Recent translational research: antiangiogenic therapy for breast cancer – where do we stand?

The central importance of angiogenesis and our understanding of how new blood vessels are formed have led to the development of novel antiangiogenic therapies. Although the number of agents in development has grown exponentially, only one phase III trial in breast cancer has been completed. In that study the addition of bevacizumab to capecitabine did not extend the progression-free survival of patients with refractory disease as compared with capecitabine monotherapy. Early enthusiasm for antiangiogenic therapy must give way to clinical reality. Our challenge now is to exploit better the activity of antiangiogenic agents seen in the early clinical studies

Cognitive Appraisals, Coping and Depressive Symptoms in Breast Cancer Patients

Depression in breast cancer patients and survivors is related to negative disease outcomes and worse quality of life. Factors that explain this depression can serve as targets of intervention. This study, guided by the Transactional Theory of Stress, examined the relationship between cognitive appraisals, coping strategies and depressive symptoms in a group of women with mostly advanced-stage breast cancer (N = 65), who scored mostly within the normal range for depressive symptoms. Path analysis was used to determine the relationships among variables, measured with the Cognitive Appraisals of Illness Scale, the Ways of Coping Questionnaire and the Center for Epidemiological Studies Depression Scale. The results of the path analysis showed that higher appraisals of harm/loss and greater use of escape–avoidance coping predicted higher depressive symptoms. These findings enhance the prediction of depression among breast cancer patients and suggest the need to examine cognitive appraisals when attempting to understand depressive symptoms

The Implications of Insurance Status on Presentation, Surgical Management and Mortality among Non-Metastatic Breast Cancer Patients in Indiana

Background The National Breast and Cervical Cancer Early Detection Program seeks to reduce health care disparities by providing uninsured and underinsured women access to screening mammograms. The objective of this study is to identify the differences in presentation, surgical management, and mortality among nonmetastatic uninsured patients diagnosed through Indiana's Breast and Cervical Cancer Program compared with patients with private and government (Medicare or Medicaid) insurance. Methods Study data were obtained using the Indiana state cancer registry and Indiana's Breast and Cervical Cancer Program. Women aged 50 to 64 with an index diagnosis of stage 0 to III breast cancer from January 1, 2006 to December 31, 2013, were included in the study. Bivariate intergroup analysis was conducted. Kaplan-Meier estimates between insurance types were compared using the log rank test. All-cause mortality was evaluated using a mixed effects model. Results The groups differed significantly for sociodemographic and clinical variables. Uninsured Indiana Breast and Cervical Cancer Program patients presented with later disease stage (P < .001) and had the highest overall mortality (hazard ratio 2.2, P = .003). Surgical management only differed among stage III patients (P = .012). Conclusion To improve insurance-based disparities in Indiana, implementation of the Breast and Cervical Cancer Program in conjunction with expansion of insurance coverage to vulnerable low-income populations need to be optimized

Fear of Breast Cancer Recurrence in African-American and Caucasian Breast Cancer Survivors

poster abstractProblem. Fear of breast cancer recurrence is a concern for 55-90% of long-term breast cancer survivors. Background. Fear of recurrence is recognized as a prevalent and long-term psychosocial consequence of surviving cancer. Breast cancer survivors often identify more than one worry about what a recurrence might threaten in their health, work, and family function (Vickberg, 2001, 2003; Ziner, 2008). Although more research has been conducted with Caucasian breast cancer survivors, less is known about the nature of fear of recurrence worries in African American breast cancer survivors. Purpose. The purpose of this study was to compare fear of recurrence and worries related to thoughts of recurrence between African-American (AA-BCS) and Caucasian breast cancer survivors ( C-BCS). Theory. Emotion theorist, such as Lazarus (1991) suggest that fear is an emotional response to an identifiable object, thought or event that is perceived as harmful. Methods. This is a secondary analysis of a larger study comparing quality of life of AA-BCS and C-BCS using a cross-section survey design. Sample. Female breast cancer survivors ( AA-BCS N = 62, C-BCS N = 72) who were 2-10 years post treatment. Measures. Concerns about Recurrence Sale (CARS) Vickberg (2003) is a scale with 30 Likerttype items and 5 sub-scales: Fear of recurrence Index (overall fear frequency, intensity and consistency). Four (4) subscales of what BCS worry about: Health worries, Role worries, Womanhood worries, and Death worries. Validity. Content analysis of focus group data (N=21) AA-BCS showed that no changes were recommended in the CARS. (Russell, Personal communication) Reliability. The CARS and subscales were found to have Good to adequate Cronbach’s alpha’ for AA-BCS and C-BCS. Specifically, FRI = .92 AA-BCS, .90 C-BCS, Health worries = .93 AA-BCS, .92 C-BCS, Role worries = .75 AA-BCS, .87 C-BCS, Womanhood worries .89, AABCS, .90, C-BCS, Death worries .81 AA-BCS, .92 C-BCS. Analysis. ANCOVA was used for analysis controlling for age, time since diagnosis, income, marital status, years of education and body mass index. Results. Fear of recurrence Indexes between AA-BCS (mean 9.8) and C-BCS (mean 11.5) were not statistically different (p = .199). Health worries (AA- BCS mean 1.1, C-BCS mean 1.6, p= .018), Role worries (AA-BCS mean .8, C- BCS mean 1.2, p = .05), and Death worries (AA- BCS mean 1.3,C- BCS mean 2.2, p = .01) were significantly different between AA-BCS and C-BCS. Womanhood worries were not significantly different. Conclusions. AA-BCS and C-BCS were equally afraid of a recurrence. Except of womanhood worries, AA-BCS had lower mean health, role and death worries than C-BCS. Implications. Understanding the underlying worries related to overall fear of recurrence can lead to more focused and perhaps effective nursing intervention for AA-BCS and C-BCS

Depression in Husbands of Breast Cancer Patients: Relationships to Coping and Social Support

PURPOSE: The purpose of the present study was to examine depression in husbands of women with breast cancer, as depression is typically as high in husbands as in patients, and impacts functioning in both. METHODS: We compared husbands of patients to husbands of women without chronic illness on depressive symptoms with the Center for Epidemiological Studies Depression Scale, social support with the Interpersonal Support Evaluation List, and coping with the Ways of Coping Questionnaire. Using the stress and coping model, we examined whether coping mediated social support and depression differently by group, as has been found in the literature. RESULTS: Husbands of patients reported higher scores on the measure of depression and lower use of problem-focused coping, while groups reported equivalent social support. Escape-avoidance coping emerged as a full mediator between social support and depression in husbands of patients, but only a partial mediator in comparison husbands. Accepting responsibility coping partially mediated social support and depression in both groups. Low social support appears particularly detrimental in husbands of patients as it is associated with ineffective coping and depression. CONCLUSIONS: Findings suggest that among husbands of patients, social support relates to depression only through its relationship with coping, indicating healthcare providers should direct attention and intervention to the coping strategies employed by husbands with low social support

Impact of primary breast cancer therapy on energetic capacity and body composition

PURPOSE: This observational study was designed to measure baseline energy parameters and body composition in early-stage breast cancer patients, and to follow changes during and after various modalities of treatment. This will provide information to aid in the development of individualized physical activity intervention strategies. METHODS: Patients with newly diagnosed stage 0-III breast cancer were enrolled into three cohorts: A (local therapy alone), B (endocrine therapy), or C (chemotherapy with or without endocrine therapy). At baseline, 6 months, and 12 months, subjects underwent a stationary bicycle protocol to assess power generation and DEXA to assess body composition. RESULTS: Eighty-three patients enrolled. Patients had low and variable levels of power generation at baseline (mean power per kilogram lean mass 1.55 W/kg, SD 0.88). Power normalized to lean body mass (W/kg) decreased significantly, and similarly, by 6 months in cohorts B (1.42-1.04 W/kg, p = 0.008) and C (1.53-1.18 W/kg, p < 0.001). In all cohorts, there was no recovery of power generation by 12 months. Cohort C lost lean body mass (- 1.5 kg, p = 0.007), while cohort B maintained lean body mass (- 0.2 kg, p = 0.68), despite a similar trajectory in loss of power. Seven patients developed sarcopenia during the study period, including four patients who did not receive any chemotherapy (cohort B). CONCLUSIONS: The stationary bike protocol was feasible, easy, and acceptable to patients as a way to measure energetic capacity in a clinical setting. Early-stage breast cancer patients had low and variable levels of power generation, which worsened following primary therapy and did not show evidence of 'spontaneous recovery' by 12 months. Effective physical activity interventions will need to be personalized, accounting for both baseline ability and the effect of treatment

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

Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy

Next-generation sequencing to detect circulating tumor DNA is a minimally invasive method for tumor genotyping and monitoring therapeutic response. The majority of studies have focused on detecting circulating tumor DNA from patients with metastatic disease. Herein, we tested whether circulating tumor DNA could be used as a biomarker to predict relapse in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. In this study, we analyzed samples from 38 early-stage triple-negative breast cancer patients with matched tumor, blood, and plasma. Extracted DNA underwent library preparation and amplification using the Oncomine Research Panel consisting of 134 cancer genes, followed by high-coverage sequencing and bioinformatics. We detected high-quality somatic mutations from primary tumors in 33 of 38 patients. TP53 mutations were the most prevalent (82%) followed by PIK3CA (16%). Of the 33 patients who had a mutation identified in their primary tumor, we were able to detect circulating tumor DNA mutations in the plasma of four patients (three TP53 mutations, one AKT1 mutation, one CDKN2A mutation). All four patients had recurrence of their disease (100% specificity), but sensitivity was limited to detecting only 4 of 13 patients who clinically relapsed (31% sensitivity). Notably, all four patients had a rapid recurrence (0.3, 4.0, 5.3, and 8.9 months). Patients with detectable circulating tumor DNA had an inferior disease free survival (p < 0.0001; median disease-free survival: 4.6 mos. vs. not reached; hazard ratio = 12.6, 95% confidence interval: 3.06-52.2). Our study shows that next-generation circulating tumor DNA sequencing of triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy can predict recurrence with high specificity, but moderate sensitivity. For those patients where circulating tumor DNA is detected, recurrence is rapid

Safety and pharmacokinetics of MM-302, a HER2-targeted antibody–liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: A phase 1 dose-escalation study

BackgroundThis phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody-liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer.MethodsPatients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w.ResultsSixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5-10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8-15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain.ConclusionMM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w

Poly-ADP-Ribosylation of Estrogen Receptor-Alpha by PARP1 Mediates Antiestrogen Resistance in Human Breast Cancer Cells

Therapeutic targeting of estrogen receptor-α (ERα) by the anti-estrogen tamoxifen is standard of care for premenopausal breast cancer patients and remains a key component of treatment strategies for postmenopausal patients. While tamoxifen significantly increases overall survival, tamoxifen resistance remains a major limitation despite continued expression of ERα in resistant tumors. Previous reports have described increased oxidative stress in tamoxifen resistant versus sensitive breast cancer and a role for PARP1 in mediating oxidative damage repair. We hypothesized that PARP1 activity mediated tamoxifen resistance in ERα-positive breast cancer and that combining the antiestrogen tamoxifen with a PARP1 inhibitor (PARPi) would sensitize tamoxifen resistant cells to tamoxifen therapy. In tamoxifen-resistant vs. -sensitive breast cancer cells, oxidative stress and PARP1 overexpression were increased. Furthermore, differential PARylation of ERα was observed in tamoxifen-resistant versus -sensitive cells, and ERα PARylation was increased by tamoxifen treatment. Loss of ERα PARylation following treatment with a PARP inhibitor (talazoparib) augmented tamoxifen sensitivity and decreased localization of both ERα and PARP1 to ERα-target genes. Co-administration of talazoparib plus tamoxifen increased DNA damage accumulation and decreased cell survival in a dose-dependent manner. The ability of PARPi to overcome tamoxifen resistance was dependent on ERα, as lack of ERα-mediated estrogen signaling expression and showed no response to tamoxifen-PARPi treatment. These results correlate ERα PARylation with tamoxifen resistance and indicate a novel mechanism-based approach to overcome tamoxifen resistance in ER+ breast cancer