Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A

Precision oncology research is challenging outside the contexts of oncogenic addiction and/or targeted therapies. We previously showed that phosphoproteomics is a powerful approach to reveal patient subsets of interest characterized by the activity of a few kinases where the underlying genomics is complex. Here, we conduct a phosphoproteomic screening of samples from HER2-negative female breast cancer receiving neoadjuvant paclitaxel (N = 130), aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 11 candidate biomarkers through 2 independent patient sets (N= 218) allowed the identification of a subgroup of patients characterized by high levels of CDK4 and filamin-A who had a 90% chance of achieving a pCR in response to paclitaxel. Mechanistically, CDK4 regulates filamin-A transcription, which in turn forms a complex with tubulin and CLIP-170, which elicits increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allows the identification of explainable factors for predicting response to paclitaxel

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Use of bevacizumab as a first-line treatment for metastatic breast cancer

Roche Farm

READ-COGvid: A Database From Reading and Media Habits During COVID-19 Confinement in Spain and Italy

The COVID-19 outbreak severely hit the population of Europe in general, and Spain and Italy in particular. By 25th May 2020, both countries accounted for 17.3% of the COVID-19 related deaths and 8.5% of infections worldwide (EU, 2020). The severity of the situation at the beginning of March led their respective governments to pass highly restrictive laws that enforced strict confinement of the vast majority of the population. Within this context, we studied the way adults in Spain and Italy adapted their reading and media habits. Several large studies on reading habits during adulthood have identified five main reading activities and goals: reading for leisure, reading study or work documents, reading news to keep up with current events, reading to socialize with others, and shared reading with children (see Scales and Rhee, 2001; Mol et al., 2008; Torppa et al., 2020). The study of reading habits in adulthood has brought extensive attention due to its relationship with psychological, emotional, and health conditions (see Marshall, 2020, for a review). Indeed, reading for leisure has a clear impact on adults' socio-cognitive well-being (Mumper and Gerrig, 2017). However, little is known about how those habits change and are affected by collective crisis in which the citizens are confined in their homes. One exception is the study of news reading habits during crisis. Extensive exposure to news related to community crisis (e.g., the 9/11 terrorist attacks) led to increased anxiety and non-adaptive health-protective and help-seeking behaviors (see Garfin et al., 2020, for a review). To the best our knowledge, no prior study has evaluated the changes in reading habits due to a collective crisis. A strict lockdown may impact people's free time available, which will set the ground for potential changes in reading habits. But such changes may depend on people's social (e.g., living alone or with minors) or individual characteristics (e.g., distress, reading motivations). In the present paper, we present the READ-COGvid database, composed of responses of 4,800 individuals from Spain and Italy. While we focus on leisure and reading habits at different moments (before the confinement, shortly after confinement, and after 1 month confined), we also collected many other indices (socio-demographic, psychological, and reading-related) that may be of interest to researchers interested in adults' reading and related areas (e.g., communication research, cognitive sciences, social studies, health sciences, cross-cultural studies). The READ-COGvid database is freely available to all users at: https://osf.io/24et3/?view_only=68613c73dd71499bbdadbad93d4ca79a

CSES Module 4 Full Release

The module was administered as a post-election interview. The resulting data are provided along with voting, demographic, district and macro variables in a single dataset. CSES Variable Table The list of variables is being provided on the CSES Website to help in understanding what content is available from CSES, and to compare the content available in each module. Themes: MICRO-LEVEL DATA: Identification and study administration variables: weighting factors; election type; date of election 1st and 2nd round; study timing (post-election study, pre-election and post-election study, between rounds of majoritarian election); mode of interview; gender of interviewer; date questionnaire administered; primary electoral district of respondent; number of days the interview was conducted after the election; language of questionnaire. Demography: year and month of birth; gender; education; marital status; union membership; union membership of others in household; business association membership, farmers´ association membership; professional association membership; current employment status; main occupation; socio economic status; employment type - public or private; industrial sector; current employment status, occupation, socio economic status, employment type - public or private, and industrial sector of spouse; household income; number of persons in household; number of children in household under the age of 18; number of children in household under the age of 6; attendance at religious services; religiosity; religious denomination; language usually spoken at home; region of residence; race; ethnicity; rural or urban residence; primary electoral district; country of birth; year arrived in current country. Survey variables: perception of public expenditure on health, education, unemployment benefits, defense, old-age pensions, business and industry, police and law enforcement, welfare benefits; perception of improving individual standard of living, state of economy, government’s action on income inequality; respondent cast a ballot at the current and the previous election; vote choice (presidential, lower house and upper house elections) at the current and the previous election; respondent cast candidate preference vote at the current and the previous election; difference who is in power and who people vote for; sympathy scale for selected parties and political leaders; assessment of parties on the left-right-scale and/or an alternative scale; self-assessment on a left-right-scale and an optional scale; satisfaction with democracy; party identification; intensity of party identification, institutional and personal contact in the electoral campaigning, in person, by mail, phone, text message, email or social networks, institutional contact by whom; political information questions; expected development of household income in the next twelve month; ownership of residence, business or property or farm or livestock, stocks or bonds, savings; likelihood to find another job within the next twelve month; spouse likelihood to find another job within the next twelve month. DISTRICT-LEVEL DATA: number of seats contested in electoral district; number of candidates; number of party lists; percent vote of different parties; official voter turnout in electoral district. MACRO-LEVEL DATA: election outcomes by parties in current (lower house/upper house) legislative election; percent of seats in lower house received by parties in current lower house/upper house election; percent of seats in upper house received by parties in current lower house/upper house election; percent of votes received by presidential candidate of parties in current elections; electoral turnout; party of the president and the prime minister before and after the election; number of portfolios held by each party in cabinet, prior to and after the most recent election; size of the cabinet after the most recent election; number of parties participating in election; ideological families of parties; left-right position of parties assigned by experts and alternative dimensions; most salient factors in the election; fairness of the election; formal complaints against national level results; election irregularities reported; scheduled and held date of election; irregularities of election date; extent of election violence and post-election violence; geographic concentration of violence; post-election protest; electoral alliances permitted during the election campaign; existing electoral alliances; requirements for joint party lists; possibility of apparentement and types of apparentement agreements; multi-party endorsements on ballot; votes cast; voting procedure; voting rounds; party lists close, open, or flexible; transferable votes; cumulated votes if more than one can be cast; compulsory voting; party threshold; unit for the threshold; freedom house rating; democracy-autocracy polity IV rating; age of the current regime; regime: type of executive; number of months since last lower house and last presidential election; electoral formula for presidential elections; electoral formula in all electoral tiers (majoritarian, proportional or mixed); for lower and upper houses was coded: number of electoral segments; linked electoral segments; dependent formulae in mixed systems; subtypes of mixed electoral systems; district magnitude (number of members elected from each district); number of secondary and tertiary electoral districts; fused vote; size of the lower house; GDP growth (annual percent); GDP per capita; inflation, GDP Deflator (annual percent); Human development index; total population; total unemployment; TI corruption perception index; international migrant stock and net migration rate; general government final consumption expenditure; public spending on education; health expenditure; military expenditure; central government debt; Gini index; internet users per 100 inhabitants; mobile phone subscriptions per 100 inhabitants; fixed telephone lines per 100 inhabitants; daily newspapers; constitutional federal structure; number of legislative chambers; electoral results data available; effective number of electoral and parliamentary parties

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

Background: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. Methods: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1–3c (modified to stage 2–3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1–3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Findings: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1–5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57–0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3–91·8) in the neratinib group and 87·7% (85·7–89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3–4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. Interpretation: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses—ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast—without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events

Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study

Background: Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications. Methods: We did a multicentre, prospective observational cohort study. Patients were recruited from 211 hospitals in 28 European countries. We included patients (aged ≥18 years) who received general anaesthesia for any in-hospital procedure except cardiac surgery. Patient characteristics, surgical and anaesthetic details, and chart review at discharge were prospectively collected over 2 weeks. Additionally, each patient underwent postoperative physical examination within 3 days of surgery to check for adverse pulmonary events. The study outcome was the incidence of postoperative pulmonary complications from the end of surgery up to postoperative day 28. Logistic regression analyses were adjusted for surgical factors and patients' preoperative physical status, providing adjusted odds ratios (ORadj) and adjusted absolute risk reduction (ARRadj). This study is registered with ClinicalTrials.gov, number NCT01865513. Findings: Between June 16, 2014, and April 29, 2015, data from 22 803 patients were collected. The use of neuromuscular blocking agents was associated with an increased incidence of postoperative pulmonary complications in patients who had undergone general anaesthesia (1658 [7·6%] of 21 694); ORadj 1·86, 95% CI 1·53–2·26; ARRadj −4·4%, 95% CI −5·5 to −3·2). Only 2·3% of high-risk surgical patients and those with adverse respiratory profiles were anaesthetised without neuromuscular blocking agents. The use of neuromuscular monitoring (ORadj 1·31, 95% CI 1·15–1·49; ARRadj −2·6%, 95% CI −3·9 to −1·4) and the administration of reversal agents (1·23, 1·07–1·41; −1·9%, −3·2 to −0·7) were not associated with a decreased risk of postoperative pulmonary complications. Neither the choice of sugammadex instead of neostigmine for reversal (ORadj 1·03, 95% CI 0·85–1·25; ARRadj −0·3%, 95% CI −2·4 to 1·5) nor extubation at a train-of-four ratio of 0·9 or more (1·03, 0·82–1·31; −0·4%, −3·5 to 2·2) was associated with better pulmonary outcomes. Interpretation: We showed that the use of neuromuscular blocking drugs in general anaesthesia is associated with an increased risk of postoperative pulmonary complications. Anaesthetists must balance the potential benefits of neuromuscular blockade against the increased risk of postoperative pulmonary complications. Funding: European Society of Anaesthesiology