Michael D. Wiese

Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials

BACKGROUNDnMonoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance.nnnMETHODSnSystematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit.nnnRESULTSnNine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 [95% confidence interval (CI) 0.50-0.76]} and OS [hazard ratio 0.87 (95% CI 0.77-0.99)] for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05).nnnCONCLUSIONnTumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.BACKGROUNDnMonoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance.nnnMETHODSnSystematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit.nnnRESULTSnNine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 [95% confidence interval (CI) 0.50-0.76]} and OS [hazard ratio 0.87 (95% CI 0.77-0.99)] for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05).nnnCONCLUSIONnTumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.

Patient barriers to and enablers of deprescribing: a systematic review.

BackgroundInappropriate medication use is common in the elderly and the risks associated with their use are well known. The term deprescribing has been utilised to describe the complex process that is required for the safe and effective cessation of inappropriate medications. Given the primacy of the consumer in health care, their views must be central in the development of any deprescribing process.ObjectivesThe aim of this study was to identify barriers and enablers that may influence a patient’s decision to cease a medication.Data sourcesA systematic search of MEDLINE, International Pharmaceutical Abstracts, EMBASE, CINAHL, Informit and Scopus was conducted and augmented with a manual search. Numerous search terms relating to withdrawal of medications and consumers’ beliefs were utilised.Study eligibility criteriaArticles were included if the barriers or enablers were directly patient/carer reported and related to long-term medication(s) that they were currently taking or had recently ceased.Study appraisal and synthesis methodsDetermination of relevance and data extraction was performed independently by two reviewers. Content analysis with coding was utilised for synthesis of results.ResultsTwenty-one articles met the criteria and were included in the review. Three themes, disagreement/agreement with ‘appropriateness’ of cessation, absence/presence of a ‘process’ for cessation, and negative/positive ‘influences’ to cease medication, were identified as both potential barriers and enablers, with ‘fear’ of cessation and ‘dislike’ of medications as a fourth barrier and enabler, respectively. The most common barrier/enabler identified was ‘appropriateness’ of cessation, with 15 studies identifying this as a barrier and 18 as an enabler.Conclusions and implications of key findingsThe decision to stop a medication by an individual is influenced by multiple competing barriers and enablers. Knowledge of these will aid in the development of a deprescribing process, particularly in approaching the topic of cessation with the patient and what process should be utilised. However, further research is required to determine if the proposed patient-centred deprescribing process will result in improved patient outcomes.

Review of deprescribing processes and development of an evidence‐based, patient‐centred deprescribing process

Inappropriate use of medication is widespread, especially in older people, and is associated with risks, including adverse drug reactions, hospitalization and increased mortality. Optimization of appropriate medication use to minimize these harms is an ongoing challenge in healthcare. The term ‘deprescribing’ has been used to describe the complex process that is required for safe and effective cessation of medication. Patients play an important role in their own health and, while they may complain about the number of medications they have to take, they may also be reluctant to cease a medication when given the opportunity to do so. A review of previously proposed deprescribing processes and relevant literature was used to develop the patient‐centred deprescribing process, which is a five‐step cycle that encompasses gaining a comprehensive medication history, identifying potentially inappropriate medications, determining whether the potentially inappropriate medication can be ceased, planning the withdrawal regimen (e.g. tapering where necessary) and provision of monitoring, support and documentation. This is the first deprescribing process developed using knowledge of the patients views of medication cessation; it focuses on engaging patients throughout the process, with the aim of improving long‐term health outcomes. Despite a comprehensive review of the literature, there is still a lack in the evidence base on which to conduct deprescribing. The next step in broadening the evidence to support deprescribing will be to test the developed process to determine feasibility in the clinical setting.

People's Attitudes, Beliefs, and Experiences Regarding Polypharmacy and Willingness to Deprescribe

To capture peoples attitudes, beliefs, and experiences regarding the number of medications they are taking and their feelings about stopping medications.

Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC. Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67–1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70–0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61–1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50–0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07). This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.

CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis.

Background—The degree to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain because of considerable heterogeneity in results between studies and potential publication bias. Clopidogrel indication and ethnic population have been proposed to influence the effect of CYP2C19 genotype. Methods and Results—A systematic review was undertaken up to 14 November 2013. Meta-analysis of the CYP2C19 genotype effect was stratified by the predominant clopidogrel indication (percutaneous coronary intervention [PCI] versus non-PCI) and ethnic population (white versus Asian) of each primary study. The primary analysis was restricted to studies with ≥500 participants, which comprised 24 studies and a total of 36 076 participants. The association between carriage of ≥1 CYP2C19 loss-of-function (LoF) allele and major cardiovascular outcomes differed significantly (P<0.001) between studies of whites not undergoing PCI (relative risk 0.99 [95% confidence interval, 0.84–1.17]; n=7043), whites undergoing PCI (1.20 [1.10–1.31]; n=19,016), and Asians undergoing PCI (1.91 [1.61–2.27]; n=10,017). Similar differences were identified in secondary analyses of 2 CYP2C19 LoF alleles, stent thrombosis outcomes, and studies with ≥200 participants. Minimal heterogeneity was apparent between studies of Asian populations. Conclusions—The reported association between CYP2C19 LoF allele carriage and major cardiovascular outcomes differs based on the ethnic population of the study and, to a lesser extent, the clopidogrel indication. This is potentially of major importance given that over 50% of Asians carry ≥1 CYP2C19 LoF alleles.

Benefits of deprescribing on patients' adherence to medications

Deprescribing is a holistic process of medication cessation that encompasses gaining a comprehensive medication list, identifying potentially inappropriate medications, deciding if the identified medication can be ceased, planning the withdrawal regimen and monitoring, support and follow-up. It is currently being investigated as a mechanism to reduce unnecessary or redundant medications. However, given the systematic and patient-centred nature of the deprescribing process, it is possible that it may also confer additional benefits such as improving adherence to medications, even if there is no net reduction in overall medication use. Specifically, deprescribing may improve adherence via reducing polypharmacy, reducing the financial costs associated with medication taking, increasing the patient’s medication knowledge through education, increasing patient engagement in medication management and resolution of adverse drug reactions. More research into deprescribing must be conducted to establish if these potential benefits can be realised, in addition to establishing any negative consequences.

The benefits and harms of deprescribing.

Deprescribing is the process of trial withdrawal of inappropriate medications. Currently, the strongest evidence for benefit of deprescribing is from cohort and observational studies of withdrawal of specific medication classes that have shown better patient outcomes, mainly through resolution of adverse drug reactions. Additional potential benefits of deprescribing include reduced financial costs and improved adherence with other medications. The harms of ceasing medication use include adverse drug withdrawal reactions, pharmacokinetic and pharmacodynamic changes and return of the medical condition. These can be minimised with proper planning (ie, tapering), monitoring after withdrawal, and reinitiation of the medication if the condition returns. More evidence is needed regarding negative, non‐reversible effects of ceasing use of certain classes of medication, such as acetylcholinesterase inhibitors. Cessation of use has not been studied for many medication classes, and large‐scale randomised controlled trials of systematic deprescribing are required before the true benefits and harms can be known.

The validity of sequence symmetry analysis (SSA) for adverse drug reaction signal detection

To determine the validity of sequence symmetry analysis (SSA) method to detect adverse drug reactions from an administrative claims database.

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

IntroductionRational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach.MethodsThis retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models.ResultsThirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea.ConclusionsCYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.