gradually reduced with increasing age (P = 0.01). A similar but weaker pattern was observed for prostate cancer. In support of these findings, the APOBEC3A/B deletion was associated with young age at diagnosis among the cancer cases for both cancer forms (lung cancer: P = 0.02; dominant model and prostate cancer: P = 0.03; recessive model). No such associations were observed for breast or colon cancer.The study was supported by grants from the Bergen Research Foundation, the Norwegian Cancer Society’s Pink Ribbon campaign, the Norwegian Research Council and the Norwegian Health Region West

Multilocus analysis of SNP and metabolic data within a given pathway

BACKGROUND: Complex traits, which are under the influence of multiple and possibly interacting genes, have become a subject of new statistical methodological research. One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common multifactorial diseases and their association to different quantitative phenotypic traits. RESULTS: Two types of data from the same metabolic pathway were used in the analysis: categorical measurements of 18 SNPs; and quantitative measurements of plasma levels of several steroids and their precursors. Using the combinatorial partitioning method we tested various thresholds for each metabolic trait and each individual SNP locus. One SNP in CYP19, 3UTR, two SNPs in CYP1B1 (R48G and A119S) and one in CYP1A1 (T461N) were significantly differently distributed between the high and low level metabolic groups. The leave one out cross validation method showed that 6 SNPs in concert make 65% correct prediction of phenotype. Further we used pattern recognition, computing the p-value by Monte Carlo simulation to identify sets of SNPs and physiological characteristics such as age and weight that contribute to a given metabolic level. Since the SNPs detected by both methods reside either in the same gene (CYP1B1) or in 3 different genes in immediate vicinity on chromosome 15 (CYP19, CYP11 and CYP1A1) we investigated the possibility that they form intragenic and intergenic haplotypes, which may jointly account for a higher activity in the pathway. We identified such haplotypes associated with metabolic levels. CONCLUSION: The methods reported here may enable to study multiple low-penetrance genetic factors that together determine various quantitative phenotypic traits. Our preliminary data suggest that several genes coding for proteins involved in a common pathway, that happen to be located on common chromosomal areas and may form intragenic haplotypes, together account for a higher activity of the whole pathway

Simultaneous Quantification of Aromatase Inhibitors and Estrogens in Postmenopausal Breast Cancer Patients

Context Currently there are no assays that can simultaneously quantify serum levels of the third-generation aromatase inhibitors (AIs): letrozole, anastrozole, and exemestane, and the ultra-low levels of estrogens in postmenopausal breast cancer patients on AI treatment. Such measurements may be pivotal for the determination of optimal and individualized treatment regimens. We aimed at developing a liquid chromatography–tandem mass spectrometry (MS/MS) method for simultaneous assessment of letrozole, anastrozole, exemestane, and 17-hydroxyexemestane as well as subpicomolar levels of estradiol and estrone. Methods Internal standards, calibrators, serum samples, and quality controls were in fully automated steps transferred to a deep-well plate for a 2-step liquid-liquid extraction. The extracts were reconstituted and analytes were separated chromatographically using 2 serially coupled columns, then subject to MS/MS in electrospray ionization mode. The method was thoroughly validated and is traceable to 2 accredited estrogen methods. Results The measurement range for estrone and estradiol was 0.2 to 12 000 pmol/L and 0.8 to 13 000 pmol/L, and covered the expected therapeutic range for the AIs. All analytes had a precision of less than or equal to 13%, and accuracies within 100 ± 8%. As proof of concept, AI and estrogen levels were determined in serum samples from postmenopausal breast cancer patients under treatment. Conclusion We present here an assay suitable for the simultaneous measurement of serum levels of all third-generation AIs and ultra-low levels of estrogens, providing a powerful new tool to study drug efficacy and compliance. The method is highly valuable for postmenopausal patients whose pretreatment estradiol levels are below the threshold of detection for most routine assays, but still require suppression.publishedVersio

DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the most frequent cancer in women and consists of a heterogeneous collection of diseases with distinct histopathological, genetic and epigenetic characteristics. In this study, we aimed to identify DNA methylation based biomarkers to distinguish patients with locally advanced breast cancer who may benefit from neoadjuvant doxorubicin treatment.</p> <p>Results</p> <p>We investigated quantitatively the methylation patterns in the promoter regions of 14 genes (<it>ABCB1</it>, <it>ATM</it>, <it>BRCA1</it>, <it>CDH3</it>, <it>CDKN2A</it>, <it>CXCR4</it>, <it>ESR1</it>, <it>FBXW7</it>, <it>FOXC</it>1, <it>GSTP1</it>, <it>IGF2</it>, <it>HMLH1</it>, <it>PPP2R2B</it>, and <it>PTEN</it>) in 75 well-described pre-treatment samples from locally advanced breast cancer and correlated the results to the available clinical and molecular parameters. Six normal breast tissues were used as controls and 163 unselected breast cancer cases were used to validate associations with histopathological and clinical parameters.</p> <p>Aberrant methylation was detected in 9 out of the 14 genes including the discovery of methylation at the <it>FOXC1 </it>promoter. Absence of methylation at the <it>ABCB1 </it>promoter correlated with progressive disease during doxorubicin treatment. Most importantly, the DNA methylation status at the promoters of <it>GSTP1</it>, <it>FOXC1 </it>and <it>ABCB1 </it>correlated with survival, whereby the combination of methylated genes improved the subdivision with respect to the survival of the patients. In multivariate analysis <it>GSTP1 </it>and <it>FOXC1 </it>methylation status proved to be independent prognostic markers associated with survival.</p> <p>Conclusions</p> <p>Quantitative DNA methylation profiling is a powerful tool to identify molecular changes associated with specific phenotypes. Methylation at the <it>ABCB1 </it>or <it>GSTP1 </it>promoter improved overall survival probably due to prolonged availability and activity of the drug in the cell while <it>FOXC1 </it>methylation might be a protective factor against tumour invasiveness. <it>FOXC1 </it>proved to be general prognostic factor, while <it>ABCB1 </it>and <it>GSTP1 </it>might be predictive factors for the response to and efficacy of doxorubicin treatment. Pharmacoepigenetic effects such as the reported associations in this study provide molecular explanations for differential responses to chemotherapy and it might prove valuable to take the methylation status of selected genes into account for patient management and treatment decisions.</p

Ny medikamentell behandling av brystkreft Adjuvant behandling med trastuzumab ved tidlig stadium av brystkreft - en helseøkonomisk analyse

Source at https://www.helsebiblioteket.no/Denne rapporten er andre del av et oppdrag fra Sosial- og helsedirektoratet og RHF - fagdirektørene med fokus på virkestoffet trastuzumab ved adjuvant behandling av brystkreft. Adjuvant behandling gis i tillegg til hovedbehandlingen (for eksempel kirurgi) for å påvirke eventuelt gjenværende kreftceller hos pasienten. Denne delen av oppdraget vurderer de helseøkonomiske konsekvensene av adjuvant behandling av brystkreft med dette virkestoffet. Trastuzumab markedsføres i Norge under produktnavnet Herceptin ®