https://www.ganjoho.org/knowledge/St.Gallen/St._Gallen2009.pdf

Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009

Breath analysis is a young field of research with great clinical potential. As a result of this interest, researchers have developed new analytical techniques that permit real-time analysis of exhaled breath with breath-to-breath resolution in addition to the conventional central laboratory methods using gas chromatography-mass spectrometry. Breath tests are based on endogenously produced volatiles, metabolites of ingested precursors, metabolites produced by bacteria in the gut or the airways, or volatiles appearing after environmental exposure. The composition of exhaled breath may contain valuable information for patients presenting with asthma, renal and liver diseases, lung cancer, chronic obstructive pulmonary disease, inflammatory lung disease, or metabolic disorders. In addition, oxidative stress status may be monitored via volatile products of lipid peroxidation. Measurement of enzyme activity provides phenotypic information important in personalized medicine, whereas breath measurements provide insight into perturbations of the human exposome and can be interpreted as preclinical signals of adverse outcome pathways.

Analysis of Exhaled Breath for Disease Detection

OBJECTIVE—There are significant individual differences in the extent to which mood and cognition change as a function of reproductive stage, menstrual phase, postpartum, and hormone therapy. This review explores the extent to which variations or polymorphisms in the estrogen receptor α gene (ESR1) predict cognitive and mood outcomes. METHODS—A literature search was conducted from 1995 to November 2009 through PubMed, EMBASE, and PsychINFO. Twenty-five manuscripts were reviewed that summarize investigations of ESR1 in mental health. RESULTS—Among studies investigating ESR1 in relation to cognition, 11 of 14 case-control studies reported an association between ESR1 polymorphisms and risk for developing dementia. Three of four prospective cohort studies reported an association between ESR1 polymorphisms and significant cognitive decline. There are inconsistencies between case-control and cohort studies regarding whether specific ESR1 alleles increase or decrease the risk for cognitive dysfunction. The relationships between ESR1 and cognitive impairment tend to be specific to or driven by women and restricted to risk for Alzheimer’s disease rather than other dementia causes. Three of five studies examining ESR1 polymorphisms in relation to anxiety or depressive symptoms found significant associations. Significant associations have also been reported between ESR1 polymorphisms and childhood-onset mood disorder and premenstrual dysphoric disorder. CONCLUSIONS—A strong relationship between ESR1 variants and cognitive outcomes is evident and preliminary evidence suggests a role of the ESR1 gene in certain mood outcomes. Insights into the discordant results will come from future studies that include haplotype analyses, analyses within specific ethnic/racial populations, and gender-stratified analyses.

A review of estrogen receptor α gene (ESR1) polymorphisms, mood, and cognition

Neurokinin B (NKB) is a hypothalamic neuropeptide binding preferentially to the neurokinin 3 receptor. Expression of the gene encoding NKB is elevated in postmenopausal women. Furthermore, rodent studies suggest that NKB signalling may mediate menopausal hot flushes. However, the effects of NKB administration on hot flushes have not been investigated in humans. To address this, we performed a randomised, double-blinded, placebo-controlled, 2-way cross-over study. Ten healthy women were admitted to a temperature and humidity-controlled research unit. Participants received 30 minute intravenous infusions of NKB and vehicle in random order. Symptoms, heart rate, blood pressure, sweating and skin temperature were compared between NKB and vehicle in a double-blinded manner. Eight of ten participants experienced flushing during NKB infusion with none experiencing flushing during vehicle infusion (P = 0.0007). Significant elevations in heart rate (P = 0.0106 vs. pre-symptoms), and skin temperature measured using skin probe (P = 0.0258 vs. pre-symptoms) and thermal imaging (P = 0.0491 vs. pre-symptoms) characteristic of menopausal flushing were observed during hot flush episodes. Our findings provide evidence that NKB administration can cause hot flushes in women. Further studies are required to determine if pharmacological blockade of NKB signalling could inhibit hot flushes during the menopause and during treatment for sex-steroid dependent cancers.

https://spiral.imperial.ac.uk/bitstream/10044/1/19634/2/Neurokinin%20B%20administration%20induces%20hot%20flushes%20in%20women..pdf

Neurokinin B administration induces hot flushes in women.

Purpose Hot flashes are a common problem for which effective and safe treatments are needed. The current trial was conducted on the basis of preliminary promising data that pregabalin decreased hot flashes. Patients and Methods A double-blind, placebo-controlled, randomized trial design was used to compare pregabalin at target doses of 75 mg twice daily and 150 mg twice daily with a placebo. Hot flash frequencies and scores (frequency times mean severity) were recorded daily during a baseline week and for six treatment weeks. The primary end point for this study was the change-from-baseline hot flash score during treatment week 6 between the 150 mg twice daily target pregabalin treatment and placebo. Nonparametric Wilcoxon rank sum tests, two-sample t tests, and χ2 tests were used to compare the primary and secondary hot flash efficacy end points between pregabalin treatments and placebo. Results Hot flash score changes available for 163 patients during the sixth treatment week compared with a baseline we...

/pdf/phase-iii-randomized-double-blind-placebo-controlled-3h4u4xq0kd.pdf

Phase III, Randomized, Double-Blind, Placebo-Controlled Evaluation of Pregabalin for Alleviating Hot Flashes, N07C1

Objective—Hot flashes are valuable indicators of physiologic condition and drug effect; however, subjective and objective measures do not always agree. No study has examined both subjective and objective hot flashes in women prescribed aromatase inhibitors. The study (1) compared subjective and objective hot flash measures, (2) examined changes in subjective and objective hot flashes over time, and (3) evaluated predictors of change in hot flashes in aromatase inhibitor-treated women. Design—Subjects (n=135) were enrolled in a randomized clinical trial comparing exemestane and letrozole for the treatment of breast cancer. Hot flashes were assessed prior to starting drug and 1, 3, and 6 months later. Subjects wore a sternal skin conductance monitor for ≥ 24 hours at each time point. With each perceived hot flash, women pressed an event button and rated intensity and bother in a paper diary. Results—Subjects were a mean age of 60 years and mainly Caucasian (92%). Across time points, monitor hot flashes were (1) significantly more frequent than diary and/or event button flashes (p<. 05) and (2) moderately correlated with subjective measures (.35< r <.56). Monitor hot flashes did not significantly change over time with aromatase inhibitor therapy, whereas both diary and event button frequency significantly varied but in dissimilar patterns (51% non-linear). No consistent predictors of hot flashes across measures or time points were identified.

Comparison of subjective and objective hot flash measures over time among breast cancer survivors initiating aromatase inhibitor therapy.

The use of exogenous estrogen to prevent cardiovascular disease in women has been a subject of controversy since data from the Women’s Health Initiative trial suggested that postmenopausal women might experience a greater number of cardiovascular events when treated with hormone replacement therapy.1 There is large interindividual variability in the response to estrogens, and Herrington et al.2 have suggested that this may be due in part to genetic variants in the estrogen receptors (ERs). As the Women’s Health Initiative study made prospective study of the effects of estrogens difficult and as the selective estrogen response modifier tamoxifen acts as an exogenous estrogen on serum lipids, we elected to study the effects of tamoxifen on serum lipids and to test the hypothesis that genetic variants are associated with variability in response.

Tamoxifen is a selective ER modulator widely used in the treatment of ER- or progesterone receptor-positive breast cancer, and it is the only agent approved for the prevention of the disease.3–6 As a selective ER modulator, tamoxifen has both estrogenic and anti-estrogenic effects depending on the target tissue. Tamoxifen effects on serum lipid concentration are largely similar to those of estrogen.7,8

Tamoxifen is documented to cause a reduction in serum total and low-density lipoprotein (LDL), but data on high-density lipoprotein (HDL) and triglycerides have not been consistent.9–14 The effects of tamoxifen vary from patient to patient, and this variability is specifically seen in the response of lipid parameters.11,14,15 The causes of this variability are not completely understood, but may be, in part, due to inherited genetic differences in the cellular receptors.16 Tamoxifen acts via binding and modulation of the ERs, which are members of the nuclear steroid receptor superfamily. Two subsets of human ERs have been identified: ER-α and ER-β. These receptors are products of different genes, designated ESR1 and ESR2, respectively.17–19 The expression of these receptors is influenced by genetic polymorphisms, as is the case for other members of the nuclear receptor superfamily.16 Single-nucleotide polymorphisms (SNPs) in the genes coding for the ERs may therefore explain some of the variability seen in the response to tamoxifen, including changes in lipid profile. The interaction of the ERs with each other may also be important, as studies have suggested that ER-β modulates some of the responses resulting from activation of ER-α targets.20

Herrington et al.2 have showed an association between HDL-cholesterol levels and polymorphisms in ER-α gene related to exogenous estrogen. They reported a significantly higher HDL response to estrogen therapy compared with placebo of postmenopausal women who carry the ER-α IVIS-401C/C genotype vs variant genotypes. Similarly, other investigators have reported an association between ER genotype and baseline concentration of LDL-cholesterol in Japanese school children, who were not exposed to any medications.21

In 2000, we initiated a prospective, multi-institutional cohort clinical trial to study SNPs in multiple candidate genes and non-tumoral effects of tamoxifen in women at high risk for or with newly diagnosed breast cancer. From this cohort, we have reported previously an association of cytochrome P450 2D6 (CYP2D6) genotypes and tamoxifen metabolite concentrations in breast cancer patients treated with tamoxifen.22–24 Endoxifen, an active metabolite of tamoxifen, is 30- to 100-fold more potent than tamoxifen as an anti-estrogen in the suppression of estrogen-responsive genes and cell proliferation.22 CYP2D6 genotypes may therefore be associated with non-tumoral responses of tamoxifen such as lipid profile change.

We report here the results of the analysis of this prospective cohort in which we tested the hypothesis that lipid profile changes in breast cancer patients on tamoxifen therapy are associated with candidate polymorphisms in ER-α, ER-β, or CYP2D6.

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

We tested the hypothesis that the stable isotope [13C]pantoprazole is O -demethylated by cytochrome P450 CYP2C19 and that the 13CO2 produced and exhaled in breath as a result can serve as a safe, rapid, and noninvasive phenotyping marker of CYP2C19 activity in vivo. Healthy volunteers who had been genotyped for the CYP2C19*2 , CYP2C19*3 , and CYP2C19*17 alleles were administered a single oral dose of [13C]pantoprazole sodium-sesquihydrate (100 mg) with 2.1 g of sodium bicarbonate. Exhaled 13CO2 and 12CO2 were measured by IR spectroscopy before (baseline) and 2.5 to 120 min after dosing. Ratios of 13CO2/12CO2 after [13C]pantoprazole relative to 13CO2/12CO2 at baseline were expressed as change over baseline (DOB). Maximal DOB, DOB15 to DOB120, and area under the DOB versus time curve (AUC0–120 and AUC0–∞) were significantly different among three genotype groups ( CYP2C19*1/*1 , n = 10; CYP2C19*1/*2 or CYP2C19*1/*3 , n = 10; and CYP2C19*2/*2 , n = 5) with predicted extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) of CYP2C19, respectively (Kruskal-Wallis test, p < 0.01); linear regression analysis indicated a gene-dose effect relationship ( r 2 ranged between 0.236 and 0.522; all p < 0.05). These breath test indices were significantly lower in PMs than IMs ( p < 0.05) or EMs ( p < 0.01) of CYP2C19. [13C]Pantoprazole plasma exposure showed significant inverse correlation with breath test indices in the respective subjects (Pearson r = -0.74; p = 0.038). These feasibility data suggest that the [13C]pantoprazole breath test is a reliable, rapid, and noninvasive probe of CYP2C19 and seems to be a useful tool to optimize drug therapy metabolized by CYP2C19.

https://jpet.aspetjournals.org/content/jpet/early/2009/01/09/jpet.108.147751.full.pdf

Rapid Identification of the Hepatic Cytochrome P450 2C19 Activity Using a Novel and Noninvasive [13C]Pantoprazole Breath Test

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Papers

Comparison of subjective and objective hot flash measures over time among breast cancer survivors initiating aromatase inhibitor therapy.

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

Rapid Identification of the Hepatic Cytochrome P450 2C19 Activity Using a Novel and Noninvasive [13C]Pantoprazole Breath Test