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

Aminkeng F1,2, Ross CJ2,3, Rassekh SR2,4, Hwang S5, Rieder MJ6, Bhavsar AP2,3, Smith A2,7, Sanatani S2, Gelmon KA8, Bernstein D9, Hayden MR1,2,10,Amstutz U2,3,11, Carleton BC2,7; CPNDS Clinical Practice Recommendations Group.

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Abstract

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.

KEYWORDS:

Anthracycline; anthracycline-induced cardiotoxicity; cancer; chemotherapy; clinical practice recommendations; congestive heart failure; pharmacogenomic testing