Faculty Bibliography

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.

Background: Survival outcomes for older patients with aggressive NHL are disproportionally inferior to those of younger patients. While differences in tumor biology may play a role, older patients are often frail with comorbidities, polypharmacy, and use potentially inappropriate medications (PIM) such as anticholinergics and benzodiazepines. Methods: Using Cox proportional hazard and logistic regression models, we analyzed all aggressive NHL patients age >= 60 treated at our two affiliated hospitals from 2009-2014 to examine the association of polypharmacy and PIM use with progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: In this updated and final analysis, we included 171 patients with complete records from these two hospitals. They share similar demographic, clinical, and laboratory characteristics except for higher International Prognostic Index (IPI) in patients from one hospital. The median age was 70 years (range 65-77). At the time of diagnosis, 46% of patients used more than 4 medications (polypharmacy) and 47% used at least one PIM. Only 43% of patients received first-line chemotherapy of adequate relative dose intensity (>85% dosage), and 65% experienced >= grade 3 toxicities. Polypharmacy and PIM use were associated with shortened PFS and OS by log-rank test. Most importantly, PIM use remained an independent predictor of PFS, OS, and >= grade 3 toxicities in multivariable analyses (Table). Conclusions: This is the first report of significantly adverse survival impacts of polypharmacy and PIM use in older patients with aggressive NHL, presumably from drug-drug interactions that increase toxicities and impair the delivery of adequate chemotherapy dosage. Our findings support the use of evidence-based geriatric principles to guide meticulous medication management to improve outcome disparity for these patients. (Table presented)

OBJECTIVES/OBJECTIVE:Clinical trials are increasingly testing the effectiveness of paying patients' financial incentives for achieving desired clinical outcomes. Some researchers and providers are concerned that patient financial incentives will harm the doctor-patient relationship. How patients feel about these approaches, and these trials, is largely unknown. This study examined patients' perceptions of a compound behavioral and financial incentive intervention used in a large multicenter trial to lower low-density lipoprotein cholesterol (LDL-C), including their perceptions of benefits and challenges and the study's effect on patients' relationship with their primary care physicians (PCPs). STUDY DESIGN/METHODS:Semi-structured telephone interviews with patients post intervention. METHODS:PCPs from 3 primary care practices in the northeastern United States were randomized to 1 of 4 arms: physician financial incentives, patient financial incentives, shared incentives between physicians and patients, and a control arm. Within each arm, 10 high, 10 medium, and 10 low performers in LDL-C reduction were interviewed. Interviews targeted reasons for enrolling in the study, the specific intervention elements that helped them reach the goal (incentives, engagement, monitoring), challenges faced in reducing cholesterol, and the impact of study participation on their relationship with their PCP. RESULTS:Patients reported positive experiences with the study: 65% described personal changes to improve health and 61% reported increased awareness. Views about financial incentives varied: 71% clearly found them motivating and 36% claimed they made no difference. Patients noted that changing lifestyle (36%) and diet (65%) was difficult. Patients who substantially lowered their LDL-C revealed themes similar to those who did not. CONCLUSIONS:Overall, behavioral interventions with financial incentives appear to be socially acceptable to patients who participate in them. Both adherence monitoring and financial incentives were well received, with little effect on the physician-patient relationship.

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), collectively referred to as 'non-melanoma skin cancer (NMSC)', are the most common cancers worldwide.1,2 Despite their considerable public health burden, there are substantial gaps in the epidemiological study of these malignancies as they are not commonly included in cancer registries.3,4

BACKGROUND: Immunosuppression nonadherence increases the risk for kidney transplant loss after transplantation. Wireless-enabled pill bottles have created the opportunity to monitor medication adherence in real time. Reminders may help patients with poor memory or organization. Provision of adherence data to providers may motivate patients to improve adherence and help providers identify adherence barriers. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: Kidney transplant recipients (n=120) at a single center. INTERVENTION: Participants were provided wireless pill bottles to store tacrolimus and record bottle openings. Participants were randomly assigned 1:1:1 to adherence monitoring with customized reminders (including alarms, texts, telephone calls, and/or e-mails), monitoring with customized reminders plus provider notification (every 2 weeks, providers received notification if adherence decreased to <90% during that period), or wireless pill bottle use alone (control). OUTCOMES: The main outcome was bottle-measured tacrolimus adherence during the last 90 days of the 180-day trial. A secondary outcome was tacrolimus whole-blood concentrations at routine clinical visits. MEASUREMENTS: Adherence for the primary outcome was assessed via wireless pill bottle openings. RESULTS: Mean participant age was 50 years; 60% were men, and 40% were black. Mean adherence was 78%, 88%, and 55% in the reminders, reminders-plus-notification, and control arms (P<0.001 for comparison of each intervention to control). Mean tacrolimus levels were not significantly different between groups. LIMITATIONS: The study did not assess clinical end points. Participants and study coordinators were not blinded to intervention arm. CONCLUSIONS: Provider notification and customized reminders appear promising in helping patients achieve better medication adherence, but these strategies require evaluation in trials powered to detect differences in clinical outcomes.

Importance: Medicare launched the mandatory Comprehensive Care for Joint Replacement bundled payment model in 67 urban areas for approximately 800 hospitals following its experience in the voluntary Acute Care Episodes (ACE) and Bundled Payments for Care Improvement (BPCI) demonstration projects. Little information from ACE and BPCI exists to guide hospitals in redesigning care for mandatory joint replacement bundles. Objective: To analyze changes in quality, internal hospital costs, and postacute care (PAC) spending for lower extremity joint replacement bundled payment episodes encompassing hospitalization and 30 days of PAC. Design, Setting, and Participants: This observational study followed 3942 total patients with lower extremity joint replacement at Baptist Health System (BHS), which participated in ACE and BPCI. Exposures: Lower extremity joint replacement surgery under bundled payment at BHS. Main Outcomes and Measures: Average Medicare payments per episode, readmissions, emergency department visits, prolonged length of stay, and hospital savings from changes in internal hospital costs and PAC spending. Results: Overall, 3942 patients (mean [SD] age, 72.4 [8.4] years) from BHS were observed. Between July 2008 and June 2015, average Medicare episode expenditures declined 20.8%, from $26785 to $21208 (P < .001) for 3738 episodes of joint replacement without complications. It declined 13.8% from $38537 to $33216 (P = .61) for 204 episodes of joint replacement with complications. Readmissions and emergency department visits declined 1.4% (P = .14) and 0.9% (P = .98), respectively, while episodes with prolonged length of stay decreased 67.0% (P < .001). Patient illness severity remained stable. By 2015, 51.2% of overall hospital savings had come from internal cost reductions and 48.8% from PAC spending reductions. Reductions in implant costs, down on average $1920.68 (29%) per case, contributed the greatest proportion of hospital savings. Average PAC spending declined $2443.12 (27%) per case, largely from reductions in inpatient rehabilitation and skilled nursing facility spending but only when bundles included financial responsibility for PAC. Conclusions and Relevance: During a period in which Medicare payments for joint replacement episodes increased by 5%, bundled payment for procedures at BHS was associated with substantial hospital savings and reduced Medicare payments. Decreases in PAC spending occurred only when it was included in the bundle.

OBJECTIVES: Medication adherence is often suboptimal, especially among patients on multiple chronic medications. We examined the association between synchronized medication refill schedules-which typically reduce organizational effort and logistical demands-and adherence. STUDY DESIGN: Retrospective study among patients enrolled in Medicare Advantage prescription drug plans. METHODS: We used 2012 pharmacy, medical, and enrollment data linked with consumer meta-data for Medicare patients filling 2 or more maintenance prescriptions for antihypertensives, lipid-lowering agents, antidiabetic agents, antidepressants, and/or antiosteoporotic agents. Medication adherence for the year was measured using the proportion of days covered (PDC) at the drug class level. Patients were deemed adherent if drug class PDC was >/=0.80. Outcomes were compared between 1:1 propensity score-matched patients on synchronized versus nonsynchronized refill schedules for maintenance medications. RESULTS: The synchronized refill group showed better adherence than the control group, although the magnitude of effects varied by drug class and specific outcome measure. Mean PDC scores ranged from 0.02 higher for antihypertensives to 0.07 higher for antidepressants in the synchronized refill group relative to the control group (P <.01). Further, compared with the control group, a larger proportion of synchronized refill group members were deemed adherent, ranging from 6 percentage points higher for antihypertensives to 15 percentage points higher for lipid-lowering agents (P <.01). Differences between the synchronized and control groups were larger among exclusive users of retail versus mail order pharmacies for maintenance medications. CONCLUSIONS: Synchronized medication refill schedules were associated with better medication adherence, particularly for patients filling maintenance medications exclusively at retail pharmacies.

Background Obesity continues to be a serious public health challenge. Rates are increasing worldwide, with nearly 70% of the US adults overweight or obese, leading to increased clinical and economic burden. While successful approaches for achieving weight loss have been identified, techniques for long-term maintenance of initial weight loss have largely been unsuccessful. Financial incentive interventions have been shown in several settings to be successful in motivating participants to adopt healthy behaviors. Purpose Keep It Off is a three-arm randomized controlled trial that compares the efficacy of a lottery-based incentive, traditional direct payment incentive, and control of daily feedback without any incentive for weight-loss maintenance. This design allows comparison of a traditional direct payment incentive with one based on behavioral economic principles that consider the underlying psychology of decision-making. Methods Participants were randomized in a 2:1 ratio for each active arm relative to control, with a targeted 188 participants in total. Eligible participants were those aged 30-80 who lost at least 11 lb (5 kg) during the first 4 months of participation in Weight Watchers, a national weight-loss program, with whom we partnered. The interventions lasted 6 months (Phase I); participants were followed for an additional 6 months without intervention (Phase II). The primary outcome is weight change from baseline to the end of Phase I, with the change at the end of Phase II a key secondary endpoint. Keep It Off is a pragmatic trial that recruited, consented, enrolled, and followed patients electronically. Participants were provided a wireless weight scale that electronically transmitted daily self-monitored weights. Weights were verified every 3 months at a Weight Watchers center local to the participant and electronically transmitted. Results Using the study web-based platform, we integrated recruitment, enrollment, and follow-up procedures into a digital platform that required little staff effort to implement and manage. We randomized 191 participants in less than 1 year. We describe the design of Keep It Off and implementation of enrollment. Lessons Learned We demonstrated that our pragmatic design was successful in rapid accrual of participants in a trial of interventions to maintain weight loss. Limitations Despite the nationwide reach of Weight Watchers, the generalizability of study findings may be limited by the characteristics of its members. The interventions under study are appropriate for settings where an entity, such as an employer or health insurance company, could offer them as a benefit. Conclusions Keep It Off was implemented and conducted with minimal staff effort. This study has the potential to identify a practical and effective weight-loss maintenance strategy.

Sezary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sezary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sezary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sezary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

PURPOSE: The expanding number of targeted therapeutics for non-small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS. EXPERIMENTAL DESIGN: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible. RESULTS: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible. CONCLUSIONS: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772-82. (c)2016 AACR.