Influence of the HER2 Ile655Val polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients

Peña, C Gómez; Dávila-Fajardo, Cristina Lucía; Martínez-González, Luis Javier; Carmona-Sáez, Pedro; Pino, María J. Soto; Ramos, J. Sánchez; Moreno‐Escobar, Eduardo; Blancas, Isabel; Fernández, Juan José Diaztagle; Fernandez, D Paredes; Correa, Concepción; Barrera, J Cabeza

doi:10.1097/fpc.0000000000000149

Cited by 30 publications

(26 citation statements)

References 23 publications

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“…Our study failed to find association of decline in LVEF with either of the published associated ERBB2 variants, rs1136201 (I655V) and rs1058808 (P1170A) 10–14 . To be consistent with published associations of the I655V variant, we also performed genotypic analyses of the AG+GG genotypes versus the AA genotype on a case control basis, where cases were defined as a decrease of at least 10% points from baseline with a resulting LVEF of less than 50%, a decrease of 15% with respect to baseline, or any decrease resulting in LVEF less than 45% at least once during the treatment or clinical manifestation of CHF 14 .…”

Section: Resultscontrasting

confidence: 93%

“…To be consistent with published associations of the I655V variant, we also performed genotypic analyses of the AG+GG genotypes versus the AA genotype on a case control basis, where cases were defined as a decrease of at least 10% points from baseline with a resulting LVEF of less than 50%, a decrease of 15% with respect to baseline, or any decrease resulting in LVEF less than 45% at least once during the treatment or clinical manifestation of CHF 14 . We did not observe any association of the I655V or P1170A variants with either linear or logistic models (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Our primary analysis used a quantitative model of maximum decline in LVEF. Published associations used a binary definition of cardiotoxicity or no cardiotoxicity, but with different definitions in each case, including decrease in LVEF of at least 20% points 10 ; decrease in LVEF of at least 10% points to less than 50% or any decrease to <45% 11 ; decrease >10% points to <50% or any decrease >15% or any decrease resulting in <45% or diagnosis of CHF 14 . Hence we also looked for association with the same binary definition as Gomez Pena 14 .…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 96%

“…Common variants in these genes are over-represented in sporadic cases 7–9 suggesting the existence of modifying or risk variants that could be exacerbated by environmental stress factors such as trastuzumab and/or chemotherapy. To date, two common genetic polymorphisms within ERBB2 , Ile655Val and Pro1170Ala, have been associated with an increased risk of trastuzumab-related cardiotoxicity, but sample sizes were small (N ranging 61–140 patients) 10–14 . Polymorphisms in several genes including ABCB1 , CBR3 15,16 , RAC2 , NCF4 17,18 and SLC28A3 19,20 have been associated with anthracycline-related cardiotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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

Serie

Crook²,

Necela

et al. 2017

Pharmacogenetics and Genomics

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Objectives The major clinical side-effect of the ERBB2 targeted breast cancer therapy, trastuzumab, is a decline in left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity. Methods The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (Arm A); paclitaxel then trastuzumab (Arm B); or concurrent paclitaxel and trastuzumab (Arm C) in patients with HER2-positive breast cancer. A GWAS was performed on all patients with available DNA (N=1,446). We used linear regression to identify SNPs associated with decline in LVEF, adjusting for age, baseline LVEF, anti-hypertensive medications and the first two principle components. Results 618,863 SNPs passed quality control (QC) and DNA from 1,191 patients passed genotyping QC and were identified as whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF (p=7.73×10−6 to 8.93×10−8), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6 and LINC01060, in patients who received chemotherapy plus trastuzumab (Arms BC, N=800). None of these loci were significant in patients who received chemotherapy only (Arm A, N=391) and did not increase in significance in analysis of all patients combined. We did not observe association, p<0.05 with SNPs previously associated with trastuzumab induced cardiotoxicity at ERBB2, I655V and P1170A. We replicated association, p<0.05, with SNPs previously associated with anthracycline cardiotoxicity at CBR3 and ABCB1. Conclusions Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity.

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Section: Resultscontrasting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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

Serie

Crook²,

Necela

et al. 2017

Pharmacogenetics and Genomics

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Novel molecular biomarkers of cancer therapy‐induced cardiotoxicity in adult population: a scoping review

et al. 2022

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Aim Cancer treatments are associated with cardiotoxic events that predispose to cardiac pathology and compromise the survival of patients, making necessary the identification of new molecular biomarkers to detect cardiotoxicity. This scoping review aims to identify the available evidence on novel molecular biomarkers associated with cardiotoxicity in the adult population undergoing cancer therapy. Methods and resultsThe databases Medline, Web of Science, Scopus, and Embase were screened for the identification of published studies until 23 August 2020, searching for novel molecular biomarkers reported in cancer therapy-related cardiac dysfunction in adult patients. A total of 42 studies that met the eligibility criteria were included. Fourteen studies reported 44 new protein biomarkers, 18 studies reported 57 new single nucleotide polymorphism biomarkers, and 11 studies reported 171 new gene expression profiles associated with cardiotoxicity. Data were extracted for 272 novel molecular biomarkers reported and evaluated in 7084 cancer patients, of which only 13 were identified in more than one study (MPO, sST2, GDF-15, TGF-B1, rs1056892, rs1883112, rs4673, rs13058338, rs1695, miR-1, miR-25-3p, miR-34a-5p, and miR-423-5p), showing values for area under the curve > 0.73 (range 0.74-0.85), odds ratio 0.26-7.17, and hazard ratio 1.28-1.80. Conclusions Multiple studies presented a significant number of novel molecular biomarkers as promising predictors for risk assessment of cardiac dysfunction related to cancer therapy, but the characteristics of the studies carried out and the determinations applied do not allow suggesting the clinical use of these molecular biomarkers in the assessment of cancer therapy-induced cardiotoxicity.

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Cardiotoxicity of Contemporary Breast Cancer Treatments

Chuy

2019

Curr. Treat. Options in Oncol.

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Treatment-related cardiotoxicity remains a significant concern for breast cancer patients undergoing cancer treatment and extends into the survivorship period, with adverse cardiovascular (CV) outcomes further compounded by the presence of pre-existing CV disease or traditional CV risk factors. Awareness of the cardiotoxicity profiles of contemporary breast cancer treatments and optimization of CV risk factors are crucial in mitigating cardiotoxicity risk. Assessment of patientand treatment-specific risk with appropriate CV surveillance is another key component of care. Mismatch between baseline cardiotoxicity risk and intensity of cardiotoxicity surveillance can lead to unnecessary downstream testing, increased healthcare expenditure, and interruption or discontinuation of potentially life-saving treatment. Efforts to identify early imaging and/or circulating biomarkers of cardiotoxicity and develop effective management strategies are needed to optimize the CV and cancer outcomes of breast cancer survivors.

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Influence of the HER2 Ile655Val polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients

Abstract: Our results support the role of the HER2 655 A>G polymorphism as a genetic marker of trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.

Cited by 30 publications

References 23 publications

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

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

Novel molecular biomarkers of cancer therapy‐induced cardiotoxicity in adult population: a scoping review

Cardiotoxicity of Contemporary Breast Cancer Treatments

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