CHICAGO (EGMN) – Anthracycline-related cardiotoxicity among childhood cancer survivors increases significantly at high cumulative exposures, but at low-exposure levels occurs more frequently in patients who carry a specific high-risk genetic variant, reported investigators from the Children’s Oncology Group.
Among all childhood cancer survivors in a case-control study, cumulative anthracycline exposures of 300 mg/m2 or greater were associated with a 22-fold increase in risk for cardiomyopathy (odds ratio 22.32), compared with no exposure, said principal investigator Dr. Smita Bhatia at a May 20 press briefing on research to be presented June 7 at the annual meeting of the American Society of Clinical Oncology.
Carriers of a polymorphism in CBR3, a gene encoding for carbonyl reductases – enzymes that catalyze the breakdown of anthracycline into toxic alcohol metabolites – had a nearly threefold risk for developing cardiotoxicity after exposure to just 1- to 100-mg/m2 doses of anthracyclines (OR 2.64), whereas the risk was only slightly increased in noncarriers (OR 1.19). At doses of 101-200 mg/m2, carriers had a nearly sixfold risk (OR 5.78 vs. OR 1.59 for noncarriers).
At larger cumulative drug doses, however, the risk for cardiotoxicity was high for both noncarriers (OR 27.93) and carriers (OR 15.33), probably from the overwhelming effects of oxidative stresses caused by unmetabolized anthracyclines, said Dr. Bhatia, a professor of population sciences at the City of Hope National Medical Center in Duarte, California.
“Patients who have the highest doses of exposure to anthracyclines develop cardiotoxicity or cardiomyopathy or congestive heart failure irrespective of what their CBR, or carbonyl reductase, genotype status is,” she said.
The findings suggest that pretreatment screening could help oncologists choose less cardiotoxic chemotherapy for children who are susceptible to anthracycline-induced heart damage, said Dr. George W. Sledge, ASCO president-elect and professor of pathology and laboratory medicine at Indiana University in Indianapolis.
“Therapeutic individualization involves the host as well as the tumor. Being able to look at host metabolism is going to be crucial in understanding how to give these agents safely,” he said. “This study is a first step to leading to safer and perhaps more effective approaches to treating our younger cancer patients.”
If the results can be validated in an independent cohort, it may be practical to genotype children with cancers that are susceptible to low-dose anthracyclines – such as acute lymphoblastic leukemia and non-Hodgkin’s lymphoma – and choose less toxic alternatives for those with high-risk genetics.
For children with other cancers for which high-dose anthracyclines are indicated – such as bone or soft-tissue sarcomas or acute myeloid leukemia – the focus should be on more aggressive surveillance, pharmacologic interventions, and cardioprotection with agents such as dexrazoxane, Dr. Bhatia suggested.
Functional polymorphisms in two CBR-encoding genes (CBR3 V244M and CBR1 G1096A) had been shown to affect CBR activity, and could affect the synthesis of metabolites. Consequently, the investigators conducted a case-control study to look at the potential effects of the polymorphisms in 165 childhood cancer survivors with cardiomyopathy, and 323 survivors with no documented cardiomyopathy. The controls were matched to the cases based on primary diagnosis, follow-up, and race/ethnicity. The authors obtained germline DNA from the participants at follow-up visits.
The participants were diagnosed and treated from 1966 through 2008. The primary diagnoses were leukemia in 164 patients, lymphoma in 111, sarcoma in 120, and other cancers in 93. The median age at diagnosis was 7.5 years; the median time from diagnosis to cardiomyopathy was 7.1 years. Cases received a median anthracycline dose of 300 mg/m2; controls received a median of 140 mg/m2.
Multivariate analysis showed that every 100 mg/m2 increase in the anthracycline dose was associated with a near doubling of cardiomyopathy (odds ratio 1.8, P less than .001), and chest radiation was associated with a trebling of risk (OR 3.13, P = .05).
Analyses that were adjusted for chest radiation showed a borderline association between CBR3V244M and cardiomyopathy among all patients (OR 1.5, P = .08), and no association for CBR1 G1096A (OR 1.0). But in an analysis adjusted for anthracycline dose, the risk for the presence of the CBR3 polymorphism was significantly higher at all dose levels below 250 mg/m2 (OR 6.4, P = .006). At higher dose levels, the association disappeared. Similar but not significant associations were seen between dose levels and the CBR1polymorphism.
The study funding source was not disclosed. The authors declared that they had no conflicts of interest.
Most of the more than 4,000 abstracts scheduled to be presented at the ASCO meeting are posted online.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
芝加哥(EGMN) ——根据来自儿童肿瘤协作组研究者的研究成果，在儿童期癌症幸存者中，蒽环类药物相关心脏毒性在蒽环类累积用药量较高时显著增加；而在累积用药量较低时，心脏毒性则更常发生于携带特异性高危遗传变异体的患者中。
主要研究者Smita Bhatia博士在5月20日就这项将公布于7月7日美国临床肿瘤学会(ASCO)年会上的研究举办的新闻发布会上称，在参与这项病例对照研究的所有儿童期癌症幸存者中，与未接受蒽环类药物治疗者相比，蒽环类药物累积用药量达到或超过300 mg/m2者患心肌病的危险性增加22倍[比值比(OR)为22.32]。
CBR3基因是编码羰基还原酶的基因，该酶催化蒽环类药物分解成有毒的乙醇代谢物。当应用蒽环类抗肿瘤药仅为1~100 mg/m2时，那些携带CBR3基因多态性的患者发生心脏毒性的危险性是未用药者的近3倍(OR为2.64)，而非携带者危险性仅轻度增加(OR为1.19)。当用药量达101~200 mg/m2时，携带者则具有近6倍的危险性(OR为5.78，而非携带者OR为1.59)。
Bhatia博士是加利福尼亚州杜阿尔特希望城国家医学中心的人口科学教授。她指出，当累积用药量更高时，无论是否为携带者，发生心脏毒性的危险性均很高(OR分别为27.93和15.33)。这可能是未代谢的蒽环类药物引起的氧化应激过度作用造成的。
Bhatia博士称：“那些蒽环类用量最大的患者，无论其具有何种CBR或羰基还原酶的基因型，均会发生心脏毒性，或心肌病，或充血性心衰。”
印第安纳波利斯印第安纳大学病理学和检验医学系教授兼ASCO候任主席George W. Sledge博士指出，该发现提示，治疗前筛选出那些对蒽环类药物致心脏损伤易感的患儿，有助于肿瘤科医生为他们选择心脏毒性小的化疗方案。
他认为：“个体化治疗既涉及患者自身，也包括肿瘤。能够了解患者新陈代谢状况，将成为理解如何安全用药的关键所在。这项研究为找到更安全、或许更有效的治疗年轻癌症患者的方法迈出了第一步。”
如果该结果能在一项独立的队列研究中得到验证，那么其可能对患有对小剂量蒽环类抗肿瘤药物敏感的癌症(如急性淋巴细胞性白血病和非霍奇金淋巴瘤)患儿有实际意义。对那些携带高危基因型的患儿可选用低毒性药物。
Bhatia博士建议，对于那些适用于高剂量蒽环类抗肿瘤药物的患儿，如患有骨或软组织肉瘤，或患有急性髓细胞样白血病，则应进行更密切的监测，加强药理学方面的干预，并使用如右丙亚胺等心脏保护性药物。
两个CBR编码基因(CBR3 V244M和CBR1 G1096A)的功能性多态性显示出影响CBR活性的能力，并能影响代谢产物的合成。因此，研究者进行了一项病例对照研究，以探讨这些基因多态性的潜在作用。他们选取了165名患有心肌病的儿童期癌症幸存者，还有323名未患心肌病的幸存者。对照组与病例组病例在初步诊断、随访情况以及人种/种族上匹配。研究者在进行随访时从参试者处获得了种系DNA。
受试者在1966~2008年间确诊并接受治疗。初步诊断为白血病者164例，淋巴瘤者111例，肉瘤者120例，其他癌症者93例。患者诊断时中位年龄为7.5岁；从诊断到发生心肌病的中位时间为7.1年。病例组接受蒽环类药物中位剂量为300 mg/m2，而对照组为140 mg/m2。
多因素分析显示，蒽环类药物药量每增加100 mg/m2，相应患心肌病的危险性便增加近1倍(OR为1.8，P＜0.001)，而胸部放疗则使危险性增加2倍(OR 为3.13，P = 0.05)。
对胸部放疗因素进行校正后分析发现，所有患者中CBR3V244M和心肌病有相关趋势(OR 为1.5，P = 0.08)，而CBR1 G1096A则没有相关性(OR 为1.0)。对蒽环类药物剂量因素进行校正后分析显示，总剂量在250 mg/m2以下时，CBR3多态性者患心肌病的危险性显著增高(OR为6.4，P =0 .006)。在更高的剂量水平上，此相关性则消失了。类似的相关性在药物剂量水平和CBR1多态性之间也存在，但不显著。
未披露该研究的经费来源。研究者声明无相关利益冲突。
在ASCO上发布的超过4,000篇论文摘要已发表在以下网站上：www.abstract.asco.org。
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