Trastuzumab-Induced Cardiotoxicity: Testing a Clinical Risk Score in a Real-World Cardio-Oncology Population

Rushton, Moira; Johnson, Christopher; Dent, Susan

doi:10.3747/co.24.3349

Cited by 30 publications

(20 citation statements)

References 21 publications

(25 reference statements)

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“…In this study, the fact that repeated TZM treatment was associated with resultant marked hypertriglyceridemia without corresponding hypercholesterolemia is a strong indication that TZM could increase the risk for an adverse cardiovascular event such as angina pectoris, ischemic heart disease, cardiomyopathy, stroke, and heart failure. This assertion is in consonance with previous studies that have reported TZM to increase the risk for coronary artery disease and ischemic heart disease ( Rushton et al, 2017 ; Yuan et al, 2018 ; Montemurro et al, 2019 ; Chaturvedi et al, 2020 ). The fact that ADP, LSP, and VAL pretreatment individually attenuated TZM -associated hypertriglyceridemia is notable and indicate cardioprotective potentials of these drugs although their fixed-dose combinations worsened TZM ’s potentials for dyslipidemia and increased risk for cardiovascular events.…”

Section: Discussionsupporting

confidence: 91%

Therapeutic Potentials of Selected Antihypertensive Agents and Their Fixed-Dose Combinations Against Trastuzumab-Mediated Cardiotoxicity

et al. 2021

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Trastuzumab (TZM) is useful in the clinical management of HER2-positive metastatic breast, gastric, and colorectal carcinoma but has been limited by its off-target cardiotoxicity. This study investigates the therapeutic potentials of 0.25 mg/kg/day amlodipine, 0.035 mg/kg/day lisinopril, 5 mg/kg/day valsartan, and their fixed-dose combinations in TZM-intoxicated Wistar rats that were randomly allotted into 10 groups of 6 rats for each group. Group I rats were treated with 10 ml/kg/day sterile water orally and 1 ml/kg/day sterile water intraperitoneally; Groups II, III, and IV rats were orally gavaged with 5 mg/kg/day valsartan and 1 ml/kg/day sterile water intraperitoneally, 0.25 mg/kg/day amlodipine and 1 ml/kg/day sterile water via the intraperitoneal route, 0.035 mg/kg/day lisinopril and 1 ml/kg/day sterile water administered intraperitoneally, respectively. Group V rats were orally treated with 10 ml/kg/day of sterile water prior to intraperitoneal administration of 2.25 mg/kg/day of TZM. Groups VI–VIII rats were equally pretreated with 5 mg/kg/day valsartan, 0.25 mg/kg/day amlodipine, and 0.035 mg/kg/day lisinopril before intraperitoneal 2.25 mg/kg/day TZM treatment, respectively; Groups IX and X rats were orally pretreated with the fixed-dose combinations of 0.25 mg/kg/day amlodipine +0.035 mg/kg/day lisinopril and 5 mg/kg/day valsartan +0.035 mg/kg/day lisinopril, respectively, before TZM treatment. Cardiac injury and tissue oxidative stress markers, complete lipids profile, histopathological, and immunohistochemical assays were the evaluating endpoints. Results showed that repeated TZM treatments caused profound increases in the serum TG and VLDL-c levels, serum cTnI and LDH levels, and cardiac tissue caspase-3 and -9 levels but decreased BCL-2 expression. TZM also profoundly attenuated CAT, SOD, GST and GPx activities, and increased MDA levels in the treated tissues. In addition, TZM cardiotoxicity was characterized by marked vascular and cardiomyocyte congestion and coronary artery microthrombi formation. However, the altered biochemical, histopathological, and immunohistochemical changes were reversed with amlodipine, lisinopril, valsartan, and fixed-dose combinations, although fixed-dose valsartan/lisinopril combination was further associated with hyperlipidemia and increased AI and CRI values and coronary artery cartilaginous metaplasia. Thus, the promising therapeutic potentials of amlodipine, lisinopril, valsartan and their fixed-dose combinations in the management of TZM cardiotoxicity, majorly mediated via antiapoptotic and oxidative stress inhibition mechanisms were unveiled through this study.

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Section: Discussionsupporting

confidence: 91%

Therapeutic Potentials of Selected Antihypertensive Agents and Their Fixed-Dose Combinations Against Trastuzumab-Mediated Cardiotoxicity

et al. 2021

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“…Currently there are two CRS that have been published: the first in the seven-year follow-up of the NSABP-31 clinical trial [38] and a more recent score by Ezaz and colleagues [24]. In comparison to a study by Rushton et al who tested the use of the CRS in a Canadian patient population [25], there was a substantially smaller percentage of patients in our study who developed cardiotoxicity (43% vs 11%, respectively). This discrepancy may have been due to the differences in definition of cardiotoxicity in addition to the fact that these patients were already high risk as they were referred to a cardiooncology clinic.…”

Section: Discussioncontrasting

confidence: 51%

“…This CRS was applied to our patient population to test its value as a predictive tool for the detection of cardiotoxicity. Two sensitivity analyses as previously tested in a Canadian setting from patients referred to a cardio-oncology clinic [25] were performed in our patient dataset. The first sensitivity analysis considered a true positive (TP) as a score of ≥4 points (includes both moderate-and high-risk group) and a score of 0-3 points (low-risk group) as a true negative (TN); the second sensitivity analysis considered a TP as a score of ≥6 points (high-risk group only) and a score of 0-5 points (includes both low-and moderate risk) as a TN.…”

Section: Methodsmentioning

confidence: 99%

Concomitant use of renin-angiotensin-aldosterone system inhibitors prevent trastuzumab-induced cardiotoxicity in HER2+ breast cancer patients: an institutional retrospective study

2019

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Background: Cardiotoxicity is an adverse effect of trastuzumab (TRA) in the treatment of human epidermal growth factor 2 positive (HER2+) breast cancer. Current literature on the cardioprotective effects of agents targeted against the renin-angiotensin-aldosterone system (RAAS) and beta-blockers (BB) in TRA-treated HER2+ breast cancer patients is conflicting. We hypothesized that concurrent use of RAAS inhibitors would prevent TRA-induced cardiotoxicity (TIC). Methods and materials: Surveillance ejection fraction (EF) at 3-month intervals up to 36 months obtained from echocardiogram or multigated acquisition (MUGA) scans were retrospectively compared to baseline EF in TRA-treated HER2+ breast cancer patients between 2011 to 2016 at a tertiary cancer center. TIC was defined as a decrease of EF by more than 15 EF percentage points from baseline on surveillance imaging. Cardiac medications and comorbidities were compared between patients with reduced EF secondary to TIC (rEF) and patients who did not experience TIC (pEF). A published clinical risk score (CRS) was applied to the patient population with calculated sensitivity analyses to determine if the CRS could predict TIC. Results: Of 127 patients with TRA-treated HER2+ breast cancer, 11% developed cardiotoxicity resulting in discontinuation of TRA. Cardiotoxicity with reduced EF was seen as early as 3 months and at subsequent 3-month follow up intervals up to the 15-month follow-up. Co-existing arrhythmia, coronary artery disease (CAD), hypertension (HTN) and diabetes mellitus (DM) tended to infer an increased risk for cardiotoxicity. Patients with pEF were found to be concurrently on a RAAS inhibitor more than the rEF group (OR of 0.24, 95% CI 0.05-1.11, p 0.06). The CRS high-risk cutoff had a sensitivity of 0.17 (95% CI 0.03-0.49), specificity of 0.89 (95% CI 0.82-0.94), positive predictive value of 0.14 (95% CI 0.03-0.44) and negative predictive value of 0.91 (95% CI 0.84-0.95). Conclusion: Our data suggest that the concurrent use of a RAAS inhibitors during TRA treatment may provide a protective effect against TIC and warrants further investigation. The low sensitivity and positive predictive value demonstrated that the CRS has minimal utility as a screening tool for prediction of patients at high risk for TIC. Therefore, closer surveillance of patients receiving TRA is warranted for early detection of TIC.

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“…Although the score was designed and validated for the prediction of mortality in CAD patients, contingency analyses and receiver operating curves showed high sensitivity, specificity and accuracy to predict cardiotoxicity in the present study ( Table 5 ). While the advantages of the ECG score are its easy calculation and cost-effectiveness, other clinical risk scores are more complex and include parameters like age, cardiovascular risk factors and chemo-/immunotherapy doses [ 25 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

ECG Scoring for the Evaluation of Therapy-Naïve Cancer Patients to Predict Cardiotoxicity

Pohl

Mincu

Mrotzek

et al. 2021

Cancers

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Objective: To evaluate a new electrocardiographic (ECG) score reflecting domains of electrical and structural alterations in therapy-naïve cancer patients to assess their risk of cardiotoxicity. Methods: We performed a retrospective analysis of 134 therapy-naïve consecutive cancer patients in our two university hospitals concerning four ECG score parameters: Contiguous Q-waves, markers of left ventricular (LV) hypertrophy, QRS duration and JTc prolongation. Cardiotoxicity was assessed after a short-term follow-up (up to 12 months). Results: Of all the patients (n = 25), 19% reached 0 points, 50% (n = 67) reached 1 point, 25% (n = 33) reached 2 points, 5% (n = 7) reached 3 points and 0.7% reached 4 or 5 points (n = 1 respectively). The incidence of cardiotoxicity (n = 28 [21%]) increased with the ECG score, with 0 points at 0%, 1 point 7.5%, 2 points 55%, 3 points 71% and ≥3 points 50%. In the ROC (Receiver operating curves) analysis, the best cut-off for predicting cardiotoxicity was an ECG score of ≥2 points (sensitivity 82%, specificity 82%, AUC 0.84, 95% CI 0.77–0.92, p < 0.0001) which was then defined as a high-risk score. High-risk patients did not differ concerning their age, LV ejection fraction, classical cardiovascular risk factors or cardiac biomarkers compared to those with a low-risk ECG score. Conclusion: ECG scoring prior to the start of anti-cancer therapies may help to identify therapy-naïve cancer patients at a higher risk for the development of cardiotoxicity.

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Trastuzumab-Induced Cardiotoxicity: Testing a Clinical Risk Score in a Real-World Cardio-Oncology Population

Abstract: Background Trastuzumab has improved survival for women with her2-positive breast cancer, but its use is

Cited by 30 publications

References 21 publications

Therapeutic Potentials of Selected Antihypertensive Agents and Their Fixed-Dose Combinations Against Trastuzumab-Mediated Cardiotoxicity

Therapeutic Potentials of Selected Antihypertensive Agents and Their Fixed-Dose Combinations Against Trastuzumab-Mediated Cardiotoxicity

Concomitant use of renin-angiotensin-aldosterone system inhibitors prevent trastuzumab-induced cardiotoxicity in HER2+ breast cancer patients: an institutional retrospective study

ECG Scoring for the Evaluation of Therapy-Naïve Cancer Patients to Predict Cardiotoxicity

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