Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes.
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ABSTRACT:
SUBMITTER: Domenyuk V
PROVIDER: S-EPMC5865185 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
Publications
Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes.
Domenyuk Valeriy V Gatalica Zoran Z Santhanam Radhika R Wei Xixi X Stark Adam A Kennedy Patrick P Toussaint Brandon B Levenberg Symon S Wang Jie J Xiao Nianqing N Greil Richard R Rinnerthaler Gabriel G Gampenrieder Simon P SP Heimberger Amy B AB Berry Donald A DA Barker Anna A Quackenbush John J Marshall John L JL Poste George G Vacirca Jeffrey L JL Vidal Gregory A GA Schwartzberg Lee S LS Halbert David D DD Voss Andreas A Magee Daniel D Miglarese Mark R MR Famulok Michael M Mayer Günter G Spetzler David D
Nature communications 20180323 1
Assessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with mo ...[more]
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Project description:The human epidermal growth factor receptor 2 (HER2) gene encodes a tyrosine kinase receptor that controls important signal transduction pathways in breast cancer. Amplification and overexpression of the HER2 gene occurs in approximately 20% of breast cancers and is associated with an aggressive clinical phenotype. Trastuzumab, a humanized monoclonal antibody that targets HER2 showed exceptional efficacy in the treatment of breast cancer. In the adjuvant treatment of breast cancer patients, five randomized trials showed significant benefit of trastuzumab, with a reduction in the rate of recurrence of approximately 50% and improvement in the rate of survival of approximately 30%. In the current study, positive early stage breast cancer samples treated with adjuvant trastuzumab provided by institute Jules Bordet (IJB) and KUL. Gene expression and clinical outcome data were available. to better understand the genetic regulations and effects of the trastuzumab, we profile the the genes expression of positive early stage breast cancer samples treated with adjuvant trastuzumab.
2016-12-31 | GSE58984 | GEO
Project description:BackgroundThere is limited evidence regarding the impact of cardiology involvement in the care of cancer patients.ObjectivesWe evaluated the impact of cardiology involvement on guideline-adherent cardiovascular monitoring and risk factor management in breast cancer patients treated with trastuzumab.MethodsIn a single-center retrospective cohort study, we evaluated electronic health records from 1,047 breast cancer patients receiving trastuzumab between January 2009 and July 2018. A visit to a cardiology provider beginning from the 3 months prior to cancer therapy initiation until the last contact date defined cardiology involvement. Guideline-adherent monitoring, defined by echocardiography assessment within the 4 months prior to trastuzumab initiation and follow-up echocardiography at least every 4 months during therapy, was compared in patients with and without cardiology involvement prior to treatment initiation. Multivariable associations between cardiology involvement and time-varying risk factors blood pressure (BP) and body mass index (BMI) were assessed using generalized estimating equations.ResultsCardiology involvement occurred in 293 (28%) patients. A higher proportion of patients with cardiology involvement prior to trastuzumab initiation had guideline-adherent monitoring (76.4% versus 60.1%, p=0.007). Cardiology involvement was associated with an average 1.5mmHg (95% CI -2.9,-0.1, p=0.035) lower systolic BP; which was more pronounced in those with hypertension (-2.7mmHg (95% CI -4.6,-0.7, p=0.007)). Cardiology involvement was associated with a lower BMI in patients with baseline BMI≥25 kg/m2 (mean difference; -0.5 (95% CI -1.0,-0.1, p=0.027)).ConclusionsCardiology involvement in breast cancer patients treated with trastuzumab is associated with greater adherence to cardiovascular monitoring and modest improvements in risk factor control.
| S-EPMC7701353 | biostudies-literature
Project description:BackgroundTrastuzumab has changed the prognosis of HER2+ breast cancer. We aimed to investigate the prognosis of ER+/HER2+ patients treated with trastuzumab, thus to guide escalation endocrine treatment in ER+ breast cancer.MethodsER-positive early breast cancer patients operated at Ruijin Hospital between Jan. 2009 and Dec. 2017 were retrospectively included. Eligible patients were grouped as HER2-negative (HER2-neg) or HER2-positive with trastuzumab treatment (HER2-pos-T). Kaplan-Meier analysis and Cox proportional hazards model were used to compare the disease-free survival (DFS) and overall survival (OS) between these two groups.ResultsA total of 3761 patients were enrolled: 3313 in the HER2-neg group and 448 in the HER2-pos-T group. Patients in the HER2-pos-T group were associated with pre/peri-menopause, higher histological grade, LVI, higher Ki-67 level, lower ER and PR levels (all P < 0.05). At a median follow-up of 62 months, 443 DFS events and 191 deaths were observed. The estimated 5-year DFS rate was 89.7% in the HER2-neg group and 90.2% in the HER2-pos-T group (P = 0.185), respectively. Multivariable analysis demonstrated that patients in the HER2-pos-T group had a better DFS than patients in the HER2-neg group (HR 0.52, 95% CI: 0.37-0.73, P < 0.001). The estimated 5-year OS rates were 96.0% and 96.3% in the two groups, respectively (P = 0.133). Multivariate analysis found that HER2-pos-T group was still associated with significantly better OS compared with the HER2-neg group (HR 0.38, 95% CI: 0.22-0.67, P = 0.037).ConclusionER+/HER2+ breast cancer patients treated with trastuzumab were associated with superior outcome compared with ER+/HER2- patients, indicating HER2-positivity itself may not be an adverse factor for ER+ patients in the era of trastuzumab.
| S-EPMC8278709 | biostudies-literature
Project description:Urinary extracellular vesicles (uEVs) reflect the biological conditions of the producing cells. The protein profiling of uEVs allow us to better understand cancer progression in several cancers such as bladder cancer, prostate cancer and kidney cancer but has not been reported in breast cancer. We have, herein, aimed at quantifying the concentration and at generating the proteomic profile of uEVs in patients with breast cancer (BC) as compared to that of healthy controls (CT). Urine samples were collected from 29 CT and 47 patients with BC. uEVs were isolated by using differential ultracentrifugation, and were then characterized by Western blotting and transmission electron microscopy. Moreover, a nanoparticle tracking analysis was used in order to measure the concentration and the size distribution of urine particles and uEVs. The proteomic profiling of the uEVs was facilitated through LC-MS/MS. The uEV concentration was not significantly different between the assessed groups. The undertaken proteomic analysis revealed 15,473 and 11,278 proteins in the BC patients' group and the CT group, respectively. Furthermore, a heat map analysis revealed a differential protein expression, while a principal component analysis highlighted two clusters. The volcano plot indicated 259 differentially expressed proteins (DEPs; 155 up- and 104 down-regulated proteins) in patients with BC compared with CT. The up-regulated proteins from BC-derived uEVs were enriched in pathways related to cancer progression (i.e., cell proliferation, cell survival, cell cycle, cell migration, carbohydrate metabolism, and angiogenesis). Moreover, we verified the expression of the upregulated DEPs using UALCAN for web-based validation. Remarkably, the results indicated that 6 of 155 up-regulated proteins (POSTN, ATAD2, BCAS4, GSK3β, HK1, and Ki-67) were overexpressed in BC compared with normal samples. Since these six proteins often act as markers of cell proliferation and progression, they may be potential biomarkers for BC screening and diagnosis. However, this requires validation in larger cohorts.
| S-EPMC10624262 | biostudies-literature
Project description:The objective of this study was to determine associations of paraoxonase-1 (PON-1) with development of cancer therapy-related cardiac dysfunction (CTRCD). PON-1 is a cardioprotective enzyme associated with high-density lipoprotein that prevents oxidized low-density lipoprotein formation. Given the role of oxidative stress in doxorubicin-induced cardiotoxicity, PON-1 activity may have relevance for the prediction of CTRCD. In 225 patients with breast cancer receiving doxorubicin with or without trastuzumab, we quantified PON-1 activity through its paraoxonase (Pon) and arylesterase (Aryl) enzymatic activity at baseline, during, and after doxorubicin completion. Echocardiograms were performed at baseline, during therapy, and annually. CTRCD was defined as a decrease in left ventricular ejection fraction by ≥10% from baseline to <50%. Associations between baseline biomarkers and clinical variables were determined using multivariable linear regression. Associations between changes in biomarker activity and time to CTRCD were evaluated using Cox regression. Pon was directly associated with Black race and inversely associated with Stage 2 cancer. Aryl was inversely associated with body mass index. After doxorubicin completion, activity levels of Pon and Aryl were significantly decreased (median ratio compared with baseline for Pon: 0.95 [Q1-Q3: 0.81-1.07, P < 0.001]; for Aryl: 0.97 [Q1-Q3: 0.85-1.08, P = 0.010]). A total of 184 patients had an available quantitated echocardiogram at baseline and at least 1 follow-up visit. Increases from baseline in Pon at doxorubicin completion were independently associated with increased CTRCD risk (per 10% increase: hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05-1.39; P = 0.007). Associations between increases in Aryl and CTRCD tended in the same direction but were of borderline statistical significance (HR: 1.17; 95% CI: 0.99-1.38; P = 0.071). In patients with breast cancer treated with doxorubicin with or without trastuzumab, increases in the Pon enzymatic activity level of PON-1 were associated with increased CTRCD risk. PON-1 activity may be relevant to mechanistic risk prediction of cardiotoxicity with anthracyclines.
| S-EPMC8807731 | biostudies-literature
Project description:BackgroundPhosphatidylinositol 3-kinase (PI3K) pathway activation has been suggested to negatively influence response to anti-HER2 therapy in breast cancer patients. The present study focused on mutations of the PIK3CA gene, encoding one of the two PI3K subunits.MethodsPIK3CA mutations were assessed by direct sequencing in 80 HER2-positive patients treated with 1 year of trastuzumab. All patients preoperatively received four cycles of anthracycline-based chemotherapy, followed by four cycles of docetaxel and 1 year of trastuzumab, starting either before surgery with the first cycle of docetaxel and continuing after surgery (neoadjuvant trastuzumab arm, n=43), or only after surgery (adjuvant trastuzumab arm, n=37).ResultsPIK3CA mutations were found in 17 tumours (21.3%). Better disease-free survival (DFS) was observed in patients with PIK3CA wild-type compared with mutated tumours (P=0.0063). By combining PIK3CA status and treatment arms, four separate prognostic groups with significantly different DFS (P=0.0013) were identified.ConclusionThese results confirm that the outcome of HER2-positive patients treated with trastuzumab is significantly worse in patients with PIK3CA-mutated compared with wild-type tumours.
| S-EPMC3658522 | biostudies-literature
Project description:BackgroundCardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting.MethodsThis is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm.ResultsWith 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m2 (vs < 25 mg/kg2, OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55-3.51]).ConclusionsDual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial.Trial registration numberClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.
| S-EPMC7217956 | biostudies-literature
Project description:BackgroundTrastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.MethodsIn this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.ResultsOverall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).ConclusionsTrastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).
| S-EPMC7458671 | biostudies-literature
Project description:Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure-response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC50 for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies.
| S-EPMC5953989 | biostudies-literature
Project description:BackgroundEarly identification of cardiac dysfunction by non-invasive imaging in HER2-positive breast cancer patients treated with trastuzumab is challenging. In particular multigated acquisition (MUGA) scan, which is most widely used, is unable to detect subclinical cardiac changes. The use of N-terminal pro-brain natriuretic peptide (NT-proBNP), a serum biomarker of myocardial stress, might improve timely diagnosis.MethodsThis prospective, single-center, cohort study included patients with HER2-positive breast cancer who started trastuzumab therapy. Echocardiography was scheduled at regular intervals every 3 months during one year follow-up for cardiac function monitoring. For research purposes, NT-proBNP was determined at the same time points. Trastuzumab-induced cardiotoxicity (TIC) was the primary study endpoint, defined as a left ventricular ejection fraction (LVEF) < 45%, and/or an absolute decline in LVEF > 10% since inclusion, and/or the incidence of a clinical cardiac event.ResultsA total of 135 patients were enrolled between April 2008 and June 2016, with a median age of 54 years (IQR: 47-61). By three-dimensional echocardiography (3DE), the median LVEF at baseline was 62% (IQR: 58-65). At a median of 6 months (IQR: 5-11), 45 patients (33%) reached the study endpoint of TIC. Patients with TIC had a mean change of - 9.5% in LVEF (95% CI -7.2 to - 11.7; p = 0.001) during 1 year of trastuzumab treatment. Both NT-proBNP at baseline (HR 1.04, 95% CI 1.02-1.07; p = 0.003) and LVEF decline during anthracycline treatment prior to the start of trastuzumab (HR 1.16, 95% CI 1.07-1.25; p < 0.001) were independently associated with development of TIC. The level of NT-proBNP during follow-up was associated too with development of TIC (HR 1.06 per 10 pmol/l difference, 95% CI 1.02-1.10; p = 0.008). No steadily or sudden increase in NT-proBNP prior to TIC was observed.ConclusionsNT-proBNP cannot be used as a surrogate monitoring tool for trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients during the first year of treatment. Patients showing an LVEF decline during anthracycline pre-treatment appeared vulnerable for trastuzumab-induced cardiotoxicity.
| S-EPMC7048136 | biostudies-literature