Significantly longer time to deterioration of quality of life due to CANKADO PRO-React eHealth support in HR+ HER2- metastatic breast cancer patients receiving palbociclib and endocrine therapy: primary outcome analysis of the multicenter randomized AGO-B WSG PreCycle trial.

BACKGROUND: The multicenter, randomized, phase IV, intergroup AGO-B WSG PreCycle trial (NCT03220178) evaluated the impact of CANKADO-based electronic patient-reported outcome (ePRO) assessment on quality of life (QoL) in hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer (MBC) patients receiving palbociclib and an aromatase inhibitor or palbociclib + fulvestrant. CANKADO PRO-React, a European Union-registered medical device, is an interactive autonomous application reacting to patient self-reported observations. PATIENTS AND METHODS: Between 2017 and 2021, 499 patients (median age 59 years) from 71 centers were randomized (2 : 1, stratified by therapy line) between an active version of CANKADO PRO-React (CANKADO-active arm) and a version with limited functionality (CANKADO-inform arm). A total of 412 patients (271 CANKADO-active; 141 CANKADO-inform) were available for analysis of the primary endpoint, time to deterioration (TTD) of QoL [10-point drop on the Functional Assessment of Cancer Therapy-General (FACT-G) score], using an Aalen-Johansen estimator for cumulative incidence function of TTD DQoL (QoL deterioration) with 95% pointwise confidence intervals (CIs). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and DQoL. RESULTS: In all patients [intention-to-treat (ITT)-ePRO], cumulative incidence of DQoL was significantly more favorable (lower) in the CANKADO-active arm (hazard ratio 0.698, 95% CI 0.506-0.963). Among first-line patients (n = 295), the corresponding hazard ratio was 0.716 (0.484-1.060; P = 0.09), and in second-line patients (n = 117) it was 0.661 (0.374-1.168; P = 0.2). Absolute patient numbers declined in later visits; FACT-G completion rates were 80% and higher until about visit 30. Mean FACT-G scores showed a steady decline from baseline and an offset in favor of CANKADO-active. No significant differences in clinical outcome were observed between arms: median PFS (ITT population) was 21.4 (95% CI 19.4-23.7) (CANKADO-active) and 18.7 (15.1-23.5) months (CANKADO-inform); median OS was not reached (CANKADO-active) and 42.6 months (CANKADO-inform). CONCLUSIONS: PreCycle is the first multicenter randomized eHealth trial demonstrating a significant benefit for MBC patients receiving oral tumor therapy when using an interactive autonomous patient empowerment application.

Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial.

INTRODUCTION: Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC). METHODS: In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459). RESULTS: Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients. CONCLUSION: In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone. TRIAL REGISTRATION: The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.

The West German Study Group Breast Cancer Intrinsic Subtype study: a prospective multicenter decision impact study utilizing the Prosigna assay for adjuvant treatment decision-making in estrogen-receptor-positive, HER2-negative early-stage breast cancer.

PURPOSE: The West German Study Group (WSG) Breast Cancer Intrinsic Subtype (BCIST) study was designed to assess the influence of Prosigna gene signature assay results on physicians' adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians' confidence in their therapeutic recommendations and on patients' decisional conflict status, anxiety levels, and functional status. METHODS: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with estrogen-receptor (ER)-positive, HER2-negative, lymph-node-negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in a WSG central pathology laboratory following manufacturer's guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay result concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. RESULTS: The present study population consisted predominantly of low-to-intermediate risk patients (N = 198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna test results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna test results. CONCLUSIONS: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors.

Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression.

BACKGROUND: Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LNs) only. PATIENTS AND METHODS: A total of 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel 100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors. RESULTS: Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥ 20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18-0.82) for EC-Doc versus FEC (test for interaction; P = 0.01). CONCLUSION: EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1-3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy. CLINICAL TRIAL NUMBER: ClinicalTrials.gov, NCT02115204.

Final results from the prospective phase III WSG-ARA trial: impact of adjuvant darbepoetin alfa on event-free survival in early breast cancer.

BACKGROUND: WSG-ARA plus trial evaluated the effect of adjuvant darbepoetin alfa (DA) on outcome in node positive primary breast cancer (BC). PATIENTS AND METHODS: One thousand two hundred thirty-four patients were randomized to chemotherapy either with DA (DA+; n = 615) or without DA (DA-; n = 619). DA (500 µg q3w) was started at hemoglobin (Hb) levels <13.0 g/dl (<12 g/dl after DA label amendment) and stopped at Hb levels ≥14.0 g/dl (12 g/dl after label amendment). Primary efficacy end point was event-free survival (EFS); secondary end points were toxicity, quality of life (QoL) and overall survival (OS). RESULTS: Venous thrombosis (DA+: 3.0%, DA-: 1.0%; P = 0.013) was significantly higher for DA+, but not pulmonary embolism (0.3% in both arms). Median Hb levels were stable in DA+ (12.6 g/dl) and decreased in DA- (11.7 g/dl). Hb levels >15 g/dl were reported in 0.8% of cycles. QoL parameters did not significantly differ between arms. At 39 months, DA had no significant impact on EFS (DA+: 89.3%, DA-: 87.5%; Plog-rank = 0.55) or OS (DA+: 95.5%, DA-: 95.4%; Plog-rank = 0.77). CONCLUSIONS: DA treatment did not impact EFS or OS in routine adjuvant BC treatment.

Prognostic impact of proteolytic factors (urokinase-type plasminogen activator, plasminogen activator inhibitor 1, and cathepsins B, D, and L) in primary breast cancer reflects effects of adjuvant systemic therapy.

PURPOSE: Prognostic and predictive impact of five proteolytic factors associated with tumor invasion and metastasis in primary breast cancer were evaluated after long-term follow-up. EXPERIMENTAL DESIGN: Antigen levels of urokinase-type plasminogen activator, plasminogen activator inhibitor-1 (PAI-1), Cathepsins B, D, and L were determined using immunochemical assays in primary tumor tissue of 276 patients. RESULTS: During follow-up (median 109 months), 119 (43%) patients relapsed, and 117 (42%) died. In the whole collective, lymph node status (P < 0.001; RR 3.8), Cathepsin L (P < 0.001; RR 2.6), and PAI-1 (P = 0.027; RR 1.7) were the only independent significant factors in multivariate analysis for disease-free survival (DFS). For overall survival (OS), lymph node status (P < 0.001; RR 2.9), Cathepsin L (P = 0.017; RR 1.9), PAI-1 (P = 0.01; RR 1.9), and grading (P = 0.026; RR 1.7) were significant. In the node-negative subgroup, PAI-1 was the only significant factor for DFS (P = 0.004; RR 3.7) and the strongest factor (P = 0.004; RR 3.7) for OS next to grading (P = 0.017; RR 3.1). In node-positive patients, Cathepsin L was the only significant factor for both DFS (P < 0.001; RR 3.2) and OS (P = 0.003; RR 2.5). For all proteolytic factors but Cathepsin L, the univariate prognostic impact on DFS was substantial in patients without adjuvant systemic therapy but was diminished if adjuvant therapy had been administered. Cathepsin L maintained its strong prognostic impact on DFS even in patients with adjuvant endocrine therapy (P = 0.01; RR 2.8). CONCLUSIONS: The observed effect of adjuvant systemic therapy on their prognostic strength suggests that the assessed proteolytic factors supply predictive information on therapy response.

Clinical relevance of the plasminogen activator inhibitor type 1--a multifaceted proteolytic factor.

The plasminogen activator inhibitor type-1 (PAI-1) is a multifaceted proteolytic factor. It not only functions as an inhibitor of the protease uPA (urokinase-type plasminogen activator), but also plays an important role in signal transduction, cell adherence, and cell migration. Thus--an apparent paradox considering its name--although it inhibits uPA during blood coagulation, it actually promotes invasion and metastasis. In the early 1990s, clinical evidence associated elevated PAI-1 levels in tumor tissue with poor clinical outcome in primary breast cancer. These clinical data have since been supported by experimental evidence that the concerted action of uPA, its cell surface receptor uPA-R, and PAI-1 facilitates invasion and metastasis. The strong prognostic impact of PAI-1 in primary breast cancer has been validated by international research groups assessing fresh tumor tissue extracts by ELISA. There is clinical evidence that high-risk patients with elevated PAI-1 in their tumor benefit from adjuvant systemic therapy. uPA also has a strong prognostic impact in primary breast cancer. In node-negative breast cancer, risk-group selection for adjuvant systemic therapy based on tumor levels of both PAI-1 and uPA is close to routine clinical use. Also in other malignancies such as ovarian, esophageal, gastric, colorectal or hepatocellular cancer, elevated PAI-1 is associated with tumor aggressiveness and poor patient outcome. This abundant clinical evidence implicating PAI-1 as a key factor for tumor invasion and metastasis renders it a promising target for tumor therapy. Novel therapeutic approaches targeting the PAI-1/uPA interaction are already in pre-clinical testing.

Invasion marker PAI-1 remains a strong prognostic factor after long-term follow-up both for primary breast cancer and following first relapse.

In 1991, our group was the first to report the prognostic strength of plasminogen activator inhibitor type 1 (PAI-1) in primary breast cancer. The prognostic impact of invasion markers PAI-1 and urokinase-type plasminogen activator (uPA) on disease-free survival (DFS) and overall survival (OS) in breast cancer has since been independently confirmed. We now report on the prognostic impact of PAI-1 and uPA after long-term median follow-up of 77 months for our cohort (n = 316). Levels of uPA, PAI-1, and cathepsin D were determined in tumor tissue extracts by immunoenzymatic methods. S-phase fraction (SPF) was measured flowcytometrically in paraffin sections. Using log-rank statistics, optimized cutoffs were found for PAI-1 (14 ng/mg), uPA (3 ng/mg), cathepsin D (41 pmol/mg), and SPF (6%). In all patients, various factors (PAI-1, uPA, nodal status, SPF, cathepsin D, grading, tumor size, hormone receptor status) showed significant univariate impact on DFS. In Cox analysis, only nodal status (p < 0.001, RR: 3.1) and PAI-1 (p < 0.001, RR: 2.7) remained significant. In node-negative patients (n = 147), PAI-1, uPA, and SPF had significant univariate impact on DFS, whereas in Cox analysis, only PAI-1 was significant. PAI-1 was also significant for DFS within subgroups defined by established factors. In CART analysis, uPA enhanced the prognostic value of PAT-1 and nodal status for determination of a very-low-risk subgroup. For OS, only lymph node status and PAI-1 were significant in multivariate analysis. PAI-1 levels in the primary tumor were also a significant prognostic marker for survival after first relapse in both univariate and multivariate analysis.

Effect of high-dose oral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positive patients.

This study was designed to investigate the interaction between high-dose oral ganciclovir (6,000 mg/day) and didanosine at steady state in patients who were seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection. The study was conducted as an open-label, randomized, three-period crossover study. Patients received (in random order) multiple oral doses of didanosine 200 mg every 12 hours alone, ganciclovir 2,000 mg every 8 hours alone, and ganciclovir 2,000 mg every 8 hours in combination with didanosine 200 mg every 12 hours. Blood and urine samples for determinations of drug concentrations were obtained on day 3 of each dose regimen. When ganciclovir was administered either before or 2 hours after didanosine, the mean increases in maximum concentration (Cmax), area under the concentration-time curve (AUC0-12), and percent excreted in urine of didanosine were 58.6% and 87.3%, 87.3% and 124%, and 100% and 153%, respectively. There were no statistically significant effects of didanosine on the steady-state pharmacokinetics of ganciclovir in the presence of didanosine, irrespective of sequence of administration. There were no significant changes in renal clearance of didanosine, suggesting that the mechanism for the interaction does not involve competition for active renal tubular secretion. The mechanism responsible for increased didanosine concentrations and percent excreted in urine during concurrent ganciclovir therapy may be a result of increased bioavailability of didanosine. However, the mechanism appears to be saturated at oral ganciclovir doses of 3 g/day.

Myocardial uptake of encainide and its two major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, in the dog.

Encainide is a new antiarrhythmic agent which is currently undergoing clinical evaluation. Two metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide (MODE), have been identified. We have investigated the myocardial accumulation of these three compounds in an anesthetized open-chested dog model. We also considered the degree of plasma protein binding and the oil/water partitioning characteristics of these three compounds to see if they explained differences in myocardial accumulation. Each compound was administered by intravenous infusion to a group of five dogs. Blood and myocardial biopsy samplings were carried out under steady-state conditions. The myocardial/plasma concentration ratios for encainide, ODE, and MODE were 8.4, 5.4, and 4.8, respectively. The ratios were compared with a completely randomized analysis of variance followed by multiple comparisons. The myocardial/plasma concentration ratio for encainide was significantly greater (p less than .05) than the ratios of the metabolites; however, the difference between ODE and MODE was not significant. Myocardial uptake of encainide, ODE, and MODE was quite rapid, and the myocardial concentration-time course of each compound followed its time course in plasma closely. Encainide and its two metabolites are only moderately bound to plasma proteins. The mean (+/- SD) percent bound for encainide, ODE, and MODE are 49 +/- 10, 55 +/- 19, 44 +/- 18, respectively. The whole blood/plasma concentration ratios are 1.04 +/- 0.16, 1.08 +/- 0.23, and 1.06 +/- 0.08 for encainide, ODE, and MODE, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial disposition and cardiac pharmacodynamics of verapamil in the dog.

The disposition of verapamil was studied in anesthetized open-chested dogs following administration of intravenous doses of 0.5 mg/kg. The plasma and myocardial verapamil concentration-time data were fit to a three-compartment model to describe the disposition kinetics. The distribution equilibrium between myocardium and plasma was achieved rapidly and the concentration of verapamil decayed in parallel in these two tissues. The partition coefficient which describes the time averaged myocardial/plasma concentration ratio was 6.21 +/- 2.38. Examination of the relationship between the plasma and myocardial concentrations and the time course of the effect of verapamil, as defined as PR interval prolongation, revealed a hysteresis effect in some dogs. Despite this hysteresis, there was a linear relationship between plasma and myocardial concentrations of verapamil and the degree of prolongation of the PR interval. The results of this study indicate that the concentration in the plasma is in equilibrium with the myocardium and changes in plasma concentration are indicative of parallel changes in myocardial levels. The effect of verapamil on the atrioventricular node is related to the concentration in the myocardium and plasma, but there is substantial interanimal variability in the sensitivity to verapamil.

Verapamil protein binding in patients and in normal subjects.

Verapamil plasma protein binding was studied in four groups of 12 subjects each: (1) normal subjects; (2) patients with moderate renal insufficiency and patients requiring dialysis; (3) patients 1 to 4 days after coronary artery surgery; and (4) patients undergoing cardiac catheterization. In normal subjects, plasma protein binding of verapamil was 89.6 +/- 0.17% and was concentration independent over a range of 35 to 1,557 ng/ml, which includes the usual clinical plasma range. In normal subjects, plasma protein binding of verapamil was not affected by addition of its major metabolite, norverapamil, in ratios of 1.2 to 26.3 (norverapamil/verapamil) or by the addition of 10 micrograms of warfarin. The plasma protein binding of verapamil was not altered in the postsurgical state or in the dialysis patients. Verapamil protein binding was initially lower in the cardiac catheterization patients (mean = 86.34 +/- 2.13%, p less than 0.001) than in normal subjects and was still lower (mean = 83.29 +/- 3.04%, p less than 0.02) after heparinization. There was also a small increase in binding in the patients with renal insufficiency (p less than 0.05). Plasma protein binding of verapamil in mongrel dogs (mean = 90.7%) was the same order. We found verapamil to be approximately 90% bound in man and dogs and not markedly changed by any of the conditions studied.

A model to describe myocardial drug disposition in the dog.

A model, employing open-chested, anesthetized dogs, was developed to facilitate the study of myocardial drug disposition. Propranolol was employed as a model compound for initial investigation. Propranolol was administered as either a single i.v. bolus of 0.5 mg/kg or by a stepwise infusion protocol employing three rates: 2.6, 6.5 and 12.0 micrograms/kg/min. Blood and myocardial biopsy samples were obtained at specified times and the concentration of propranolol in tissue homogenates and plasma was determined by a high-pressure liquid chromotographic procedure. The concentration-time data obtained from the i.v. bolus studies were fitted to a three-compartment model where one of the compartments represented the myocardium. The model predicts that plasma and myocardial concentrations achieve distribution equilibrium within 2 min after administration. The myocardial-to-plasma concentration ratios ranged from 6.2 to 20.3 and were constant with time for each dog. The myocardial-to-plasma concentration ratios also remained constant during the infusion protocol, indicating linear accumulation up to myocardial concentrations of 6.7 micrograms/ml. To assess regional myocardial concentration differences, the concentration of drug in the right atrium was compared with the concentration of drug in the right atrium was compared with the concentration in the left ventricle at the end of the infusion protocol. The concentrations were not significantly different. The model developed will be used to study the myocardial disposition of several antiarrhythmic drugs and the factors which affect their rate and extent of accumulation.

Safety and rationale for continuation of propranolol therapy during coronary bypass operation.

Thirty consecutive patients undergoing coronary bypass were studied. Oral propranolol therapy was maintained up to 4 to 10 hours before operation. Nineteen of the patients had a history of myocardial infarction (MI), 14 had hypoakinetic areas, and 8 had decreased ejection fraction indicating advanced coronary artery disease. Twenty-four-hour urinary epinephrine and norepinephrine obtained the day before operation were markedly increased at 136 +/- 12 microgram per 24 hours (normal, 39 +/- 4 microgram, rho less than 0.01). There were 4 perioperative MIs (13%) and no deaths. Plasma propranolol 1 hour before operation was 43.3 +/- 8 ng per milliliter, indicating good beta blockade. Propranolol was started within 24 hours postoperatively. There were no preoperative, intraoperative, or postoperative complications related to propranolol therapy. We conclude that because of markedly increased adrenergic tone the day before operation and transient hypersensitivity to adrenergic stimulation after withdrawal of propranolol, this agent should be continued through coronary bypass operation.