Assessing relinquishment of positivity as a central symptom bridging anxiety and depression.

Anxiety and depression are often comorbid and chronic disorders. Previous research indicates that positivity relinquishment is a moderator of anxiety and depression, such that only anxious individuals who endorsed relinquishing positivity were also depressed. We sought to extend those findings by conducting three network analyses with self-report measures of anxiety, depression, activity avoidance, and perceived positivity of avoided activities (N = 104). We pre-registered our hypothesis for the first two networks that relinquishment of positivity would emerge as a central bridge symptom between anxiety and depressive symptoms. After combining redundant nodes, we estimated three networks and investigated the bridge symptoms in each network. Relinquishment of positivity bridged the symptom clusters in the first network, and avoidance of positivity was found to bridge the two symptom clusters of anxiety and depression in networks two and three. Additionally, an anhedonia circuit was uncovered in all three networks in which loss of interest/worthlessness, loss of energy, and loss of pleasure/pessimism connected to anxiety through relinquishment or avoidance. Our findings suggest that both relinquishment of positivity as well as avoidance of positivity could be potential pathways explaining the development and maintenance of anxiety and depression and should be properly targeted in treatment.

Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

How etiological beliefs contribute to the structure of depression symptom networks.

OBJECTIVES: Each person possesses a unique view surrounding depressive symptomology and etiology that is shaped by idiosyncratic experiences. However, the influence that subjective etiological beliefs regarding a person's depressive symptoms have on actual symptom presentation and organization is seldom considered. METHODS: The current study employed network analytic techniques to examine how subjective views surrounding the cause of depressive symptoms altered actual symptom presentation networks. Additionally, the interaction between depressive symptoms and various etiological beliefs was examined. RESULTS: The results revealed that characterological beliefs, representing the idea that depression is caused by an internal sense of self, are strongly connected to a negative view of self, as well as a saddened mood. Additionally, the characterological beliefs node exhibited the greatest node predictability in its respective network, as well as in an omnibus network consisting of all depression symptoms and potential etiological beliefs. Whereas an achievement-based view of depression has a strong connection with concentration difficulties, a physical view of depression tends to form strong connections with physically based depressive symptoms. CONCLUSION: Subjective views regarding the cause of depression have the potential to influence symptom presentation and organization within a network, which may influence a person's willingness to engage in treatment or specific treatment preferences.

Mapping the Relationship between Health-related Beliefs, Fear, Avoidance, and Depression: Lessons from the Pandemic and Beyond.

The COVID-19 pandemic brought a mental health crisis, with depression symptoms increasing nearly three-fold compared to pre-pandemic levels. To explain this surge and to outline related novel treatment targets for post-pandemic psychiatric interventions, the current study examined cognitive, emotional, and behavioral predictors of depression (in the context of the recent pandemic). Participants completed measures assessing perceived danger, perceived infectiousness, and fear of the coronavirus (COVID-19). Participants also reported symptoms of depression and behavioral tendencies: pandemic-related compulsive checking, cleaning, and avoidance (of activities, situations, places, and people). A multiple mediation model revealed that the relationship between perceived infectiousness of the virus and depression was atemporally mediated by fear of the virus and pandemic-related avoidance of activities, situations, places, and people. Furthermore, avoidance played a uniquely important role in the mediation model. First, it directly mediated the relationship between perceived infectiousness and depression, even when omitting fear from the model. Second, avoidance was a discriminant predictor of depression, as neither pandemic-related checking and reassurance-seeking nor cleaning behavior mediated the relationship between cognition and depressive symptoms. Clinical implications are discussed, including how addressing the relationship between anxiety about viral infections and depression can prospectively increase treatment success as we move beyond the pandemic.

Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

BACKGROUND: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. RESULTS: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10-4 (range 7.9 × 10-7-4.9 × 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12. CONCLUSIONS: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.

Does grit protect against the adverse effects of depression on academic achievement?

Depressive symptoms have been shown to be negatively related to academic achievement, as measured by grade point average (GPA). Grit, or the passion for and the ability to persevere toward a goal despite adversity, has been linked to GPA. Thus, grit may potentially buffer against the negative effects of depressive symptoms in relation to academic achievement. However, social desirability may might impact the validity of grit when assessed by self-report measures, so how these constructs are all related is unknown. The current study explored the relationship between depressive symptoms, grit, social desirability, and GPA among University students (N = 520) in the United States using a cross-sectional design. We conducted a moderated-moderation model to examine how social desirability moderated the relationship between depressive symptoms, grit, and GPA. Findings replicated prior work and indicated negative relationships between depressive symptoms and social desirability with GPA and a positive relationship, albeit non-significant, between grit and GPA. However, results suggest that grit did not moderate the relationship between depressive symptoms and GPA when including social desirability in the model. Future research should investigate this relationship in a longitudinal setting to further examine how grit and depressive symptoms influence one another in academic domains.

Longitudinal and experimental investigations of implicit happiness and explicit fear of happiness.

ABSTRACTSome individuals devalue positivity previously associated with negativity (Winer & Salem, 2016). Positive emotions (e.g. happiness) may be seen as threatening and result in active avoidance of future situations involving positivity. Although some self-report measures can capture emotions of happiness-averse individuals, they are not always capable of capturing automatic processing. Thus, we examined the association between implicitly-assessed happiness and explicit (i.e. self-reported) fear of happiness in three studies. In Study 1, participants completed the Fear of Happiness Scale (FHS) and an implicit measure of emotions at four-time points over approximately one year. The implicit measure required participants to choose which emotion (i.e. anger, fear, happiness, sadness, or none) best corresponded to 20 individual Chinese characters. In Studies 2 and 3, we utilized an experimental design, implementing a mood induction to emphasise the relationship between explicit fear of happiness and implicitly-assessed happiness. Participants completed the FHS and chose which emotion they believed the artist tried to convey in 20 abstract images. Results indicated that greater self-reported fear of happiness was related to reduced implicit happiness. Findings from these studies provide compound evidence that individuals who hold negative views of positivity may process implicit happiness in a devaluative manner.

Recalling Self-efficacious Memories Reduces COVID-19-Related Fear.

Purpose: Manipulating perceived self-efficacy can mitigate the negative impact of trauma and increase ability to adapt to stress. It is possible that a similar domain-based manipulation aimed at anxiety around the pandemic might mitigate the negative mental health impact of COVID-19. The current experimental study assessed whether a self-efficacy induction would be effective in reducing COVID-19 distress. Methods: Participants were randomized to a self-efficacy autobiographical memory induction or control condition. We hypothesized that individuals in the self-efficacy group would exhibit lower levels of fear on an implicit measure of emotional states following exposure to COVID-19-related stimuli. Results: A significant increase in general self-efficacy and self-confidence was found in the self-efficacy group from pre- to post-induction. Individuals in the self-efficacy group had significantly lower levels of fear counts on the implicit measure of emotional states than the control group following exposure to COVID-19-related stimuli. Conclusions: Results suggest that (1) self-efficacy can be increased among individuals with high levels of COVID-19-related distress using an autobiographical memory induction and (2) doing so reduces fear processing among these individuals when exposed to COVID-19 stimuli. This is relevant for future intervention as it reveals a possible mechanism for reducing and recovering from COVID-19-related distress. Supplementary Information: The online version contains supplementary material available at 10.1007/s10608-023-10377-6.

A network analytic investigation of avoidance, dampening, and devaluation of positivity.

BACKGROUND AND OBJECTIVES: Reward Devaluation Theory suggests that devaluation of positivity may be integral in understanding depression (Winer & Salem, 2016). Specifically, the anticipatory (e.g., fear of happiness) and responsive (e.g., dampening) behaviors related to the processing of positivity may play a role in the development and maintenance of depression. METHODS: The goal of this study was to examine the potential overlap between measures that operationalize positivity avoidance, two Fear of Happiness Scales (Gilbert et al., 2012; Joshanloo, 2013), as well as positivity dampening, measured via the dampening subscale of the Responses to Positive Affect Questionnaire (Feldman et al., 2008). Network and community analyses were employed to examine the extent to which the items of these measures clustered into their parent measures and investigate the dynamic interactions between items. RESULTS: The results of the community analysis revealed that the three self-report measures overall clustered into their parent measures, except for the Gilbert et al. (2012) Fear of Happiness Scale, which clustered into two separate communities. The most influential nodes represented the concept that good feelings are often followed by negative outcomes. Additionally, nodes related to the theme of fear of letting oneself become happy emerged as the strongest bridge nodes. LIMITATIONS: One limitation of this study is the use of a cross-sectional design; thus, causality cannot be inferred, but the results can guide future longitudinal network designs. CONCLUSIONS: These findings demonstrate how anticipatory avoidance and responsive dampening may influence depression, thus providing evidence for unique targets for treatment.

Individuals fearing positivity do not perceive positive affect treatments as strong fits: A novel experimental finding and replication.

BACKGROUND AND OBJECTIVES: Positive affect treatments, which hold great promise to connect with those who are otherwise resistant to depression treatments, attempt to upregulate positive emotions. These treatments have potential advantages over standard therapies because they target cross-diagnostic core symptoms (e.g., anhedonia) that may respond better to interventions aimed at increased positivity. However, the extent to which these treatments are a perceived fit by individuals for whom they were developed (i.e., individuals who are afraid of, avoid, or experience less positivity) is unclear. METHODS: We conducted two independent studies utilizing a cross-sectional, experimental design to examine perceived treatment fit. Participants (Study 1: N = 416; Study 2: N = 321) read counterbalanced treatment descriptions of (1) positive affect treatment and (2) psychodynamic psychotherapy and answered questions regarding perceived treatment fit, effectiveness, and preference of the two treatments. RESULTS: Our findings suggest that individuals fearful of happiness perceived a prospective depression treatment specifically targeting positivity as a poorer fit, demonstrating an opposite pattern to the overall samples' treatment preference in both studies. Thus, as predicted by Reward Devaluation Theory, those fearing positivity exhibited avoidance behaviors for treatments that are to an extent designed, and might otherwise be most effective, for them. LIMITATIONS: The current study utilized a college student sample. CONCLUSION: These empirical findings may ultimately inform psychoeducation of why positive affect treatments, which are in direct contrast with clients' preferences, may be the very treatments they need the most.

Using theory to guide exploratory network analyses.

The use of exploratory network analysis has increased in psychopathology research over the past decade. A benefit of exploratory network analysis is the wealth of information it can provide; however, a single analysis may generate more inferences than what can be discussed in one manuscript (e.g., centrality indices of each node). This necessitates that authors choose which results to discuss in further detail and which to omit. Without a guide for this process, the likelihood of a biased interpretation is high. We propose that the integration of theory throughout the research process makes the interpretation of exploratory networks more manageable for the researcher and more likely to result in an interpretation that advances science. The goals of this paper are to differentiate between exploratory and confirmatory network analyses, discuss the utility of exploratory work, and provide a practical framework that uses theory as a guide to interpret exploratory network analyses.

Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.

BACKGROUND: In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB. PATIENTS AND METHODS: HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized. RESULTS: Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. CONCLUSIONS: With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

How we treat HER2-positive brain metastases.

Overexpression of the human epidermal growth factor 2 (HER2)/neu glycoprotein receptor in breast cancer is associated with increased risk of brain metastases, especially in patients with advanced disease. Improvements in the treatment of HER2-positive breast cancer has led to prolonged survival of patients with advanced disease, but the prevention and management of central nervous system metastases still poses unique clinical challenges given the associated morbidity and mortality of this site of disease. HER2-positive brain metastases are treated with surgery, radiation (stereotactic radiosurgery or whole brain radiotherapy), and systemic therapies, and are best managed by an experienced multidisciplinary team. The present article aims to provide an overview to our approach to treatment of HER2-positive brain metastases, including a review of agents with central nervous system activity, as well as management suggestions for several nuanced clinical scenarios.

Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.

The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the far-reaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis.

BACKGROUND: Guidelines recommend atezolizumab plus nab-paclitaxel (A + nP) for first-line treatment of unresectable, locally advanced, or metastatic triple-negative breast cancer expressing programmed death-ligand 1 (PD-L1) on tumor-infiltrating immune cells (IC), based on IMpassion130. We report the final overall survival (OS) and safety of that study as per the prespecified analysis plan. PATIENTS AND METHODS: Patients were randomized to nP 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) with atezolizumab 840 mg (A + nP) or placebo (P + nP; days 1 and 15), until progression or unacceptable toxicity. Coprimary endpoints were progression-free survival [intention-to-treat (ITT) and PD-L1 IC-positive populations] and OS (tested hierarchically in the ITT population and, if significant, in the PD-L1 IC-positive population). RESULTS: Each arm comprised 451 patients; 666 (73.8%) had died by the final OS analysis cut-off (median follow-up, 18.8 months; interquartile range, 8.9-34.7 months). Median OS in the ITT population was 21.0 months [95% confidence interval (CI), 19.0-23.4 months] with A + nP, and 18.7 months (95% CI, 16.9-20.8 months) with P + nP [stratified hazard ratio (HR), 0.87; 95% CI, 0.75-1.02; P = 0.077]. Exploratory analysis in the PD-L1 IC-positive population showed a median OS of 25.4 months (95% CI, 19.6-30.7 months) with A + nP (n = 185) and 17.9 months (95% CI, 13.6-20.3 months) with P + nP (n = 184; stratified HR, 0.67; 95% CI, 0.53-0.86). Safety outcomes were consistent with previous analyses and the known toxicity profiles of each agent. Immune-mediated adverse events of special interest were reported in 58.7% and 41.6% of patients treated with A + nP and P + nP, respectively. CONCLUSION: Although the OS benefit in the ITT population was not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed with A + nP in PD-L1 IC-positive patients, consistent with prior interim analyses. This combination remained safe and tolerable with longer follow-up.