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.

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.

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.

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.

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.

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.

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.

Does psychological functioning mediate the relationship between bullying involvement and weight loss preoccupation in adolescents? A two-stage cross-sectional study.

BACKGROUND: Adolescent bullying is associated with a range of adversities for those who are bullied i.e., victims and bully-victims (e.g., those who bully others and get victimised), including reduced psychological functioning and eating disorder symptoms. Bullies are generally well-adjusted psychologically, but previous research suggests that bullies may also engage in problematic diet behaviours. This study investigates a) whether adolescents involved in bullying (bullies, victims, bully-victims) are at increased risk of weight loss preoccupation, b) whether psychological functioning mediates this relationship and c) whether sex is a key moderator. METHOD: A two-stage design was used. In stage 1, adolescents (n = 2782) from five UK secondary schools were screened for bullying involvement using self and peer reports. In stage 2, a sample of bullies, victims, bully-victims and uninvolved adolescents (n = 767) completed a battery of assessments. The measures included the eating behaviours component of the Child and Adolescent Psychiatric Assessment, which was reduced to one factor (weight loss preoccupation) and used as the outcome variable. Measures of self-esteem, body-esteem and emotional problems were reduced to a latent (mediator) variable of psychological functioning. Multi-group analysis examined the effects of sex and all models were adjusted for covariates (BMI, pubertal stage, age, parental education and ethnicity). RESULTS: Bullies, victims and bully-victims were at increased risk of weight loss preoccupation compared to adolescents uninvolved in bullying. The mechanism by which bullying involvement related to increased weight loss preoccupation varied by bullying role: in bullies the effect was direct, in victims the effect was indirect (via reduced psychological functioning) and in bully-victims the effect was both direct and indirect. Sex significantly moderated the relationship in bullies: weight loss preoccupation was only statistically significant in bullies who were boys. CONCLUSION: Bullying involvement during adolescence is associated with weight loss preoccupation. Bullies are likely driven by a desire to increase attractiveness and social status; whereas weight loss preoccupation in bullied adolescents may have maladaptive influences on diet and exercise behaviours due to its association with reduced psychological functioning. Future research should consider peer victimisation as a potential modifiable risk factor for reduced psychological functioning and weight loss preoccupation, which if targeted, may help to prevent maladaptive diet and exercise behaviours.

Cyberbullying: a storm in a teacup?

Cyberbullying has been portrayed as a rising 'epidemic' amongst children and adolescents. But does it create many new victims beyond those already bullied with traditional means (physical, relational)? Our aim was to determine whether cyberbullying creates uniquely new victims, and whether it has similar impact upon psychological and behavioral outcomes for adolescents, beyond those experienced by traditional victims. This study assessed 2745 pupils, aged 11-16, from UK secondary schools. Pupils completed an electronic survey that measured bullying involvement, self-esteem and behavioral problems. Twenty-nine percent reported being bullied but only 1% of adolescents were pure cyber-victims (i.e., not also bullied traditionally). Compared to direct or relational victims, cyber-victimization had similar negative effects on behavior (z = -0.41) and self-esteem (z = -0.22) compared to those not involved in bullying. However, those bullied by multiple means (poly-victims) had the most difficulties with behavior (z = -0.94) and lowest self-esteem (z = -0.78). Cyberbullying creates few new victims, but is mainly a new tool to harm victims already bullied by traditional means. Cyberbullying extends the reach of bullying beyond the school gate. Intervention strategies against cyberbullying may need to include approaches against traditional bullying and its root causes to be successful.

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.

Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response.

BACKGROUND: The oncogenic PI3K/Akt/mTOR pathway is frequently activated in HCC. Data on the mTOR inhibitor, temsirolimus, is limited in HCC patients with concomitant chronic liver disease. The objectives of this study were: (1) In phase I, to determine DLTs and MTD of temsirolimus in HCC patients with chronic liver disease; (2) In phase II, to assess activity of temsirolimus in HCC, and (3) to explore potential biomarkers for response. METHODS: Major eligibility criteria included histologically confirmed advanced HCC and adequate organ function. In Phase I part of the study, temsirolimus was given weekly in 3-weekly cycle; dose levels were 20 mg (level 1), 25 mg (level 2) and 30 mg (level 3). The MTD was used in the subsequent phase II part; the primary endpoint was PFS and secondary endpoints were response and OS. In addition, exploratory analysis was conducted on pre-treatment tumour tissues to determine stathmin, pS6, pMTOR or p-AKT expressions as potential biomarkers for response. Overall survival and PFS were calculated using the Kaplan-Meier method. Reassessment CT scans were done every 6 weeks. All adverse events were reported using CTCAE v3. RESULTS: The Phase I part consisted of 19 patients, 2 of 6 patients at level 3 experienced DLT; dose level 2 was determined to be the MTD. The phase II part consisted of 36 patients. Amongst 35 assessable patients, there were 1 PR, 20 SD and 14 PD. Overall, the median PFS was 2.83 months (95% C.I. 1.63-5.24). The median OS was 8.89 months (95% C.I. 5.89-13.30). Grade ≥ 3 that occurred in > 10% of patients included thrombocytopenia (4) and hyponatraemia (4). Exploratory analysis revealed that disease stabilization (defined as CR + PR + SD > 12 weeks) in tumours having high and low pMTOR H-scores to be 70% and 29% respectively (OR 5.667, 95% CI 1.129-28.454, p = 0.035). CONCLUSIONS: In HCC patients with chronic liver disease, the MTD of temsirolimus was 25 mg weekly in a 3-week cycle. The targeted PFS endpoint was not reached. However, further studies to identify appropriate patient subgroup are warranted. TRIAL REGISTRATION: This study has been registered in ClinicalTrials.gov (Id: NCT00321594) on 1 December 2010.

Dacomitinib for the treatment of advanced or metastatic non-small-cell lung cancer.

Dacomitinib (PF-00299804) is a second-generation irreversible HER tyrosine kinase inhibitor (TKI). In preclinical studies, dacomitinib has demonstrated anti-tumor activity in lung cancer cell lines with sensitive and resistant EGFR mutations (including the T790 mutation). Safety and well tolerability of dacomitinib were demonstrated in Phase I studies with stomatitis, diarrhea and skin toxicities being the dose-limiting toxicities. The maximum tolerated dose was established to be 45 mg/day. In Phase II and III studies, dacomitinib has shown clinical activity in both HER tyrosine kinase-naive and HER tyrosine kinase failure settings. Further clinical trials are underway to evaluate the efficacy of dacomitinib in non-small-cell lung cancer.

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.

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.

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.