Long-term irreversible trastuzumab-induced cardiotoxicity for metastatic breast cancer in a patient without cardiac risk factors.
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ABSTRACT:
SUBMITTER: Tanaka S
PROVIDER: S-EPMC5499211 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:PurposePatients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted.MethodsWe included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40-50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab.ResultsIn total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8-31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity.ConclusionsSerial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.
| S-EPMC8019427 | biostudies-literature
Project description:In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab.268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression.Overall, 47.1% of patients (95% confidence interval (CI): 39.9-54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0-6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression.HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.
| S-EPMC4230522 | biostudies-other
Project description:PurposeSignificant improvement in survival outcomes has been established with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2) -positive early breast cancer treatment. However, trastuzumab may increase the risk of cardiac toxicity, and long-term evaluation of its incidence and risk factors are warranted.MethodsNCCTG (Alliance) N9831 trial compared adjuvant doxorubicin and cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab followed by trastuzumab alone (arm C) in patients with HER2-positive breast cancer. Cumulative incidence of cardiac events (CE) and left ventricular ejection fraction (LVEF) were evaluated in 1,944 women who proceeded to post-AC therapy. Risk factors for trastuzumab-induced cardiac toxicity were identified by Cox regression models.ResultsThe 6-year cumulative incidence of CE was 0.6% in arm A, 2.8% in arm B, and 3.4% in arm C. At a median follow-up of 9.2 years, only two additional CHF diagnoses (of 1,046 patients) occurred beyond our previously reported follow-up time of 3.75 years. LVEF recovered in the majority of the patients who developed CHF. There were two cardiac deaths in arm A and one each in arms B and C. Age of 60 years or older, registration LVEF less than 65%, and use of antihypertensive medications were associated with an increased risk of CE in arms B and C.ConclusionThe cumulative incidence of CE at 6 years was slightly higher with the addition of trastuzumab; however, the late development of CE is infrequent. Trastuzumab (in the context of anthracycline- and taxane-based therapy) continues to have a favorable benefit-risk ratio.
| S-EPMC4980566 | biostudies-literature
Project description:The reliable identification of chronic cardiotoxic effects in in vitro screenings is fundamental for filtering out toxic molecular entities before in vivo animal experimentation and clinical trials. Present techniques such as patch-clamp, voltage indicators, and standard microelectrode arrays do not offer at the same time high sensitivity for measuring transmembrane ion currents and low-invasiveness for monitoring cells over long time. Here, we show that optoporation applied to microelectrode arrays enables measuring action potentials from human-derived cardiac syncytia for more than 1 continuous month and provides reliable data on chronic cardiotoxic effects caused by known compounds such as pentamidine. The technique has high potential for detecting chronic cardiotoxicity in the early phases of drug development.
| S-EPMC9859891 | biostudies-literature
Project description:BackgroundLong-term breast cancer survivors are at risk for cardiotoxicity after treatment, but there is insufficient evidence to provide long-term (~10 years) cardiovascular disease (CVD) screening recommendations. We sought to evaluate a tri-modality CVD screening approach.MethodsThis single-arm, feasibility study enrolled 201 breast cancer patients treated ≥6 years prior without CVD at diagnosis. Patients were sub-grouped: cardiotoxic (left-sided) radiation (RT), cardiotoxic (anthracycline-based) chemotherapy, both cardiotoxic chemotherapy and RT, and neither cardiotoxic treatment. Patients underwent electrocardiogram (EKG), transthoracic echocardiogram with strain (TTE with GLS), and coronary artery calcium computed tomography (CAC CT). The primary endpoint was preclinical or clinical CVD.ResultsMedian age was 50 (29-65) at diagnosis and 63 (37-77) at imaging; median interval was 11.5 years (6.7-14.5). Among sub-groups, 44% had no cardiotoxic treatment, 31.5% had cardiotoxic RT, 16% had cardiotoxic chemotherapy, and 8.5% had both. Overall, 77.6% showed preclinical and/or clinical CVD and 51.5% showed clinical CVD. Per modality, rates of any CVD and clinical CVD were, respectively: 27.1%/10.0% on EKG, 50.0%/25.3% on TTE with GLS, and 50.8%/45.8% on CAC CT. No statistical difference was seen among the treatment subgroups (NS, χ2 test, p = 0.58/p = 0.15).ConclusionThis study identified a high incidence of CVD in heterogenous long-term breast cancer survivors, most >10 years post-treatment. Over half had clinical CVD findings warranting follow-up and/or intervention. Each imaging test independently contributed to the detection rate. This provides early evidence that long-term cardiac screening may be of value to a wider group of breast cancer survivors than previously recognized.
| S-EPMC8335805 | biostudies-literature
Project description:Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1 year of treatment or exceptional cases of complete response to trastuzumab for ≥10 years. Identification of the underlying genomic aberrations of "exceptional responders (ExRs)" compared to "rapid non-responders (NRs)" increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole-exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P = 0.07), while more significantly pronounced in copy number gains (P = 0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within Chr8 (P = 0.02) and in Chr17 (P = 0.06) and conferred a statistically significant benefit in overall survival. Clinical trial number: NCT01722890 [ICORG 12/09].
| S-EPMC7553955 | biostudies-literature
Project description:AimsAn improved understanding of the pathophysiology of trastuzumab-mediated cardiotoxicity is required to improve outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to characterize the cardiac and cardiometabolic phenotype of trastuzumab-mediated toxicity and potential interactions with cardiac pharmacotherapy.Methods and resultsThis study was an analysis of serial magnetic resonance imaging (MRI) and circulating biomarker data acquired from patients with HER2-positive early-stage breast cancer participating in a randomized-controlled clinical trial for the pharmaco-prevention of trastuzumab-associated cardiotoxicity. Circulating biomarkers (B-type natriuretic peptide, troponin I, MMP-2 and -9, GDF-15, neuregulin-1, and IGF-1) and MRI of cardiac structure and function and abdominal fat distribution were acquired prior to trastuzumab, post-cycle 4 and post-cycle 17. Ninety-four participants (51 ± 8 years) completed the study with 30 on placebo, 33 on perindopril, and 31 on bisoprolol. Post-cycle 4, global longitudinal strain deteriorated from baseline in both placebo (+2.0 ± 2.7%, P = 0.002) and perindopril (+0.9 ± 2.5%, P = 0.04), but not with bisoprolol (-0.2 ± 2.1%, P = 0.55). In all groups combined, extracellular volume fraction and GDF-15 increased post-cycle 4 (+1.3 ± 4.4%, P = 0.004; +130 ± 150%, P ≤ 0.001, respectively). However, no significant change in troponin I was detected throughout trastuzumab. In all groups combined, visceral and intermuscular fat volume increased post-cycle 4 (+7 ± 17%, P = 0.02, +8 ± 23%, P = 0.02, respectively), while muscle volume and IGF-1 decreased from post-cycle 4 to 17 (-2 ± 10%, P = 0.008, -18 ± 28%, P < 0.001, respectively).ConclusionTrastuzumab results in impaired cardiac function and early myocardial inflammation. Trastuzumab is also associated with deleterious changes to the cardiometabolic phenotype which may contribute to the increased cardiovascular risk in this population.
| S-EPMC8847070 | biostudies-literature
Project description:Gene expression data of HER2+ breast tumor samples Increasing evidence indicates that a subset of patients with HER2-positive breast cancer may achieve significant clinical benefit with anti-HER2 targeted therapy without chemotherapy. Thus, identification of biomarkers of long-term benefit from anti-HER2 agents is needed, especially in the metastatic setting. In the HERLAP study (NCT00842998), patients with HER2-positive metastatic breast cancer were randomized to trastuzumab or lapatinib as first-line therapy. Patients showing radiological signs of tumor regression after 8 weeks of treatment were allowed to continue on single agent anti-HER2 therapy until disease progression. Chemotherapy was added to anti-HER-2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded in 17 primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. The association of the expression of each biomarker with clinical outcome endpoints was evaluated. Nineteen patients were enrolled. In 4 patients (21.1%) we observed disease control lasting longer than 12 months with single agent anti-HER2 therapy (range 14.9-38.8 months). High expression of 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were found significantly associated with 8-week overall response rate and with the duration of disease control during single agent anti-HER2 therapy. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile, was found associated with reduced benefit from single agent anti-HER2 therapy. Conclusions: Our data indicate that gene expression-based biomarkers can identify patients with HER2-positive metastatic breast cancer that benefit substantially from single agent chemo-free anti-HER2 targeted therapy. In the study presented here, a well-defined cohort of 21 breast cancer cases from the HERLAP trial, was used to acquire expression profiles of a total of 105 unique genes
2013-10-25 | E-GEOD-46350 | biostudies-arrayexpress
Project description:Trastuzumab is a monoclonal targeted therapy widely used to treat human epidermal growth factor receptor 2 (HER2+) over expressed breast cancer which confers an aggressive cancer type and comprises ~25% of breast cancer. Trastuzumab yields improved breast cancer related outcomes, but survival benefits are in part offset by cardiotoxicity - as evidenced by 10-15% of patients develop cardiomyopathy and 2-4% develop congestive heart failure. Approximately 20-30% of patients have either temporary or permanent discontinuation of trastuzumab therapy due to its cardiotoxicity, raising concern for inadequate cancer treatment and recurrence. Current screening strategies for trastuzumab-induced cardiotoxicity rely on non-invasive imaging such as echocardiography, but conventional imaging techniques provide limited a priori risk stratification for cardiotoxicity. We have utilized patient-specific iPSC-CMs derived from HER2+ breast cancer patients with and without evidence of TIC as a model to better elucidate the mechanisms of Trastuzumab-indued cardiotoxicity.
2024-06-05 | GSE264120 | GEO
Project description:In 2009 a prospective, randomized Phase II trial (NCT00842998) was initiated to evaluate the activity of HER2-targeting agents without chemotherapy (CT) in HER2-positive metastatic breast cancer (MBC) patients. The primary tumors of the patients enrolled in this study offered a unique opportunity to identify biomarkers that could predict durable clinical benefit from CT-free anti-HER2 therapy. Patients with HER2-positive MBC were randomized to trastuzumab or lapatinib as first-line therapy. CT was added to anti-HER2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and in those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. Additionally, quantitative HER2 (H2T) and p95HER2 (p95) protein expression were evaluated by HERmark® and VeraTag® assay, respectively. Predictors of persistence on protocol (PP) were studied by Cox univariate and multivariate analysis. Nineteen patients were enrolled. Median overall survival was 43 months and median PP was 3.8 months (0.8-38.8+), with 4 patients (21.1%) persisting on single agent trastuzumab or lapatinib for longer than 12 mo (14.9-38.8 + mo). Seventeen patients were evaluable for PP. Gene expression analysis revealed that high expression of the 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were significantly associated with longer PP. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile correlated with reduced PP. Moreover, increasing H2T/p95 ratio was found to be significantly associated with longer PP (HR 0.56 per 2-fold increase in H2T/p95, P = 0.0015). Our data suggest that patients belonging to the "HER2-enriched" subtype and/or having high H2T/p95 protein expression ratio are exquisitely sensitive to anti-HER2 agents. MBC patients with these tumors could be candidates for studies aimed at establishing chemotherapy-free regimens.
| S-EPMC5528507 | biostudies-literature