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.

Risk of Cerebral Venous Thrombosis in Obese Women.

IMPORTANCE Obesity is a risk factor for deep vein thrombosis of the leg and pulmonary embolism. To date, however, whether obesity is associated with adult cerebral venous thrombosis (CVT) has not been assessed. OBJECTIVE To assess whether obesity is a risk factor for CVT. DESIGN, SETTING, AND PARTICIPANTS A case-control study was performed in consecutive adult patients with CVT admitted from July 1, 2006 (Amsterdam), and October 1, 2009 (Berne), through December 31, 2014, to the Academic Medical Center in Amsterdam, the Netherlands, or Inselspital University Hospital in Berne, Switzerland. The control group was composed of individuals from the control population of the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study, which was a large Dutch case-control study performed from March 1, 1999, to September 31, 2004, and in which risk factors for deep vein thrombosis and pulmonary embolism were assessed. Data analysis was performed from January 2 to July 12, 2015. MAIN OUTCOMES AND MEASURES Obesity was determined by body mass index (BMI). A BMI of 30 or greater was considered to indicate obesity, and a BMI of 25 to 29.99 was considered to indicate overweight. A multiple imputation procedure was used for missing data. We adjusted for sex, age, history of cancer, ethnicity, smoking status, and oral contraceptive use. Individuals with normal weight (BMI <25) were the reference category. RESULTS The study included 186 cases and 6134 controls. Cases were younger (median age, 40 vs 48 years), more often female (133 [71.5%] vs 3220 [52.5%]), more often used oral contraceptives (97 [72.9%] vs 758 [23.5%] of women), and more frequently had a history of cancer (17 [9.1%] vs 235 [3.8%]) compared with controls. Obesity (BMI ≥30) was associated with an increased risk of CVT (adjusted odds ratio [OR], 2.63; 95% CI, 1.53-4.54). Stratification by sex revealed a strong association between CVT and obesity in women (adjusted OR, 3.50; 95% CI, 2.00-6.14) but not in men (adjusted OR, 1.16; 95% CI, 0.25-5.30). Further stratification revealed that, in women who used oral contraceptives, overweight and obesity were associated with an increased risk of CVT in a dose-dependent manner (BMI 25.0-29.9: adjusted OR, 11.87; 95% CI, 5.94-23.74; BMI ≥30: adjusted OR, 29.26; 95% CI, 13.47-63.60). No association was found in women who did not use oral contraceptives. CONCLUSIONS AND RELEVANCE Obesity is a strong risk factor for CVT in women who use oral contraceptives.

Development of risk assessment methodology for surface disposal of municipal sludge.

"EPA/600/6-90/001."

The Role of health research in support of EPA's regulatory programs.

Mode of access: Internet.

Health assessment document for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds.

"Draft, do not quote or cite."

Technical support document on risk assessment of chemical mixtures.

"EPA/600/8-90/064."

Public health assessment, Kessman/Cross County Landfill, Patterson, Putnam County, New York /

"CERCLIS no. NYD980528491."

Public health assessment, 150 Fulton Avenue/Garden City Park industrial area, Garden City Park, Nassau County, New York /

"July 8, 2002; CERCLIS No. NYD000110247."

Public health assessment, Huntington Landfill, Town of Huntington, Suffolk County, New York /

"Cerclis No. NYD980506844."

Health consultation, Hertel landfill site, Plattekill, Ulster County, New York /

"Cerclis No. NYD980780779."

Public health assessment, Al Turi Landfill, town of Goshen, Orange County, New York /

"Prepared under a Cooperative Agreement with U.S. Department of Health & Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry."

Public health assessment, Cayuga County groundwater contamination, towns of Aurelius, Fleming, & Springport, Cayuga County, New York /

"June 11, 2003; CERCLIS No. NYN000204289."

Public health assessment, Hudson Technologies, village of Hillburn, Rockland County, New York /

"CERCLIS No. NY0001392463."

Public health assessment, Cayuga County groundwater contamination, towns of Aurelius, Fleming & Springport, Cayuga County, New York /

"September 30, 2002; CERCLIS Number NYN000204289."

Public health assessment, Liberty Industrial Finishing Corporation, Farmingdale, Nassau County, New York /

"March 22, 2005; CERCLIS no. NYD000337295."