Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease.

Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.

Sibling and peer bullying victimization in adolescence: Masculinity, femininity, and the moderating role of sex and popularity.

INTRODUCTION: We investigated whether gender-typed traits (masculinity and femininity) contemporaneously predicted self-reported peer victimization, peer-reported peer victimization, and sibling victimization. We also tested the moderating role of sex and popularity. METHODS: A sample of 2782 British pupils aged 11-16 from Central England, UK was screened for bullying involvement and popularity using self-report and peer nominations, and a subsample of 704 (52.7% girls) completed a measure of gender-typed traits (masculinity and femininity). RESULTS: Hierarchical multiple regression analyses revealed that low levels of masculine traits were associated with greater risk of self-reported peer victimization, there were no associations with peer-reported peer victimization, and low levels of feminine traits were associated with greater risk of self-reported sibling victimization. The effects were not moderated by sex, while popularity decreased the risk of self- and peer-reported peer victimization. CONCLUSIONS: Bullying prevention interventions could benefit from including the positive facets of feminine and masculine traits.

Sexual victimisation, peer victimisation, and mental health outcomes among adolescents in Burkina Faso: a prospective cohort study.

BACKGROUND: Sexual victimisation and peer victimisation are pervasive and increase risk for mental illness. Longitudinal studies that compare their unique and cumulative effects are scarce and have been done predominantly in high-income countries. The aims of this study were to examine the prevalence, prospective associations, and gender differences in sexual and peer victimisation and mental health in a low-income, African setting. METHODS: In this prospective cohort study, data were obtained from the 2017 ARISE Adolescent Health Study, a population-representative, two-wave, prospective study of adolescents (aged 12-20 years) from Burkina Faso. A random sample of adolescents was drawn from ten villages, selected to capture the five main ethnic groups, and from one of the seven sectors of Nouna town, Burkina Faso, at two timepoints: Nov 12 to Dec 27, 2017, and Nov 15 to Dec 20, 2018. Standardised interviews were conducted in French or a local language by trained researchers. We measured victimisation exposure as sexual victimisation, peer victimisation, and polyvictimisation, using lifetime frequency of exposure, and we measured mental health symptoms and disorders using the Kutcher Adolescent Depression Scale, the Primary Care Post-Traumatic Stress Disorder screen IV and 5, and a question on lifetime self-harm and number of incidents in the past year. We calculated prevalence of victimisation and mental health symptoms and disorders at the two timepoints, and we used lifetime victimisation at the first timepoint to predict mental health at the second timepoint using logistic and negative binomial regressions. Gender differences were examined using interaction terms. FINDINGS: Of 2544 eligible adolescents, 1644 participated at time 1 and 1291 participated at time 2. The final sample with data at both timepoints included 1160 adolescents aged 12-20 years (mean 15·1, SE 0·2), of whom 469 (40·4%) were girls and 691 (59·6%) were boys. The majority ethnic group was Dafin (626 [39·1%]), followed by Bwaba (327 [20·5%]), Mossi (289 [16·0%]), Samo (206 [13·0%]), Peulh (166 [9·7%]), and other (30 [1·6%]). After survey weight adjustment, sexual victimisation (weighted percentages, time 1, 256 [13·8%] of 1620; time 2, 93 [7·2%] of 1264) and peer victimisation (weighted percentages, time 1, 453 [29·9%] of 1620; time 2, 272 [21·9%] of 1264) were common, whereas polyvictimisation was more rare (weighted percentages, time 1, 116 [6·6%] of 1620; time 2, 76 [5·7%] of 1264). Longitudinally, sexual victimisation was associated with probable clinical disorder (adjusted odds ratio 2·59, 95% CI 1·15-5·84), depressive symptoms (adjusted incidence rate ratio [aIRR] 1·39, 95% CI 1·12-1·72), and symptoms of post-traumatic stress disorder (aIRR 2·34, 1·31-4·16). Peer victimisation was associated with symptoms of post-traumatic stress disorder (aIRR 1·89, 1·13-3·17) and polyvictimisation was associated with depressive symptoms (aIRR 1·34, 1·01-1·77). Girls reported more sexual victimisation (weighted percentages, 130 [17·3%] of 681 vs 126 [11·4%] of 939), boys reported more peer victimisation (weighted percentages, 290 [33·1%] of 939 vs 163 [25·2%] of 681), and there was a significant interaction between lifetime victimisation and gender for probable clinical disorder (F [degrees of freedom 7, sample 376] 2·16; p=0·030). INTERPRETATION: Sexual and peer victimisation were common in the study setting and increased risk for mental health problems. Adolescent girls who have been sexually victimised are especially at risk of mental health problems. Interventions targeting sexual and peer violence in low-income settings are needed. FUNDING: Alexander von Humboldt Foundation, the Wellcome Trust, Fondation Botnar, and Harvard TH Chan School of Public Health.

Trajectories, comorbidity, and risk factors for adolescent disordered eating and borderline personality disorder features.

PURPOSE: Borderline personality disorder (BPD) and eating disorders are highly comorbid, but the shared course of symptoms and associated risks remain poorly understood. The aim of this study was to examine joint symptom trajectories, temporal precedence, risk factors, and population attributable fractions (PAFs) in a community sample of adolescents, using a developmental psychopathology and psychosocial framework. METHODS: Across five years (age 14-18 years), adolescents (n = 544, 56% girls) reported on BPD features and disordered eating behavior. Sociodemographic, interpersonal, and clinical risks were assessed in childhood (age 10-13 years). We used a person-centered approach to examine latent class growth analyses, joint trajectory models, and calculated PAFs. RESULTS: Three-class solutions were found for both disordered eating and BPD features (low, moderate, high), creating nine joint trajectories. High levels of disordered eating were a stronger indicator of high levels of BPD features than was the reverse. Girls and LGBTQ+ youth were most likely to be in a high symptom trajectory. Bullying perpetration and clinical hyperactivity were unique risks for BPD features. Bullying victimization contributed the largest PAF to disordered eating and BPD features. CONCLUSION: We identified several novel and clinically relevant findings related to temporality, risks, screening, and the treatment of adolescent eating problems and BPD.

Testing for EGFR Variants in Pleural and Pericardial Effusion Cell-Free DNA in Patients With Non-Small Cell Lung Cancer.

Importance: Molecular testing in non-small cell lung cancer (NSCLC) is commonly limited by inadequate tumor sample. Plasma cell-free DNA (cfDNA) genotyping as a complementary test is specific but only moderately sensitive. Genotyping of cfDNA in pleural and pericardial effusion (PE-cfDNA) can further optimize molecular diagnostic yield and reduce the need for repeated biopsies. Objective: To prospectively validate droplet digital polymerase chain reaction (ddPCR) for detection of sensitizing EGFR variants and acquired Thr790Met variant (T790M) from PE-cfDNA in patients with NSCLC. Design, Setting, and Participants: This prospective diagnostic validation study was conducted between September 6, 2016, and January 21, 2021 at 2 major Hong Kong cancer centers. Patients with advanced NSCLC with both wild-type and variant EGFR status and exudative PE who underwent thoracocentesis or pericardiocentesis were randomly enrolled. Patients were either EGFR-tyrosine kinase inhibitor (TKI) naive (cohort 1) or EGFR-TKI treated but osimertinib naive (cohort 2). Enrolled patients underwent pleural- or pericardial-fluid and blood sampling for ddPCR EGFR testing. EGFR status results with ddPCR testing of PE-cfDNA and blood were compared with EGFR status in matched tumor biopsy or PE cell block samples. Main Outcomes and Measures: Specificity, sensitivity, and concordance of PE-cfDNA for detection of sensitizing EGFR variants and acquired T790M variation. Results: Among 171 patients (54% female) enrolled, there were 104 in cohort 1 and 67 in cohort 2. In cohort 1, 37% (38/102) were EGFR-variant positive; PE-cfDNA showed 97% sensitivity (95% CI, 92%-100%), 97% specificity (95% CI, 93%-100%), and 97% concordance (ĸ = 0.94, P < .001) for the detection of sensitizing EGFR variants. It was more sensitive than plasma in detecting sensitizing EGFR variants (97% vs 74%, P < .001). In cohort 2, 38% (15 of 40) were positive for the EGFR T790M variant; PE-cfDNA showed 87% sensitivity (95% CI, 69%-100%), 60% specificity (95% CI, 41%-79%), and 70% concordance (ĸ = 0.42, P = .004) for acquired T790M. The EGFR T790M variant was detected in 51% of PE-cfDNA vs 25% of PE cell block samples. Conclusions and Relevance: In this diagnostic study, EGFR variants could be accurately detected from PE-cfDNA in patients with NSCLC. More EGFR T790M was detected in PE-cfDNA than in guideline-recommended PE cell block preparations. These results suggest that PE-cfDNA can complement plasma and tumor genotyping for detecting EGFR variants in patients with advanced NSCLC.

Incorporating circulating tumor DNA detection to radiographic assessment for treatment response in advanced EGFR-mutant lung cancer.

PURPOSE: Response Evaluation Criteria in Solid Tumors (RECIST) has limitations but remains the conventional approach for tumor assessments. We explored whether circulating tumor DNA (ctDNA) can be incorporated into RECIST to provide a more robust measure of tumor response in advanced EGFR-mutant NSCLC. PATIENTS AND METHODS: In FASTACT-2, patients with advanced NSCLC received platinum/gemcitabine intercalated with erlotinib or placebo. EGFR mutation (tumor and plasma ctDNA) was detected using cobas v2. Patients selected for this hypothesis-generating analysis had EGFR mutations (on either tumor or plasma) at baseline and evaluable week 8 plasma EGFR. Week 8 ctDNA and radiologic response status were correlated with survival using landmark cox regression analyses. RESULTS: Of the original 451 patients, 86 (19.1%) were eligible for this analysis. 73% (n = 63) had detectable ctDNA at baseline. At week 8, 40% (n = 34) had radiologic partial response (PR), 60% (n = 52) had stable disease (SD); 80% (n = 69) had a ctDNA response (undetectable ctDNA). In patients who had initial PR and undetectable ctDNA, 93% (28/30) had ongoing PR subsequently at week 16. The median duration of response was 14.9 months. In patients with SD and undetectable ctDNA at week 8, 28% had radiological PR at week 16. Amongst those with PR at week 8, survival outcomes for those with undetectable vs detectable ctDNA were not statistically significant (PFS HR 0.49, 95%CI 0.16-1.48, p = 0.21; OS HR 0.39, 95%CI 0.13-1.19, p = 0.10). Amongst those with SD at week 8, there was significantly longer survival for those with undetectable vs detectable ctDNA (PFS HR 0.27, 95% CI 0.13-0.57, p < 0.0001; OS HR 0.40, 95% CI 0.20-0.80, p = 0.009). CONCLUSION: In patients with SD, undetectable ctDNA at week 8 correlated with survival improvement. Both radiologic and ctDNA responses are prognostic of PFS. Incorporation of ctDNA with RECIST may improve tumor response assessment in EGFR-mutant NSCLC.

Multiplexed immunofluorescence identifies high stromal CD68+PD-L1+ macrophages as a predictor of improved survival in triple negative breast cancer.

Triple negative breast cancer (TNBC) comprises 10-15% of all breast cancers and has a poor prognosis with a high risk of recurrence within 5 years. PD-L1 is an important biomarker for patient selection for immunotherapy but its cellular expression and co-localization within the tumour immune microenvironment and associated prognostic value is not well defined. We aimed to characterise the phenotypes of immune cells expressing PD-L1 and determine their association with overall survival (OS) and breast cancer-specific survival (BCSS). Using tissue microarrays from a retrospective cohort of TNBC patients from St George Hospital, Sydney (n = 244), multiplexed immunofluorescence (mIF) was used to assess staining for CD3, CD8, CD20, CD68, PD-1, PD-L1, FOXP3 and pan-cytokeratin on the Vectra Polaris™ platform and analysed using QuPath. Cox multivariate analyses showed high CD68+PD-L1+ stromal cell counts were associated with improved prognosis for OS (HR 0.56, 95% CI 0.33-0.95, p = 0.030) and BCSS (HR 0.47, 95% CI 0.25-0.88, p = 0.018) in the whole cohort and in patients receiving chemotherapy, improving incrementally upon the predictive value of PD-L1+ alone for BCSS. These data suggest that CD68+PD-L1+ status can provide clinically useful prognostic information to identify sub-groups of patients with good or poor prognosis and guide treatment decisions in TNBC.

Clinical utility of plasma EGFR mutation detection with quantitative PCR in advanced lung cancer: A meta-analysis.

OBJECTIVES: To assess the clinical utility of quantitative PCR (qPCR) assays, a routinely used test for detection of epidermal growth factor receptor (EGFR) mutation in circulating tumour DNA (ctDNA) in treatment-naive advanced lung cancer patients. MATERIALS AND METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) with individual patient data. Eligible RCTs compared EGFR-tyrosine kinase inhibitor (EGFR-TKI) and chemotherapy in first line setting for advanced lung cancer, and included tumour EGFR+ (tEGFR+) with paired ctDNA results using real-time (quantitative) PCR. We assessed the proportion of tEGFR + detected by ctDNA, and compared the effectiveness of EGFR-TKI versus chemotherapy in ctDNA + and ctDNA- subgroups. RESULTS: Six randomized clinical trials included 1058 tEGFR + patients with paired baseline EGFR ctDNA testing. Of these, 460 (43 %) tested ctDNA- (ctDNA+ 57 %). Progression-free survival was longer for EGFR-TKI versus chemotherapy for both ctDNA+ (HR 0.28; 95 % CI 0.22-0.36, p < 0.00001) and ctDNA- subgroups (HR 0.37; 95 % CI 0.28-0.49, p < 0.00001; p-interaction = 0.14). Objective response rate (odds ratio 6.21; 95 % CI 4.25-9.07, p < 0.00001 vs 6.44; 95 % CI 4.21-9.87, p < 0.00001) and overall survival (HR 0.82; 95 % CI 0.70-1.04 vs HR 0.77; 95CI% 0.59-1.00) similarly favoured EGFR-TKI in both ctDNA + and ctDNA- subgroups respectively. CONCLUSION: Our findings indicate that approximately two in five tissue EGFR mutation-positive patients will not be detected using a qPCR assay, but would still potentially benefit from highly effective EGFR-TKI treatment. A negative EGFR ctDNA result via qPCR testing is therefore insufficient to exclude benefit from EGFR-TKI. Attempts should be made to repeat EGFR testing with a tissue biopsy in this patient group. As newer ctDNA assays with better sensitivity become available, the clinical impact for any false negatives will remain an important consideration.

Tumour Stroma Ratio Assessment Using Digital Image Analysis Predicts Survival in Triple Negative and Luminal Breast Cancer.

We aimed to determine the clinical significance of tumour stroma ratio (TSR) in luminal and triple negative breast cancer (TNBC) using digital image analysis and machine learning algorithms. Automated image analysis using QuPath software was applied to a cohort of 647 breast cancer patients (403 luminal and 244 TNBC) using digital H&E images of tissue microarrays (TMAs). Kaplan-Meier and Cox proportional hazards were used to ascertain relationships with overall survival (OS) and breast cancer specific survival (BCSS). For TNBC, low TSR (high stroma) was associated with poor prognosis for both OS (HR 1.9, CI 1.1-3.3, p = 0.021) and BCSS (HR 2.6, HR 1.3-5.4, p = 0.007) in multivariate models, independent of age, size, grade, sTILs, lymph nodal status and chemotherapy. However, for luminal tumours, low TSR (high stroma) was associated with a favourable prognosis in MVA for OS (HR 0.6, CI 0.4-0.8, p = 0.001) but not for BCSS. TSR is a prognostic factor of most significance in TNBC, but also in luminal breast cancer, and can be reliably assessed using quantitative image analysis of TMAs. Further investigation into the contribution of tumour subtype stromal phenotype may further refine these findings.

The role of childhood generalized anxiety in the internalizing cluster.

BACKGROUND: Anxiety, depression and somatization (the internalizing cluster) are highly comorbid, prevalent and associated with significant individual and societal costs. Although prior studies have examined their natural course, there has been a little investigation into how symptoms unfold at the individual level. We examined the intraindividual (within-person) temporal patterning of symptom development and the impact of risk factors (sex, ethnicity, socioeconomic indicators, bullying victimization, child maltreatment) on symptom means and trajectories (between-person), comparing youth and parent reports. METHOD: Over a 7-year interval from age 11 to 17, children (n = 669; 54% girls; 79% White) and parents (89% mothers) reported on symptoms of anxiety and depression from age 11 and somatization from age 13. Autoregressive latent trajectory models with structured residuals were used to uncouple within- and between-person sources of variance. RESULTS: According to self-reports, generalized anxiety consistently predicted depression, while anxiety and depression consistently predicted somatization. Anxiety also had an indirect effect on somatization via depression. According to parent reports, there were several bidirectional effects between anxiety and depression and between depression and somatization. Experiences of abuse were consistent risk factors for self-reported internalizing symptoms, and across informants, girls had higher symptom means and rising trajectories compared to boys. CONCLUSION: Generalized anxiety plays an important role in adolescent depressive and somatic symptoms. Primary prevention of anxiety may be warranted to curb symptom continuity and the development of comorbidity. Research is needed to determine whether self-reports of anxiety should be prioritized over parent reports and continued efforts are needed to reduce bullying and child maltreatment.

Efficacy of immune checkpoint inhibitors in older adults with advanced stage cancers: A meta-analysis.

OBJECTIVES: There is uncertainty whether older patients derive a similar benefit from immune checkpoint inhibitors (ICI) as younger patients. We performed a meta-analysis of ICI trials in advanced cancers to better estimate treatment benefit in the older population. MATERIALS AND METHODS: We performed an electronic search for randomized trials of ICI, either as monotherapy or in combination with other agents. Hazard ratios (HR) for subgroups defined by different age cut-offs were extracted. Pooled overall survival (OS) treatment estimates were calculated using the inverse variance weighted method. RESULTS: In nineteen trials comparing ICI monotherapy versus non-ICI treatment, there was no significant treatment-age interaction (age ≥ 65 years: N = 6064, HR 0.73; age < 65 years: N = 7250, HR 0.79; P-interaction = 0.27). Findings were similar at older age cut-offs of 70 years (age ≥ 70 years: N = 433, HR = 0.93; age < 70 years: N = 169, HR = 0.95; P-interaction = 0.91) and 75 years (age ≥ 75 years: N = 139, HR = 0.75; age < 75 years: N = 1133, HR = 0.61; P-interaction = 0.72) respectively, and for trials of ICI combination therapy. CONCLUSION: ICI therapy improves OS in both younger and older patients with advanced cancers, and the magnitude of improvement does not depend on age. Patient selection for ICI therapy should be done based on performance status and adequate organ function independently of age.

Comparisons Between Adolescent Bullies, Victims, and Bully-Victims on Perceived Popularity, Social Impact, and Social Preference.

This study investigated the effect of bullying role, i.e., bully, victim, and bully-victim, on three measures of peer status; perceived popularity, social preference, and social impact. In addition to completing peer nominations for these measures of peer status, adolescents (n = 2,721) aged 11 to 16 years from 5 secondary schools completed an online survey that assessed bullying involvement (self- and peer-reported), self-esteem, and behavioral difficulties. Compared to uninvolved adolescents, all bullying roles had a greater social impact. Bullies scored higher than all other roles for perceived popularity, whereas victims and bully-victims were the lowest in social preference. These significant group comparisons remained when controlling for demographic variables, behavioral difficulties, self-esteem and prosocial behavior. Overall, the perceived popularity found for bullies suggests that these adolescents are socially rewarded by peers for their victimization of others. These findings highlight the need to address the whole peer system in raising the social status of those who are victimized, whilst reducing the rewards received by bullies for their behavior.

A Four-Year Prospective Study of Bullying, Anxiety, and Disordered Eating Behavior Across Early Adolescence.

We investigated the developmental pathways by which bullying perpetration and victimization, anxiety, and disordered eating behavior were related. Participants were drawn from the Canadian McMaster Teen Study. From Grade 5-8 (age 10-14), students (n = 657) were assessed on bullying involvement and symptoms of anxiety, and in Grade 7 and 8, students additionally completed a measure of clinically significant disordered eating behavior. Bullying victimization initiated a cascading effect on bullying perpetration, which subsequently led to disordered eating behavior. Anxiety had direct effects on disordered eating behavior at multiple time points and initiated a cascading effect on bullying victimization, and subsequently, perpetration. There was no evidence of moderation by sex. Bullying perpetration and anxiety may serve as early signals of eating pathology. Bullying prevention programs may attenuate the risk of disordered eating in both sexes, and the high continuity of disordered eating behavior suggests that early intervention is critical.

Body mass index, peer victimization, and body dissatisfaction across 7 years of childhood and adolescence: Evidence of moderated and mediated pathways.

Numerous studies have reported that children and adolescents who are overweight are more likely to get bullied, yet the literature is replete with methodological limitations. We examined the transactional associations between peer victimization and body mass index (BMI), considering potential mediating (body dissatisfaction) and moderating (biological sex) factors. Participants (n = 631) came from the McMaster Teen Study, where students were assessed annually between Grades 5-11, approximately half were girls (53.9%), and the majority were white (76.4%). Peer victimization (from Grade 5) and body dissatisfaction (from Grade 6) were self-reported by students, while parents reported their child's height and weight (from Grade 5). Cascade models were built up sequentially using path analysis across 2-year increments (Grades 5, 7, 9, and 11). The final model had excellent fit to the data (χ2  = 73.961, df = 66, p = 0.234). Grade 5 peer victimization had a direct effect on BMI across a 2-year period in girls (b = 0.59, SE = 0.21, p = 0.005) and boys (b = 0.82, SE = 0.30, p = 0.006), and an indirect effect on BMI via body dissatisfaction across a 4-year period (b = 0.074, 95% CI = 0.012-0.152, p = 0.036). At no point did BMI directly increase risk for peer victimization, yet there were indirect effects via body dissatisfaction among girls but not boys. Peer victimization and body dissatisfaction were proximally and longitudinally related at every time point and there was a transactional association in late-adolescence among girls but not boys. Targeting modifiable factors in the social (peer victimization) and psychological (body dissatisfaction) domains may limit accelerated weight gain and the health risks associated with excess adiposity.

The impact of ethnicity on efficacy and toxicity of cyclin D kinase 4/6 inhibitors in advanced breast cancer: a meta-analysis.

PURPOSE: Adding cyclin-dependent kinase (CDK) 4/6 inhibitor to endocrine therapy improves progression-free survival (PFS) in advanced breast cancer but the impact of ethnicity on efficacy and toxicity is unclear. We aimed to estimate the relative treatment efficacy and toxicity of endocrine therapy with and without CDK4/6 inhibitors, and compare between Asian/non-Asian subgroups. METHOD: This meta-analysis included published first-line randomized trials comparing CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy. Hazard ratios (HR) and 95% confidence intervals (CI) for the overall population and Asian/non-Asian subgroups were extracted. The inverse-variance-weighted method was used to pool treatment estimates of PFS. RESULTS: Four trials (N = 2499) were included. Patients received combination CDK4/6 inhibitor-endocrine therapy (N = 1441; ribociclib, [46.4%]; palbociclib, [30.8%]; or abemaciclib, [22.8%]) versus endocrine monotherapy (N = 1058). CDK4/6 inhibitor-endocrine therapy was associated with prolonged PFS compared with endocrine monotherapy (HR 0.56; 95% CI 0.50-0.62). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29-0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54-0.71, P < 0.0001). There was a significant treatment-by-ethnicity interaction (P = 0.002). Toxicity data by ethnic subgroup were only available from two trials (n = 1334) with no convincing evidence that the risk of toxicity between CDK4/6 inhibitor-endocrine therapy and endocrine monotherapy varied by ethnicity. CONCLUSION: Adding CDK4/6 inhibitor to endocrine therapy prolongs PFS compared to endocrine therapy alone as first-line treatment in advanced breast cancer. The magnitude of PFS benefit is ethnicity-dependent but there is no interethnic differences in relative treatment-related toxicities. These findings may assist in the design and interpretation of trials, inform economic analyses, and stimulate pharmacogenomic research.

Longitudinal Associations Among Bullying by Peers, Disordered Eating Behavior, and Symptoms of Depression During Adolescence.

Importance: Bullying by peers has been associated with disordered eating behavior and symptoms of depression among adolescents as both an antecedent and an outcome. Identification of the temporal pattern of associations among bullying by peers, disordered eating behavior, and depression in adolescence is needed for the optimal targeting of intervention and prevention. Objective: To assess the concurrent and longitudinal associations among bullying by peers, disordered eating behavior, and symptoms of depression using a cascade model that controlled for within-time and across-time (ie, stability paths) associations while examining cross-lag effects. Design, Setting, and Participants: In this 5-year longitudinal cohort study, 612 participants of the McMaster Teen Study were included. This ongoing Canadian study examines the associations among bullying, mental health, and educational outcomes. Data collection began in 2008 when students were in grade 5 (10 years of age) and have since been collected annually. Data analysis was performed between August 20 and October 18, 2017. Exposures: Bullying by peers was assessed in grades 7 to 11 using a composite measure of 5 items. Main Outcomes and Measures: Disordered eating behavior was assessed in grades 7 to 11 using the Short Screen for Eating Disorders, and depressive symptoms were assessed in grades 7 to 11 using the Behavior Assessment System for Children-Second Edition. Results: The 612 students included in the analytic sample had a mean age (SD) of 13.03 (0.38) years in grade 7; 331 (54.1%) were girls and 392 (71.1%) were white. Bullying by peers was concurrently associated with disordered eating behavior and depressive symptoms at every time point during the 5-year period (r range [SE], 0.15-0.48 [0.04-0.08]; P < .01). Disordered eating behavior was associated longitudinally with depressive symptoms at every time point (ß range [SE], 0.14-0.19 [0.06-0.08]; P < .02) and bullying by peers at 2 time points (ß range [SE], 0.12-0.22 [0.06-0.07]; P < .04) in girls and boys. Conclusions and Relevance: Bullying by peers was proximally associated with multiple psychopathologic symptoms, whereas symptoms of disordered eating behavior were a key risk factor for future depressive symptoms and bullying by peers. Interventions aimed at reducing problematic eating behavior in adolescents may attenuate the risk of future depressive symptoms and relational problems.

Predicting dating behavior from aggression and self-perceived social status in adolescence.

We investigated the longitudinal associations between self-reported aggression, self-perceived social status, and dating in adolescence using an intrasexual competition theoretical framework. Participants consisted of 536 students in Grade 9 (age 15), recruited from a community sample, who were assessed on a yearly basis until they were in Grade 11 (age 17). Adolescents self-reported their use of direct and indirect aggression, social status, and number of dating partners. A cross-lagged panel model that controlled for within-time covariance and across-time stability while examining cross-lagged pathways was used to analyze the data. The findings revealed that direct aggression did not predict dating behavior and was negatively associated with self-perceived social status in Grade 10. Self-perceived social status in Grade 9 was positively associated with greater use of indirect aggression in Grade 10. Regarding dating, in Grade 9, self-perceived social status positively predicted more dating partners the following year, while in Grade 10, it was higher levels of indirect aggression that predicted greater dating activity the following year. Overall, there were no significant sex differences in the model. The study supports the utility of evolutionary psychological theory in explaining peer aggression, and suggests that although social status can increase dating opportunities, as adolescents mature, indirect aggression becomes the most successful and strategic means of competing intrasexually and gaining mating advantages.

Bullying and negative appearance feedback among adolescents: Is it objective or misperceived weight that matters?

This study investigated (1) whether involvement in bullying as a bully, victim or bully-victim was associated with objectively measured overweight or underweight, or whether it was related to weight misperception (i.e., inaccurate perceptions), and (2) whether appearance-specific feedback mediated the relationship between bullying and weight misperception. In Stage 1, 2782 adolescents aged 11-16 years from British secondary schools were screened for peer bullying and victimisation. In Stage 2, 411 adolescents with weight and height data (objective n = 319, self-report n = 92) also self-reported on their weight perception and appearance-specific feedback. Neither bullying nor victimisation were related to objective underweight or overweight. Victims were at increased odds of overweight misperception, while bully-victims were at increased odds of underweight misperception. Additionally, there was an indirect effect of appearance feedback on overweight misperception in bully-victims. Both victims and bully-victims are at increased risk of weight misperception, posing further detrimental effects to their health and wellbeing.

Differences in the early stages of social information processing for adolescents involved in bullying.

Bullying victimization has commonly been associated with deficiencies in social information processing (SIP). In contrast, findings regarding bullying perpetration are mixed, with some researchers claiming that bullies may have superior SIP abilities than victimized or uninvolved youth. This study investigated the effects of bullying and victimization on early SIP; specifically the recognition and interpretation of social information. In stage 1, 2,782 adolescents (11-16 years) were screened for bullying involvement, and in stage 2, 723 of these participants (mean age = 13.95) were assessed on measures of emotion recognition, hostile attribution bias, and characterological self-blame (CSB). No associations between bullying and early SIP were found. In contrast, victimization was associated with more hostile attribution bias and CSB attributions. Girls performed better than boys on the emotion recognition task while boys showed greater hostile attribution biases. No interaction effects of bullying or victimization with gender were found. Follow-up categorical analyses that considered pure victims versus victims who also bullied (bully-victims) on SIP, found a similar pattern of findings. These findings suggest that those who purely bully others are neither superior nor deficient in the early stages of SIP. Victimized adolescents, however, show biases in their interpretations of social situations and the intentions of others. These biases may lead to maladaptive responses and may increase risk for further victimization by peers.