Genetic and RNA-related molecular markers of trastuzumab-chemotherapy-associated cardiotoxicity in HER2 positive breast cancer: a systematic review

Abstract

Cancer-therapy related cardiotoxicity (CTRCT) is a significant and frequent complication of monoclonal antibody directed therapy, especially Trastuzumab, for human epidermal growth factor receptor 2 (HER2) overexpressing breast cancers. Reliable, clinically available molecular predictive markers of CTRCT have not yet been developed. Identifying specific genetic variants and their molecular markers, which make the host susceptible to this complication is key to personalised risk stratification. A systematic review was conducted until April 2021, using the Medline, Embase databases and Google Scholar, to identify studies genetic and RNA-related markers associated with CTRCT in HER2 positive breast cancer patients. So far, researchers have mainly focused on HER2 related polymorphisms, revealing codons 655 and 1170 variants as the most likely SNPs associated with cardiotoxicity, despite some contradictory results. More recently, new potential genetic markers unrelated to the HER2 gene, and linked to known cardiomyopathy genes or to genes regulating cardiomyocytes apoptosis and metabolism, have been detected. Moreover, microRNAs are gaining increasing recognition as additional potential molecular markers in the cardio-oncology field, supported by encouraging preliminary data about their relationship with cardiotoxicity in breast cancers. In this review, we sought to synthesize evidence for genetic variants and RNA-related molecular markers associated with cardiotoxicity in HER2-positive breast cancer.

Heart Failure Association-International Cardio-Oncology Society Risk Score Validation in HER2-Positive Breast Cancer

“…These factors are likely the reason why the level of adverse cardiac events is closely balanced across the age groups. Further study needs to investigate other possible risk factors for chemotherapy-induced cardiotoxicity, such as genetic factors [ 19 ]. These risk factors, along with the changes regarding hypertension and trastuzumab use we have proposed, should be included in any future risk scoring methods.…”

Field Effect Detection by Light Scattering in the Breast Cancer Risk Determination

“…Until now, the most predominant idea about the malignant transformation of breast tissue has been attributed to changes in genetic structure, which may be due to epigenetic [46][47][48] or genetic effects per se 49,50 . These changes generate a process that alters the synthesis of proteins, their behavior and therefore the signaling around the tissue, from a biochemical and molecular point of view 51,52 .…”

Pharmacogenomics in drug-induced cardiotoxicity: Current status and the future

“…A genome wide association study (GWAS) carried out in 481 patients with (11 cases) and without (257 controls) trastuzumab-induced cardiotoxicity in Japanese showed that five SNPs including rs9316695, rs28415722, rs7406710, rs11932853, and rs8032978 were independent predictors of trastuzumab cardiotoxicity ( P combined = 7.82 × 10 −15 , OR = 40.0) ( 47 ). The HER-2 SNPs Ile654Val (rs1801201), Ile655/Val (rs1136201), and Pro1170Ala (rs1058808) were also associated with susceptibility to cardiotoxicity ( 48 ). In a meta-analysis of 344 patients with 43 developed drug induced cardiotoxicity, 67% of the patients carried the Ile/Val genotype, resulting in an OR of 5.35.…”

“…In a meta-analysis of 344 patients with 43 developed drug induced cardiotoxicity, 67% of the patients carried the Ile/Val genotype, resulting in an OR of 5.35. HER-2 Ile655Val is an independent predictor of cancer-therapy related cardiotoxicity ( 24 , 48 ). By comparing HER-2 genotype distribution in 29 cases with cardiotoxicity and 111 controls underwent trastuzumab treatment, Stanton et al, observed association between Pro1170Ala polymorphism and increased risk of trastuzumab induced cardiomyopathy ( 49 ).…”