Recommendations for genetic testing to reduce the incidence of anthracycline‐induced cardiotoxicity

Abstract

Aims 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.

Cardiovascular Complications of Cancer Therapy

“…Nonetheless, some patients had no significant cardiac complications despite receiving doses as high as 1000 mg/m 2 (19). Individual susceptibility is most likely due to genetic variants in genes that regulate anthracycline cardiotoxicity (20). Other risk factors for anthracycline toxicity include cumulative dose, intravenous bolus administration, higher single doses, history of prior irradiation, use of concomitant agents known to have cardiotoxicity, female gender, underlying CV disease, age (young and elderly), delayed diagnosis, and increase in cardiac biomarkers such as troponins during and after administration (9,21–23).…”

Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial

“…Several SNPs have been associated with anthracycline-induced cardiotoxicity 16,19,20,27,28 . Under our linear model of decline in LVEF, we observed a significant association of the CBR3 V244M variant in combined analyses of all patients (N=1,191), p=0.004, Beta=0.84 when A (Met) allele is reference 15,16 .…”

“…We also report on published associations of trastuzumab-related cardiotoxicity of the variants ERBB2 Ile655Val and Pro1170Ala 10,12–14 from patients in Arms BC and on published associations of anthracycline-related cardiotoxicity at the ABCB1 , CBR3 , RAC2 , NCF4 , SLC28A3 , RARG and UGT1A6 loci 27 in patients from Arms A, B and C combined, who all received doxorubicin and paclitaxel.…”

Treatment patterns, outcomes and long-term toxicity among patients with Hodgkin’s lymphoma in real world: results of a hospital based registry

“…Кардио-токсичность хорошо охарактеризована, и идентифи-цировано множество факторов, ассоциированных с ней. К наиболее важным факторам риска антрациклиновой токсичности относятся общая кумулятивная доза [21], возраст [22], женский пол [23], генетические полимор-физмы RARG (S427L), SLC28A3 (L461L) и UGT1A6*4 (V209V) [24][25][26], сочетанное применение лучевой те-рапии и антрациклинов и, наконец, срок наблюдения [27]. Если говорить о лучевой кардиотоксичности, клю-чевое значение имеют кумулятивная доза > 30 Гр [28], разовая доза > 2 Гр [29], доза облучения на область сердца [30], одновременное использование антраци-клинов [31,32], факторы риска по развитию сердечно-сосудистых заболеваний и, наконец, срок наблюдения за больными [31].…”