Acceptance and commitment therapy for symptom interference in metastatic breast cancer patients: a pilot randomized trial

PURPOSE: Breast cancer is the leading cause of cancer mortality in women worldwide. With medical advances, metastatic breast cancer (MBC) patients often live for years with many symptoms that interfere with activities. However, there is a paucity of efficacious interventions to address symptom-related suffering and functional interference. Thus, this study examined the feasibility and preliminary efficacy of telephone-based acceptance and commitment therapy (ACT) for symptom interference with functioning in MBC patients. METHODS: Symptomatic MBC patients (N = 47) were randomly assigned to six telephone sessions of ACT or six telephone sessions of education/support. Patients completed measures of symptom interference and measures assessing the severity of pain, fatigue, sleep disturbance, depressive symptoms, and anxiety. RESULTS: The eligibility screening rate (64%) and high retention (83% at 8 weeks post-baseline) demonstrated feasibility. When examining within-group change, ACT participants showed decreases in symptom interference (i.e., fatigue interference and sleep-related impairment; Cohen's d range = - 0.23 to - 0.31) at 8 and 12 weeks post-baseline, whereas education/support participants showed minimal change in these outcomes (d range = - 0.03 to 0.07). Additionally, at 12 weeks post-baseline, ACT participants showed moderate decreases in fatigue and sleep disturbance (both ds = - 0.43), whereas education/support participants showed small decreases in these outcomes (ds = - 0.24 and - 0.18 for fatigue and sleep disturbance, respectively). Both the ACT and education/support groups showed reductions in depressive symptoms (ds = - 0.27 and - 0.28) at 12 weeks post-baseline. Group differences in all outcomes were not statistically significant. CONCLUSIONS: ACT shows feasibility and promise in improving fatigue and sleep-related outcomes in MBC patients and warrants further investigation

A Computational Statistics Approach to Evaluate Blood Biomarkers for Breast Cancer Risk Stratification

Breast cancer is the second leading cause of cancer mortality among women. Mammography and tumor biopsy followed by histopathological analysis are the current methods to diagnose breast cancer. Mammography does not detect all breast tumor subtypes, especially those that arise in younger women or women with dense breast tissue, and are more aggressive. There is an urgent need to find circulating prognostic molecules and liquid biopsy methods for breast cancer diagnosis and reducing the mortality rate. In this study, we systematically evaluated metabolites and proteins in blood to develop a pipeline to identify potential circulating biomarkers for breast cancer risk. Our aim is to identify a group of molecules to be used in the design of portable and low-cost biomarker detection devices. We obtained plasma samples from women who are cancer free (healthy) and women who were cancer free at the time of blood collection but developed breast cancer later (susceptible). We extracted potential prognostic biomarkers for breast cancer risk from plasma metabolomics and proteomics data using statistical and discriminative power analyses. We pre-processed the data to ensure the quality of subsequent analyses, and used two main feature selection methods to determine the importance of each molecule. After further feature elimination based on pairwise dependencies, we measured the performance of logistic regression classifier on the remaining molecules and compared their biological relevance. We identified six signatures that predicted breast cancer risk with different specificity and selectivity. The best performing signature had 13 factors. We validated the difference in level of one of the biomarkers, SCF/KITLG, in plasma from healthy and susceptible individuals. These biomarkers will be used to develop low-cost liquid biopsy methods toward early identification of breast cancer risk and hence decreased mortality. Our findings provide the knowledge basis needed to proceed in this direction

Metastatic breast cancer patients' expectations and priorities for symptom improvement

PURPOSE: Little research has examined cancer patients' expectations, goals, and priorities for symptom improvement. Thus, we examined these outcomes in metastatic breast cancer patients to provide patients' perspectives on clinically meaningful symptom improvement and priorities for symptom management. METHODS: Eighty women with metastatic breast cancer participated in a survey with measures of comorbidity, functional status, engagement in roles and activities, distress, quality of life, and the modified Patient-Centered Outcomes Questionnaire that focused on 10 common symptoms in cancer patients. RESULTS: On average, patients reported low to moderate severity across the 10 symptoms and expected symptom treatment to be successful. Patients indicated that a 49% reduction in fatigue, 48% reduction in thinking problems, and 43% reduction in sleep problems would represent successful symptom treatment. Cluster analysis based on ratings of the importance of symptom improvement yielded three clusters of patients: (1) those who rated thinking problems, sleep problems, and fatigue as highly important, (2) those who rated pain as moderately important, and (3) those who rated all symptoms as highly important. The first patient cluster differed from other subgroups in severity of thinking problems and education. CONCLUSIONS: Metastatic breast cancer patients report differing symptom treatment priorities and criteria for treatment success across symptoms. Considering cancer patients' perspectives on clinically meaningful symptom improvement and priorities for symptom management will ensure that treatment is consistent with their values and goals

Estimating breast tissue-specific DNA methylation age using next-generation sequencing data

Background DNA methylation (DNAm) age has been widely accepted as an epigenetic biomarker for biological aging. Emerging evidence suggests that DNAm age can be tissue-specific and female breast tissue ages faster than other parts of the body. The Horvath clock, which estimates DNAm age across multiple tissues, has been shown to be poorly calibrated in breast issue. We aim to develop a model to estimate breast tissue-specific DNAm age. Methods Genome-wide DNA methylation sequencing data were generated for 459 normal, 107 tumor, and 45 paired adjacent-normal breast tissue samples. We determined a novel set of 286 breast tissue-specific clock CpGs using penalized linear regression and developed a model to estimate breast tissue-specific DNAm age. The model was applied to estimate breast tissue-specific DNAm age in different breast tissue types and in tumors with distinct clinical characteristics to investigate cancer-related aging effects. Results Our estimated breast tissue-specific DNAm age was highly correlated with chronological age (r = 0.88; p = 2.9 × 10−31) in normal breast tissue. Breast tumor tissue samples exhibited a positive epigenetic age acceleration, where DNAm age was on average 7 years older than respective chronological age (p = 1.8 × 10−8). In age-matched analyses, tumor breast tissue appeared 12 and 13 years older in DNAm age than adjacent-normal and normal breast tissue (p = 4.0 × 10−6 and 1.0 × 10−6, respectively). Both HER2+ and hormone-receptor positive subtypes demonstrated significant acceleration in DNAm ages (p = 0.04 and 3.8 × 10−6, respectively), while no apparent DNAm age acceleration was observed for triple-negative breast tumors. We observed a non-linear pattern of epigenetic age acceleration with breast tumor grade. In addition, early-staged tumors showed a positive epigenetic age acceleration (p = 0.003) while late-staged tumors exhibited a non-significant negative epigenetic age acceleration (p = 0.10). Conclusions The intended applications for this model are wide-spread and have been shown to provide biologically meaningful results for cancer-related aging effects in breast tumor tissue. Future studies are warranted to explore whether breast tissue-specific epigenetic age acceleration is predictive of breast cancer development, treatment response, and survival as well as the clinical utility of whether this model can be extended to blood samples

Protocol of a randomized trial of acceptance and commitment therapy for fatigue interference in metastatic breast cancer

Fatigue interference with activities, mood, and cognition is one of the most prevalent and distressing concerns of metastatic breast cancer patients. To date, there are no evidence-based interventions for reducing fatigue interference in metastatic breast cancer and other advanced cancer populations. In pilot studies, Acceptance and Commitment Therapy (ACT) has shown potential for reducing symptom-related suffering in cancer patients. The current Phase II trial seeks to more definitively examine the efficacy of telephone-based ACT for women with metastatic breast cancer who are experiencing fatigue interference. In this trial, 250 women are randomly assigned to either the ACT intervention or an education/support control condition. Women in both conditions attend six weekly 50-min telephone sessions. The primary aim of this study is to test the effect of telephone-based ACT on fatigue interference. Secondary outcomes include sleep interference, engagement in daily activities, and quality of life. Outcomes are assessed at baseline, 2 weeks post-intervention, and 3 and 6 months post-intervention. This trial also examines whether increases in psychological flexibility, defined as full awareness of the present moment while persisting in behaviors aligned with personal values, account for the beneficial effect of ACT on fatigue interference. After demonstrating ACT's efficacy, the intervention can be widely disseminated to clinicians who care for metastatic breast cancer patients. Our findings will also inform future ACT trials with various cancer populations and functional outcomes

Relations of Mindfulness and Illness Acceptance With Psychosocial Functioning in Patients With Metastatic Breast Cancer and Caregivers

Objectives: To examine relationships in mindfulness and illness acceptance and psychosocial functioning in patients with metastatic breast cancer and their family caregivers. Sample & setting: 33 dyads from an academic cancer center in the United States. Methods & variables: Participants completed questionnaires on mindfulness, illness acceptance, relationship quality, anxiety, and depressive symptoms. Dyadic, cross-sectional data were analyzed using actor-partner interdependence models. Results: Greater nonjudging, acting with awareness, and illness acceptance among caregivers were associated with patients' and caregivers' perceptions of better relationship quality. Higher levels of these processes were associated with reduced anxiety and depressive symptoms in patients and caregivers. Implications for nursing: Aspects of mindfulness and illness acceptance in dyads confer benefits that are primarily intrapersonal in nature. Nurses may consider introducing mindfulness and acceptance-based interventions to patients and caregivers with adjustment difficulties

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERα)-positive (ER+) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER+ breast cancer cells. FFAs activated both the ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERα and mTOR signaling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER+ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERα and mTOR signaling cross-talk would be tested to prevent ER+ breast cancers in obese postmenopausal women

Next-generation transcriptome sequencing of the premenopausal breast epithelium using specimens from a normal human breast tissue bank

Introduction Our efforts to prevent and treat breast cancer are significantly impeded by a lack of knowledge of the biology and developmental genetics of the normal mammary gland. In order to provide the specimens that will facilitate such an understanding, The Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center (KTB) was established. The KTB is, to our knowledge, the only biorepository in the world prospectively established to collect normal, healthy breast tissue from volunteer donors. As a first initiative toward a molecular understanding of the biology and developmental genetics of the normal mammary gland, the effect of the menstrual cycle and hormonal contraceptives on DNA expression in the normal breast epithelium was examined. Methods Using normal breast tissue from 20 premenopausal donors to KTB, the changes in the mRNA of the normal breast epithelium as a function of phase of the menstrual cycle and hormonal contraception were assayed using next-generation whole transcriptome sequencing (RNA-Seq). Results In total, 255 genes representing 1.4% of all genes were deemed to have statistically significant differential expression between the two phases of the menstrual cycle. The overwhelming majority (221; 87%) of the genes have higher expression during the luteal phase. These data provide important insights into the processes occurring during each phase of the menstrual cycle. There was only a single gene significantly differentially expressed when comparing the epithelium of women using hormonal contraception to those in the luteal phase. Conclusions We have taken advantage of a unique research resource, the KTB, to complete the first-ever next-generation transcriptome sequencing of the epithelial compartment of 20 normal human breast specimens. This work has produced a comprehensive catalog of the differences in the expression of protein-coding genes as a function of the phase of the menstrual cycle. These data constitute the beginning of a reference data set of the normal mammary gland, which can be consulted for comparison with data developed from malignant specimens, or to mine the effects of the hormonal flux that occurs during the menstrual cycle