Faculty Bibliography

PURPOSE/OBJECTIVE:To test the effects of employer subsidies on employee enrollment, attendance, and weight loss in a nationally available weight management program. DESIGN/METHODS:A randomized trial tested the impact of employer subsidy: 100%; 80%, 50%, and a hybrid 50% subsidy that could become a 100% subsidy by attaining attendance targets. TRIAL REGISTRATION/BACKGROUND:NCT01756066. SETTING AND PARTICIPANTS/METHODS:Twenty three thousand twenty-three employees of 2 US companies. MEASURES/METHODS:The primary outcome was the percentage of employees who enrolled in the weight management program. We also tested whether the subsidies were associated with differential attendance and weight loss over 12 months, as might be predicted by the expectation that they attract employees with differing degrees of motivation. Analysis and Results: Enrollment differed significantly by subsidy level ( P < .0001). The 100% subsidy produced the highest enrollment (7.7%), significantly higher than each of the lower subsidies (vs 80% subsidy: 6.2%, P = .002; vs 50% subsidy: 3.9%, P < .0001; vs hybrid: 3.7%, P < .0001). Enrollment in the 80% subsidy group was significantly higher than both lower subsidy groups (vs 50% subsidy: 3.9%, P < .0001; vs hybrid: 3.7%, P < .0001). Among enrollees, there were no differences among the 4 groups in attendance or weight loss. CONCLUSION/CONCLUSIONS:This pragmatic trial, conducted in a real-world workplace setting, suggests that higher rates of employer subsidization help individuals to enroll in weight loss programs, without a decrement in program effectiveness. Future research could explore the cost-effectiveness of such subsidies or alternative designs.

Physical activity is associated with a lower risk of disease recurrence among colon cancer survivors. The pathways through which physical activity may alter disease outcomes are unknown, but may include changes in metabolic growth factors, such as insulin. METHODS: Between January 2015 and August 2015, 39 stage I-III colon cancer survivors were randomized to one of three groups: usual-care control, 150 minwk-1 of aerobic exercise (low-dose), and 300 minwk-1 of aerobic exercise (high-dose) for six months. The pre-specified key metabolic growth factor outcome was fasting insulin. Insulin resistance was quantified using the homeostatic model assessment. RESULTS: Mean age was 56.5+/-10.0 years, 51% had stage III disease, 72% were treated with chemotherapy, and the mean time since finishing treatment was 10.9+/-6.1 months. Over six months, the low-dose group completed 141.5+/-9.9 minwk-1 of aerobic exercise, and the high-dose group completed 247.2+/-10.7 minwk-1 of aerobic exercise. Fasting insulin concentrations decreased 7.4+/-9.4 pmol/L in the control group, 28.0+/-8.3 pmol/L in the low-dose group, and 20.7+/-9.3 pmol/L in the high-dose group (nonlinear Ptrend=0.042). Insulin resistance decreased 0.11+/-0.20 in the control group, 0.63+/-0.17 in the low-dose group, and 0.43+/-0.19 in the high-dose group (nonlinear Ptrend=0.012). DISCUSSION: Aerobic exercise reduces insulin concentrations and insulin resistance among patients with stage I-III colon cancer. Prescribing 150 minwk-1 of aerobic exercise may be sufficient for reducing insulin concentrations and insulin resistance, which may partially mediate the relationship between physical activity and colon cancer prognosis.

Survival outcomes for elderly lymphoma patients are disproportionally inferior to those of younger patients. We examined medication usage at diagnosis for 171 elderly patients (median age 70 years) with aggressive non-Hodgkin lymphoma treated between 2009 and 2014. At least one potentially inappropriate medication was used in 47% of patients according to the Beers Criteria, 59% experienced treatment delays and/or dose reduction and 65% experienced >/= grade 3 treatment-related toxicities. We report here for the first time that potentially inappropriate medication use was associated with reduced progression-free survival and overall survival, and increased >/= grade 3 treatment-related toxicities in multivariate analysis.

BACKGROUND:Physical activity is associated with a lower risk of disease recurrence among colon cancer patients. Circulating tumor cells (CTC) are prognostic of disease recurrence among stage I-III colon cancer patients. The pathways through which physical activity may alter disease outcomes are unknown, but may be mediated by changes in CTCs. METHODS:Participants included 23 stage I-III colon cancer patients randomized into one of three groups: usual-care control, 150 min∙wk-1 of aerobic exercise (low-dose), and 300 min∙wk-1 of aerobic exercise (high-dose) for six months. CTCs from venous blood were quantified in a blinded fashion using an established microfluidic antibody-mediated capture device. Poisson regression models estimated the logarithmic counts of CTCs. RESULTS:At baseline, 78% (18/23) of patients had ≥1 CTC. At baseline, older age (-0.12±0.06; P = 0.04), lymphovascular invasion (0.63±0.25; P = 0.012), moderate/poor histology (1.09±0.34; P = 0.001), body mass index (0.07±0.02; P = 0.001), visceral adipose tissue (0.08±0.04; P = 0.036), insulin (0.06±0.02; P = 0.011), sICAM-1 (0.04±0.02; P = 0.037), and sVCAM-1 (0.06±0.03; P = 0.045) were associated with CTCs. Over six months, significant decreases in CTCs were observed in the low-dose (-1.34±0.34; P<0.001) and high-dose (-1.18±0.40; P = 0.004) exercise groups, whereas no significant change was observed in the control group (-0.59±0.56; P = 0.292). Over six months, reductions in body mass index (-0.07±0.02; P = 0.007), insulin (-0.08±0.03; P = 0.014), and sICAM-1 (-0.07±0.03; P = 0.005) were associated with reductions in CTCs. The main limitations of this proof-of-concept study are the small sample size, heterogenous population, and per-protocol statistical analysis. CONCLUSION:Exercise may reduce CTCs among stage I-III colon cancer patients. Changes in host factors correlated with changes in CTCs. Exercise may have a direct effect on CTCs and indirect effects through alterations in host factors. This hypothesis-generating observation derived from a small pilot study warrants further investigation and replication.

BACKGROUND: Physical activity is associated with a lower risk of disease recurrence among colon cancer survivors. Excess visceral adipose tissue is associated with a higher risk of disease recurrence among colon cancer survivors. The pathways through which physical activity may alter disease outcomes are unknown, but may be mediated by changes in visceral adipose tissue. METHODS: Thirty-nine stage I-III colon cancer survivors were randomised to one of three groups: usual-care control, 150 min wk-1 of aerobic exercise (low dose) and 300 min wk-1 of aerobic exercise (high dose) for 6 months. The prespecified key body composition outcome was visceral adipose tissue quantified using dual energy X-ray absorptiometry. RESULTS: Exercise reduced visceral adipose tissue in dose-response fashion (Ptrend=0.008). Compared with the control group, the low- and high-dose exercise groups lost 9.5 cm2 (95% CI: -22.4, 3.5) and 13.6 cm2 (95% CI: -27.0, -0.1) in visceral adipose tissue, respectively. Each 60 min wk-1 increase in exercise predicted a 2.7 cm2 (95% CI: -5.4, -0.1) reduction in visceral adipose tissue. CONCLUSIONS: Aerobic exercise reduces visceral adipose tissue in dose-response fashion among patients with stage I-III colon cancer. Visceral adipose tissue may be a mechanism through which exercise reduces the risk of disease recurrence among colon cancer survivors.British Journal of Cancer advance online publication 21 September 2017; doi:10.1038/bjc.2017.339 www.bjcancer.com.

INTRODUCTION: Breast cancer survivors face dual challenges: long term sequelae of treatment, and risk of recurrent disease. Obesity and a sedentary lifestyle complicate both challenges. The WISER Survivor trial assessed the effects of exercise and/or weight-loss on lymphedema, biomarkers of breast cancer recurrence, and quality of life. We report on the innovative transdisciplinary design of this trial and report attrition rates. METHODS: This one year trial randomized breast cancer survivors who had a BMI of >/=25kg/m2, were sedentary and had breast-cancer-related-lymphedema to 1) exercise (weight training and aerobic exercise) 2) weight-loss 3) exercise and weight-loss 4) or control group. Innovative aspects included: adaptation of a community-based weight training program to a largely home-based program; use of a commercial meal replacement system as part of the lifestyle modification weight-loss program; inclusion of measures of cost-effectiveness to enable economic evaluations; and alignment with a parallel mouse model for breast cancer recurrence to enable transdisciplinary research. In this model, mice bearing dormant residual tumor cells, which spontaneously relapse, were placed on a high-fat diet. Overweight animals were randomly assigned to exercise, calorie restriction, both, or control group and followed for cancer recurrence. The animal model will guide mechanistic biomarkers to be tested in the human trial. RESULTS & DISCUSSION: 351 participants were randomized; 13 experienced breast cancer recurrence during the trial. Of the 338 participants without recurrence, 83% completed the trial. The WISER Survivor trial will show the effects of exercise and weight-loss on lymphedema outcomes, biomarkers of recurrence and quality of life. NCT ClinicalTrials.gov registration #: NCT01515124.

BACKGROUND: There are no biomarkers for assessment of disease burden or activity of therapy in SCLC. PATIENTS AND METHODS: We conducted a prospective study enumerating serial CTCs in patients with newly diagnosed limited disease (LD) and extensive stage (ED) SCLC. CTCs demonstrating DNA damage and apoptosis based on gammaH2AX and M30 staining were also assessed. We correlated CTC number with disease stage, survival outcomes and tumor burden by RECIST. RESULTS: Between 03/2011-10/2013, 50 evaluable patients were enrolled (20 LD). Baseline CTC number was higher for ED (median CTC 71 vs. 1.5 for LD; p 0.0004). Patients with <5 CTC had longer PFS but not OS (11 vs. 6.7 months, p 0.0259 and 15.5 vs. 12.9 months, p 0.4357). A higher cutoff (CTC<50 or CTC>/=50) was significantly correlated with both OS (20.2 vs. 11.8 months, p 0.0116) and PFS (10 vs. 4.8 months, p 0.0002). Patients with <5 CTC on day 1 of cycle 2 had longer PFS (10 vs. 3.17 months, p<0.001) and OS (18 vs. 9 months, p 0.0001). Patients with an increase in gamma2HAX-positive CTCs after chemotherapy had longer OS compared to patients without an increase (25.3 vs. 9 months, p 0.15). CONCLUSIONS: This study demonstrates that CTCs at baseline and Cycle 2 of chemotherapy correlate with disease stage and survival in patients with SCLC, suggesting that CTCs may be used as a surrogate biomarker for clinical response. Confirmatory prospective clinical trials are needed before we can incorporate routine evaluation of CTCs into clinical practice.

Importance: Adherence to medications prescribed after acute myocardial infarction (AMI) is low. Wireless technology and behavioral economic approaches have shown promise in improving health behaviors. Objective: To determine whether a system of medication reminders using financial incentives and social support delays subsequent vascular events in patients following AMI compared with usual care. Design, Setting, and Participants: Two-arm, randomized clinical trial with a 12-month intervention conducted from 2013 through 2016. Investigators were blinded to study group, but participants were not. Design was a health plan-intermediated intervention for members of several health plans. We recruited 1509 participants from 7179 contacted AMI survivors (insured with 5 large US insurers nationally or with Medicare fee-for-service at the University of Pennsylvania Health System). Patients aged 18 to 80 years were eligible if currently prescribed at least 2 of 4 study medications (statin, aspirin, beta-blocker, antiplatelet agent), and were hospital inpatients for 1 to 180 days and discharged home with a principal diagnosis of AMI. Interventions: Patients were randomized 2:1 to an intervention using electronic pill bottles combined with lottery incentives and social support for medication adherence (1003 patients), or to usual care (506 patients). Main Outcomes and Measures: Primary outcome was time to first vascular rehospitalization or death. Secondary outcomes were time to first all-cause rehospitalization, total number of repeated hospitalizations, medication adherence, and total medical costs. Results: A total of 35.5% of participants were female (n = 536); mean (SD) age was 61.0 (10.3) years. There were no statistically significant differences between study arms in time to first rehospitalization for a vascular event or death (hazard ratio, 1.04; 95% CI, 0.71 to 1.52; P = .84), time to first all-cause rehospitalization (hazard ratio, 0.89; 95% CI, 0.73 to 1.09; P = .27), or total number of repeated hospitalizations (hazard ratio, 0.94; 95% CI, 0.60 to 1.48; P = .79). Mean (SD) medication adherence did not differ between control (0.42 [0.39]) and intervention (0.46 [0.39]) (difference, 0.04; 95% CI, -0.01 to 0.09; P = .10). Mean (SD) medical costs in 12 months following enrollment did not differ between control ($29811 [$74850]) and intervention ($24038 [$66915]) (difference, -$5773; 95% CI, -$13682 to $2137; P = .15). Conclusions and Relevance: A compound intervention integrating wireless pill bottles, lottery-based incentives, and social support did not significantly improve medication adherence or vascular readmission outcomes for AMI survivors. Trial Registration: clinicaltrials.gov Identifier: NCT01800201.

PURPOSE: Breast cancer metastases differ biologically from primary disease; therefore, metastatic biopsies may assist in treatment decision making. Commercial genomic testing of both tumor and circulating tumor DNA have become available clinically, but utility of these tests in breast cancer management remains unclear. METHODS: Patients undergoing a clinically indicated metastatic tumor biopsy were consented to the ongoing METAMORPH registry. Tumor and blood were collected at the time of disease progression before subsequent therapy, and patients were followed for response on subsequent treatment. Tumor testing (n = 53) and concurrent cell-free DNA (n = 32) in a subset of patients was performed using CLIA-approved assays. RESULTS: The proportion of patients with a genomic alteration was lower in tumor than in blood (69 vs. 91%; p = 0.06). After restricting analysis to alterations covered on both platforms, 83% of tumor alterations were detected in blood, while 90% of blood alterations were detected in tumor. Mutational load specific for the panel genes was calculated for both tumor and blood. Time to progression on subsequent treatment was significantly shorter for patients whose tumors had high panel-specific mutational load (HR 0.31, 95% CI 0.12-0.78) or a TP53 mutation (HR 0.35, 95% CI 0.20-0.79), after adjusting for stage at presentation, hormone receptor status, prior treatment type, and number of lines of metastatic treatment. CONCLUSIONS: Treating oncologists must distinguish platform differences from true biological heterogeneity when comparing tumor and cfDNA genomic testing results. Tumor and concurrent cfDNA contribute unique genomic information in metastatic breast cancer patients, providing potentially useful biomarkers for aggressive metastatic disease.