Patient preferences for features of HER2-targeted treatment of advanced or metastatic breast cancer: a discrete-choice experiment study.

BACKGROUND: We aimed to quantify patients' benefit-risk preferences for attributes associated with human epidermal growth factor receptor 2 (HER2)-targeted breast cancer treatments and estimate minimum acceptable benefits (MABs), denominated in additional months of progression-free survival (PFS), for given treatment-related adverse events (AEs). METHODS: We conducted an online discrete-choice experiment (DCE) among patients with self-reported advanced/metastatic breast cancer in the United States, United Kingdom, and Japan (N = 302). In a series of nine DCE questions, respondents chose between two hypothetical treatment profiles created by an experimental design. Profiles were defined by six attributes with varying levels: PFS, nausea/vomiting, diarrhea, liver function problems, risk of heart failure, and risk of serious lung damage and infections. Data were analyzed using an error component random-parameters logit model. RESULTS: Among the attributes, patients placed the most importance on a change in PFS from 5 to 26 months; change from no diarrhea to severe diarrhea was the least important. Avoiding a 15% risk of heart failure had the largest MAB (5.8 additional months of PFS), followed by avoiding a 15% risk of serious lung damage and infections (4.6 months), possible severe liver function problems (4.2 months), severe nausea/vomiting (3.7 months), and severe diarrhea (2.3 months) compared with having none of the AEs. The relative importance of 21 additional months of PFS (increasing from 5 to 26 months) increased for women with HER2-negative disease and those with children. CONCLUSIONS: Patients valued PFS gain higher than the potential risk of AEs when deciding between hypothetical breast cancer treatments.

Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review.

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-targeted therapies improve survival for patients with HER2-positive breast cancer but carry risks of hematologic, cardiopulmonary, gastro-hepatobiliary, and other adverse events (AEs). In this review, we describe published AE incidences for HER2-targeted therapies for metastatic breast cancer (mBC). METHODS: We searched PubMed and Embase to identify studies on HER2-targeted therapies in HER2-positive mBC, reporting on AEs of special interest, and published between January 1, 2009, and February 6, 2020. Treatment regimens were categorized into mutually exclusive therapy-based categories, with primary therapy determined by worldwide approval date. RESULTS: One hundred and fifty-three included articles assessed a combined 29,238 patients treated with the following therapy-based regimens: trastuzumab or biosimilars (78 studies), lapatinib (40), T-DM1 (ado-trastuzumab emtansine) (20), pertuzumab (14), neratinib (8), MM-302 (1), T-DXd (2), tucatinib (3), and pyrotinib (3). While direct comparisons of AE incidence are not warranted owing to study heterogeneity, proportions of patients experiencing any Grade 3 + AE ranged across therapy-based regimens from 39.4% (lapatinib) to 66.3% (neratinib). The most common hematologic AE of special interest, of any grade and regardless of causality, was leukopenia/white blood cells decreased [21.4% (T-DXd)-46.2% (pyrotinib)]. Cardiopulmonary AEs of special interest included interstitial lung disease [2.7% (trastuzumab)-5.2% (T-DXd)], pneumonitis [0.2% (lapatinib)-7.4% (trastuzumab)], and decreased ejection fraction [1% (T-DXd)-13.6% (trastuzumab)]. Gastro-hepatobiliary AEs of special interest included nausea [33.9% (trastuzumab)-78.3% (T-DXd)], vomiting [19.2% (T-DM1)-48.2% (T-DXd)], diarrhea [19.6% (T-DM1)-96.9% (pyrotinib)], and hepatotoxicity [5.9% (lapatinib)-53.6% (T-DM1)]. CONCLUSION: Differing AE profiles for anti-HER2 therapies should be considered when assessing benefit-risk profile for treatment options.

Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia.

BACKGROUND: The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy. METHODS: In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival. RESULTS: Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P<0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P<0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P=0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P<0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P=0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy. CONCLUSIONS: The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials.gov number, NCT01564784.).

The Evolution of Nephrectomy and Patient Characteristics in Metastatic Renal Cell Carcinoma Patients Enrolled Into First-Line Tyrosine Kinase Inhibitors Clinical Trials.

INTRODUCTION: The objective of this study was to compare rates of nephrectomy (Nx) in, and characteristics of, patients with metastatic renal cell carcinoma (mRCC) enrolled in prospective clinical trials of tyrosine kinase inhibitors (TKIs) that were completed through (Group 1) versus after (Group 2) 2007. PATIENTS AND METHODS: Searching online databases, we retrospectively identified phase I to III trials with ≥ 15 patients with mRCC treated with first-line TKIs, alone or in combination with other agent(s). RESULTS: Of 70 trials identified, 42 were included in the analysis (n = 6074 patients). Compared with Group 1, Group 2 patients had significantly less Nx (85.7% vs. 93.7%; P < .001) and prior cytokine therapy (11.1% vs. 46.8%; P < .001). Group 2 also had significantly fewer patients with good prognostic risk (based on Memorial Sloan-Kettering Cancer Center criteria) or performance status (both P < .001). Group 2 patients had a significantly greater objective response rate than Group 1 patients (intent-to-treat analysis: 28.6% vs. 23.1%, respectively; P < .001), whereas Group 1 patients had significantly more stable disease. Clinical benefit was similar in both groups (P = .157), and the means of median progression-free survival were comparable (8.2 and 9.0 months in Groups 1 and 2, respectively; P = .2528). CONCLUSIONS: Use of Nx in mRCC patients participating in clinical trials has declined in the TKI era. More patients with worse prognostic risk profiles are participating in first-line TKI trials after 2007, but objective response rates are higher. Despite patient characteristics that favor the earlier group, progression-free survival is similar as TKIs have replaced cytokines as first-line therapy.

Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer.

PURPOSE: Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two). PATIENTS AND METHODS: Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR). RESULTS: In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively. CONCLUSION: Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib.

Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial.

PURPOSE: To prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In a randomized, open-label, multicenter, phase III study, patients with previously untreated predominantly clear-cell mRCC were randomly assigned, stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center prognostic group, to receive the combination of either temsirolimus (25 mg intravenously, weekly) or IFN (9 MIU subcutaneously thrice weekly) with bevacizumab (10 mg/kg intravenously, every 2 weeks). The primary end point was independently assessed progression-free survival (PFS). RESULTS: Median PFS in patients treated with temsirolimus/bevacizumab (n = 400) versus IFN/bevacizumab (n = 391) was 9.1 and 9.3 months, respectively (hazard ratio [HR], 1.1; 95% CI, 0.9 to 1.3; P = .8). There were no significant differences in overall survival (25.8 ν 25.5 months; HR, 1.0; P = .6) or objective response rate (27.0% ν 27.4%) with temsirolimus/bevacizumab versus IFN/bevacizumab, respectively. Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) -15 and FKSI-Disease Related Symptoms subscale compared with IFN/bevacizumab (indicating improvement); however, no differences in global health outcome measures were observed. Treatment-emergent all-causality grade ≥ 3 adverse events more common (P < .001) with temsirolimus/bevacizumab were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia, whereas neutropenia was more common with IFN/bevacizumab. Incidence of pneumonitis with temsirolimus/bevacizumab was 4.8%, mostly grade 1 or 2. CONCLUSION: Temsirolimus/bevacizumab combination therapy was not superior to IFN/bevacizumab for first-line treatment in clear-cell mRCC.

A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer.

BACKGROUND: The safety and efficacy of neratinib monotherapy were compared with that of lapatinib plus capecitabine in patients with human epidermal growth factor receptor-2-positive (HER2+), locally advanced/metastatic breast cancer and prior trastuzumab treatment. METHODS: Patients received neratinib 240 mg/d continuously (n=117) or lapatinib 1250 mg/d continuously plus capecitabine 2000 mg/m(2) per day on days 1-14 of each 21-d cycle (n=116). The primary aim was to demonstrate non-inferiority of neratinib for progression-free survival (PFS). FINDINGS: The non-inferiority of neratinib was not demonstrated when compared with lapatinib plus capecitabine (hazard ratio, 1.19; 95% confidence interval, 0.89-1.60; non-inferiority margin, 1.15). Median PFS for neratinib was 4.5 months versus 6.8 months for lapatinib plus capecitabine and median overall survival was 19.7 months versus 23.6 months. Objective response rate (neratinib, 29% versus lapatinib plus capecitabine, 41%; P=0.067) and clinical benefit rate (44% versus 64%; P=0.003) were lower for the neratinib arm but consistent with previously reported results. In both treatment arms, diarrhoea was the most frequently reported treatment-related adverse event of any grade (neratinib, 85% versus lapatinib plus capecitabine, 68%; P=0.002) and of grade 3/4 (28% versus 10%; P<0.001), but was typically managed with concomitant anti-diarrhoeal medication and/or study treatment modification. Importantly, neratinib had no significant skin toxicity. INTERPRETATION: The results are considered as inconclusive since neither inferiority nor non-inferiority of treatment with neratinib versus lapatinib plus capecitabine could be demonstrated. The study confirmed relevant single-agent clinical activity and acceptable overall tolerability of neratinib in patients with recurrent HER2+ advanced breast cancer.

Resting EEG in offspring of male alcoholics: beta frequencies.

This study examines the differences in beta (12-28 Hz) band power in offspring of male alcoholics from densely affected alcoholic families. We have attempted to investigate if the increase in beta power is a 'state' or 'trait' marker for alcoholism. This study also explores the gender differences in the expression of this potential risk marker. Absolute beta power in three bands-beta 1(12-16 Hz), beta 2 (16-20 Hz), and beta 3 (20-28 Hz)-in the eyes closed EEG of 171 high risk (HR) subjects who were offspring of male alcoholics and 204 low risk (LR) subjects with no family history of alcoholism, were compared for each gender separately using a repeated measures analysis of variance design. Alcoholic and non-alcoholic subjects within the high risk group were compared using a repeated measures design as a follow-up analysis. The present study demonstrated increased beta power in the resting EEG of offspring of male alcoholics. Male HR subjects had higher beta 1 (12-16 Hz) power and female HR subjects had increased power in beta 2 (16-20 Hz) and beta 3 (20-28 Hz) as compared with low risk participants. Female HR subjects also showed significantly increased beta 2 and beta 3 power if they had two or more alcoholic first-degree relatives when compared with HR females having only an affected father. Risk characteristics are expressed differentially in males and females and may be an index of differential vulnerability to alcoholism. The results indicate that increased EEG beta power can be considered as a likely marker of risk for developing alcoholism and may be used as a predictive endophenotype.

Auditory P3 in female alcoholics.

BACKGROUND: The P3 (P300) has been considered to be a phenotypical marker of the risk for alcoholism. Although reductions in visual P3 in male and female alcoholics have been replicated, studies of auditory target P3 have been inconsistent. Our objective was to study the magnitude of auditory P3 reduction in female alcoholics and to establish the association between P3 reduction and alcoholism while taking into account comorbid depression and psychoactive drug dependence. The characteristics of P3 reduction were further examined by studying the reduction in family history-positive and -negative individuals. METHODS: Auditory target P3s recorded from 61 scalp electrodes in female alcoholics (n = 71) were compared with P3s from female controls (n = 159) ranging in age from 18 to 50 years. The amplitudes and latencies were statistically analyzed, by using repeated-measures ANOVA, in six regional electrode arrays and at representative electrode sites, with age and comorbid depression as covariates. The effects of family density and clinical variables such as depression and drug dependence were also examined with correlation analysis. RESULTS: Alcoholic women had significantly lower P3 amplitudes in all six regions and at midline electrode sites. The reductions were not associated with comorbid depression, as shown by low correlations and similar P3 amplitudes at Pz in female alcoholics with and without depression. The P3 amplitudes in women with a high family density were smaller than those in women with a low family density of alcohol dependence. Drug dependency did not influence P3 amplitude, as shown by similar responses in drug-dependent and non-drug-dependent alcoholic women. CONCLUSIONS: These findings highlight the significance of P3 reductions associated with alcoholism in women, independently of comorbid depression. Family density effects further support the evidence that these findings are heritable. These results suggest that P3 can be considered as a phenotypical marker of vulnerability to alcoholism in women.

Theta power in the EEG of alcoholics.

BACKGROUND: In this study, the magnitude and spatial distribution of theta power in the resting EEG were examined to explore the changes in the neurophysiological status of the alcoholic brain. Some state- and trait-related issues of theta power increases in the EEG of alcoholics were also examined. METHODS: Absolute theta (3-7 Hz) power in eyes-closed EEGs of 307 alcohol-dependent subjects and 307 age- and gender-matched unaffected controls were compared by using a repeated-measures ANOVA for the entire region and three subregions (frontal, central, and parietal) separately. Supplementary to the main analysis, the effect of three clinical variables on absolute theta power was examined separately for each gender by using correlation and regression analyses. Gender differences in the theta log power difference between alcoholics and controls were explored by using regional repeated-measures ANOVA. RESULTS: Increased absolute theta power was seen in alcohol-dependent subjects at all scalp locations. The theta log power increase in male alcoholics was prominent at the central and parietal regions and in female alcoholics at the parietal region when compared with the respective matched controls. Correlation of drinking variables with log theta power exhibited no group-specific differences. CONCLUSIONS: Increased tonic theta power in the EEG may reflect a deficiency in the information-processing capacity of the central nervous system in alcoholics. The theta power increase may also be an electrophysiological index of the imbalance in the excitation-inhibition homeostasis in the cortex. It is likely that the theta power increase is a trait-related phenomenon and is expressed to differing degrees in the two genders.

Beta power in the EEG of alcoholics.

BACKGROUND: In this study, the magnitude and spatial distribution of beta power in the resting electroencephalogram (EEG) were examined to address the possibility of an excitation-inhibition imbalance in the central nervous system of alcoholics. METHODS: Log transformed absolute power in the Beta 1 (12.5-16 Hz), Beta 2 (16.5-20 Hz), and Beta 3 (20.5-28 Hz) bands in the eyes-closed EEG of 307 alcohol-dependent subjects and 307 unaffected age- and gender-matched control subjects were compared using a multivariate repeated measures design. Effect of gender, age, and drinking variables was examined separately. RESULTS: Increased Beta 1 (12.5-16 Hz) and Beta 2 (16.5-20 Hz) absolute power was observed in alcohol-dependent subjects at all loci over the scalp. The increase was most prominent in the central region. Increased Beta 3 (20.5-28 Hz) power was frontal in the alcoholics. Age and clinical variables did not influence the increase. Male alcoholics had significantly higher beta power in all three bands. In female alcoholics the increase did not reach statistical significance. CONCLUSIONS: Beta power in all three bands of resting EEG is elevated in alcoholics. This feature is more prominent in male alcoholics. The increased beta power in the resting EEG may be an electrophysiological index of the imbalance in the excitation-inhibition homeostasis in the cortex.

Linkage and linkage disequilibrium mapping of ERP and EEG phenotypes.

Linkage analyses of highly heritable electrophysiological phenotypes (EEG, ERP) that can potentially identify individuals at risk for alcoholism were performed on a large sample of families with a high density of alcohol dependence as part of the Collaborative Study on the Genetics of Alcoholism (COGA); these genetic findings are summarized. Quantitative trait loci (QTLs) were identified for several ERP characteristics (P300, N100, N400) and for the beta frequencies of the EEG where we report linkage and linkage disequilibrium at a GABA(A) receptor gene on chromosome 4. Genetic analyses of ERPs suggest that several regions of the human genome contain genetic loci related to the generation of N100, N400 and P300, which are possible candidate loci underlying the functional organization of human neuroelectric activity. The advent of genomics and proteomics and a fuller understanding of gene regulation, will open new horizons on the critical electrical events so essential for human brain function.

Complexity measures of event related potential surface Laplacian data calculated using the wavelet packet transform.

We describe a method to obtain estimates of EEG signal complexity using the well-established wavelet packet transform with best basis selection. In particular, we use the two-dimensional wavelet packet transform to obtain estimates of the complexity of two-dimensional images. This allows us to calculate complexity estimates of high-resolution brain potential maps generated from 61 scalp electrode Visual Oddball paradigm, grand-mean data. A significant reduction in the complexity of the surface Laplacian time-slices is observed during and after the Visual Potential 300 (P3) event for the target case, possibly as a result of increased spatial synchrony associated with visual-related tasks. We also present the results of a statistical analysis of the largest principal component of the time-varying complexity curves, for control, high-risk, and alcoholic groups of male subjects. Parametric and non-parametric analyses show differences in the complexity data which are significant between the control group and the alcoholic and high-risk groups.

Linkage disequilibrium between the beta frequency of the human EEG and a GABAA receptor gene locus.

Human brain oscillations represent important features of information processing and are highly heritable. A common feature of beta oscillations (13-28 Hz) is the critical involvement of networks of inhibitory interneurons as pacemakers, gated by gamma-aminobutyric acid type A (GABA(A)) action. Advances in molecular and statistical genetics permit examination of quantitative traits such as the beta frequency of the human electroencephalogram in conjunction with DNA markers. We report a significant linkage and linkage disequilibrium between beta frequency and a set of GABA(A) receptor genes. Uncovering the genes influencing brain oscillations provides a better understanding of the neural function involved in information processing.