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

Folefac Aminkeng; Colin J D Ross; Shahrad R Rassekh; Soomi Hwang; Michael J Rieder; Amit P Bhavsar; Anne Smith; Shubhayan Sanatani; Karen A Gelmon; Daniel Bernstein; Michael R Hayden; Ursula Amstutz; Bruce C Carleton; CPNDS Clinical Practice Recommendations Group

doi:10.1111/bcp.13008

. 2016 Jun 30;82(3):683–695. doi: 10.1111/bcp.13008

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

Folefac Aminkeng ^1,², Colin J D Ross ^2,³, Shahrad R Rassekh ^2,⁴, Soomi Hwang ⁵, Michael J Rieder ⁶, Amit P Bhavsar ^2,³, Anne Smith ^2,^7,^†, Shubhayan Sanatani ², Karen A Gelmon ⁸, Daniel Bernstein ⁹, Michael R Hayden ^1,^2,¹⁰, Ursula Amstutz ^2,^3,^11,^‡, Bruce C Carleton ^2,^7,^‡,^✉; CPNDS Clinical Practice Recommendations Group^§

^¹Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

^²Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada

^³Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

^⁴Division of Pediatric Hematology/Oncology/BMT, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

^⁵Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

^⁶Department of Pediatrics, University of Western Ontario, London, ON, Canada

^⁷Pharmaceutical Outcomes & Policy Innovations Programme, BC Children's Hospital, Vancouver, BC, Canada

^⁸British Columbia Cancer Agency, Vancouver, BC, Canada

^⁹Department of Pediatrics, Division of Cardiology, Stanford University, Stanford, CA, USA

^¹⁰Translational Laboratory in Genetic Medicine, National University of Singapore and Association for Science, Technology and Research (A*STAR), Singapore

^¹¹University Institute of Clinical Chemistry, Inselspital Bern University Hospital and University of Bern, Switzerland

Correspondence Dr Bruce C. Carleton, Pharmaceutical Outcomes Programme, Department of Pediatrics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. Tel.: +1 604 875 3609; Fax: +1 604 875 2494; E‐mail: bcarleton@popi.ubc.ca

^†

Deceased.

^‡

Authors are co‐senior authors to this work.

^§

Canadian Pharmacogenomics Network for Drug Safety (CPNDS) Clinical Practice Recommendations Group: Vancouver, BC, Canada: University of British Columbia, British Columbia Children's Hospital and Child and Family Research Institute; Folefac Aminkeng, Ursula Amstutz, Shahrad R. Rassekh, Francois Dionne, Soomi Hwang, Amit P. Bhavsar, Anne Smith, Liam R. Brunham, Stuart MacLeod, Shubhayan Sanatani, Colin J.D. Ross, Karen A. Gelmon, Michael R. Hayden, Bruce C. Carleton; London, ON, Canada: University of Western Ontario and London Health Sciences Centre: Michael J. Rieder, Richard B. Kim. Toronto, ON, Canada: Sunnybrook Health Sciences Centre: Neil H. Shear; University of Toronto and Hospital for Sick Children: Gideon Koren, Shinya Ito, Parvaz Madadi; Ontario Cancer Institute: Geoffrey Liu. Ottawa, ON, Canada: University of Ottawa: Maurica Maher. Indiana, IN, USA: Indiana University; David A. Flockhart. Stanford, CA, USA: Stanford University; Daniel Bernstein.

^✉

Corresponding author.

PMCID: PMC5338111 PMID: 27197003

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.

Keywords: anthracycline, cardiotoxicity, heart‐failure, guidelines, pharmacogenomics, cancer

Introduction

Anthracyclines are highly effective anticancer drugs that have contributed to 5‐year survival rates of over 80% for some cancer types 1, 2. They are among the most commonly used agents for the treatment of adult and childhood leukaemia, lymphoma and various solid tumours including breast, ovarian and lung cancers as well as sarcomas. Anthracyclines block DNA and RNA synthesis by inhibiting the topoisomerase II enzyme. The ensuing disruption of DNA replication and transcription prevents the replication of rapidly dividing cells. Through the creation of iron‐mediated free oxygen radicals, anthracyclines also damage DNA, proteins and cell membranes of rapidly dividing cells 3.

The clinical utility of anthracyclines is limited primarily by high inter‐individual variability in cumulative dose‐dependent cardiac toxicity known as anthracycline‐induced cardiotoxicity (ACT). ACT is the deleterious effect of anthracyclines on normal cardiac function due to the toxic effect on cardiac muscles and their conducting system. The clinical diagnosis, classification and grading of ACT according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0 is shown in Table 1 4. Although most studies use the definition of ACT based on CTCAE, the specific grading criteria varies between studies. ACT manifests as asymptomatic cardiac dysfunction in up to 57% of treated patients 5, 6, 7, 8, and as restrictive or dilated cardiomyopathy resulting in congestive heart failure (CHF) in up to 16–20% of patients 9, 10, 11, 12. Anthracycline‐induced CHF is often resistant to therapy and has a mortality rate of up to 79% 10, 13, 14. While some patients tolerate high anthracycline doses without ACT, others are affected even at low doses. ACT can be divided into three types based on the temporal relationship to treatment: acute/subacute cardiotoxicity develops within a week of anthracycline administration, is rare (<1% of childhood cancer patients) and usually resolves after discontinuation of treatment 12, 13; early‐onset chronic progressive cardiotoxicity occurs within a year after completion of therapy and is observed in approximately 2% of treated children 15, 16; and most commonly, ACT manifests as late‐onset chronic progressive cardiotoxicity developing more than a year after therapy completion with up to 65% of patients affected 7, 8.

Table 1.

Clinical characterization of anthracycline‐induced cardiotoxicity

Patients	National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0 4 .
No ACT	▪ No cardiotoxicity
No ACT	– SF ≥ 30%, ≥5yr follow‐up
ACT	▪ Grade 1 toxicity:
	– Shortening fraction: 24% ≤ SF < 30%
	– Resting ejection fraction: 50% ≤ EF < 60%
	▪ Grade 2 toxicity: Moderate to severe cardiotoxicity
	– Shortening fraction: 15% ≤ SF < 24%
	– Resting ejection fraction: 40% ≤ EF < 50%
	▪ Grade 3 toxicity: Symptomatic congestive heart failure
	– Shortening fraction: SF < 15% or
	– Resting ejection fraction: 20% ≤ SF < 40%
	▪ Grade 4 toxicity: Congestive heart failure requiring heart transplant or ventricular assist device
	– Resting ejection fraction < 20%

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The pathophysiology of ACT is not fully understood. It is thought to be mediated in part by reactive oxygen species formed as a result of anthracycline treatment, leading to lipid peroxidation and DNA damage in cardiomyocytes 13, 17. Other suggested causes of ACT include the accumulation of cardiotoxic anthracycline metabolites in the heart, disruption of calcium homeostasis, mitochondrial damage, and induction of apoptosis 13, 17, 18, 19, 20, 21. Higher lifetime cumulative anthracycline dose, concurrent or prior cardiac irradiation, concomitant administration of other cardiotoxic chemotherapeutic agents (particularly paclitaxel, trastuzumab and cyclophosphamide), pre‐existing cardiovascular disease, comorbidities (including renal dysfunction, pulmonary disease, infection, pregnancy), higher individual dose, shorter infusion time, age extremes (younger or elderly age at treatment), female sex, African American ancestry and Trisomy 21 5, 9, 11, 13, 22, 23, 24, 25, 26 are known risk factors for ACT. The variable susceptibility to ACT, even when considering these clinical and demographic risk factors, suggests a genetic component. Candidate gene and genome‐wide association studies have identified genetic variants associated with ACT 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49. However, no recommendations have been developed on the incorporation of genetic information into clinical therapeutic, management and follow‐up decisions for cancer patients with an indication of anthracycline‐based treatment regimens. Therefore, the intentions of this review were to: (1) review and summarize current evidence on genomic markers associated with ACT; (2) provide evidence‐based recommendations as a basis for the use of a patient's genetic information to predict ACT risk and for guiding treatment, management and follow‐up decisions; and (3) identify gaps in knowledge to prioritize future research. Specifically, recommendations for the following key questions were developed:

Should genetic testing be performed in patients with an indication for anthracycline therapy to predict risk of ACT? Which genetic test(s) should be performed and who should be tested?
How should patients with an indication for anthracycline therapy be managed based on the genetic test results?

These recommendations are intended to provide guidance on the use of pharmacogenomic testing to improve the management of ACT risk and reduce the occurrence of cardiotoxicity and congestive heart failure in patients receiving anthracyclines for their cancer treatment.

Methods

A standard guideline development process was followed, as previously described 50. A comprehensive systematic search of the relevant English‐language, published, peer‐reviewed literature was performed to identify available evidence on the association of different genetic variants and ACT. Embase from the period 1974–June 2011 (using the OVID interface) and MEDLINE from the period 1946–July 2011 (using the OVID interface) were searched. Titles and abstracts of all records retrieved were scanned for relevance to the guideline key questions. English language original studies relevant to the guideline questions were selected for full‐text review. Conference abstracts, editorials, notes, short surveys, and review articles were not included in the full‐text review. All studies involving patients treated with anthracycline as part of their chemotherapy were included, whereas experimental in vitro and animal studies were excluded. The outcome of the studies included any clinical assessment of cardiac function (left ventricular (LV) ejection fraction (EF), ventricular shortening fraction (SF), LV volume, diastolic function, strain, molecular imaging, circulating biomarkers and others) and any grading of ACT (CTCAE and others). Study inclusion was not restricted with respect to the study design. Updates of the systematic literature search were performed until January 2016 (Supplementary Methods online). This was followed by an evaluation of the strength of evidence on pharmacogenomic markers for the prediction of ACT.

A level of evidence was assigned to each genetic biomarker, which reflects the consistency of independent study results, the magnitude of effect (e.g., reported as odds ratio), and the number and quality of studies conducted, expert clinical opinion and the deliberations of the CPNDS Clinical Recommendations Group (Table 2). The quality of individual studies and available evidence were assessed based on the quality of the clinical characterization (clinical and demographic information), the genotyping (e.g. call rates, reproducibility/replication error, Hardy‐Weinberg equilibrium, cryptic relatedness verification and population stratification) and the data analysis and interpretation (statistical analytic approach and conclusions). Clinical practice recommendations were developed during a workshop meeting of recommendation development group members (Supplementary Methods online). Each clinical practice recommendation was assigned a level of strength, based on the strength of supporting evidence, the balance between benefits and risks of genotype‐guided treatment, and the likelihood of variability in the individual values and preferences of patients (Table 3) 50. Draft recommendations were submitted to a tiered review process, which included internal review by the Recommendation Group members, followed by external review by content experts and members of the intended target audience (Supplementary Methods online). Pharmacogenomic test performance measures (e.g. sensitivity, specificity, posttest probabilities) were calculated as described in the Supplementary Methods online for variants with a recommendation for testing.

Table 2.

Grading scheme used for critical appraisal of evidence

Grade	Results	Description
++++	Consistent, generalizable	Strong general conclusions can be drawn that are unlikely to change based on further research
+++	Consistent, but limited quantity, quality or generalizability	Evidence allows general conclusions, but with reduced confidence; further research is likely to have an important impact on confidence in conclusions
++	Inconsistent or insufficient quantity/quality, encouraging	No general conclusions can be drawn or conclusions are likely to change based on further research, but current evidence is encouraging
+	Inconsistent or insufficient quantity/quality, discouraging	No conclusions can be drawn or conclusions are likely to change based on future studies, and current evidence is discouraging

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Table 3.

Grading scheme used for grading of clinical practice recommendations

Level	Strength	Evidence basis
A	Strong	Based on strong scientific evidence; benefits clearly outweigh risks
B	Moderate	Based on reduced confidence scientific evidence and expert opinion; benefits likely to outweigh risks
C	Optional	Based mainly on expert opinion, for use with evidence development in a research context

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The nomenclature of the drug and molecular targets including phase I and phase II drug metabolism enzymes, drug transporters, drug receptors, ion channels, transcription factors and other drug targets included in this review conforms to the British Journal of Pharmacology's Guide to Receptors and Channels 51.

Results

Evidence synthesis and critical appraisal

Overall, existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher, moderate and lower risk for ACT. RARG rs2229774, SLC28A3 rs7853758 and UGT1A6*4 rs17863783 currently have the strongest evidence (+++ evidence) as pharmacogenomic markers for ACT 27, 28, 29. Associations of these biomarkers with ACT have been consistently shown and replicated at least twice in large well‐characterized patient populations with clinically relevant effect sizes (reported as odds ratios > 3 or < 0.3) 27, 28, 29. Genetic variants in other genes (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 these associations require additional validation (++/+ evidence) 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49. A brief summary of the evidence regarding these associations with ACT is provided below. A more detailed discussion of these potential genetic risk factors for ACT is provided online in the Supplementary Material and in the Supplementary Tables (S1‐S14).

Retinoic acid receptor gamma (RARG)

RARG has been shown to be involved in cardiac development and remodelling, which may implicate critical processes in the pathophysiology of ACT 52, 53, 54, 55, 56, 57, 58. A recent genome‐wide association study (GWAS) uncovered a non‐synonymous coding variant (rs2229774, S427L) in RARG that was associated with ACT in children 29. This association was replicated in European, African, East Asian, Hispanic and Aboriginal Canadian patient populations 29. The RARG rs2229774 variant has been shown to alter RARG function leading to a reduced repression of the key ACT genetic determinant, TOP2B (Table S1) 29. Although the number of studies is limited, the evidence for the role of RARG in ACT is consistent across different populations, and is further supported by mechanistic studies (+++ evidence).

Solute carrier (SLC) transporters

Two variants in the SLC transporter SLC28A3 (rs7853758, rs885004) have shown consistent associations with doxorubicin and daunorubicin‐induced cardiotoxicity in three independent well‐characterized paediatric cohorts with the minor allele of the variant conferring a reduced ACT risk (+++ evidence; Table S2) 27, 28. Current evidence indicates that the effect of SLC28A3 may be specific to children receiving doxorubicin and daunorubicin, as two recent studies in adult cancer survivors did not detect any association with ACT 31, 32. The two associated variants are in high linkage disequilibrium and rs7853758 has been associated with altered SLC28A3 mRNA levels, suggesting a functional effect related to this synonymous (L461L) variant 59. In addition, genetic associations of SLC22A17 rs4982753 and SLC22A7 rs4149178 have been discovered and replicated in large well‐characterized paediatric patient populations (++ evidence) 30. The known function of the SLC super family as drug transporters (80) and the reported transport of anthracyclines by SLC transporters 60 provides biological support for these genetic associations.

UDP‐glucuronosyltransferase family 1A, isoform 6 (UGT1A6)

A synonymous coding variant (rs17863783, V209V) in UGT1A6 showed evidence for an association with an increased risk of ACT in three independent paediatric patient populations (+++ evidence; Table S3) 27, 28. Rs17863783 is a tag marker of the UGT1A6*4 haplotype, which has been reported to cause a 30–100% reduction in enzyme activity 61, 62. Given the role of UGT1A6 in the drug detoxification glucuronidation pathway 63, reduced UGT1A6‐mediated glucuronidation of anthracycline metabolites may lead to accumulation of toxic metabolites in patients carrying UGT1A6*4, resulting in the observed increased ACT risk.

ATP binding cassette (ABC) transporters

Associations of genetic polymorphisms in ABC transporter genes with ACT have been reported by several studies, including ABCC1 (rs45511401, rs246221, rs4148350, rs246214), ABCC2 (rs8187694‐rs8187710 haplotype, rs4148391, rs4148399), ABCC5 (rs7627754), ABCB1 (rs2235047) and ABCB4 (rs1149222, rs4148808) (Table S4) 27, 31, 33, 34, 36. Only three of these associations (ABCC1 rs246221, ABCC2 rs8187694‐rs8187710 haplotype and ABCC5 rs7627754) have been replicated in independent cohorts 29, 31, 32, 35, but the consistency of findings, and the quantity and quality of the evidence remains limited. All other genetic associations in ABC transporters have not yet been replicated. Considering the role of ABC transporters in the transport of a variety of drugs including anthracyclines 64, more studies are required to clarify the relevance of these genetic variants in ACT (++ evidence).

Carbonyl reductases (CBR). The rs1056892 variant of CBR3 was found to be associated with ACT in two paediatric studies 38, 39, with additional supporting evidence from a third investigation (Table S5) 40. In addition, functional studies suggest an effect of this variant on the metabolism of doxorubicin into the cardiotoxic metabolite doxorubicinol by CBR3 39. However, no association of rs1056892 with ACT was observed in other studies (Table S5) 27, 29, 35, 41. Overall, the evidence regarding this association is thus inconsistent (++ evidence).

Nicotinamide adenine dinucleotide phosphate (NADPH) multienzymes complex

Evidence of genetic associations with polymorphisms in NAD(P)H oxidase subunits involved in the production of reactive oxygen species (ROS) have been reported. Associations for NCF4 rs1883112, CYBA rs4673 and RAC2 rs13058338 have been discovered and replicated at least once in independent studies (Table S6) 31, 33, 35, 37, 44. In addition, it was shown that mice deficient in NAD(P)H oxidase activity were protected from the adverse cardiac effects of chronic doxorubicin treatment 33. However, the reported genetic associations could not be replicated in other studies 27, 29, 31 and current evidence for genetic associations of NAD(P)H oxidase subunits with ACT thus remains limited and conflicting (++ evidence).

Glutathione S‐transferase (GST) enzymes

An association of genetic variants in GSTP1 with ACT has been reported in two small studies 40, 65, but has not been replicated elsewhere 27, 29, 37, 46, resulting in inconsistent evidence overall (++ evidence; Table S7).

Catalase (CAT) enzyme

A relatively small paediatric study (<100 patients) focused on genes involved in ROS metabolism identified an intronic variant (rs10836235) in CAT as marginally associated with ACT (Table S8) 47. However, a recent GWAS in children did not find any associations with this and other variants in CAT with ACT 29. Current evidence thus remains unclear (+ evidence).

Sulfotransferase family cytosolic 2B member 1 (SULT2B1) enzyme

An association of the rs10426377 variant in SULT2B1 involved in the sulfate conjugation of drugs with ACT has been identified and replicated in independent paediatric patient populations 27, 28 (Table S9). The replication of SULT2B1 rs10426377 was only marginally significant and additional evidence is required to confirm this association (++ evidence).

Hyaluronan synthase 3 (HAS3) enzyme

A coding variant in HAS3 (rs2232228) was reported to be associated with cardiomyopathy with evidence of replication in a case‐only cohort (Table S10) 36. Specifically, an association of HAS3 rs2232228 with the risk of ACT was observed in patients with high cumulative anthracycline exposure (>250 mg m⁻²) 36. Conversely, no association of HAS3 variants was observed in a recent GWAS 29. The association of HAS3 rs2232228 thus requires further independent replication (++ evidence). However, the known role of HAS3 in cardiac remodelling 66 provides mechanistic and biological support for this genetic association.

Histamine N‐methyltransferase (HNMT) enzyme

An association of HNMT rs17583889 with ACT has been reported in childhood cancer survivors 27, 28, 29. In addition, the presence of the HNMT rs17583889 homozygous (high risk) and heterozygous (intermediate risk) genotypes, respectively, was detected in two adult sisters who developed cardiotoxicity after low dose doxorubicin treatment 48 (Table S11). However, the quantity of the evidence remains limited and additional studies are needed to further investigate the potential role of HNMT variants in ACT and to strengthen the confidence in this association (++ evidence).

Human haemochromatosis (HFE) protein

HFE deficiency increases the susceptibility to ACT 67. The HFE variants rs1799945 (H63D) and rs1800562 (C282Y) have been associated with the risk of CHF and anthracycline‐induced cardiac injury, respectively 35, 49 (Table S12). Furthermore, the association between anthracycline treatment and dose‐dependent myocardial iron overload was shown to be modulated by HFE variants (C282Y and H63D) 43. No additional studies have observed the association of HFE mutations with ACT to date (++ evidence).

Cytochrome P450 oxidoreductase (CYPOR/POR)

Genetic associations with ACT for three intronic variants in POR (rs2868177, rs13240755, rs4732513) have been reported in a small study (<100 patients) of acute myeloid leukaemia patients receiving daunorubicin 42. Conversely, a previous study investigating rs13240755 and rs4732513 did not find any association with ACT 27 (Table S13). The quantity and the strength of the evidence remain limited, thereby reducing the confidence in the associations (+ evidence). Considering the role of POR enzymes in the cytochrome P450 system and in the biotransformation of a variety of drugs including anthracyclines, more studies will be required to clarify the effect of these genetic variants in ACT.

Nitric oxide synthase 3 (NOS3) enzyme

A genetic association of NOS3 rs1799983 with doxorubicin cardiotoxicity has been reported in a study that included survivors of childhood acute lymphoblastic leukaemia (Table S14) 68, but not in a recent GWAS that included other anthracycline and tumour types 29. Despite the essential role of NOS3 in cardiovascular function, the evidence for the association of NOS3 polymorphism with ACT remains limited and inconsistent. Additional genetic and functional studies are needed to further clarify the relevance of the NOS3 gene in ACT (+ evidence).

Clinical practice recommendations

The goals of these recommendations are to provide guidance on the use of pharmacogenomic testing to reduce the incidence of cardiotoxicity and congestive heart failure in patients that receive anthracycline chemotherapy for cancer treatment. Genetic information on risk of adverse effects are an important part of chemotherapy decision making; therefore these guidelines are designed to assist clinicians in the interpretation of genetic test results and in the use of this information in providing optimal clinical care for patients. They have been developed based on the quantity, quality and consistency of the current scientific evidence and the deliberations of the CPNDS clinical recommendations group.

Should genetic testing be performed in patients with an indication for anthracycline therapy to predict the risk of ACT? Which genetic test (s) should be performed and who should be tested?

Pharmacogenomic testing should be performed in all childhood cancer patients with an indication for doxorubicin or daunorubicin therapy for RARG rs2229774, SLC28A3 rs7853758 and UGT1A6*4 rs17863783 variants (Level B – moderate recommendation). Genetic testing is currently not recommended in adult patients and in children receiving other types of anthracyclines (Level C – optional recommendation).

Considerations: Current evidence regarding the association of these variants with ACT is consistent with a similar effect observed across studies conducted so far (+++ evidence). As the number of studies remains small (<5 studies), additional retrospective and prospective studies would further strengthen the confidence in the associations. Similarly, as all studies so far were performed in paediatric patients receiving primarily doxorubicin or daunorubicin, the generalizability of these findings to adult populations and other anthracyclines is unknown. Therefore, based on current evidence, this recommendation cannot be extrapolated to adults and to other anthracyclines.

How Should Patients be Managed Based on Genetic Testing Results?

Interpretation of the genetic test results

The RARG rs2229774 (G>A) risk variant (A‐allele) and the UGT1A6*4 rs17863783 (G>T) risk variant (T‐allele) have been associated with significantly increased risk of developing ACT in childhood cancer survivors. Childhood cancer patients carrying the RARG rs2229774A or UGT1A6*4 risk variants should therefore be considered at increased risk (high risk) of ACT compared to a classification based on clinical risk factors alone. The SLC28A3 rs7853758 A‐allele has been associated with a reduced risk of ACT. For patients carrying the rs7853758A protective variant who do not carry RARG rs2229774 or UGT1A6*4 risk variants, classification into a lower ACT risk group should be considered. All other patients should be considered at moderate genetic risk. Predictive performance measures for RARG rs2229774, SLC28A3 rs7853758 and UGT1A6*4 rs17863783 are shown in Table 4 29.

Table 4.

Pharmacogenomic testing to assess the risk of ACT and inform treatment decisions in childhood cancer

Genetic marker	Sensitivity (95% CI)	Specificity (95% CI)	Positive post‐test probability (%)	Negative post‐test probability (%)	PPV (95% CI)	NPV (95% CI)	LR+ (95% CI)	LR‐ (95% CI)	NNT
*RARG rs2229774*	45.7 (30.9–61)	86.3 (81.8–90)	55.1	18.9	34.4 (22.7–47.7)	90.9 (86.9–94.1)	3.3 (2.2–5.1)	0.63 (0.48–0.82)	3.6
*UGT1A64 rs17863783**	15.2 (6.3–28.9)	96.2 (93.3–98.1)	59.8	24.6	38.9 (17.3–64.3)	87.8 (83.7–91.2)	4.0 (1.6–9.9)	0.88 (0.78–1.00)	3.0
*SLC28A3 rs7853758*	17.4 (7.8–31.4)	64.6 (58.8–70.1)	15.4	32.1	7.2 (3.2–13.7)	83.2 (77.7–87.8)	0.49 (0.26–0.94)	1.30 (1.09–1.5)	8.6

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Calculations were based on a well‐characterized multiethnic population of 337 paediatric oncology patients treated with anthracycline chemotherapy 29, described in further detail in the Supplementary Methods online. Post‐test probability is also known as exposure specific risk (absolute risk) and was estimated using the prevalence of ACT in childhood cancer survivors (27%) 6. We used the ‘number needed to treat (NNT)’ to estimate the number of patients that need to be screened in order to prevent one case of ACT in childhood cancer. NNT = 1/ARR, where ARR is the absolute risk reduction. LR+ = positive likelihood ratio, LR− = negative likelihood ratio, NPV = negative predictive value, PPV = positive predictive value. Methodological details are available in the supplementary method online.

Management options based on ACT risk

The management of patients based on the recommendations below should be within the current standard of care guidelines, taking into consideration both the risk of cardiotoxicity and possible effects of management options on treatment effectiveness. Management options based on risk stratification also vary as evidence on specific treatment options may only be available for certain cancer types. The recommended management options address treatment considerations, monitoring and prevention and should be interpreted individually within the unique circumstances for each patient.

Low risk patients: normal follow‐up (level A recommendation)

Patients genetically and clinically determined to be at low risk of ACT should receive echocardiogram follow‐up as usual. The Children's Oncology Group (COG) Long Term Follow‐Up Guidelines v3.0 currently recommend cardiac follow‐up every 5 years for those deemed to be low risk based on clinical factors 69, 70.

Moderate risk patients: increase frequency of monitoring (level A recommendation)

Patients initially determined to be at low risk of ACT with a moderate genetic risk should receive increased echocardiogram follow‐up and monitoring for cardiotoxicity. Based on COG guidelines for patients deemed to be at moderate ACT risk based on clinical risk factors 69, 70, we recommend cardiac follow‐up every 2 years for patients with a moderate genetic risk.

High risk patients

For patients determined to be at high risk of ACT based on genetic testing and clinical risk factors, the following management options should be considered:

Increase frequency of monitoring (level A recommendation). Patients with a high risk of ACT should be followed more closely, with serial yearly echocardiographic monitoring and follow‐up as recommended by COG guidelines 69, 70 for high risk anthracycline‐treated childhood cancer survivors. High risk patients should also receive additional heart monitoring before each administration of anthracyclines.
Aggressive screening and management of cardiovascular risk factors (level A recommendation). In high risk patients, cardiovascular risk factors such as obesity, diabetes, arterial hypertension, coronary artery disease, lipid disorders and peripheral vascular disease should be screened regularly and treated aggressively.
Prescription of dexrazoxane (level B recommendation). Dexrazoxane is an iron chelator that protects the myocardium from oxidative damage. It is approved for cardioprotection in adult cancer patients but is also prescribed off‐label to children. Several randomized control trials (RCTs) have shown that dexrazoxane is effective in preventing myocardial damage without compromising anti‐tumour response and survival outcomes (Table S15) 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82. However, as a result of a suggested increased risk of secondary malignancies, the European Medicines Agency limited its indication to adult patients with advanced or metastatic breast cancer and contraindicated its use in children and adolescents 83. Furthermore, the use of dexrazoxane can be associated with nausea, vomiting, stomatitis, diarrhoea, enhanced myelosuppression and other adverse effects. Therefore, we recommend its use when a high risk of ACT is expected with careful consideration of potential benefits and risks individually for each patient.
Use of liposomal encapsulated anthracycline preparations (level C recommendation). Liposomal formulations of daunorubicin and doxorubicin are thought to lower the amount of the drug that is delivered to the heart, potentially making treatment less cardiotoxic. Several clinical trials compared the efficacy, safety and antitumour response of liposomal anthracyclines to conventional preparations (Table S16). Liposomal doxorubicin was found to have similar efficacy and survival outcomes as regular doxorubicin but significantly lower risks of ACT and congestive heart failure in adult patients 84, 85, 86, 87. However, the number of studies is relatively small with a lack of long‐term follow‐up data, and no RCTs so far in children. Therefore, it is difficult to draw strong conclusions regarding the relative cardiac safety of these formulations. Nevertheless, available data indicates that liposomal anthracycline formulations may offer a clinical benefit for patients with a high ACT risk. We therefore recommend the use of liposomal anthracyclines in the context of well‐designed clinical trials to further evaluate their benefits, safety and effects on antitumour response.
Use of continuous infusion or slower infusion rates (level C recommendation). Anthracycline administration by continuous intravenous infusion or with slower infusion rates have been used in an attempt to lower peak drug concentration and reduce ACT risk (Table S17). Three RCTs in adult cancer patients suggested that ACT can be reduced with the use of continuous intravenous infusion 88, 89, 90, whereas two RCTs in children did not find any cardioprotective advantage of this mode of administration 91, 92. Similarly, studies with adult patients have suggested that prolonged administration to minimize circulating dose volume may decrease the risk of ACT 23, 90, 91, 93, 94, 95, 96. However, no high quality evidence regarding the cardiac safety and effectiveness of slower infusion rates is available in children. Given the small number of studies conducted overall, no definitive conclusions can be made about the effect of anthracycline administration rate on ACT risk and drug effectiveness. We therefore recommend considering these alternative administration options only in the context of well‐designed clinical trials to generate further evidence.
Use of less cardiotoxic types of anthracyclines (level C recommendation). Although there is some debate about the type of anthracycline used with significant differences between Europe and North America, the quantity and quality of evidence directly comparing different types of anthracyclines is very limited (Table S18). An RCT comparing chemotherapy response for epirubicin and doxorubicin treatment in advanced breast cancer patients found no difference in the efficacy, safety, response rates and survival outcomes between both treatments 97. Another RCT comparing idarubicin and daunorubicin in the treatment of AML in childhood cancer patients reported a better efficacy for idarubicin but no difference in toxicity rates between treatment arms 98 (Table S18). Taken together, no definitive conclusions can be made about a possible reduction in ACT risk related to the use of different anthracycline types. Further evaluation in high‐quality trials is needed to determine the potential of this management option for patients with high ACT risk.
Use of other cardioprotective agents (level C recommendation). Other cardioprotective drugs such as l‐carnitine, probucol, deferoxamine, ethylenediaminetetraacetic acid (EDTA), coenzyme Q10, N‐acetylcysteine, vitamin E, digoxin, enalapril, phenethylamines, superoxide dismutase, monohydroxyethylrutoside and other ACE inhibitors or beta‐blockers have demonstrated significant cardioprotective effects 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 but have been less well investigated compared to dexrazoxane. RCTs have been performed for some of these agents 82, 103, 111, 112, 113, 114. Based on the quantity and quality of the evidence, no definitive conclusions can be made about their cardioprotective effects in ACT, effects on antitumour efficacy, adverse effects, and long‐term cardiac safety. Therefore, we recommend these cardioprotective agents only for the purpose of generating further evidence.
Prescribe alternative chemotherapy regimens for certain tumour types where alternative regimens have been shown to be equally effective (level C recommendation). There is an ongoing COG trial evaluating the use of chemotherapy protocols without anthracyclines in children with acute lymphoblastic leukaemia (AALL0932). This trial and other similar trials are needed to ascertain whether alternative chemotherapy regimens have similar antitumour efficacy and survival outcomes compared to anthracycline‐based chemotherapy. In the meantime, no conclusions can be drawn about whether this intervention can help prevent heart damage without reducing the antitumour efficacy of chemotherapy.

Discussion

Significant advances have been made with the discovery of pharmacogenomic biomarkers to predict ACT risk. However, inconsistent findings across studies and implementation in clinical practice remain a substantial challenge. In particular, the variability in the clinical diagnosis, classification and grading of ACT introduces heterogeneity between studies, which needs to be addressed. Differences in study design and data analysis approaches may also contribute to discrepant study results and make it difficult to compare and combine studies. The heterogeneity in findings between studies and the lack of independent replication may be related to the variability in study populations (e.g. adult vs. paediatric and different ethnic composition of cohorts), different types of cancer or anthracyclines studied and different chemotherapy protocols used in different studies. A number of other factors may be implicated as well, including the technology used for assessing cardiac toxicity, duration of follow‐up and competing risk factors. Furthermore, many of the genetic association studies for ACT carried out so far were performed in relatively small cohorts with little or no independent replication and functional validation. It is thus essential to further validate these genetic findings in independent patient cohorts and assess their generalizability across different study populations and different types of cancers and anthracyclines and different treatment protocols. In addition, functional validation (e.g., in vitro functional studies and in vivo pharmacokinetic studies) could significantly strengthen the evidence for the role of specific genes or genetic variants in ACT as well as provide insight into potential novel preventive or therapeutic strategies for ACT.

Variable follow‐up time between studies investigating ACT risk factors could also affect results and make study comparisons challenging as the relevance of specific genetic risk factors might differ between acute, early and late cardiotoxicity. ACT can occur at any time during or after treatment and defining a feasible time course for cardiac monitoring remains a key challenge. Currently, there is no consensus on the optimal monitoring regimen in patients receiving anthracycline therapy and studies evaluating monitoring regimens are lacking 115, 116. Knowledge on the efficacy and cost‐effectiveness of different monitoring strategies in the context of clinical and genetic risk factors would be beneficial to further tailor cardiac monitoring and long‐term follow‐up towards the individual needs of each patient.

Studies are needed to evaluate the association of RARG rs2229774, SLC28A3 rs7853758 and UGT1A6*4 with ACT in adult cancer patients. There is encouraging evidence about the potential role of several other genetic variants for ACT such as ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SLC22A17, HFE and NOS3 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49. Further studies should be conducted to strengthen the evidence, and assess their generalizability and clinical utility. Studies should also be performed that aim to identify additional, novel genetic factors for ACT to improve the sensitivity and specificity of current prediction models. So far, all of the association studies for ACT have been retrospective. To better assess the clinical utility of genetic tests, prospective studies are needed that investigate the genetic risk factors in the context of different management options. Similarly, evidence supporting management strategies to reduce ACT is limited and remains conflicting. Well‐designed RCTs and other prospective studies with long‐term follow‐up, and standardized monitoring and reporting of cardiac outcomes are needed to further evaluate preventive strategies. New techniques for assessing subtle changes in cardiac function may aid in assessing the impact of these interventions. Until such studies are completed, recommended management options are restricted to those available within current standards of care.

Conclusions

Anthracycline‐induced cardiotoxicity is a common, complex and devastating adverse drug reaction (ADR), associated with substantial morbidity and mortality and increased health, psychological, social and economic burden for patients, their families and the health care system. The burgeoning evidence of the role of genetic factors is rapidly expanding our knowledge and ability to predict and manage ACT. However, the uptake of available genetic information in treatment and follow‐up decisions is very limited. Also, no recommendations have been proposed for the incorporation of available genetic information into clinical therapeutic decisions. We performed a systematic review and developed a number of evidence‐based recommendations to provide a useful reference tool to guide physicians, clinical pharmacologists and other healthcare professionals in translating the best available evidence into clinical practice. The hope is that these recommendations will provide the evidence needed to enable prioritized access to genetic testing for cancer patients prior to anthracycline‐based chemotherapy.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: FA, CJD, APB, MRH and BCC have applied for patents based upon some of the work related to the predictive markers of ADRs to anthracyclines described in this review; SRR, SH, MJR, JWL, AS, SS, KAG, DB and UA declare no conflict of interest. The funding agencies had no role in study design; collection, analysis and interpretation of data; writing of the report; or the decision to submit the report for publication. The corresponding author had the final responsibility for the decision to submit for publication

This work was funded through a Canadian Institutes of Health Research (CIHR) Meetings, Planning and Dissemination Grant – Knowledge Translation Supplement, FRN 114403. Additional funding was provided by Genome British Columbia, CIHR Training Program in Bridging Scientific Domains for Drug Safety and Effectiveness – DSECT program (Postdoctoral Fellowship Award for Folefac Aminkeng), Child & Family Research Institute, Vancouver BC (Bertram Hoffmeister Postdoctoral Fellowship Award for Folefac Aminkeng), Michael Smith Foundation for Health Research (Postdoctoral Fellowship Award for Folefac Aminkeng), the Canada Foundation for Innovation, and the University of British Columbia.

Contributors

The conception and design of the study was the work of FA, BCC, UA, SRR, CJDR and MRH. The systematic literature search was performed by FA, SH, and UA, FA, UA, SRR, SH, CJDR, DB, SS, KAG and BCC were responsible for the evidence synthesis and critical appraisal. FA, UA, SRR, APB, AS, CJDR, DB, SS, KAG, MRH, BCC and the CPNDS Clinical Recommendations Group developed the evidence‐based clinical practice recommendations. The article was reviewed and revised by FA, SRR, MJR, SS, KAG, DB, UA, APB, AS, CJDR, MRH, BCC and the CPNDS Clinical Recommendations Group. All authors critically reviewed the report, made suggestions for improving the report for important intellectual content, and approved the final version of the manuscript.

Supporting information

Table S1 Association of RARG with Anthracycline‐induced Cardiotoxicity

Table S2 Association of SLC Transporters with Anthracycline‐induced Cardiotoxicity

Table S3 Association of UGT1A6 Enzyme with Anthracycline‐induced Cardiotoxicity

Table S4 Association of ABC Transporters with Anthracycline‐induced Cardiotoxicity

Table S5 Association of CBR3 Enzymes with Anthracycline‐induced Cardiotoxicity

Table S6 Association of NADPH Enzymes with Anthracycline‐induced Cardiotoxicity

Table S7 Association of GSTP1 Enzyme with Anthracycline‐induced Cardiotoxicity

Table S8 Association of Catalase Enzymes with Anthracycline‐induced Cardiotoxicity

Table S9 Association of SULT2B1 Enzyme with Anthracycline‐induced Cardiotoxicity

Table S10 Association of Hyaluronan Synthase 3 gene with Anthracycline‐induced Cardiotoxicity

Table S11 Association of Histamine N‐Methyltransferase gene with Anthracycline‐induced Cardiotoxicity

Table S12 Association of Hemochromatosis gene with Anthracycline‐induced Cardiotoxicity

Table S13 Association of P450 oxidoreductase gene with Anthracycline‐induced Cardiotoxicity

Table S14 Association of Nitric oxide synthase 3 gene with Anthracycline‐induced Cardiotoxicity

Table S15 Systematic review of the evidence for the use of dexrazoxane and other cardioprotectants in cancer patients receiving anthracyclines

Table S16 Systematic review of the evidence for the use of liposomal encapsulated vs. conventional drug preparations in cancer patients receiving anthracyclines on the risk and incidence of anthracycline‐induced cardiotoxicity

Table S17 Systematic review of the evidence for the use of continuous intravenous infusions versus bolus injection in cancer patients receiving anthracyclines, on the risk and incidence of anthracycline‐induced cardiotoxicity

Table S18 Systematic review of the evidence for the use of different types of anthracyclines on the risk and incidence of anthracycline‐induced cardiotoxicity in cancer patients

Supporting info item

Click here for additional data file.^{(615.6KB, docx)}

Aminkeng, F. , Ross, C. J. D. , Rassekh, S. R. , Hwang, S. , Rieder, M. J. , Bhavsar, A. P. , Smith, A. , Sanatani, S. , Gelmon, K. A. , Bernstein, D. , Hayden, M. R. , Amstutz, U. , Carleton, B. C. , and CPNDS Clinical Practice Recommendations Group (2016) Recommendations for genetic testing to reduce the incidence of anthracycline‐induced cardiotoxicity. Br J Clin Pharmacol, 82: 683–695. doi: 10.1111/bcp.13008.

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