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The majority of cancer patients with advanced disease experience weight loss, including loss of lean body mass. Severe weight loss is characteristic for cancer cachexia, a condition that significantly impairs functional status and survival. The underlying causes of cachexia are incompletely understood, and currently no therapeutic approach can completely reverse the condition. Autophagy coordinates lysosomal destruction of cytosolic constituents and is systemically induced by starvation. We hypothesized that starvation-mimicking signaling compounds secreted from tumor cells may cause a systemic acceleration of autophagy during cachexia. We found that IL-6 secreted by tumor cells accelerates autophagy in myotubes when complexed with soluble IL-6 receptor (trans-signaling). In lung cancer patients, were cachexia is prevalent, there was a significant correlation between elevated IL-6 expression in the tumor and poor prognosis of the patients. We found evidence for an autophagy-inducing bioactivity in serum from cancer patients and that this is clearly associated with weight loss. Importantly, the autophagy-inducing bioactivity was reduced by interference with IL-6 trans-signaling. Together, our findings suggest that IL-6 trans-signaling may be targeted in cancer cachexia.

Objective: The objective of the present study was to determine whether genetic variability in UDP-glucuronosyltransferase (UGT) genes, together with clinical factors, contribute to variability in morphine glucuronide (M6G and M3G) to morphine serum concentration ratios in patients with advanced cancer receiving chronic morphine therapy., Materials and Methods: A total of 41 polymorphisms and predicted haplotypes in the UGT2B7, UGT1A1, and UGT1A8 genes were analyzed in 759 patients who were recruited from the European Pharmacogenetic Opioid Study and received chronic morphine therapy by the oral route (n=635) or parenterally (n=124). The administration groups were analyzed separately by multiple linear regression analyses., Results: Two haplotypes in UGT1A1/UGT1A8 were weak predictors of reduced M6G/morphine and M3G/morphine serum ratios after oral administration (false discovery rate-corrected P-values<0.1). No effect of genotype was seen in the parenteral group. Of the clinical variables (age, sex, BMI, renal function, Karnofsky performance status, and presence of liver metastases), renal function was the major contributor to variation in serum concentration ratios. Concomitant administration of paracetamol predicted significantly higher morphine metabolic ratios after oral administration of morphine (false discovery rate-corrected P-values<2.1E-12). The regression models explained about 35% of the total variability in the data., Conclusion: Genetic variation in the UGT genes together with clinical factors influence morphine metabolic ratios in patients with advanced cancer disease and who are scheduled with oral morphine. This information may be included in future research that develop and test new classification systems for opioid treatment in patients with advanced cancer.

Objective: This study examined whether the choice of pain-related outcome to represent opioid efficacy influenced findings in a genetic association study. Data from the European Pharmacogenetic Opioid Study, which used opioid dose as the outcome, were analysed in respect of six alternative outcomes: average pain intensity, pain right now, worst pain intensity, pain at its least, pain relief and pain interference., Design: Cancer pain patients using an opioid for moderate or severe pain were included. The pain outcomes were obtained using the Brief Pain Inventory. Genetic variation was analysed for 112 single nucleotide polymorphisms (SNPs) in 25 candidate genes relevant for opioid efficacy. The patients were randomly divided into a development and a validation sample and linear regression was used to compare the equality of means in the six outcomes. The influence of non-genetic factors was controlled for, the regression analyses were stratified by country, and the results were corrected for multiple testing., Results: 2201 cancer pain patients were included. Their mean age was 62.4 years and mean average pain was 3.5. None of the examined SNPs exceeded p values corrected for multiple testing for any of the outcomes., Conclusions: None of the outcomes were associated with variation in the selected SNPs, as previously shown for opioid dose. Thus, we observed that findings related to associations between genetic variability and opioid efficacy were consistent for several alternative outcomes.

The European Pharmacogenetic Opioid Study (EPOS) of a large series of European cancer patients treated with opioids was carried out to assess the influence of genetics on cancer pain relief. As response to opioid therapy was associated with the patients' country of origin, we tested whether population stratification might represent a confounding factor in the analysis of genetic control of response to opioid therapy. From the whole EPOS series representing 2294 patients' genotypes for 379 single-nucleotide polymorphisms (SNPs), we extracted 117 autosomal SNPs with minor allele frequency>0.28 to obtain highly informative genetic markers, and analyzed the SNPs in 1724 individuals showing <20% missing genotypes. Use of the AWclust program to detect clusters of genetically related individuals in the EPOS series showed that the 117-SNP panel distinguished four main European subgroups statistically associated with ethnicity, but not with country of origin or with the pain relief phenotype. Subethnic European groups of genetically related individuals exist that can be correctly identified using an ∼100-SNP panel. Such genetic clustering may control for admixture in association studies and may allow discrimination between genetic and environmental effects on phenotypes showing association with country of origin, as in the case of pain relief.

The variable predisposition to cachexia may, in part, be due to the interaction of host genotype. We analyzed 129 single nucleotide polymorphisms (SNPs) in 80 genes for association with cachexia based on degree of weight loss (>5, >10, >15%) as well as weight loss in the presence of systemic inflammation (C-reactive protein, > 10 mg/l). 775 cancer patients were studied with a validation association study performed on an independently recruited cohort (n = 101) of cancer patients. The C allele (minor allele frequency 10.7%) of the rs6136 (SELP) SNP was found to be associated with weight loss >10% both in the discovery study (odds ratio (OR) 0.52; 95% confidence intervals (CI), 0.29-0.93; p = 0.026) and the validation study (OR 0.09, 95% CI 0.01-0.98, p = 0.035). In separate studies, induction of muscle atrophy gene expression was investigated using qPCR following either tumour-induced cachexia in rats or intra-peritoneal injection of lipopolysaccharide in mice. P-selectin was found to be significantly upregulated in muscle in both models. Identification of P-selectin as relevant in both animal models and in cachectic cancer patients supports this as a risk factor/potential mediator in cachexia., (Copyright © 2012 EMBO Molecular Medicine.)

Background: Cachexia has major impact on cancer patients' morbidity and mortality. Future development of cachexia treatment needs methods for early identification of patients at risk. The aim of the study was to validate nine single-nucleotide polymorphisms (SNPs) previously associated with cachexia, and to explore 182 other candidate SNPs with the potential to be involved in the pathophysiology., Method: A total of 1797 cancer patients, classified as either having severe cachexia, mild cachexia or no cachexia, were genotyped., Results: After allowing for multiple testing, there was no statistically significant association between any of the SNPs analysed and the cachexia groups. However, consistent with prior reports, two SNPs from the acylpeptide hydrolase (APEH) gene showed suggestive statistical significance (P=0.02; OR, 0.78)., Conclusion: This study failed to detect any significant association between any of the SNPs analysed and cachexia; although two SNPs from the APEH gene had a trend towards significance. The APEH gene encodes the enzyme APEH, postulated to be important in the endpoint of the ubiquitin system and thus the breakdown of proteins into free amino acids. In cachexia, there is an extensive breakdown of muscle proteins and an increase in the production of acute phase proteins in the liver.

Purpose: Patients treated with opioid drugs for cancer pain experience different relief responses, raising the possibility that genetic factors play a role in opioid therapy outcome. In this study, we tested the hypothesis that genetic variations may control individual response to opioid drugs in cancer patients., Experimental Design: We tested 1 million single-nucleotide polymorphisms (SNP) in European cancer patients, selected in a first series, for extremely poor (pain relief ≤40%; n = 145) or good (pain relief ≥90%; n = 293) responses to opioid therapy using a DNA-pooling approach. Candidate SNPs identified by SNP-array were genotyped in individual samples constituting DNA pools as well as in a second series of 570 patients., Results: Association analysis in 1,008 cancer patients identified eight SNPs significantly associated with pain relief at a statistical threshold of P < 1.0 × 10⁻³, with rs12948783, upstream of the RHBDF2 gene, showing the best statistical association (P = 8.1 × 10⁻⁹). Functional annotation analysis of SNP-tagged genes suggested the involvement of genes acting on processes of the neurologic system., Conclusion: Our results indicate that the identified SNP panel can modulate the response of cancer patients to opioid therapy and may provide a new tool for personalized therapy of cancer pain.

Background: This study investigates whether demographical, disease-related and genetic factors contribute to inter-individual differences in nausea and vomiting among patients receiving opioids for cancer pain., Methods: Cancer patients receiving opioids were included from 17 centres in 11 European countries. Intensities of nausea and vomiting were reported by 1579 patients on four-point categorical scales. In stratified regression models including demographical and disease-related factors as covariates, 96 single nucleotide polymorphisms (SNPs) in 16 candidate genes related to opioid- or nausea/vomiting signalling pathways (ABCB1, OPRM1, OPRK1, ARRB2, STAT6, COMT, CHRM3, CHRM5, HRH1, DRD2, DRD3, TACR1, HTR3A, HTR3B, HTR3C, CNR1) were analysed for association with nausea and vomiting., Findings: Age, body mass index, Karnofsky Performance Status, gender, use of antiemetics, type of opioid, type of cancer and eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids (p<0.01). The SNPs were rs1176744, rs3782025 and rs1672717 in HTR3B; rs165722, rs4680 and rs4633 in COMT; rs10802789 and rs685550 in CHRM3. Only the SNP rs1672717 in HTR3B passed the Benjamini-Hochberg criterion for a 10% false discovery rate., Interpretation: Clinical characteristics and SNPs within the HTR3B, COMT and CHRM3 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids. This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cancer cachexia is a polygenic and complex syndrome. Genetic variations in regulation of the inflammatory response, muscle and fat metabolic pathways, and pathways in appetite regulation are likely to contribute to the susceptibility or resistance to developing cancer cachexia. A systematic search of Medline and EmBase databases, covering 1986-2008 was performed for potential candidate genes/genetic polymorphisms relating to cancer cachexia. Related genes were then identified using pathway functional analysis software. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Genes with variants which had functional or clinical associations with cachexia and replicated in at least one study were entered into pathway analysis software to reveal possible network associations between genes. A total of 184 polymorphisms with functional or clinical relevance to cancer cachexia were identified in 92 candidate genes. Of these, 42 polymorphisms (in 33 genes) were replicated in more than one study with 13 polymorphisms found to influence two or more hallmarks of cachexia (i.e. inflammation, loss of fat mass and/or lean mass and reduced survival). Thirty-three genes were found to be significantly interconnected in two major networks with four genes (ADIPOQ, IL6, NFKB1 and TLR4) interlinking both networks. Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides an initial framework to select genes/polymorphisms for further study in cancer cachexia, and to develop their potential as susceptibility biomarkers of developing cachexia.

Background: Many patients with advanced cancer depend upon health care providers for symptom assessment. The extent of agreement between patient and provider symptom assessments and the association of agreement with demographic- and disease-related factors was examined., Methods: This cross-sectional study included 1933 patient-health care provider dyads, from 11 European countries. Patients reported symptoms by using the four-point scales of the European Organization of Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) version 3, and providers used corresponding four-point categorical scales. Level of agreement was addressed at the group level (Wilcoxon Signed-Rank test), by difference scores (provider score minus patient score), at the individual level (Intraclass Correlation Coefficients, ICCs) and visually by Bland-Altman plots. Absolute numbers and chi-square tests were used to investigate the relationship between agreement and demographic-, as well as disease-related factors., Results: The prevalence of symptoms assessed as moderate or severe by patients and providers, respectively, were for pain (67 vs.47%), fatigue (71 vs. 54%), generalized weakness (65 vs. 47%), anorexia (47 vs. 25%), depression (31 vs. 17%), constipation (45 vs. 30%), poor sleep (32 vs. 21%), dyspnea (30 vs. 16%), nausea (27 vs. 14%), vomiting (14 vs. 6%) and diarrhea (14 vs. 6%). Symptom scores were identical or differed by only one response category in the majority of patient-provider assessment pairs (79-93%). Providers underestimated the symptom in approximately one of ten patients and overestimated in 1% of patients. Agreement at the individual level was moderate (ICC 0.38 to 0.59). Patients with low Karnofsky Performance Status, high Mini Mental State-score, hospitalized, recently diagnosed or undergoing opioid titration were at increased risk of symptom underestimation by providers (all p < 0.001). Also, the agreement was significantly associated with drug abuse (p = 0.024), provider profession (p < 0.001), cancer diagnosis (p < 0.001) and country (p < 0.001)., Conclusions: Considerable numbers of health care providers underestimated symptom intensities. Clinicians in cancer care should be aware of the factors characterizing patients at risk of symptom underestimation.

Background: Genetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the COMT gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the COMT gene also contributes to interindividual variability in morphine efficacy., Results: We genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype., Conclusion: This study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.

Pain is a complex human trait. It is likely that the interaction of multiple genes, each with a small individual effect, along with the effect of environmental factors, influences the clinical efficacy of opioids rather than a single gene alone. Polymorphisms in genes coding for the mu-opioid receptor (A118G) and catechol-O-methyl transferase (Val158Met) may be important modulators of opioid efficacy. We assessed joint effects of the OPRM1 and COMT genes in predicting morphine dose for cancer pain relief. We used genotype and clinical data from a pharmacokinetic study of morphine in 207 inpatients treated with stable morphine dose for at least 3 days by Palliative Medicine Specialists. Results showed significant variation in morphine dose requirement by genotype groups: carriers of COMT Val/Val and Val/Met genotype required 63% and 23%, respectively, higher morphine dose compared to carriers of Met/Met genotype (p=0.02). Carriers of OPRM1 GG genotype required 93% higher morphine dose compared to carriers of AA genotypes (p=0.012). When we explored for joint effects, we found that carriers of the OPRM1 AA and COMT Met/Met genotype required the lowest morphine dose to achieve pain relief (87 mg/24 h; 95%CI=57,116) and those with neither Met/Met nor AA genotype needed the highest morphine dose (147 mg/24 h; 95%CI=100,180). The significant joint effects for the Met/Met and AA genotypes (p<0.012) persisted, even after controlling for demographic and clinical variables in the multivariable analyses. Future studies are needed to further characterize the joint effects of multiple genes, along with demographic and clinical variables, in predicting opioid dose.

Background: Dispositions for genes encoding opioid receptors may explain some variability in morphine efficacy. Experimental studies show that morphine and morphine-6-glucuronide are less effective in individuals carrying variant alleles caused by the 118 A > G polymorphism in the mu-opioid receptor gene (OPRM1). The purpose of the study was to investigate whether this and other genetic polymorphisms in OPRM1 influence the efficacy of morphine in cancer pain patients., Methods: We screened 207 cancer pain patients on oral morphine treatment for four frequent OPRM1 gene polymorphisms. The polymorphisms were the -172 G > T polymorphism in the 5'untranslated region of exon 1, the 118 A > G polymorphism in exon 1, and the IVS2 + 31 G > A and IVS2 + 691 G > C polymorphisms, both in intron 2. Ninety-nine patients with adequately controlled pain were included in an analysis comparing morphine doses and serum concentrations of morphine and morphine metabolites in the different genotypes for the OPRM1 polymorphisms., Results: No differences related to the -172 G > T, the IVS2 + 31 G > A and the IVS2 + 691 G > C polymorphisms were observed. Patients homozygous for the variant G allele of the 118 A > G polymorphism (n = 4) needed more morphine to achieve pain control, compared to heterozygous (n = 17) and homozygous wild-type (n = 78) individuals. This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, time until death, or adverse symptoms., Conclusion: Patients homozygous for the 118 G allele of the mu-opioid receptor need higher morphine doses to achieve pain control. Thus, genetic variation at the gene encoding the mu-opioid receptor contributes to variability in patients' responses to morphine.

We have screened a cohort of 239 Norwegian cancer patients for sequence variation in the coding and regulatory regions of the UDP-glucuronosyltransferase 2B7 gene (UGT2B7) and analyzed the impact of gene variants on morphine glucuronidation in vivo. In all, 12 single nucleotide polymorphisms (SNPs) were identified, 10 of which have not been previously described. Only one SNP causes a change in amino acid sequence (H268Y). Seven UGT2B7 genotypes were observed and three main haplotypes predicted. There was no correlation between UGT2B7 genotype or haplotype and morphine glucuronide to morphine serum ratios among 175 patients who received chronic oral morphine therapy, and who had normal renal and hepatic function. The apparent lack of functional polymorphisms fits well with the near unimodal, but broad, distributions of the ratios (morphine 3-glucuronide/morphine: 6.4-309.2; morphine 6-glucuronide/morphine: 0.5-72.8). Our results suggest that factors other than UGT2B7 polymorphism may be more deciding for the variability in morphine glucuronide to morphine serum ratios.

Objective: UDP-glucuronosyltransferase (UGT) 2B7 is the major UGT isoform responsible for the 3- and 6-glucuronidation of morphine in humans. Studies in rats have indicated that UGT1A1 may also contribute to the formation of morphine 3-glucuronide (M3G). Our objective was to investigate whether the UGT2B7 H268Y and UGT1A1*28 polymorphisms contribute to the variability in morphine glucuronide-to-morphine plasma ratios among cancer patients undergoing analgesic therapy with morphine., Methods: Seventy patients with normal hepatic and renal function using slow-release morphine to relieve cancer pain were included. UGT2B7 genotyping was performed using restriction enzyme analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Wild-type and variant alleles of the UGT1A1 gene were identified using sizing of PCR-amplified fragments. Morphine 6-glucuronide (M6G)/morphine, M3G/morphine, and M3G/M6G plasma ratios were compared between genotypes., Results: The M3G/morphine, M6G/morphine, and M3G/M6G plasma ratios varied 16-, 42-, and sevenfold, respectively, among individuals. No statistically significant differences in plasma ratios were found between individuals possessing UGT2B7 H/H ( n=20), H/Y ( n=30), or Y/Y ( n=20) genotypes. Five patients were homozygous for the UGT1A1 TA(7) allele, which is associated with reduced UGT1A1 gene expression. However, the mean M3G/M6G and M3G/morphine plasma ratios in TA(7) homozygous subjects did not differ significantly from those of heterozygous or homozygous wild-type (TA(6)) individuals., Conclusion: The UGT2B7 H268Y polymorphism cannot account for the considerable variation in glucuronide-to-morphine ratios in cancer patients. Moreover, the contribution of UGT1A1 to the formation of M3G appears to be of minor biological significance, at least in a UGT2B7 background.