Effects of a change in recall period on reporting severe symptoms: an analysis of a pragmatic multisite trial.

BACKGROUND: Optimal methods for deploying electronic patient-reported outcomes (ePROs) to manage symptoms in routine oncologic practice remain uncertain. The eSyM symptom management program asks chemotherapy and surgery patients to self-report 12 symptoms regularly. Feedback from nurses and patients led to changing the recall period from the past 7 days to the past 24 hours. METHODS: Using questionnaires submitted during the 16-weeks surrounding the recall period change, we assessed the likelihood of reporting a severe, or a moderate-severe, symptom across all 12 symptoms and separately for the 5 most prevalent symptoms. Interrupted time series analyses modeled the effects of the change using generalized linear mixed-effects models. Surgery and chemotherapy cohorts were analyzed separately. Study-wide effects were estimated using a meta-analysis method. RESULTS: In total, 1,692 patients from 6 institutions submitted 7,823 eSyM assessments during the 16-weeks surrounding the recall period change. Shortening the recall period was associated with lower odds of severe symptom reporting in the surgery cohort (OR 0.65; 95% CI 0.46 to 0.93; p = .02) and lower odds of moderate-severe symptom reporting in the chemotherapy cohort (OR 0.83, 95% CI 0.71 to 0.97; p = .02). Among the most prevalent symptoms, 24-hour recall was associated with lower rate of reporting post-operative constipation, but no differences in reporting rates for other symptoms. CONCLUSION: A shorter recall period was associated with a reduction in the proportion of patients reporting moderate-severe symptoms. The optimal recall period may vary depending on whether ePROs are collected for active symptom management, as a clinical trial endpoint, or another purpose. (Clinicaltrails.gov (NCT03850912).

Treatment of Internal Mammary Nodes is Associated With Improved Overall Survival in Breast Cancer: A Meta-Analysis.

INTRODUCTION: The role of internal mammary nodal irradiation (IMNI) as a component of regional nodal radiotherapy is a controversial issue in breast radiation oncology with conflicting results presented in recent landmark trials. We thus created a meta-analysis of available data to better ascertain the potential benefit of IMNI. We hypothesize that with the increased power available within a meta-analysis, IMNI will prove to improve overall survival (OS) in breast cancer. METHODS: Literature search was conducted for prospective studies comparing IMNI to no IMNI. Primary endpoint was OS and secondary endpoints included local recurrence, regional recurrence, disease-free survival (DFS), breast cancer mortality (BCM), distant metastasis-free survival (DMFS), grade 2+ skin toxicity, cardiac events, and pneumonitis events. Subgroup analyses were performed for tumor location (medial/central vs. lateral), and nodal status (pN+ vs. pN0). Fixed-effect model was used if there was no heterogeneity, random-effects model otherwise. RESULTS: Four studies with a total of 5258 patients (IMNI: n=2592; control: n=2666) were included in the study. Pooled results showed IMNI significantly improved OS for all-comers (hazard ratio [HR]=0.89; 95% CI 0.81-0.97; P =0.008), as well as subgroups of pN+ with medial/central tumor location (HR=0.84; 95% CI 0.73-0.96; P =0.01) and pN+ with lateral tumor location (HR=0.87; 95% CI 0.77-0.99; P =0.04). There was no significant difference in OS for subgroups of pN0 and medial/central tumor location. There was no difference in local recurrence, but regional recurrence was significantly improved ( P =0.04). Endpoints of DFS (HR 0.91, 95% CI 0.84-0.99 P =0.03), BCM (HR 0.87, 95% CI 0.77-0.98, P =0.03), and DMFS (HR=0.87; 95% CI, 0.78-0.98; P =0.02) were all improved with IMNI. Grade 2+ skin toxicity, cardiac events and pneumonitis events were not significantly different between patient in the IMNI and no IMNI groups. CONCLUSION: Inclusion of IMN irradiation improves OS, DFS, BCM, and DMFS in breast cancer. Largest effect on OS was noted in the subgroup of patients with pN+ and medial/central tumor location.

Communication with physicians and family about breast Cancer recurrence.

Objective: Adequate physician-patient communication about cancer recurrence is vital to quality of life and to informed decision-making related to survivorship care. The current study was guided by a cognitive-affective framework to examine communication with family and physicians about breast cancer recurrence risk. Methods: A survey of recently-diagnosed, early-stage breast cancer patients in Appalachia investigated physician-patient and familial communication about breast cancer recurrence risk. Results: Over 30% of participants reported not talking to family or physicians about breast cancer recurrence risk. Younger patients reported more conversations, and speaking with physicians was associated with greater perception risk factors associated with recurrence risk. Greater worry about recurrence was associated with more communication with family and plans to talk to family, physicians, and friends about recurrence risk in the future. Conclusion: Additional supports for patients and physicians are needed to improve understanding of breast cancer recurrence risk and risk factors for recurrence. Innovation: Family communication about breast cancer recurrence risk is understudied. The combination of physician and family communication adds novelty to our analysis.

Cancer Screening Behaviors and Associations with Childhood Trauma, Resiliency, and Patient-Provider Relationships: Findings from an Exploratory Study of Appalachian Cervical Cancer Survivors.

Introduction: Adverse childhood experiences (ACEs) are associated with increased cancer risk. ACEs may affect this risk in a variety of ways, including cancer screening compliance. ACEs can contribute to mistrust in the medical profession, inhibit patient-provider relationships and cause at-risk individuals to miss critical access points to preventive services. Protective factors may play an important role in mitigating ACE-related consequences by supporting resiliency. Purpose: This study assesses the associations between ACEs, protective factors, patient-provider relationships, stage of cancer at diagnosis, and cancer screening behaviors for West Virginia (WV) cervical cancer survivors. Methods: WV cervical cancer survivors diagnosed between 2000 and 2020 were mailed a survey which included questions on demographic information and cancer screening behaviors, alongside three scales to measure depth of patient-provider relationships, ACEs, and protective factors. Results: Ninety participants completed the survey. ACEs were associated with weaker patient-provider relationships (p < .01) and fewer protective factors (p < .01). More protective factors were associated with stronger patient-provider relationships (p < .01), earlier stage of cancer at diagnosis (p < .05) and positive cancer screening behaviors. Positive cancer screening behaviors were associated with deeper patient-provider relationships (p < .05). A statistically significant model (p = .004) using ACE and resilience scores was able to account for 13% of the explained variability in depth of patient-provider relationships. Implications: These findings suggest an important interplay between ACEs, protective factors, and patient-provider relationships on cancer screening behaviors. Future studies should consider these variables in different populations. In addition, interventions focused on enhancing patient-provider relationships and supporting acquisition of protective factors should be considered.

The Effect of Lumpectomy and Cavity Shave Margin Status on Recurrence and Survival in Breast-Conserving Surgery.

BACKGROUND/OBJECTIVE: Cavity shave margins (CSMs) decrease rate of positive margins and need for re-excision. Recurrence data following breast-conserving surgery (BCS) are not always available in large cancer registries. We sought to define our recurrence and survival data in BCS with routine excision of CSMs. METHODS: A single institution, 10-year retrospective review of breast cancer patients who underwent BCS with routine CSMs was conducted. Cavity shave margin technique was standard. Cox proportional hazard analyses and the Kaplan-Meier method were used to estimate recurrence and survival. RESULTS: Breast-conserving surgery with CSM was performed in 839 patients. Re-excision rate to achieve negative margins was 8.5%. Fifty-two patients (75%) underwent margin re-excision vs 18 patients (25%) underwent salvage mastectomy. Positive margin rate stratified by tumor histology was highest for invasive lobular carcinoma followed by mixed invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS), followed by pure DCIS and lowest for IDC. Length of follow-up was (4.7 ± 2.6, years). Overall recurrence rate (locoregional and systemic) was 4.3%: highest in patients with negative lumpectomy margin but positive CSM (L-S+ = 15%) followed by positive lumpectomy and CSMs (L+S+ = 14%), followed by patients with positive lumpectomy margin but negative CSMs (L+S- = 13%) and lowest for negative lumpectomy and CSM (L-S- = 5%), (P = .0008). There was no difference in 5-year breast cancer-specific survival between the 4 subgroups: 96% for L-S-, 86.7% L-S+, 94.7% L+S+ and 90% L+S- (P = .094). CONCLUSIONS: Recurrence following BCS with CSMs can be stratified based on both lumpectomy and cavity shave margin positivity. Routine excision of CSMs allows identification of these patient subsets.

Addressing Lung Cancer Health Disparities in West Virginia: An Academic-Industry Collaboration Model.

Lung cancer screening is underused nationwide, particularly in rural areas where incidence and mortality rates are high, suggesting the need for innovative methods to reach underserved populations. Partners from national, state, and community positions can combine the service and science needed to save lives with mobile lung cancer screening.

Breast Cancer Survivorship-Mitigating Treatment Effects on Quality of Life and Improving Survival.

Cancer survivorship is complex and varies by individual, disease type, geographic area, and socioeconomic resources. As cancer treatments and survival improves, the survivorship population continues to grow. Communication between oncologists, patients, health care providers, patient advocates, and other stakeholders is critical to improved outcomes in cancer survivors. Important areas of study relate to improving the quality of life in survivors and include health promotion, psychosocial distress, and financial toxicity of cancer treatment. As survivorship begins at diagnosis, cancer programs must incorporate survivorship treatment goals into the care plan initially to positively effect the quality of life and improve health outcomes.

Atypical Hyperplasia Found Incidentally during Routine Breast Reduction Mammoplasty: Incidence and Management.

Atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) of the breast are premalignant lesions. Although the literature on ADH and ALH as a whole is well-developed, research on ADH and ALH incidentally discovered during breast reduction is less robust. METHODS: In this study, 355 patients undergoing bilateral reduction mammoplasty at West Virginia University were retrospectively reviewed. A variety of demographic and clinicopathologic variables were collected for each patient, and the incidence of atypical hyperplasia was calculated. Four patients (1.13%) were found to have atypical hyperplasia, three ALH, and one ADH, which is within the range reported in the literature. For patients incidentally found to have atypical hyperplasia, an in-depth analysis of postoperative management was performed. RESULTS: Of the four patients with atypical hyperplasia, three were referred to a cancer center, and one patient followed only with plastic surgery. The three patients who were referred to a cancer center saw a breast surgeon, whereas the patient followed only by plastic surgery did not. None of the four patients received anti-estrogen therapy, but each patient who followed with a cancer center was offered treatment and declined. CONCLUSIONS: As a relatively uncommon finding with complex management guidelines, atypical hyperplasia discovered on breast reduction should be referred to a cancer center for long-term follow-up and management when possible. Further research is needed to assess if the management of atypical hyperplasia discovered incidentally after routine reduction should mimic treatment of atypical hyperplasia found after biopsy for suspicion of malignancy.

eSyM: An Electronic Health Record-Integrated Patient-Reported Outcomes-Based Cancer Symptom Management Program Used by Six Diverse Health Systems.

PURPOSE: Collecting patient-reported outcomes (PROs) can improve symptom control and quality of life, enhance doctor-patient communication, and reduce acute care needs for patients with cancer. Digital solutions facilitate PRO collection, but without robust electronic health record (EHR) integration, effective deployment can be hampered by low patient and clinician engagement and high development and deployment costs. The important components of digital PRO platforms have been defined, but procedures for implementing integrated solutions are not readily available. METHODS: As part of the NCI's IMPACT consortium, six health care systems partnered with Epic to develop an EHR-integrated, PRO-based electronic symptom management program (eSyM) to optimize postoperative recovery and well-being during chemotherapy. The agile development process incorporated user-centered design principles that required engagement from patients, clinicians, and health care systems. Whenever possible, the system used validated content from the public domain and took advantage of existing EHR capabilities to automate processes. RESULTS: eSyM includes symptom surveys on the basis of the PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE) plus two global wellness questions; reminders and symptom self-management tip sheets for patients; alerts and symptom reports for clinicians; and population management dashboards. EHR dependencies include a secure Health Insurance Portability and Accountability Act-compliant patient portal; diagnosis, procedure and chemotherapy treatment plan data; registries that identify and track target populations; and the ability to create reminders, alerts, reports, dashboards, and charting shortcuts. CONCLUSION: eSyM incorporates validated content and leverages existing EHR capabilities. Build challenges include the innate technical limitations of the EHR, the constrained availability of site technical resources, and sites' heterogenous EHR configurations and policies. Integration of PRO-based symptom management programs into the EHR could help overcome adoption barriers, consolidate clinical workflows, and foster scalability and sustainability. We intend to make eSyM available to all Epic users.

Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype.

Increased susceptibility to fatigue is a negative predictor of survival commonly experienced by women with breast cancer (BC). Here, we sought to identify molecular changes induced in human skeletal muscle by BC regardless of treatment history or tumor molecular subtype using RNA-sequencing (RNA-seq) and proteomic analyses. Mitochondrial dysfunction was apparent across all molecular subtypes, with the greatest degree of transcriptomic changes occurring in women with HER2/neu-overexpressing tumors, though muscle from patients of all subtypes exhibited similar pathway-level dysregulation. Interestingly, we found no relationship between anticancer treatments and muscle gene expression, suggesting that fatigue is a product of BC per se rather than clinical history. In vitro and in vivo experimentation confirmed the ability of BC cells to alter mitochondrial function and ATP content in muscle. These data suggest that interventions supporting muscle in the presence of BC-induced mitochondrial dysfunction may alleviate fatigue and improve the lives of women with BC.

Translation of Patient-Reported Outcomes in Oncology Clinical Trials to Everyday Practice.

PURPOSE: Clinical trials in oncology evaluating the effects of patient-reported outcomes (PRO) collection have found that monitoring of symptoms with PROs is associated with improved clinical care through reduced acute care utilization and decreased patient symptom burden. This educational review will evaluate strategies for systematic PRO integration into everyday oncology clinical practice. METHODS: We outline key considerations for using PROs in clinical practice, highlighting evidence from published studies. We also discuss the benefits and challenges of PRO implementation in oncology. RESULTS: Implementing PRO collection in clinical practice can improve care delivery and facilitate patient-centered clinical research. Considerations for using PROs in clinical practice include choice of instrument, method of delivery, and frequency of query. Challenges with implementing systematic PRO collection include the costs and resources needed for implementation, impact on clinical workflow, and controlling/monitoring physician burnout. CONCLUSIONS: While challenges exist in terms of financial resources and staff participation/burnout, patient-reported outcomes in clinical practice provide a number of benefits, including symptom monitoring, clinical research, and potential real-time personalized clinical-decision support.

The Stem Cell Phenotype of Aggressive Breast Cancer Cells.

Aggressive cancer cells are characterized by their capacity to proliferate indefinitely and to propagate a heterogeneous tumor comprised of subpopulations with varying degrees of metastatic propensity and drug resistance properties. Particularly daunting is the challenge we face in the field of oncology of effectively targeting heterogeneous tumor cells expressing a variety of markers, especially those associated with a stem cell phenotype. This dilemma is especially relevant in breast cancer, where therapy is based on traditional classification schemes, including histological criteria, differentiation status, and classical receptor markers. However, not all patients respond in a similar manner to standard-of-care therapy, thereby necessitating the need to identify and evaluate novel biomarkers associated with the difficult-to-target stem cell phenotype and drug resistance. Findings related to the convergence of embryonic and tumorigenic signaling pathways have identified the embryonic morphogen Nodal as a promising new oncofetal target that is reactivated only in aggressive cancers, but not in normal tissues. The work presented in this paper confirms previous studies demonstrating the importance of Nodal as a cancer stem cell molecule associated with aggressive breast cancer, and advances the field by providing new findings showing that Nodal is not targeted by standard-of-care therapy in breast cancer patients. Most noteworthy is the linkage found between Nodal expression and the drug resistance marker ATP-binding cassette member 1 (ABCA1), which may provide new insights into developing combinatorial approaches to overcome drug resistance and disease recurrence.

Human Breast Cancer Xenograft Model Implicates Peroxisome Proliferator-activated Receptor Signaling as Driver of Cancer-induced Muscle Fatigue.

PURPOSE: This study tested the hypothesis that a patient-derived orthotopic xenograft (PDOX) model would recapitulate the common clinical phenomenon of breast cancer-induced skeletal muscle (SkM) fatigue in the absence of muscle wasting. This study additionally sought to identify drivers of this condition to facilitate the development of therapeutic agents for patients with breast cancer experiencing muscle fatigue. EXPERIMENTAL DESIGN: Eight female BC-PDOX-bearing mice were produced via transplantation of tumor tissue from 8 female patients with breast cancer. Individual hind limb muscles from BC-PDOX mice were isolated at euthanasia for RNA-sequencing, gene and protein analyses, and an ex vivo muscle contraction protocol to quantify tumor-induced aberrations in SkM function. Differentially expressed genes (DEG) in the BC-PDOX mice relative to control mice were identified using DESeq2, and multiple bioinformatics platforms were employed to contextualize the DEGs. RESULTS: We found that SkM from BC-PDOX-bearing mice showed greater fatigability than control mice, despite no differences in absolute muscle mass. PPAR, mTOR, IL6, IL1, and several other signaling pathways were implicated in the transcriptional changes observed in the BC-PDOX SkM. Moreover, 3 independent in silico analyses identified PPAR signaling as highly dysregulated in the SkM of both BC-PDOX-bearing mice and human patients with early-stage nonmetastatic breast cancer. CONCLUSIONS: Collectively, these data demonstrate that the BC-PDOX model recapitulates the expected breast cancer-induced SkM fatigue and further identify aberrant PPAR signaling as an integral factor in the pathology of this condition.

Receipt of Guideline-Concordant Care Among Older Women With Stage I-III Breast Cancer: A Population-Based Study.

Background: This study examined receipt of guideline-concordant care (GCC) according to evidence-based treatment guidelines and quality measures and specific types of treatment among older women with breast cancer. Patients and Methods: A total of 142,433 patients aged ≥66 years diagnosed with stage I-III breast cancer between 2007 and 2011 were identified in the SEER-Medicare linked database. Algorithms considering cancer characteristics and the appropriate course of care as per guidelines versus actual care received determined receipt of GCC. Multivariable logistic regression estimated the likelihood of GCC and specific types of treatment for women aged ≥75 versus 66 to 74 years. Results: Overall, 39.7% of patients received GCC. Patients diagnosed at stage II or III, with certain preexisting conditions, and of nonwhite race were less likely to receive GCC. Patients with hormone-negative tumors, higher grade tumors, and greater access to oncology care resources were more likely to receive GCC. Patients aged ≥75 years were approximately 40% less likely to receive GCC or adjuvant endocrine therapy, 78% less likely to have any surgery, 61% less likely to have chemotherapy, and about half as likely to have radiation therapy than those aged 66 to 74 years. Conclusions: Fewer than half of older women with breast cancer received GCC, with the lowest rates observed among the oldest age groups, racial/ethnic minorities, and women with later-stage cancers. However, patients with more aggressive tumor characteristics and greater access to oncology resources were more likely to receive GCC. Considering that older women have the highest incidence of breast cancer and that many are diagnosed at stages requiring more aggressive treatment, efforts to increase rates of earlier stage diagnosis and the development of less toxic treatments could help improve GCC and survival while preserving quality of life.

Dysregulation of metabolic-associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin-15 targeting fatigue.

BACKGROUND: Breast cancer patients report a perception of increased muscle fatigue, which can persist following surgery and standardized therapies. In a clinical experiment, we tested the hypothesis that pathways regulating skeletal muscle fatigue are down-regulated in skeletal muscle of breast cancer patients and that different muscle gene expression patterns exist between breast tumour subtypes. In a preclinical study, we tested the hypothesis that mammary tumour growth in mice induces skeletal muscle fatigue and that overexpression of the cytokine interleukin-15 (IL-15) can attenuate mammary tumour-induced muscle fatigue. METHODS: Early stage non-metastatic female breast cancer patients (n = 14) and female non-cancer patients (n = 6) provided a muscle biopsy of the pectoralis major muscle during mastectomy, lumpectomy, or breast reconstruction surgeries. The breast cancer patients were diagnosed with either luminal (ER+ /PR+ , n = 6), triple positive (ER+ /PR+ /Her2/neu+ , n = 5), or triple negative (ER- /PR- /Her2/neu- , n = 3) breast tumours and were being treated with curative intent either with neoadjuvant chemotherapy followed by surgery or surgery followed by standard post-operative therapy. Biopsies were used for RNA-sequencing to compare the skeletal muscle gene expression patterns between breast cancer patients and non-cancer patients. The C57BL/6 mouse syngeneic mammary tumour cell line, E0771, was used to induce mammary tumours in immunocompetent mice, and isometric muscle contractile properties and fatigue properties were analysed following 4 weeks of tumour growth. RESULTS: RNA-sequencing and subsequent bioinformatics analyses revealed a dysregulation of canonical pathways involved in oxidative phosphorylation, mitochondrial dysfunction, peroxisome proliferator-activated receptor signalling and activation, and IL-15 signalling and production. In a preclinical mouse model of breast cancer, the rate of muscle fatigue was greater in mice exposed to mammary tumour growth for 4 weeks, and this greater muscle fatigue was attenuated in transgenic mice that overexpressed the cytokine IL-15. CONCLUSIONS: Our data identify novel genes and pathways dysregulated in the muscles of breast cancer patients with early stage non-metastatic disease, with particularly aberrant expression among genes that would predispose these patients to greater muscle fatigue. Furthermore, we demonstrate that IL-15 overexpression can attenuate muscle fatigue associated with mammary tumour growth in a preclinical mouse model of breast cancer. Therefore, we propose that skeletal muscle fatigue is an inherent consequence of breast tumour growth, and this greater fatigue can be targeted therapeutically.