The Road so Far in Colorectal Cancer Pharmacogenomics: Are We Closer to Individualised Treatment?
ABSTRACT: In recent decades, survival rates in colorectal cancer have improved greatly due to pharmacological treatment. However, many patients end up developing adverse drug reactions that can be severe or even life threatening, and that affect their quality of life. These remain a limitation, as they may force dose reduction or treatment discontinuation, diminishing treatment efficacy. From candidate gene approaches to genome-wide analysis, pharmacogenomic knowledge has advanced greatly, yet there is still huge and unexploited potential in the use of novel technologies such as next-generation sequencing strategies. This review summarises the road of colorectal cancer pharmacogenomics so far, presents considerations and directions to be taken for further works and discusses the path towards implementation into clinical practice.
Project description:Health disparities exist among minorities in the United States, with differences seen in disease prevalence, mortality, and responses to medications. These differences are multifactorial with genetic variation explaining a portion of this variability. Pharmacogenomics aims to find the effect of genetic variations on drug response, with the goal of optimizing drug therapy and development. Although genome-wide association studies have been useful in unbiasedly surveying the genome for genetic drivers of clinically relevant phenotypes, most of these studies have been conducted in mainly participants of European and Asian descent, contributing to a growing health disparity in precision medicine. Diversity is important to pharmacogenomic studies, and there may be real advantages to the use of these complex genomes in pharmacogenomics. In this review we will outline some of the advantages and confounders of pharmacogenomics in minorities, describe the role of genetic variation in pharmacologic pathways, and highlight a number of population-specific findings.
Project description:Introduction: Intensive oncological treatment integrated with resection of metastases raised the clinical outcome of metastatic colorectal cancer (MCRC). In clinical practice, complex evaluation of clinical (age, performance status, comorbidities), and biological (tumoral genotype, pharmacogenomic) parameters addresses tailored, personalized multidisciplinary treatment strategies. Patients with MCRC unsuitable for first-line intensive medical treatments are prevalent and showed worse clinical outcome. After progression to oxaliplatin-based chemotherapy, aflibercept/FOLFIRI significantly improved clinical outcome, even if no survival benefit was reported in adjuvant fast relapsers by aflibercept addition. The case reported a young-elderly (yE) patient with KRAS mutant colorectal cancer rapidly progressing to adjuvant chemotherapy, unfit owing to comorbidities, with multiple pharmacogenomic alterations, who gained long-term survival in clinical practice by multidisciplinary treatment strategy consisting of first-line and re-introduction of aflibercept-containing chemotherapy and two-stage lung metastasectomies. Case presentation: A 71-years-old yE patient, unfit for intensive oncological treatments owing to Cumulative Illness Rating Scale (CIRS) stage secondary, affected by KRAS c.35 G>T mutant colorectal cancer, rapidly progressing with lung metastases after adjuvant XelOx chemotherapy, reached long-term survival 66 months with no evidence of disease after first-line and re-introduction of tailored, modulated aflibercept (4 mg/kg) d1,15-irinotecan (120 mg/m2) d1,15-5-fluorouracil (750 mg/m2/day) dd1-4, 15-18; and secondary radical bilateral two-stage lung metastasectomies. Safety profile was characterized by limiting toxicity syndrome at multiple sites (LTS-ms), requiring 5-fluorouracil discontinuation and aflibercept reduction (2 mg/kg), because of G2 hand-foot syndrome (HFS) for >2 weeks, and G3 hypertension. Pharmacogenomic analyses revealed multiple alterations of fluoropyrimidine and irinotecan metabolism: severe deficiency of fluorouracil degradation rate (FUDR), single nucleotide polymorphisms of UGT1A1 *28 variable number of tandem repeats (VNTR) 7R/7R homozygote, ABCB1 c.C3435T, c.C1236T, MTHFR c.C667T homozygote, DPYD c.A166G, TSER 28bp VNTR 2R/3R heterozygote. Conclusions: In clinical practice, a complex management evaluating clinical parameters and RAS/BRAF genotype characterizing an individual patient with MCRC, particularly elderly and/or unfit owing to comorbidities, is required to properly address tailored, multidisciplinary medical and surgical treatment strategies, integrated with careful monitoring of superimposing toxicity syndromes, also related to pharmacogenomic alterations, to gain optimal activity, and long-term efficacy.
Project description:INTRODUCTION:Pharmacogenomic testing is important in developing individualized therapeutic approaches. In the phase 3 IDEAL (Individualized Dosing to Assess Optimal Pegylated Interferon Therapy) clinical trial, a subset of patients receiving peginterferon and ribavirin for treatment of chronic hepatitis C agreed to provide blood samples for genetic testing. Genome-wide association studies subsequently identified associations between IL28B polymorphism and sustained virologic response, and ITPA polymorphism and ribavirin-associated anemia. OBJECTIVE:To characterize the groups of patients who accepted or declined pharmacogenomic testing in the IDEAL study. METHODS:Clinical and demographic factors and treatment outcomes were compared at all sites that had approved pharmacogenomic testing. Differences between patients who consented to and declined pharmacogenomic testing were analyzed using Student's t-test and ?²-test. RESULTS:In total, 109 of 118 sites participated in the pharmacogenomic substudy, and 1674 of 2949 (57%) patients enrolled at these sites consented to pharmacogenomic testing. More patients treated in academic medical centers than in community centers (60 vs. 52%, P<0.001) provided consent. More men than women (58 vs. 54%, P=0.04) consented to pharmacogenomic testing. There was no significant difference in pharmacogenomic participation between patients from different racial groups, including whites and African Americans (58 vs. 54%, P=0.07). Treatment outcomes were also similar according to pharmacogenomic participation. CONCLUSION:In the IDEAL study, patient consent to pharmacogenomic testing did not introduce selection bias. Treatment at an academic center and male sex were associated with higher rates of pharmacogenomic testing consent. Efficacy and safety outcomes were similar in patients who accepted and declined pharmacogenomic testing.
Project description:The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs have been designed to target additional deregulated pathways in CRC, such as MAPK (mitogen-activated protein kinase)/PI3K-AKT (phosphatidylinositol-3-kinase-AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin), HER-2 and 3 ( human epidermal growth factor receptor-2 and -3), and BRAF. A major issue with targeted treatment is early identification of patients with primary or secondary drug resistance. Pharmacogenomic research has demonstrated its value in this field, highlighting some tumor mutations that could discriminate responders from non-responders. The tumor genetic profile of the RAS/RAF pathway is needed before treatment with anti-EGFR agents; mutations in EGFR pathway genes have also been explored in relation to antiangiogenic molecules although further data are required prior to their integration into clinical practice. The introduction of immunotherapy has paved the way for a new generation of predictive markers, including genome-wide assessment of the tumor landscape. Furthermore, the development of next generation sequencing technology and non-invasive approaches to analyze circulating tumor DNA will make real-time monitoring of the tumor pharmacogenomic markers possible in the clinical routine, rendering precision medicine available to every patient.
Project description:Antimicrobial efficacy and toxicity varies between individuals owing to multiple factors. Genetic variants that affect drug-metabolizing enzymes may influence antimicrobial pharmacokinetics and pharmacodynamics, thereby determining efficacy and/or toxicity. In addition, many severe immune-mediated reactions have been associated with HLA class I and class II genes. In the last two decades, understanding of pharmacogenomic factors that influence antimicrobial efficacy and toxicity has rapidly evolved, leading to translational success such as the routine use of HLA-B*57:01 screening to prevent abacavir hypersensitivity reactions. This article examines recent advances in the field of antimicrobial pharmacogenomics that potentially affect treatment efficacy and toxicity, and challenges that exist between pharmacogenomic discovery and translation into clinical use.
Project description:Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green = genomically favorable, yellow = genomic caution, red = high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. In all, 2,279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio (OR) = 26.2 (9.0-75.3), P < 0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR = 2.4 (1.7-3.5), P < 0.0001). No pharmacogenomically high-risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision-making is achievable through clinical integration of genomic medicine.
Project description:Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children.
Project description:The limited formal study of the clinical feasibility of implementing pharmacogenomic tests has thus far focused on providers at large medical centers in urban areas. Our research focuses on small metropolitan, rural and tribal practice settings.We interviewed 17 healthcare providers in western Montana regarding pharmacogenomic testing.Participants were optimistic about the potential of pharmacogenomic tests, but noted unique barriers in small and rural settings including cost, adherence, patient acceptability and testing timeframe. Participants in tribal settings identified heightened sensitivity to genetics and need for community leadership approval as additional considerations.Implementation differences in small metropolitan, rural and tribal communities may affect pharmacogenomic test adoption and utilization, potentially impacting many patients. Original submitted 3 September 2014; Revision submitted 3 December 2014.
Project description:We set out to test the hypothesis that pharmacometabolomic data could be efficiently merged with pharmacogenomic data by single-nucleotide polymorphism (SNP) imputation of metabolomic-derived pathway data on a 'scaffolding' of genome-wide association (GWAS) SNP data to broaden and accelerate 'pharmacometabolomics-informed pharmacogenomic' studies by eliminating the need for initial genotyping and by making broader SNP association testing possible.We previously genotyped 131 tag SNPs for six genes encoding enzymes in the glycine synthesis and degradation pathway using DNA from 529 depressed patients treated with citalopram/escitalopram to pursue a glycine metabolomics 'signal' associated with selective serotonine reuptake inhibitor response. We identified a significant SNP in the glycine dehydrogenase gene. Subsequently, GWAS SNP data were generated for the same patients. In this study, we compared SNP imputation within 200 kb of these same six genes with the results of the previous tag SNP strategy as a rapid strategy for merging pharmacometabolomic and pharmacogenomic data.Imputed genotype data provided greater coverage and higher resolution than did tag SNP genotyping, with a higher average genotype concordance between genotyped and imputed SNP data for '1000 Genomes' (96.4%) than HapMap 2 (93.2%) imputation. Many low P-value SNPs with novel locations within genes were observed for imputed compared with tag SNPs, thus altering the focus for subsequent functional genomic studies.These results indicate that the use of GWAS data to impute SNPs for genes in pathways identified by other 'omics' approaches makes it possible to rapidly and cost efficiently identify SNP markers to 'broaden' and accelerate pharmacogenomic studies.
Project description:Pharmacogenomic studies of antidepressant treatment-emergent suicidal events in depressed patients report associations with polymorphisms in genes involved in transcription (CREB1), neuroprotection (BDNF and NTRK2), glutamatergic and noradrenergic neurotransmission (GRIA3, GRIK2 and ADRA2A), the stress and inflammatory responses (FKBP5 and IL28RA), and the synthesis of glycoproteins (PAPLN). Nearly all of the reported events in these studies were modest one-time increases in suicidal ideation. In 3231 unique subjects across six studies, 424 (13.1%) patients showed increases in suicidal ideation, eight (0.25%) attempted suicide and four (0.12%) completed suicide. Systems related to most of these genes have also been implicated in studies of suicidal behavior irrespective of treatment. Future pharmacogenomic studies should target events that are clinically significant, related clinical phenotypes of response and medication side effects, and biological pathways that are involved in these outcomes in order to improve treatment approaches.