Analysis of tumor template from multiple compartments in a blood sample provides complementary access to peripheral tumor biomarkers.

Targeted cancer therapeutics are promised to have a major impact on cancer treatment and survival. Successful application of these novel treatments requires a molecular definition of a patient\u27s disease typically achieved through the use of tissue biopsies. Alternatively, allowing longitudinal monitoring, biomarkers derived from blood, isolated either from circulating tumor cell derived DNA (ctcDNA) or circulating cell-free tumor DNA (ccfDNA) may be evaluated. In order to use blood derived templates for mutational profiling in clinical decisions, it is essential to understand the different template qualities and how they compare to biopsy derived template DNA as both blood-based templates are rare and distinct from the gold-standard. Using a next generation re-sequencing strategy, concordance of the mutational spectrum was evaluated in 32 patient-matched ctcDNA and ccfDNA templates with comparison to tissue biopsy derived DNA template. Different CTC antibody capture systems for DNA isolation from patient blood samples were also compared. Significant overlap was observed between ctcDNA, ccfDNA and tissue derived templates. Interestingly, if the results of ctcDNA and ccfDNA template sequencing were combined, productive samples showed similar detection frequency (56% vs 58%), were temporally flexible, and were complementary both to each other and the gold standard. These observations justify the use of a multiple template approach to the liquid biopsy, where germline, ctcDNA, and ccfDNA templates are employed for clinical diagnostic purposes and open a path to comprehensive blood derived biomarker access

US Cancer Centers of Excellence Strategies for Increased Inclusion of Racial and Ethnic Minorities in Clinical Trials

PURPOSE:: Participation of racial and ethnic minority groups (REMGs) in cancer trials is disproportionately low despite a high prevalence of certain cancers in REMG populations. We aimed to identify notable practices used by leading US cancer centers that facilitate REMG participation in cancer trials. METHODS:: The National Minority Quality Forum and Sustainable Healthy Communities Diverse Cancer Communities Working Group developed criteria by which to identify eligible US cancer centers-REMGs comprise 10% or more of the catchment area; a 10% to 50% yearly accrual rate of REMGs in cancer trials; and the presence of formal community outreach and diversity enrollment programs. Cancer center leaders were interviewed to ascertain notable practices that facilitate REMG accrual in clinical trials. RESULTS:: Eight cancer centers that met the Communities Working Group criteria were invited to participate in in-depth interviews. Notable strategies for increased REMG accrual to cancer trials were reported across five broad themes: commitment and center leadership, investigator training and mentoring, community engagement, patient engagement, and operational practices. Specific notable practices included increased engagement of health care professionals, the presence of formal processes for obtaining REMG patient/caregiver input on research projects, and engagement of community groups to drive REMG participation. Centers also reported an increase in the allocation of resources to improving health disparities and increased dedication of research staff to REMG engagement. CONCLUSION:: We have identified notable practices that facilitate increased participation of REMGs in cancer trials. Wide implementation of such strategies across cancer centers is essential to ensure that all populations benefit from advances in an era of increasingly personalized treatment of cancer

Redlining−associated methylation in breast tumors: the impact of contemporary structural racism on the tumor epigenome

PurposePlace-based measures of structural racism have been associated with breast cancer mortality, which may be driven, in part, by epigenetic perturbations. We examined the association between contemporary redlining, a measure of structural racism at the neighborhood level, and DNA methylation in breast tumor tissue.MethodsWe identified 80 Black and White women diagnosed and treated for a first-primary breast cancer at Emory University Hospitals (2008–2017). Contemporary redlining was derived for census tracts using the Home Mortgage Disclosure Act database. Linear regression models were used to calculate the association between contemporary redlining and methylation in breast tumor tissue. We also examined epigenetic age acceleration for two different metrics, regressing β values for each cytosine-phosphate-guanine dinucleotide (CpG) site on redlining while adjusting for covariates. We employed multivariable Cox-proportional hazards models and 95% confidence intervals (CI) to estimate the association between aberrant methylation and mortality.ResultsContemporary redlining was associated with 5 CpG sites after adjustment for multiple comparisons (FDR<0.10). All genes were implicated in breast carcinogenesis, including genes related to inflammation, immune function and stress response (ANGPT1, PRG4 and PRG4). Further exploration of the top 25 CpG sites, identified interaction of 2 sites (MRPS28 and cg11092048) by ER status and 1 site (GDP1) was associated with all-cause mortality. Contemporary redlining was associated with epigenetic age acceleration by the Hannum metric (β=5.35; CI 95%=0.30,10.4) and showed positive but non-significant correlation with the other clock.ConclusionWe identified novel associations between neighborhood contemporary redlining and the breast tumor DNA methylome, suggesting that racist policies leading to inequitable social and environmental exposures, may impact the breast tumor epigenome. Additional research on the potential implications for prognosis is needed

A Review of Systemic Treatment in Metastatic Triple-Negative Breast Cancer

Patients with breast cancer along with metastatic estrogen and progesterone receptor (ER/PR)- and human epidermal growth factor receptor 2 (HER2)-negative tumors are referred to as having metastatic triple-negative breast cancer (mTNBC) disease. Although there have been many new treatment options approved by the Food and Drug Administration for ER/PR-positive and Her2/neu-amplified metastatic breast cancer, relatively few new agents have been approved for patients with mTNBC. There have been several head-to-head chemotherapy trials performed within the metastatic setting, and much of what is applied in clinical practice is extrapolated from chemotherapy trials in the adjuvant setting, with taxanes and anthracyclines incorporated early on in the patient's treatment course. Select synergistic combinations can produce faster and more significant response rates compared with monotherapy and are typically used in the setting of visceral threat or symptomatic disease. Preclinical studies have implicated other possible targets and mechanisms in mTNBC. Ongoing clinical trials are underway assessing new chemotherapeutic strategies and agents, including targeted therapy and immunotherapy. In this review, we evaluate the standard systemic and future treatment options in mTNBC

Cognitive Behavioral Therapy for Insomnia, Mindfulness, and Yoga in Patients With Breast Cancer with Sleep Disturbance: A Literature Review

The number of patients with breast cancer diagnosed with sleep disturbance has grown substantially within the United States over the past 20 years. Meanwhile, there have been significant improvements in the psychological treatment of sleep disturbance in patients with breast cancer. More specifically, cognitive behavioral therapy for insomnia (CBT-I), mindfulness, and yoga have shown to be 3 promising treatments with varying degrees of benefit, supporting data, and inherent limitations. In this article, we will outline the treatment approach for sleep disturbance in patients with breast cancer and conduct a comprehensive review of CBT-I, mindfulness, and yoga as they pertain to this patient population

Panoptic View of Prognostic Models for Personalized Breast Cancer Management

The efforts to personalize treatment for patients with breast cancer have led to a focus on the deeper characterization of genotypic and phenotypic heterogeneity among breast cancers. Traditional pathology utilizes microscopy to profile the morphologic features and organizational architecture of tumor tissue for predicting the course of disease, and is the first-line set of guiding tools for customizing treatment decision-making. Currently, clinicians use this information, combined with the disease stage, to predict patient prognosis to some extent. However, tumoral heterogeneity stubbornly persists among patient subgroups delineated by these clinicopathologic characteristics, as currently used methodologies in diagnostic pathology lack the capability to discern deeper genotypic and subtler phenotypic differences among individual patients. Recent advancements in molecular pathology, however, are poised to change this by joining forces with multiple-omics technologies (genomics, transcriptomics, epigenomics, proteomics, and metabolomics) that provide a wealth of data about the precise molecular complement of each patient’s tumor. In addition, these technologies inform the drivers of disease aggressiveness, the determinants of therapeutic response, and new treatment targets in the individual patient. The tumor architecture information can be integrated with the knowledge of the detailed mutational, transcriptional, and proteomic phenotypes of cancer cells within individual tumors to derive a new level of biologic insight that enables powerful, data-driven patient stratification and customization of treatment for each patient, at each stage of the disease. This review summarizes the prognostic and predictive insights provided by commercially available gene expression-based tests and other multivariate or clinical -omics-based prognostic/predictive models currently under development, and proposes a more inclusive multiplatform approach to tackling the challenging heterogeneity of breast cancer to individualize its management. “The future is already here—it’s just not very evenly distributed.”-William Ford Gibso

Type 2 diabetes, breast cancer specific and overall mortality: Associations by metformin use and modification by race, body mass, and estrogen receptor status.

INTRODUCTION:While type 2 diabetes (T2D) has been associated with increased all-cause mortality among women diagnosed with breast cancer (BC), the association between T2D and breast cancer-specific (BCS) mortality is unresolved. The goal of this study was to examine the association between T2D and BCS mortality and examine the influence of metformin treatment on mortality rates. METHODS:A retrospective cohort study was conducted between 2002 and 2008 at Emory University Hospitals among non-Hispanic black and white women who had confirmed diagnosis of stage I-III BC and known diabetes status (T2D: n = 73; non-T2D: n = 514). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS:Compared to non-T2D patients, T2D women had almost a 2-fold increase in BCS mortality after adjusting for covariates (HR = 2.01; 95%CI = 1.02-3.98). Though attenuated, the increased hazard of death was also observed for all-cause mortality (HR = 1.74; 95%CI = 1.06-2.87). T2D patients who were not on metformin had substantially higher hazard of BCS mortality compared to non-diabetic patients (HR = 4.54; 95%CI = 1.98-10.44), whereas the association among T2D patients treated with metformin was weak (HR = 1.20; 95%CI = 0.36-3.97) and included the null. CONCLUSIONS:Among women with BC, T2D is associated with increased BCS mortality. Metformin treatment for T2D during the initial diagnosis of BC may improve outcomes