Changes in vascular function and correlation with cardiotoxicity in women with newly diagnosed breast cancer undergoing HER2-directed therapy with and without anthracycline/cyclophosphamide
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PROVIDER: S-EPMC10794877 | biostudies-literature | 2023 Dec
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Project description:PurposeThe present study aimed to investigate correlations between uridine glucuronosyltransferase 2B7 (UGT2B7) -161 single nucleotide polymorphism C to T (C>T) and the occurrence of cardiotoxicity in Chinese breast cancer (BC) patients undergoing epirubicin/cyclophosphamide-docetaxel (EC-D) adjuvant chemotherapy.Materials and methods427 BC patients who had underwent surgery were consecutively enrolled in this prospective cohort study. All patients were scheduled to receive EC-D adjuvant chemotherapy regimen, and they were divided into UGT2B7 -161 CC (n=141), UGT2B7 -161 CT (n=196), and UGT2B7 -161 TT (n=90) groups according to their genotypes. Polymerase chain reaction was performed for determination of UGT2B7 -161 genotypes. Cardiotoxicity was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10% points from baseline to a value less than 53%, heart failure, acute coronary artery syndrome, or fatal arrhythmia.ResultsLVEF values were lower at cycle (C) 4, C8, 3 months after chemotherapy (M3), M6, M9, and M12 compared to C0 (all p<0.001), in BC patients undergoing EC-D adjuvant chemotherapy. Cardiotoxicity was recorded for 4.2% of the overall population and was lowest in the UGT2B7 -161 TT group (1.1%), compared to UGT2B7 -161 CT (3.1%) and UGT2B7 -161 CC (7.8%) group (p=0.026). Multivariate logistic regression revealed that UGT2B7 -161 T allele could independently predict a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy (p=0.004).ConclusionA UGT2B7 -161 T allele serves as a potential biomarker for predicting a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy.
| S-EPMC6298890 | biostudies-literature
Project description:Anthracyclines are a major component of chemotherapies used in many pediatric and adult malignancies. Anthracycline-associated cardiotoxicity (ACT) is a dose-dependent adverse effect that has substantial impact on morbidity and mortality. Therefore, the identification of genetic variants associated with increased risk of ACT has the potential for significant clinical impact to improve patient care. The goal of this review is to summarize the current evidence supporting genetic variants associated with ACT, identify gaps and limitations in current knowledge, and propose future directions for incorporating genetics into clinical practice for patients treated with anthracyclines. We will discuss mechanisms of ACT that could be illuminated by genetics and discuss clinical applications for the cardiologist/cardio-oncologist.
| S-EPMC9068960 | biostudies-literature
Project description:Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease. Anthracycline induced cardiotoxicity (AIC) ranges from asymptomatic LV dysfunction to highly morbid end- stage heart failure. As cancer survivorship improves, the detection and treatment of AIC becomes more crucial to improve patient outcomes. Current treatment modalities for AIC have been largely extrapolated from treatment of conventional heart failure, but developing effective therapies specific to AIC is an area of growing research interest. This review summarizes the current evidence behind the use of neurohormonal agents, dexrazoxane, and resynchronization therapy in AIC, evaluates the clinical outcomes of advanced therapy and heart transplantation in AIC, and explores future horizons for treatment utilizing gene therapy, stem cell therapy, and mechanism-specific targets.
| S-EPMC9072636 | biostudies-literature
Project description:PurposeCarbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homozygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults.MethodsWe retrospectively identified female breast cancer patients in the Columbus Breast Tissue Bank Registry treated with adriamycin and cytoxan (AC) from 2003 to 2012. We selected patients who developed cardiomyopathy, defined as a drop in ejection fraction to <50 % or >15 % decrease from pre-therapy. Univariate and multivariate logistic regressions were performed to identify cardiotoxicity risk factors. SNPs were genotyped, and frequency of the major allele (G)/minor allele (A) of the CBR3 and CBR1 genes was calculated.ResultsWe identified 52 cases of cardiotoxicity after AC and 110 controls. Multivariate analysis showed that trastuzumab (p = 0.009), diabetes (p = 0.05), and consumption of >8 alcoholic drinks/week (p = 0.024) were associated with higher cardiotoxicity risk. Moderate alcohol consumption (<8 drinks/week) was associated with lower risk (p = 0.009). No association was identified between CBR SNPs and cardiotoxicity (CBR1 p = 0.261; CBR3 p = 0.556).ConclusionsThis is the first study to evaluate SNPs in the CBR pathway as predictors of AC cardiotoxicity in adults. We did not observe any significant correlation between cardiotoxicity and SNPs within the CBR pathway. Further investigation into CBR SNPs in a larger adult sample is needed. Additional exploration into genomic predictors of anthracycline cardiotoxicity may allow for the development of preventative and therapeutic strategies for those at risk.
| S-EPMC4874738 | biostudies-literature
Project description:Background: Several cardiovascular risk factors have been suggested to be associated with anthracycline-induced cardiotoxicity, but their quantitative effects have not reached a consensus. Methods: We searched PubMed, EMBASE, and Cochrane Library databases for manuscripts published from inception to February 2021, which reported the results of cardiotoxicity due to anthracycline chemotherapy without trastuzumab. Cardiotoxicity defined by any reduction of left ventricular eject fraction (LVEF) to below 50% or a >10% reduction from baseline was defined as the primary endpoint. Odd ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model meta-analysis. Results: A total of 7,488 patients receiving anthracycline chemotherapy without trastuzumab were included, who had at least one risk factor at baseline. Hypertension (OR: 1.99; 95% CI: 1.43-2.76), diabetes mellitus (OR: 1.74; 95% CI: 1.11-2.74), and obesity (OR: 1.72; 95% CI: 1.13-2.61) were associated with increased risk of cardiotoxicity. In addition, the relative reduction of global longitudinal strain (GLS) from baseline after anthracycline treatment could significantly improve the detection ability of cardiotoxicity (28.5%, 95% CI: 22.1-35.8% vs. 16.4%, 95% CI: 13.4-19.9%) compared with LVEF. The early detection rate of anthracycline-induced cardiotoxicity (3 months after chemotherapy) by GLS was 30.2% (95% CI: 24.9-36.1%), which is similar with the overall result of GLS. Conclusions: Hypertension, diabetes mellitus, and obesity are associated with increased risk of anthracycline-induced cardiotoxicity, which indicates that corresponding protective strategies should be used during and after anthracycline treatment. The findings of higher detection rate and better early detection ability for cardiotoxicity than LVEF added new proofs for the advantages of GLS in detection of AIC.
| S-EPMC8511483 | biostudies-literature
Project description:AimsThe aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment.Methods and resultsLarge-white male pigs (n=40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure [0.45 mg/kg intracoronary (IC) doxorubicin per injection] and follow-up: control (no doxorubicin); single injection and sacrifice either at 48 h (ExPr. 1) or 2 weeks (ExPr. 2); 3 injections 2 weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; five injections 2 weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (three bi-weekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibres even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime.ConclusionSerial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.
| S-EPMC8803079 | biostudies-literature
Project description:BackgroundThe aim of this study was to compare the efficacy, cardiotoxicity and factors affecting pathologic complete response (pCR) of neoadjuvant chemotherapy (NACT) regimen TCbHP (docetaxel/nab-paclitaxel, carboplatin, trastuzumab and pertuzumab) and AC-THP (doxorubicin, cyclophosphamide followed by docetaxel/nab-paclitaxel, trastuzumab and pertuzumab) for human epidermal growth factor receptor 2-positive (HER2+) early-stage breast cancer at a retrospective cohort.MethodsThis retrospective study included the patients with HER2+ early-stage breast cancer who received NACT with the regimen TCbHP or AC-THP and then underwent surgery from 2019 to 2022. pCR rate and breast-conserving rate were calculated to evaluate the efficacy of the regimens. Left ventricular ejection fraction (LVEF) from echocardiograms and abnormal electrocardiographs (ECGs) were collected to evaluate the cardiotoxicity of the two regimens. Association between the characteristics of the breast cancer lesions by magnetic resonance imaging (MRI) and the pCR rate were also explored.ResultsA total of 159 patients were enrolled, including 48 patients in the AC-THP group and 111 patients in the TCbHP group. The pCR rate of the TCbHP group 64.0% (71/111) was significantly higher than that of for the the AC-THP group 37.5% (18/48) (P=0.002). Estrogen receptor (ER) status (P=0.011, OR: 0.437, 95% CI: 0.231-0.829), progesterone receptor (PR) status (P=0.001, OR: 0.309, 95% CI: 0.157-0.608) and IHC HER2 status (P=0.003, OR: 7.167, 95% CI: 1.970-26.076) were significantly correlated with the pCR rate. LVEF decreased at 6 and 12 months after treatment in the AC-THP group (P=0.024 and 0.040), which only decreased after 6 months of treatment in the TCbHP group (P=0.048). Post-NACT MRI characteristics including mass features (P<0.001) and enhancement type (P<0.001) were significantly associated with pCR rate.ConclusionsEarly-stage HER2+ breast cancer treated with the TCbHP regimen has a higher pCR rate than the AC-THP group. The TCbHP regimen appears to have lower cardiotoxicity than the AC-THP regimen in terms of LVEF. Mass features and enhancement type at post-NACT MRI significantly associated with the pCR rate of breast cancer patients.
| S-EPMC10331454 | biostudies-literature
Project description:This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D-VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4-8 induction cycles of bortezomib 1·5 mg/m2 , cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split-first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty-six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12-month progression-free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment-emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D-VCd was well tolerated, split-first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1-year PFS rate was 87%.
| S-EPMC6593455 | biostudies-literature
Project description:AimsDoxorubicin (DOX) is an effective anti-cancer therapeutic, but is associated with both acute and late-stage cardiotoxicity. Children are particularly sensitive to DOX-induced heart failure. Here, the impact of p53 inhibition on acute vs. late-stage DOX cardiotoxicity was examined in a juvenile model.Methods and resultsTwo-week-old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) and their non-transgenic (NON-TXG) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), MHC-CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON-TXG mice. Surprisingly, by 13 weeks following the last DOX treatment (late stage), MHC-CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON-TXG mice. p53 inhibition blocked transient DOX-induced STAT3 activation in MHC-CB7 mice, which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80. Mice with cardiomyocyte-restricted deletion of STAT3 exhibited worse cardiac function, higher levels of cardiomyocyte apoptosis, and a greater induction of Ku70 and Ku80 in response to DOX treatment during the acute stage when compared with control animals.ConclusionThese data support a model wherein a p53-dependent cardioprotective pathway, mediated via STAT3 activation, mitigates DOX-induced myocardial stress during drug delivery. Furthermore, these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and, paradoxically, enhanced cardiotoxicity long after the cessation of drug treatment.
| S-EPMC4133592 | biostudies-literature
Project description:Advances in cancer treatment have significantly improved the survival of patients with cancer, but, unfortunately, many of these treatments also have long-term complications. Cancer treatment-related cardiotoxicities are becoming a significant clinical problem that a new discipline, Cardio-Oncology, was established to advance the cardiovascular care of patients with growing cancer populations. Anthracyclines are a class of chemotherapeutic agents used to treat many cancers in adults and children. Their clinical use is limited by anthracycline-induced cardiotoxicity (AIC), which can lead to heart failure. Early-onset cardiotoxicity appears within a year of treatment, whereas late-onset cardiotoxicity occurs > 1 year and even up to decades after treatment completion. The pathophysiology of AIC was hypothesized to be caused by generation of reactive oxygen species that lead to lipid peroxidation, defective mitochondrial biogenesis, and DNA damage of the cardiomyocytes. The accumulation of anthracycline metabolites was also proposed to cause mitochondrial damage and the induction of cardiac cell apoptosis, which induces arrhythmias, contractile dysfunction, and cardiomyocyte death. This paper will provide a general overview of cardiotoxicity focusing on the effect of anthracyclines and their epigenetic molecular mechanisms on cardiotoxicity.
| S-EPMC7877852 | biostudies-literature