Sarah C. Reed

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.Significance: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37-48. ©2017 AACR.See related commentary by Sundar and Tan, p. 14See related article by Janjigian et al., p. 49This article is highlighted in the In This Issue feature, p. 1.

Shared Medical Appointments in Cancer Survivorship Care: A Review of the Literature

PURPOSE The physical and psychological effects of a cancer diagnosis and treatment on an individual may be significant and require appropriate monitoring and management. Furthermore, attention to preventive care and comorbid medical conditions is critical. Innovative approaches are needed to provide quality care to this growing population. METHODS We reviewed the literature evaluating shared medical appointments (SMAs) in noncancer and cancer care settings. Supported by a conceptual framework and adhering to the goals of patient-centered communication, we propose how SMAs may be used in clinical practice to enhance survivorship care. RESULTS The literature suggests that SMAs are an effective model in noncancer settings, showing improved blood pressure and health-related quality of life, among others. Although evidence for SMAs in cancer care is limited, there is significant potential for improved patient outcomes and costs. In particular, SMAs may provide an opportunity to address medical and psychological needs while creating a structure for enhanced communication. CONCLUSION SMAs may offer an innovative care model for cancer survivors and their providers. Implementation and evaluation of SMAs in the care of cancer survivors is warranted.

Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing

Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.

A Systematic Review of Emergency Department Use Among Cancer Patients.

Background: Recent reports call for reductions in costly and potentially avoidable services such as emergency department (ED) visits. Providing high-quality and safe care for oncology patients remains challenging for ED providers given the diversity of patients seeking care and the unpredictable clinical environment. While ED use by oncology patients is appropriate for acute health concerns, some ED visits may be preventable with well-coordinated care and adequate symptom management. Objective: The aim of this study was to summarize available evidence regarding the incidence, predictors of, and reasons for ED visits among oncology patients. Methods: Keyword/MeSH term searches were conducted using 4 online databases. Inclusion criteria were publication date between April 1, 2003, and December 5, 2014; sample size of 50 or more; and report of the incidence or predictors of ED use among oncology patients. Results: The 15 studies that met criteria varied in study aim, design, and time frames for calculating ED utilization rates. The incidence of ED visits among oncology patients ranged from 1% to 83%. The 30-day standardized visit rate incidence ranged from 1% to 12%. Collectively, the studies lack population-based estimates for all cancers combined. Conclusions: The studies included in this review suggest that rates of ED use among cancer patients exceed those of the general population. However, the extent of ED use by oncology patients and the reasons for ED visits remain understudied. Implications for Practice: Nurses are involved in the treatment of cancer, patient education, and symptom management. Nurses are well positioned to develop patient-centered treatment and care coordination plans to improve quality of care and reduce ED visits.

Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma

Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (~99%) and copy number alterations (~81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.Circulating tumor cells (CTCs) and cell-free DNA (cfDNA) enables characterization of a patient’s cancer. Here, the authors analyse CTCs, cfDNA, and tumor biopsies from multiple myeloma patients to show these approaches are complementary for mutation detection, together enabling a greater fraction of patient tumors to be profiled.

Systematic Review of Hospital Readmissions Among Patients With Cancer in the United States

Purpose/Objectives: To review the existing literature on readmission rates, predictors, and reasons for readmission among adults with cancer. Data Sources: U.S.‐based empirical studies reporting readmission rates from January 2005 to December 2015 were identified using four online library databases—PubMed, CINAHL®, EconLit, and the online bibliography of the National Cancer Institute’s Surveillance Epidemiology and End Results Program. Some articles were identified by the authors outside the database and bibliography searches. Data Synthesis: Of the 1,219 abstracts and 271 full‐text articles screened, 56 studies met inclusion criteria. The highest readmission rates were observed in patients with bladder, pancreatic, ovarian, or liver cancer. Significant predictors of readmission included comorbidities, older age, advanced disease, and index length of hospital stay. Common reasons for readmission included gastrointestinal and surgical complications, infection, and dehydration. Conclusions: Clinical efforts to reduce the substantial readmission rates among adults with cancer may target high‐rate conditions, infection prevention, proactive management of nausea and vomiting, and nurse‐led care coordination interventions for older adult patients with multiple comorbid conditions and advanced cancer. Implications for Nursing: Commonly reported reasons for readmission were nursing‐sensitivepatient outcomes (NSPOs), amenable to nursing intervention in oncology settings. These findings underscore the important role oncology nurses play in readmission prevention by implementing evidence‐based interventions to address NSPOs and testing their impact in future research.

Social Networking and Mental Health

From Facebook to Twitter, social networking has become an integral part of the way many Americans communicate. In this chapter, we review the development and current uses of social networking and its impact on mental health care. Though relatively new, there is a growing evidence base for the effectiveness and utilization of social networking in mental health care. Taking this increasing popularity into account, we consider ethical and legal dilemmas as well as practical guidelines for mental health clinicians interested in developing a social networking site to support their professional practice. Finally, we discuss ethical implications for clinicians to consider in the use of personal social networking sites.

A novel personal health network for patient-centered chemotherapy care coordination

Cancer is the second leading cause of death in the United States. Cancer care is a complex and complicated process involving diverse practitioners, multiple specialists, and a range of inpatient, outpatient, and home care services with numerous transitions for the patients. Cancer patients undergoing chemotherapy are at risk of unplanned emergency visits and hospitalizations and can benefit from care coordination. There are few examples of systems that fully engage patients, family and caregivers along with clinicians and other care resources to collaboratively coordinate chemotherapy. This paper reports on the development of a prototype “personal health network” (PHN) using social networking technology to support patient-centered chemotherapy care coordination in a comprehensive cancer center. Requirements for the prototype were generated by analyzing two frameworks, the cancer continuum framework and the framework for information technology in care coordination, and reviewing the literature on self-management and care coordination. The resulting requirements were implemented and reviewed with a trans-disciplinary team of clinicians and researchers. The PHN was found to fulfill the key requirements identified through the analysis of frameworks. A prototype was built rapidly and reviewed by an internal trans-disciplinary team. The refined prototype will be field tested with patients and nurse care coordinators to assess usefulness and usability in preparation for a larger scale clinical trial.

Coordination at the Point of Need

Abstract For individuals with chronic and prolonged conditions such as cancer, care is complicated, fragmented, and poorly coordinated. Individuals with cancer experience transitions from home to physician office, clinic, outpatient service, emergency department, inpatient hospital, and community-based settings attended by different practitioners and numerous specialists at each. Because health care systems have not addressed community-wide care coordination, the burden of coordinating is often left to the individual and their family to manage. Chronic disease care coordination frameworks help unpack the challenges and provide ways to understand how to intervene to improve care coordination for cancer. These frameworks elucidate the importance of the comprehensive person-centered, community-wide, and life span approach to coordination. Health information technology (HIT) is a critical enabler of solutions to these challenges. HIT-enabled care coordination is in a nascent stage in which most examples are within health care teams with limited interactions with patients. There are a number of examples of HIT solutions involving electronic health records, single-purpose mobile applications, or patient portals in chronic disease and fewer in cancer care coordination. There are few examples of platforms that support the comprehensive approaches needed. This offers great opportunity for collaboration among informatics, clinical, and patient participants to design, develop, implement, and evaluate HIT that effectively addresses the comprehensive nature of care coordination. This chapter offers an overview of care coordination frameworks, HIT functions needed for care coordination, examples of HIT-enabled care coordination, and opportunities to move the field forward.