Importance of endocrine treatment adherence and persistence in breast cancer survivorship: a systematic review.

PURPOSE: Adjuvant endocrine treatment is essential for treating luminal subtypes of breast cancer, which constitute 75% of all breast malignancies. However, the detrimental side effects of treatment make it difficult for many patients to complete the guideline-required treatment. Such non-adherence may jeopardize the lifesaving ability of anti-estrogen therapy. In this systematic review, we aimed to assess the consequences of non-adherence and non-persistence from available studies meeting strict statistical and clinical criteria. METHODS: A systematic literature search was performed using several databases, yielding identification of 2,026 studies. After strict selection, 14 studies were eligible for systematic review. The review included studies that examined endocrine treatment non-adherence (patients not taking treatment as prescribed) or non-persistence (patients stopping treatment prematurely), in terms of the effects on event-free survival or overall survival among women with non-metastatic breast cancer. RESULTS: We identified 10 studies measuring the effects of endocrine treatment non-adherence and non-persistence on event-free survival. Of these studies, seven showed significantly poorer survival for the non-adherent or non-persistent patient groups, with hazard ratios (HRs) ranging from 1.39 (95% CI, 1.07 to 1.53) to 2.44 (95% CI, 1.89 to 3.14). We identified nine studies measuring the effects of endocrine treatment non-adherence and non-persistence on overall survival. Of these studies, seven demonstrated significantly reduced overall survival in the groups with non-adherence and non-persistence, with HRs ranging from 1.26 (95% CI, 1.11 to 1.43) to 2.18 (95% CI, 1.99 to 2.39). CONCLUSION: The present systematic review demonstrates that non-adherence and non-persistence to endocrine treatment negatively affect event-free and overall survival. Improved follow-up, with focus on adherence and persistence, is vital for improving health outcomes among patients with non-metastatic breast cancer.

Liquid biopsies and patient-reported outcome measures for integrative monitoring of patients with early-stage breast cancer: a study protocol for the longitudinal observational Prospective Breast Cancer Biobanking (PBCB) study.

INTRODUCTION: Breast cancer is still the most common malignancy among women worldwide. The Prospective Breast Cancer Biobank (PBCB) collects blood and urine from patients with breast cancer every 6 or 12 months for 11 years from 2011 to 2030 at two university hospitals in Western Norway. The project aims to identify new biomarkers that enable detection of systemic recurrences at the molecular level. As blood represents the biological interface between the primary tumour, the microenvironment and distant metastases, liquid biopsies represent the ideal medium to monitor the patient's cancer biology for identification of patients at high risk of relapse and for early detection systemic relapse.Including patient-reported outcome measures (PROMs) allows for a vast number of possibilities to compare PROM data with biological information, enabling the study of fatigue and Quality of Life in patients with breast cancer. METHODS AND ANALYSIS: A total of 1455 patients with early-stage breast cancer are enrolled in the PBCB study, which has a one-armed prospective observational design. Participants consent to contribute liquid biopsies (i.e., peripheral blood and urine samples) every 6 or 12 months for 11 years. The liquid biopsies are the basis for detection of circulating tumour cells, circulating tumour DNA (ctDNA), exosomal micro-RNA (miRNA), miRNA in Tumour Educated Platelet and metabolomic profiles. In addition, participants respond to 10 PROM questionnaires collected annually. Moreover, a control group comprising 200 women without cancer aged 25-70 years will provide the same data. ETHICS AND DISSEMINATION: The general research biobank PBCB was approved by the Ministry of Health and Care Services in 2007, by the Regional Ethics Committee (REK) in 2010 (#2010/1957). The PROM (#2011/2161) and the biomarker study PerMoBreCan (#2015/2010) were approved by REK in 2011 and 2015 respectively. Results will be published in international peer reviewed journals. Deidentified data will be accessible on request. TRIAL REGISTRATION NUMBER: NCT04488614.

Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites.

BACKGROUND: Tamoxifen, as a treatment of estrogen receptor positive (ER+) breast cancer, is a weak anti-estrogen that requires metabolic activation to form metabolites with higher anti-estrogenic activity. Endoxifen is the most-studied active tamoxifen metabolite, and endoxifen concentrations are highly associated with CYP2D6 activity. Associations of tamoxifen efficacy with measured or CYP2D6-predicted endoxifen concentrations have been inconclusive. Another active metabolite, 4-OHtam, and other, less active metabolites, Z-4'-endoxifen and Z-4'-OHtam, have also been reported to be associated with tamoxifen efficacy. METHOD: Genotype for 20 pharmacogenes was determined by VeriDose® Core Panel and VeriDose®CYP2D6 CNV Panel, followed by translation to metabolic activity phenotype following standard activity scoring. Concentrations of tamoxifen and seven metabolites were measured by UPLC-MS/MS in serum samples collected from patients receiving 20 mg tamoxifen per day. Metabolic activity was tested for association with tamoxifen and its metabolites using linear regression with adjustment for upstream metabolites to identify genes associated with each step in the tamoxifen metabolism pathway. RESULTS: A total of 187 patients with genetic and tamoxifen concentration data were included in the analysis. CYP2D6 was the primary gene associated with the tamoxifen metabolism pathway, especially the conversion of tamoxifen to endoxifen. CYP3A4 and CYP2C9 were also responsible for the metabolism of tamoxifen. CYP2C9 especially impacted the hydroxylation to 4-OHtam, and this involved the OATP1B1 (SLCO1B1) transporter. CONCLUSION: Multiple genes are involved in tamoxifen metabolism and multi-gene panels could be useful to predict active metabolite concentrations and guide tamoxifen dosing.

Carvedilol-Enriched Cold Oxygenated Blood Cardioplegia Improves Left Ventricular Diastolic Function After Weaning From Cardiopulmonary Bypass.

OBJECTIVES: To investigate whether adding carvedilol, a nonselective ß- and selective α1-receptor blocking agent with antioxidant properties, to oxygenated blood cardioplegia improves myocardial function after weaning from bypass. DESIGN: A randomized controlled study. SETTING: A university laboratory. PARTICIPANTS: Twenty anesthetized pigs, Norwegian Landrace. INTERVENTIONS: On cardiopulmonary bypass, cardiac arrest was induced with cold (12°C), oxygenated blood cardioplegia, enriched with carvedilol or vehicle, and repeated every 20 minutes. After 100 minutes, the heart was reperfused and weaned. MEASUREMENTS AND MAIN RESULTS: Left ventricular function was evaluated with pressure-volume loops, local myocardial systolic strain, and strain rate from Speckle tracking analysis and multilayer short-axis tissue Doppler Imaging. In the carvedilol group, the load-independent logarithmic end-diastolic pressure volume relationship, ß, decreased from 1 to 3 hours of reperfusion and was low, 0.028±0.004 v 0.042±0.007 (p<0.05) in controls at 3 hours, demonstrating improved left ventricular compliance. The diastolic relaxation constant τ was decreased, 28.9±0.6 ms v 34.6±1.3 ms (pg<0.035), and dP/dtmin was more negative,-1,462±145 mmHg/s v-1,105±105 mmHg/s (pg = 0.024), for carvedilol v control group. The systolic variables, preload recruitable stroke work and end-systolic pressure-volume relationship, did not differ between groups, neither did left ventricular systolic strain and strain rate. Myocardial oxidative stress, measured as tissue levels of malondialdehyde, was reduced by carvedilol, 0.19±0.01 compared to 0.24±0.01 nmol/mg (p = 0.004) in controls. CONCLUSIONS: Carvedilol added to blood cardioplegia improved diastolic cardiac function and reduced oxidative stress during the first 3 hours after reperfusion in a porcine model, with 100 minutes of cardioplegic arrest.

Myocardial function after polarizing versus depolarizing cardiac arrest with blood cardioplegia in a porcine model of cardiopulmonary bypass.

OBJECTIVES: Potassium-based depolarizing St Thomas' Hospital cardioplegic solution No 2 administered as intermittent, oxygenated blood is considered as a gold standard for myocardial protection during cardiac surgery. However, the alternative concept of polarizing arrest may have beneficial protective effects. We hypothesize that polarized arrest with esmolol/adenosine/magnesium (St Thomas' Hospital Polarizing cardioplegic solution) in cold, intermittent oxygenated blood offers comparable myocardial protection in a clinically relevant animal model. METHODS: Twenty anaesthetized young pigs, 42 ± 2 (standard deviation) kg on standardized tepid cardiopulmonary bypass (CPB) were randomized (10 per group) to depolarizing or polarizing cardiac arrest for 60 min with cardioplegia administered in the aortic root every 20 min as freshly mixed cold, intermittent, oxygenated blood. Global and local baseline and postoperative cardiac function 60, 120 and 180 min after myocardial reperfusion was evaluated with pressure-conductance catheter and strain by Tissue Doppler Imaging. Regional tissue blood flow, cleaved caspase-3 activity, GRK2 phosphorylation and mitochondrial function and ultrastructure were evaluated in myocardial tissue samples. RESULTS: Left ventricular function and general haemodynamics did not differ between groups before CPB. Cardiac asystole was obtained and maintained during aortic cross-clamping. Compared with baseline, heart rate was increased and left ventricular end-systolic and end-diastolic pressures decreased in both groups after weaning. Cardiac index, systolic pressure and radial peak systolic strain did not differ between groups. Contractility, evaluated as dP/dtmax, gradually increased from 120 to 180 min after declamping in animals with polarizing cardioplegia and was significantly higher, 1871 ± 160 (standard error) mmHg/s, compared with standard potassium-based cardioplegic arrest, 1351 ± 70 mmHg/s, after 180 min of reperfusion (P = 0.008). Radial peak ejection strain rate increased and the load-independent variable preload recruitable stroke work was increased with polarizing cardioplegia after 180 min, 64 ± 3 vs 54 ± 2 mmHg (P = 0.018), indicating better preserved left ventricular contractility with polarizing cardioplegia. Phosphorylation of GRK2 in myocardial tissue did not differ between groups. Fractional cytoplasmic volume in myocytes was reduced in hearts arrested with polarizing cardioplegia, indicating reduction of cytoplasmic oedema. CONCLUSIONS: Polarizing oxygenated blood cardioplegia with esmolol/adenosine/magnesium offers comparable myocardial protection and improves contractility compared with the standard potassium-based depolarizing blood cardioplegia.

Esmolol added in repeated, cold, oxygenated blood cardioplegia improves myocardial function after cardiopulmonary bypass.

OBJECTIVE: This study investigated if the ß-receptor blocking agent esmolol, added to standard oxygenated blood cardioplegia, improved myocardial function after weaning from bypass. DESIGN: A block-randomized, blinded study. SETTING: A university laboratory. PARTICIPANTS: Twenty anesthetized pigs, Norwegian Landrace. INTERVENTIONS: After cardiopulmonary bypass, cardiac arrest was induced with cold (12°C), oxygenated blood cardioplegia, enriched with either esmolol or vehicle, repeated every 20 minutes. After 100 minutes the heart was reperfused and weaned. MEASUREMENTS AND MAIN RESULTS: Left ventricular function was evaluated with pressure-volume loops, local myocardial function with multilayer strain and strain rate by epicardial short-axis tissue Doppler imaging. One hour after declamping, preload recruitable stroke work did not differ between groups, but increased to 72±3 mmHg in esmolol-treated animals v 57±4 mmHg (p<0.001) in controls after 3 hours. Radial peak ejection strain rate also was increased by esmolol; 6.0±1.0 s(-1)v 2.9±0.3 s(-1) (p<0.001) in subendocardium and 3.9±0.5 s(-1)v 2.3±0.2 s(-1) (p<0.005) in the midmyocardium. Cardiac index was increased, 4.0±0.2 L/min/m(2) by esmolol v 3.3±0.1 L/min/m(2) for controls (p<0.05). Isovolumetric relaxation time constant was reduced by esmolol, 23±1 ms v 26±1 ms (p<0.025). Troponin-T did not differ and was 339±48 ng/L for the esmolol group and 357±55 ng/L for the control group (p = 0.81). CONCLUSIONS: Esmolol added to blood cardioplegia preserved systolic cardiac function during the first 3 hours after reperfusion in a porcine model with 100 minutes of cardioplegic arrest.

Antiapoptotic intervention in repeated blood cardioplegia: a porcine study of myocardial function.

BACKGROUND: Lethal reperfusion injury has been associated with apoptotic cell death. Insulin and insulin-like growth factors (IGF-I/IGF-II) may modulate this cell death when administered at the onset of reperfusion after ischemia. We explored if antiapoptotic treatment with IGF-II could influence left ventricular function in an experimental model with cardiopulmonary bypass and repeated oxygenated blood cardioplegia. METHODS: Twenty pigs underwent cardiopulmonary bypass with aortic cross-clamping for 60 minutes. In controls, hearts were arrested with cold, oxygenated blood cardioplegia repeated after 20 and 40 minutes. In the intervention group IGF-II was added to the cardioplegic solution at 20 and 40 minutes. After declamping and weaning from cardiopulmonary bypass, left ventricular global and local function was evaluated with a conductance catheter and tissue velocity imaging. Three hours after declamping the anterior left ventricle wall was divided in three layers and studied for blood flow rate with microspheres, Akt phosphorylation, and caspase-3 cleavage. Troponin-T levels were measured at baseline and after 3 hours of reperfusion. RESULTS: A reduction of myocardial levels of cleaved caspase-3 (p < 0.001) was found in the subendocardial wall layer and serum troponin-T was reduced (p < 0.025) in the IGF-II group 3 hours after declamping. In the IGF-II treated animals, left ventricular preload recruitable stroke work was low 1 hour after declamping and increased to levels higher than in controls (p < 0.025) 3 hours after declamping. Other cardiac variables did not differ between groups. CONCLUSIONS: When added to repeated cold blood cardioplegia, IGF-II reduces apoptosis and ischemia-reperfusion injury with minor effects on cardiac function.

Multidose cold oxygenated blood is superior to a single dose of Bretschneider HTK-cardioplegia in the pig.

BACKGROUND: A single-dose strategy for cardioplegia is desired in minimal invasive approaches to valve surgery and aortic arch repairs. We hypothesized that a single infusion of Bretschneider HTK solution offers myocardial protection comparable to repeated cold oxygenated blood. METHODS: Sixteen pigs on bypass with 60 minutes of aortic cross-clamping were randomized to a single dose of Custodiol (HTK group) or repeated oxygenated blood cardioplegia (CBC group). Left ventricular function and perfusion were evaluated by conductance catheter, echocardiography, and microspheres. Myocardial injury was assessed with serum troponin-T. RESULTS: Baseline values showed no group differences. One hour after declamping cardiac index was reduced in the HTK group, 3.5 +/- 0.2 L x min(-1) x m(-2) (mean +/- standard error of the mean) compared with 4.7 +/- 0.4 L x min(-1) x m(-2) in the CBC group (p < 0.0005), decreasing to 4.0 +/- 0.2 and 3.9 +/- 0.2 L x min(-1) x m(-2) after 2 and 3 hours, respectively (p < 0.005 versus 1 hour). In the HTK group cardiac index remained low and unchanged. In the CBC group preload recruitable stroke work was 72.6 +/- 1.2 mm Hg 1 hour after declamping, decreasing to 65.2 +/- 2.5 and 60.3 +/- 3.9 mm Hg after 2 and 3 hours, respectively (p < 0.05 versus 1 hour). In the HTK group corresponding values after 1, 2, and 3 hours were low at 47.2 +/- 4.4, 48.4 +/- 4.2, and 50.7 +/- 4.3 mm Hg, respectively (p < 0.025 versus CBC for all). Subendocardial radial peak systolic strain averaged 80.5% +/- 4.8% after declamping in the CBC group versus 53.4% +/- 5.5% in the HTK group (p = 0.002). Serum troponin-T release was lower in the CBC group. CONCLUSIONS: Repeated oxygenated blood cardioplegia provides better myocardial protection and preservation of left ventricular function than a single dose of HTK during the early hours after declamping.

Esmolol before 80 min of cardiac arrest with oxygenated cold blood cardioplegia alleviates systolic dysfunction. An experimental study in pigs.

OBJECTIVE: Myocardial dysfunction after reperfusion can be a clinical problem in the early postoperative phase after on-pump cardiac surgery. The aim was, in an experimental setting, to investigate if administration of the beta-adrenergic receptor blocker esmolol prior to cross-clamping for 80 min with cold oxygenated blood cardioplegia would improve myocardial protection and early postoperative function. METHODS: Twenty-four anaesthetised pigs were randomly allocated into one of two equally sized groups and put on mild hypothermic cardiopulmonary bypass. Esmolol 1 mg kg(-1) or saline was administered into the arterial line 4 min prior to aortic cross-clamp. Cardiac arrest during 80 min of cross-clamp was obtained with repeated antegrade cold oxygenated blood cardioplegia; the pigs were weaned from bypass following a standardised protocol. Left ventricular global and regional myocardial function and tissue blood flow were evaluated with conductance catheter, echocardiography and coloured microspheres at baseline and at 1, 2 and 3 h after declamping. Four animals did not fulfil the protocol and were excluded. RESULTS: No significant differences between groups could be demonstrated for left ventricular global and local function and tissue blood flow at baseline. At 1h after declamping the slope of preload recruitable stroke work (PRSW(slope)) averaged 73.7+/-12.7 mm Hg (SD) in controls and 72.7+/-11.1 mm Hg in esmolol-treated animals. In controls PRSW(slope) decreased to 62.1+/-11.0 and 58.4+/-12.7 mm Hg after 2 and 3h, respectively (p<0.005 vs 1h for both). In the esmolol-treated animals PRSW(slope) remained unchanged at 72.0+/-11.4 and 73.7+/-12.9 mm Hg at 2 and 3 h after declamp and were significantly higher (p<0.025 and <0.001) than the corresponding values in the control group. The slope of the end systolic pressure volume relationship did not differ between groups at 1 and 2 h after declamp, but were 1.85+/-0.86 and 2.51+/-0.96 mm Hg ml(-1) in controls and in esmolol-treated animals, respectively, after 3h (p<0.025). CONCLUSIONS: Esmolol administered prior to cold oxygenated cardioplegic arrest alleviates left ventricular dysfunction in the early hours after cardiopulmonary bypass.