Recommendations for Genetic Testing to Reduce the Incidence of Anthracycline-induced Cardiotoxicity

AIM Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. METHODS We followed a standard guideline development process; including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RESULTS RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. CONCLUSIONS Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.

Using pharmacogenetics and pharmacogenomics in the treatment of psychiatric disorders: some ethical and economic considerations"

Current pharmacotherapies for psychiatric disorders are generally incompletely effective. Many patients do not respond well or suffer adverse reactions to these drugs, which can result in poor patient compliance and poor treatment outcome. Adverse drug reactions and non-response are likely to be influenced by genetic polymorphisms. Pharmacogenetics holds some promise for improving the treatment of mood disorders by utilising information about genetic polymorphisms to match patients to the drug therapy that is the most effective with the fewest side effects. Pharmacogenomics promises to facilitate the development of new drugs for treatment. However, these technologies raise many ethical, economic and regulatory issues that need to be addressed before they can be integrated into psychiatry, and medicine more generally. We discuss ethical and policy issues arising from pharmacogenetic testing and pharmacogenomics research, such as informed consent, privacy and confidentiality, research on vulnerable persons and discrimination; and economic viability of pharmacogenetics and pharmacogenomics. We conclude with recommendations for the regulation and distribution of pharmacogenetic testing services and pharmacogenomic drugs.

Does pharmacogenomics provide an ethical challenge to the utilisation of cost-effectiveness analysis by public health systems?

Pharmacogenomics promotes an understanding of the genetic basis for differences in efficacy or toxicity of drugs in different individuals. Implementation of the outcomes of pharmacogenomic research into clinical practice presents a number of difficulties for healthcare. This paper aims to highlight one of the Unique ethical challenges which pharmacogenomics presents for the utilisation of cost-effectiveness analysis by public health systems. This paper contends that pharmacogenomics provides a challenge to fundamental principles which underlie most systems for deciding which drugs should be publicly subsidised. Pharmacogenomics brings into focus the conflict between equality and utility in the context of using cost-effectiveness analysis to aid distribution of a limited national drug budget.

FcγRIIa and FcγRIIIa polymorphisms and cetuximab benefit in the microscopic disease

Purpose: FcγR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX ± cetuximab in high-risk, locally advanced rectal cancer.

Experimental Design: FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan–Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.

Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX = 54, CAPOX-C = 51). No deviation from the Hardy–Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcγRIIa-131R (HR, 0.38; P = 0.058) and FcγRIIIa-158F alleles (HR, 0.21; P = 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P = 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P = 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P = 0.017) and remained significant after adjusting for prognostic variables (P = 0.003).

Conclusion: This is the first study investigating FcγRIIa and FcγRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

A systematic review of the cost-effectiveness of targeted therapies for metastatic non-small cell lung cancer (NSCLC)

Background: Non-small cell lung cancer (NSCLC) imposes a substantial burden on patients, health care systems and society due to increasing incidence and poor survival rates. In recent years, advances in the treatment of metastatic NSCLC have resulted from the introduction of targeted therapies. However, the application of these new agents increases treatment costs considerably. The objective of this article is to review the economic evidence of targeted therapies in metastatic NSCLC. Methods: A systematic literature review was conducted to identify cost-effectiveness (CE) as well as cost-utility studies. Medline, Embase, SciSearch, Cochrane, and 9 other databases were searched from 2000 through April 2013 (including update) for full-text publications. The quality of the studies was assessed via the validated Quality of Health Economic Studies (QHES) instrument. Results: Nineteen studies (including update) involving the MoAb bevacizumab and the Tyrosine-kinase inhibitors erlotinib and gefitinib met all inclusion criteria. The majority of studies analyzed the CE of first-line maintenance and second-line treatment with erlotinib. Five studies dealt with bevacizumab in first-line regimes. Gefitinib and pharmacogenomic profiling were each covered by only two studies. Furthermore, the available evidence was of only fair quality. Conclusion: First-line maintenance treatment with erlotinib compared to Best Supportive Care (BSC) can be considered cost-effective. In comparison to docetaxel, erlotinib is likely to be cost-effective in subsequent treatment regimens as well. The insights for bevacizumab are miscellaneous. There are findings that gefitinib is cost-effective in first- and second-line treatment, however, based on only two studies. The role of pharmacogenomic testing needs to be evaluated. Therefore, future research should improve the available evidence and consider pharmacogenomic profiling as specified by the European Medicines Agency. Upcoming agents like crizotinib and afatinib need to be analyzed as well. © Lange et al.

Variability in the international normalised ratio (INR) in patients with antiphospholipid syndrome and positive lupus anticoagulant: should the INR targets be higher?

El síndrome antifosfolípido es un desorden autoinmune caracterizado por hipercoagulabilidad que requiere terapia anticoagulante como pilar fundamental, siendo la warfarina el tratamiento de elección en los casos que requieren manejo por largos periodos. Sin embargo, los pacientes con anticoagulante lúpico positivo representan un reto porque tienen mayor riesgo de presentar eventos trombóticos, sumado a que el seguimiento con el International Normalized Ratio (INR) no es confiable, ya que estos anticuerpos generan interferencia con las pruebas de laboratorio basadas en fosfolípidos, como es el caso del tiempo de protrombina (PT) con INR basal prolongado, incluso antes del inicio de la terapia anticoagulante. Por tal razón, se ilustra el caso de una paciente con síndrome antifosfolípido primario y anticoagulante lúpico positivo quien ha presentado múltiples episodios trombóticos, a pesar de recibir terapia anticoagulante. Además se hace una revisión de la literatura disponible y se postulan nuevas metas de INR en estos pacientes diferentes de las que se plantean actualmente.