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

Impact of social distancing during COVID-19 pandemic on crime in Los Angeles and Indianapolis

Governments have implemented social distancing measures to address the ongoing COVID-19 pandemic. The measures include instructions that individuals maintain social distance when in public, school closures, limitations on gatherings and business operations, and instructions to remain at home. Social distancing may have an impact on the volume and distribution of crime. Crimes such as residential burglary may decrease as a byproduct of increased guardianship over personal space and property. Crimes such as domestic violence may increase because of extended periods of contact between potential offenders and victims. Understanding the impact of social distancing on crime is critical for ensuring the safety of police and government capacity to deal with the evolving crisis. Understanding how social distancing policies impact crime may also provide insights into whether people are complying with public health measures. Examination of the most recently available data from both Los Angeles, CA, and Indianapolis, IN, shows that social distancing has had a statistically significant impact on a few specific crime types. However, the overall effect is notably less than might be expected given the scale of the disruption to social and economic life

Classification of large circulating tumor cells isolated with ultra-high throughput microfluidic Vortex technology.

Circulating tumor cells (CTCs) are emerging as rare but clinically significant non-invasive cellular biomarkers for cancer patient prognosis, treatment selection, and treatment monitoring. Current CTC isolation approaches, such as immunoaffinity, filtration, or size-based techniques, are often limited by throughput, purity, large output volumes, or inability to obtain viable cells for downstream analysis. For all technologies, traditional immunofluorescent staining alone has been employed to distinguish and confirm the presence of isolated CTCs among contaminating blood cells, although cells isolated by size may express vastly different phenotypes. Consequently, CTC definitions have been non-trivial, researcher-dependent, and evolving. Here we describe a complete set of objective criteria, leveraging well-established cytomorphological features of malignancy, by which we identify large CTCs. We apply the criteria to CTCs enriched from stage IV lung and breast cancer patient blood samples using the High Throughput Vortex Chip (Vortex HT), an improved microfluidic technology for the label-free, size-based enrichment and concentration of rare cells. We achieve improved capture efficiency (up to 83%), high speed of processing (8 mL/min of 10x diluted blood, or 800 μL/min of whole blood), and high purity (avg. background of 28.8±23.6 white blood cells per mL of whole blood). We show markedly improved performance of CTC capture (84% positive test rate) in comparison to previous Vortex designs and the current FDA-approved gold standard CellSearch assay. The results demonstrate the ability to quickly collect viable and pure populations of abnormal large circulating cells unbiased by molecular characteristics, which helps uncover further heterogeneity in these cells

A Personalized, Dynamic Physical Activity Intervention Is Feasible and Improves Energetic Capacity, Energy Expenditure, and Quality of Life in Breast Cancer Survivors

Purpose: Despite survival and quality of life benefits associated with physical activity, many breast cancer survivors remain inactive. Effective, sustainable interventions must account for individual differences in capability, motivation, and environment. Here, we evaluate the feasibility, mechanics, and efficacy of delivering an individualized, dynamic intervention to increase energetic capacity and energy expenditure. Methods: Stage 0-III breast cancer patients who had completed primary treatment were enrolled. Prior to the intervention, detailed movement data was collected with a wearable GPS and accelerometer for 3 weeks to establish baseline activity. Movement data was collected continuously throughout the 12-week intervention, during which patients received electronically delivered, tailored, dynamic activity "prescriptions", adjusted based on demonstrated individual capability, daily movement in their environment, and progress. Results: Of 66 enrolled, 57 participants began and completed the intervention. The intervention resulted in significant improvements in average steps (+558 steps/day, p = 0.01), energetic capacity measured by power generation on a stationary bicycle (1.76 to 1.99 W/kg lean mass, p < 0.01), and quality of life (FACT-B TOI, 72.8 to 74.8, p = 0.02). The greatest improvement in functional energetic capacity was seen in the lowest performing tertile at baseline (0.76 to 1.12 W/kg, p < 0.01). Discussion: Wearable technology delivery of personalized activity prescriptions based on individual capability and movement behaviors demonstrates feasibility and early effectiveness. The high variability seen in baseline activity and function, as well as in response to the intervention, supports the need for future work in precision approaches to physical activity (NCT03158519)

Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer

BACKGROUND The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS We performed a prospective trial involving 9427 women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

BACKGROUND The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger

Prospective Validation of a 21-Gene Expression Assay in Breast Cancer

Prior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker

Liquid biopsy enters the clinic — implementation issues and future challenges

Historically, studies of disseminated tumour cells in bone marrow and circulating tumour cells in peripheral blood have provided crucial insights into cancer biology and the metastatic process. More recently, advances in the detection and characterization of circulating tumour DNA (ctDNA) have finally enabled the introduction of liquid biopsy assays into clinical practice. The FDA has already approved several single-gene assays and, more recently, multigene assays to detect genetic alterations in plasma cell-free DNA (cfDNA) for use as companion diagnostics matched to specific molecularly targeted therapies for cancer. These approvals mark a tipping point for the widespread use of liquid biopsy in the clinic, and mostly in patients with advanced-stage cancer. The next frontier for the clinical application of liquid biopsy is likely to be the systemic treatment of patients with ‘ctDNA relapse’, a term we introduce for ctDNA detection prior to imaging-detected relapse after curative-intent therapy for early stage disease. Cancer screening and diagnosis are other potential future applications. In this Perspective, we discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow.SCOPUS: re.jinfo:eu-repo/semantics/publishe