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Abstract Introduction Chronic pain is common among Veterans, some of whom use cannabis for pain. We conducted a feasibility pilot study of a novel coaching intervention to help Veterans optimize use of medical cannabis products for pain management (NCT06320470). Methods The intervention drew from scientific literature, consultation with cannabis experts, Veteran input via a Community Advisory Board, and tenets of motivational interviewing. Participants were Veterans with chronic pain who endorsed current use or interest in using cannabis for pain management. Participants received up to 4 individual coaching sessions via videoconference, spaced approximately 2 weeks apart. We assessed feasibility (adherence, satisfaction, acceptability) and preliminary effects on pain symptoms 14 weeks after baseline. The primary outcome was the Patient Global Impression of Change (PGIC), and exploratory outcomes included domains from the Patient-Reported Outcomes Measurement Information System (PROMIS)-29. Results Of 22 enrolled participants, 17 attended 4 coaching sessions, 2 attended 3 sessions, and 2 attended 2 sessions. Among those who completed end of intervention surveys (16/21), 87.5% were very or completely satisfied with the intervention and 81.3% rated coaching as very or extremely helpful. All participants reported improvement on the PGIC, with 63% reporting much or very much improvement. Participants reported statistically significant decreased pain intensity (7.1/10 vs. 5.7/10) and pain interference (T-score 66.3 vs. 61.8), and increased social satisfaction (T-score 41.4 vs. 44.3). Participants noted helpful intervention factors, including co-developing a personalized plan, discussing questions/concerns, and trying different approaches to cannabis-based treatment. Conclusions In this feasibility pilot study of coaching on cannabis use for chronic pain among Veterans, participants were satisfied with the intervention and reported clinically significant improvements in pain symptoms. Our results support evaluating this intervention in a larger, efficacy trial.

Abstract Background Chronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD’s analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD’s effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC). Methods We designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance). Discussion Once complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD’s analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans. Trial registration This protocol is registered at clinicaltrials.gov under study number NCT06213233.

This study investigated reasons for lower-than-expected uptake of germline genetic testing compared to national guidelines amongst adult patients with cancer, self-reporting clinician recommendation for genetic testing. Cross-sectional survey of 596 patients with a personal history of cancer, responded about their cancer diagnosis, physician recommendation for and status of genetic testing and demographics. Adjusting for potential confounding factors (cancer type, education, income and insurance status) male sex significantly decreased odds of receiving a clinical recommendation for genetic testing (Odds Ratio: 0.06; 95% Confidence Interval: 0.04–0.10). Females, with a diagnosis of breast cancer, were more likely to receive a recommendation than other cancer types (64.8% vs. 90.9%, p < 0.001). Participants who received a physician recommendation were significantly more likely to receive genetic testing (p < 0.001). Clinician recommendation is an important driver of genetic testing, necessitating efforts to increase clinician recommendations, particularly for males and patients with cancers other than breast.

Abstract Background Only a small proportion of patients who qualify for clinical genetic testing for cancer susceptibility get testing. Many patient‐level barriers contribute to low uptake. In this study, we examined self‐reported patient barriers and motivators for cancer genetic testing. Methods A survey comprised of both new and existing measures related to barriers and motivators to genetic testing was emailed to patients with a diagnosis of cancer at a large academic medical center. Patients who self‐reported receiving a genetic test were included in these analyses (n = 376). Responses about emotions following testing as well as barriers and motivators prior to getting testing were examined. Group differences in barriers and motivators by patient demographic characteristics were examined. Results Being assigned female at birth was associated with increased emotional, insurance, and family concerns as well as increased health benefits compared to patients assigned male at birth. Younger respondents had significantly higher emotional and family concerns compared to older respondents. Recently diagnosed respondents expressed fewer concerns about insurance implications and emotional concerns. Those with a BRCA‐related cancer had higher scores on social and interpersonal concerns scale than those with other cancers. Participants with higher depression scores indicated increased emotional, social and interpersonal, and family concerns. Conclusions Self‐reported depression emerged as the most consistent factor influencing report of barriers to genetic testing. By incorporating mental health resources into clinical practice, oncologists may better identify those patients who might need more assistance following through with a referral for genetic testing and the response afterwards.

Abstract Background Although most cancers are sporadic, germline genetic variants are implicated in 5–10% of cancer cases. Clinical genetic testing identifies pathogenic germline genetic variants for hereditary cancers. The Michigan Genetic Hereditary Testing (MiGHT) study is a three-arm randomized clinical trial that aims to test the efficacy of two patient-level behavioral interventions on uptake of cancer genetic testing. Methods The two interventions being tested are (1) a virtual genetics navigator and (2) motivational interviewing by genetic health coaches. Eligible participants are adults with a diagnosis of breast, prostate, endometrial, ovarian, colorectal, or pancreatic cancer who meet the National Comprehensive Cancer Network (NCCN) criteria for genetic testing. Participants are recruited through community oncology practices affiliated with the Michigan Oncology Quality Consortium (MOQC) and have used the Family Health History Tool (FHHT) to determine testing eligibility. The recruitment goal is 759 participants, who will be randomized to usual care or to either the virtual genetics navigator or the motivational interviewing intervention arms. The primary outcome will be the proportion of individuals who complete germline genetic testing within 6 months. Discussion This study addresses patient-level factors which are associated with the uptake of genetic testing. The study will test two different intervention approaches, both of which can help address the shortage of genetic counselors and improve access to care. Trial registration This study has been approved by the Institutional Review Board of the University of Michigan Medical School (HUM00192898) and registered in ClinicalTrials.gov (NCT05162846).

Abstract Background Prevention of major depressive disorder (MDD) is a public health priority. Strategies targeting individuals at elevated risk for MDD may guide effective preventive care. Insomnia is a reliable precursor to depression, preceding half of all incident and relapse cases. Thus, insomnia may serve as a useful entry point for preventing MDD. Cognitive-behavioral therapy for insomnia (CBT-I) is recommended as the first-line treatment for insomnia, but widespread implementation is limited by a shortage of trained specialists. Innovative stepped-care approaches rooted in primary care can increase access to CBT-I and reduce rates of MDD. Methods/design We propose a large-scale stepped-care clinical trial in the primary care setting that utilizes a sequential, multiple assignment, randomized trial (SMART) design to determine the effectiveness of dCBT-I alone and in combination with clinician-led CBT-I for insomnia and the prevention of MDD incidence and relapse. Specifically, our care model uses digital CBT-I (dCBT-I) as a first-line intervention to increase care access and reduce the need for specialist resources. Our proposal also adds clinician-led CBT-I for patients who do not remit with first-line intervention and need a more personalized approach from specialty care. We will evaluate negative repetitive thinking as a potential treatment mechanism by which dCBT-I and CBT-I benefit insomnia and depression outcomes. Discussion This project will test a highly scalable model of sleep care in a large primary care system to determine the potential for wide dissemination and implementation to address the high volume of population need for safe and effective insomnia treatment and associated prevention of depression. Trial registration ClinicalTrials.gov NCT03322774. Registered on October 26, 2017

Abstract Background Design and analysis of clinical trials for rare and ultra-rare disease pose unique challenges to the practitioners. Meeting conventional power requirements is infeasible for diseases where sample sizes are inherently very small. Moreover, rare disease populations are generally heterogeneous and widely dispersed, which complicates study enrollment and design. Leveraging all available information in rare and ultra-rare disease trials can improve both drug development and informed decision-making processes. Main text Bayesian statistics provides a formal framework for combining all relevant information at all stages of the clinical trial, including trial design, execution, and analysis. This manuscript provides an overview of different Bayesian methods applicable to clinical trials in rare disease. We present real or hypothetical case studies that address the key needs of rare disease drug development highlighting several specific Bayesian examples of clinical trials. Advantages and hurdles of these approaches are discussed in detail. In addition, we emphasize the practical and regulatory aspects in the context of real-life applications. Conclusion The use of innovative trial designs such as master protocols and complex adaptive designs in conjunction with a Bayesian approach may help to reduce sample size, select the correct treatment and population, and accurately and reliably assess the treatment effect in the rare disease setting.

Abstract Background The concomitant use of anticoagulant and antiplatelet medications increases the risk of upper gastrointestinal (GI) bleeding. Two underused evidence-based practices (EBPs) can reduce the risk: de-prescribe unnecessary antiplatelet therapy or initiate a proton pump inhibitor. We describe the development of a multicomponent intervention to increase use of these EBPs in patients treated with warfarin and followed by an anticoagulation monitoring service (AMS), and the design of a pilot pragmatic implementation trial. Methods A participatory planning group iteratively used Implementation Mapping and the Multiphase Optimization Strategy to develop implementation strategies and plan the trial. Informed by qualitative interviews with patients and clinicians, we drew on several implementation science theories, as well as self-determination theory, to design interventions. For patients, we developed an activation guide to help patients discuss the EBPs with their clinicians. For clinicians, we developed two electronic health record (EHR)-based interventions: (1) clinician notification (CN) consists of a templated message that identifies a patient as high risk, summarizes the EBPs, and links to a guidance statement on appropriate use of antiplatelet therapy. (2) Clinician notification with nurse facilitation (CN+NF) consists of a similar notification message but includes additional measures by nursing staff to support appropriate and timely decision-making: the nurse performs a chart review to identify any history of vascular disease, embeds indication-specific guidance on antiplatelet therapy in the message, and offers to assist with medication order entry and patient education. We will conduct a pilot factorial cluster- and individual-level randomized controlled trial with a primary objective of evaluating feasibility. Twelve clinicians will be randomized to receive either CN or CN+NF for all their patients managed by the AMS while 50 patients will be individually randomized to receive either the activation guide or usual care. We will explore implementation outcomes using patient and clinician interviews along with EHR review. Discussion This pilot study will prepare us to conduct a larger optimization study to identify the most potent and resource conscious multicomponent implementation strategy to help AMSs increase the use of best practices for upper GI bleeding risk reduction. Trial registration ClinicalTrials.gov NCT05085405 . Registered on October 19, 2021—retrospectively registered.

Abstract Background Reach Out is a factorial trial studying multicomponent behavioral interventions to reduce blood pressure in hypertensive emergency department patients. The original study protocol was published in June 2020. Here, we describe the updated protocol, including a supplemental study, Reach Out Cognition. Reach Out Cognition is a remote study that will assess the acceptability, feasibility, and satisfaction of digital, self-administered cognitive assessments and Bluetooth-enabled, self-measured blood pressure monitoring in the Reach Out population. We will also estimate the prevalence of mild cognitive impairment in Reach Out participants. Methods Reach Out Cognition includes remote enrollment and follow-up assessments. Reach Out Cognition extends Reach Out data collection past the current 12 months to 15 and 18 months. Participants will be Reach Out participants who complete their 12-month outcome assessments and opt to continue in the cohort study. Participants will continue to receive the Reach Out intervention, consisting of (1) daily healthy behavior text messaging and (2) weekly self-measured blood pressure monitoring. Blood pressure will be measured using Bluetooth-enabled self-measured blood pressure monitoring devices, and cognition will be measured using digital self-administered cognitive assessments at 12, 15, and 18 months. Discussion Reach Out Cognition will explore the potential of remote, digital, self-administered assessments of blood pressure and cognition among predominantly working-age Black Americans. Reach Out Cognition will inform future clinical trials and clinical remote monitoring of blood pressure and cognition that may lead to new approaches to treating and reducing hypertension and cognitive disparities. Trial registration ClinicalTrials.gov NCT03422718. The record was first available to the public on January 30, 2018, prior to the enrollment of patients on March 25, 2019.

Summary: Triple-negative breast cancers (TNBCs) are frequently poorly differentiated with high propensity for metastasis. Enhancer of zeste homolog 2 (EZH2) is the lysine methyltransferase of polycomb repressive complex 2 that mediates transcriptional repression in normal cells and in cancer through H3K27me3. However, H3K27me3-independent non-canonical functions of EZH2 are incompletely understood. We reported that EZH2 phosphorylation at T367 by p38α induces TNBC metastasis in an H3K27me3-independent manner. Here, we show that cytosolic EZH2 methylates p38α at lysine 139 and 165 leading to enhanced p38α stability and that p38 methylation and activation require T367 phosphorylation of EZH2. Dual inhibition of EZH2 methyltransferase and p38 kinase activities downregulates pEZH2-T367, H3K27me3, and p-p38 pathways in vivo and reduces TNBC growth and metastasis. These data uncover a cooperation between EZH2 canonical and non-canonical mechanisms and suggest that inhibition of these pathways may be a potential therapeutic strategy.

Abstract Background Hypertension is the most important modifiable risk factor for cardiovascular disease, the leading cause of mortality in the United States. The Emergency Department represents an underutilized opportunity to impact difficult-to-reach populations. There are 136 million visits to the Emergency Department each year and nearly all have at least one blood pressure measured and recorded. Additionally, an increasing number of African Americans and socioeconomically disadvantaged patients are overrepresented in the Emergency Department patient population. In the age of electronic health records and mobile health, the Emergency Department has the potential to become an integral partner in chronic disease management. The electronic health records in conjunction with mobile health behavior interventions can be leveraged to identify hypertensive patients to impact otherwise unreached populations. Methods Reach Out is a factorial trial studying multicomponent, behavioral interventions to reduce blood pressure in the Emergency Department patient population. Potential participants are identified by automated alerts from the electronic health record and, following consent, receive a blood pressure cuff to take home. During the initial screening phase, they are prompted to submit weekly blood pressure readings. Responders with persistent hypertension are then randomized into one of three component arms, consisting of varying intensity levels: (1) healthy behavior text messaging (daily vs. none), (2) blood pressure self-monitoring (daily vs. weekly), and (3) facilitated primary care provider appointment scheduling and transportation (yes vs. no). If participants are randomized to receive facilitated primary care provider appointment scheduling and are not established with a primary care provider, care will be established at a local Federally Qualified Health Center. Participants are followed for 12 months. Discussion The Reach Out study is designed to determine which behavioral intervention components or ‘dose’ of components contributes to a reduction in systolic blood pressure after 1 year (Aim 1). The study will also assess the effect of primary care provider appointment assistance on total primary care follow-up visits of hypertensive patients treated in an urban, safety net Emergency Department (Aim 2). Ideally, the Reach Out system will contribute to hypertension management, serving as a model for safety net hospitals and Federally Qualified Health Centers to improve chronic disease management in underserved communities. Trial registration This study was registered at clinicaltrials.gov, identifier NCT03422718 . The record was first available to the public on January 30, 2018 prior to the enrollment of patients on March 25, 2019.

BackgroundAromatase inhibitors (AI) reduce recurrence and death in patients with early-stage hormone receptor-positive (HR +) breast cancer. Treatment-related toxicities, including AI-induced musculoskeletal symptoms (AIMSS), are common and may lead to early AI discontinuation. The objective of this study was to replicate previously reported associations for candidate germline genetic polymorphisms with AIMSS.MethodsWomen with stage 0-III HR + breast cancer initiating adjuvant AI were enrolled in a prospective clinic-based observational cohort. AIMSS were assessed by patient-reported outcomes (PRO) including the PROMIS pain interference and physical function measures plus the FACT-ES joint pain question at baseline and after 3 and 6 months. For the primary analysis, AIMSS were defined as ≥ 4-point increase in the pain interference T-score from baseline. Secondary AIMSS endpoints were defined as ≥ 4-point decrease in the physical function T-score from baseline and as ≥ 1-point increase on the FACT-ES joint pain question from baseline. The primary hypothesis was that TCL1A rs11849538 would be associated with AIMSS. Twelve other germline variants in CYP19A1, VDR, PIRC66, OPG, ESR1, CYP27B1, CYP17A1, and RANKL were also analyzed assuming a dominant genetic effect and prespecified direction of effect on AIMSS using univariate logistic regression with an unadjusted α = 0.05. Significant univariate associations in the expected direction were adjusted for age, race, body mass index (BMI), prior taxane, and the type of AI using multivariable logistic regression.ResultsA total of 143 participants with PRO and genetic data were included in this analysis, most of whom were treated with anastrozole (78%) or letrozole (20%). On primary analysis, participants carrying TCL1A rs11849538 were not more likely to develop AIMSS (odds ratio = 1.29, 95% confidence interval: 0.55–3.07, p = 0.56). In the statistically uncorrected secondary analysis, OPG rs2073618 was associated with AIMSS defined by worsening on the FACT-ES joint pain question (OR = 3.33, p = 0.004), and this association maintained significance after covariate adjustment (OR = 3.98, p = 0.003).ConclusionCarriers of OPG rs2073618 may be at increased risk of AIMSS. If confirmed in other cohorts, OPG genotyping can be used to identify individuals with HR + early breast cancer in whom alternate endocrine therapy or interventions to enhance symptom detection and implement strategies to reduce musculoskeletal symptoms may be needed.

Background Immune checkpoint inhibition is effective in several cancers. Expression of programmed death-ligand 1 (PD-L1) on circulating tumor or immune effector cells could provide insights into selection of patients for immune checkpoint inhibition. Methods Whole blood was collected at serial timepoints from metastatic breast cancer patients and healthy donors for circulating tumor cell (CTC) and platelet PD-L1 analysis with a phycoerythrin-labeled anti-human PD-L1 monoclonal antibody (Biolegend clone 29E.2A3) using the CellSearch® assay. CTC PD-L1 was considered positive if detected on at least 1% of the cells; platelet PD-L1 was considered positive if ≥100 platelets per CellSearch frame expressed PD-L1. Results A total of 207 specimens from 124 metastatic breast cancer patients were collected. 52/124 (42%) samples at timepoint-1 (at or close to time of progressive disease) had ≥5 CTC/7.5ml whole blood. Of those, 21 (40%) had positive CTC PD-L1. In addition, platelet PD-L1 expression was observed in 35/124 (28%) at timepoint-1. Platelet PD-L1 was not detected in more than 70 specimens from 12 healthy donors. Platelet PD-L1 was associated with ≥5 CTC/7.5ml whole blood (p = 0.0002), less likely in patients with higher red blood cell counts (OR = 0.72, pConclusion PD-L1 expression was found in metastatic breast cancer patients on both CTC and platelets in an independent fashion. Inter-patient platelet PD-L1 expression was highly heterogeneous suggesting that it is a biological event associated with cancer in some but not all patients. Taken together, our data suggest that CTC and platelet PD-L1 expression could play a role in predicting which patients should receive immune checkpoint inhibition and as a pharmacodynamics biomarker during treatment.

OBJECTIVES/GOALS: Side effects are why up to 50% of women with hormone-positive breast cancer prematurely discontinue aromatase inhibitor (AI) therapy. Pain from altered nociception without clear tissue/nerve damage (nociplastic) is a hypothesized contributing factor to this. Our objective was to evaluate the relationship between nociplastic pain and AI duration. METHODS/STUDY POPULATION: Patients with breast cancer diagnosed between 2012-19 were identified from the University of Michigan Genomics Initiative (MGI). Patients who were female, >65 years old at time of breast cancer diagnosis, and had hormone receptor-positive disease met inclusion criteria. Prior to undergoing surgery, patients completed validated surveys about overall worst pain (Brief Pain Inventory [BPI]), nociplastic pain (2011 Fibromyalgia Survey [FS]), and life satisfaction, with higher scores representing more of the factor. Breast cancer history, treatment, and patient demographics were abstracted from the medical record. Univariate analysis was conducted to evaluate the relationship between age, body-mass index (BMI), chemotherapy, BPI, FS, life satisfaction, and time to discontinuation of initial AI. RESULTS/ANTICIPATED RESULTS: 207 patients were eligible, 133 of whom initiated AI therapy. Of the 133 analyzed patients, mean age was 70.7 years and mean BMI was 30.3. 28 (21%) underwent adjuvant chemotherapy and 79 (59%) received adjuvant radiation prior to initiation of AI therapy. Average nociplastic pain score was 4.0/31 (standard deviation [SD] 4.6), worst pain was 1.5/10 (SD 1.9), and life satisfaction score was 7.3/10 (SD 2.8). The initial AI for 94% of patients (125 patients) was anastrozole. On univariate analysis, only higher nociplastic pain score was statistically associated with premature discontinuation of AI with a HR 1.07 (95%CI 1.00-1.13, p = 0.036). On multivariable analysis, no factors remained statistically significant, although there was a trend for nociplastic pain (HR 1.06, 95%CI 1.00-1.13, p = 0.068). DISCUSSION/SIGNIFICANCE: It is important to identify variables predicting tolerance to therapy so patients can be optimally counseled. Our study suggests that patients with pre-existing baseline pain disorders may be more likely to be nonpersistent with AI therapy. Future study should be conducted to determine if treatments for nocipastic pain improve AI persistence.

Purpose: T-DM1 is an antibody drug conjugate with proven efficacy in metastatic breast cancer for progressive disease refractory to trastuzumab. Drug-induced pneumonitis is a rare serious potential adverse effect. The purpose of this review was to estimate the incidence of pulmonary toxicity at our institution. Methods: A retrospective analysis of electronic medical record data inclusive of all women and men aged 18 years and older treated with T-DM1 at out institution was undertaken. The records were reviewed for clinical symptoms and/or radiographic evidence concerning for pneumonitis. We identified variables of interest with regard to potential risk factors for toxicity. Results: A total of 50 patients were included, 6 (12%) of whom had radiographic and/or clinical symptoms concerning for T-DM1-induced pneumonitis. All 6 patients had metastatic or unresectable breast cancer. Of the 6 patients, 5 (83%) had suspected pulmonary metastases, 1 (17%) had a history of underlying lung disease, and 5 (83%) had a history of prior taxane therapy. Pulmonary metastases (p = 0.38), the median number of treatment cycles (p = 0.29), prior taxane therapy (p = 0.99), underlying lung disease (p = 0.99), and hormone receptor positivity (p = 0.66) did not have any statistical significance for an association with pneumonitis. Conclusion: Pneumonitis is a recognized toxic effect of T-DM1. While our sample size was small, the number of events was higher than described in the literature, which may be an artifact of referral bias. Future studies with a larger sample population may detect potential risk factors for toxicity.

Polycomb group protein EZH2 is overexpressed in ER- breast cancer, promoting metastasis. Here, the authors show that independent of the polycomb group, phosphorylation of EZH2 at T367 by p38 promotes cytoplasmic localization of EZH2, binding to vinculin and other regulators of cell migration and invasion.

Purpose: Breast cancer, the most common cancer worldwide, is the leading cause of cancer mortality in Ghanaian women. Previous studies find Ghanaian women are diagnosed at a younger age and at more advanced stages (III and IV), and have tumors with characteristics similar to African American women. We sought to remedy gaps in knowledge about breast cancer survival in Ghana and its relation to demographic and biologic factors of the tumors at diagnosis to assist in cancer control and registration planning. Methods: Individuals with a breast cancer diagnosis who sought care at Komfo Anokye Teaching Hospital from 2009 to 2014 were identified via medical records. Follow-up telephone interviews were held to assess survival. Kaplan-Meier plots and Cox proportional hazards models assessed survival associated with clinical and demographic characteristics. Results: A total of 223 patients completed follow-up and were analyzed. The median survival was 3.8 years. Approximately 50% of patients were diagnosed with grade 3 tumors, which significantly increased the risk of recurrence or death (hazard ratio [HR] for grade 2 versus 1, 2.98; 95% CI, 1.26 to 7.02; HR grade 3 v 1, 2.56; 95% CI, 1.08 to 6.07; P = .04). No other variables were significantly associated with survival. Conclusion: Higher tumor grade was significantly associated with shorter survival, indicating impact of aggressive biology at diagnosis on higher risk of cancer spread and recurrence. Contrary to prevailing notions, telephone numbers were not reliable for follow-up. Collecting additional contact information will likely contribute to improvements in patient care and tracking. A region-wide population-based active registry is important to implement cancer control programs and improve survival in sub-Saharan Africa.

Introduction It is increasingly essential for medical researchers to be literate in statistics, but the requisite degree of literacy is not the same for every statistical competency in translational research. Statistical competency can range from ‘fundamental’ (necessary for all) to ‘specialized’ (necessary for only some). In this study, we determine the degree to which each competency is fundamental or specialized. Methods We surveyed members of 4 professional organizations, targeting doctorally trained biostatisticians and epidemiologists who taught statistics to medical research learners in the past 5 years. Respondents rated 24 educational competencies on a 5-point Likert scale anchored by ‘fundamental’ and ‘specialized.’ Results There were 112 responses. Nineteen of 24 competencies were fundamental. The competencies considered most fundamental were assessing sources of bias and variation (95%), recognizing one’s own limits with regard to statistics (93%), identifying the strengths, and limitations of study designs (93%). The least endorsed items were meta-analysis (34%) and stopping rules (18%). Conclusion We have identified the statistical competencies needed by all medical researchers. These competencies should be considered when designing statistical curricula for medical researchers and should inform which topics are taught in graduate programs and evidence-based medicine courses where learners need to read and understand the medical research literature.

Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.

Fulvestrant is a dose dependent selective estrogen receptor (ER) down‐regulator (SERD) used in ER‐positive metastatic breast cancer (MBC). Nearly all patients develop resistance. We performed molecular analysis of circulating tumor cells (CTC) to gain insight into fulvestrant resistance. Preclinical studies were performed with cultured breast cancer cells spiked into human blood and analyzed on the CellSearch® system. Clinical data are limited to a subset of patients with ER‐positive MBC from a previously reported pilot trial whose disease was progressing on fulvestrant (N = 7) or aromatase inhibitors (AIs) (N = 10). CTCs were enumerated and phenotyped for ER and B‐cell lymphoma (BCL2) using the CellSearch® CXC kit. In preclinical modeling, tamoxifen and AIs resulted in stabilized ER expression, whereas fulvestrant eliminated it. Five of seven patients progressing on fulvestrant had ≥5CTC/7.5 ml WB. Two of these five, treated with 500 mg/month fulvestrant, had no detectable CTC‐expression of ER and BCL2 (an ER regulated gene). Three patients had heterogeneous CTC‐ER and BCL2 expression indicating incomplete degradation of the ER target by fulvestrant. Two of these patients received 250 mg/month whereas the third patient received 500 mg/month fulvestrant. Her cancer harbored a mutation (Y537S) in the estrogen receptor alpha gene (ESR1). All seven ER positive patients progressing on AIs had heterogeneous CTC‐ER expression. These results suggest heterogeneous mechanisms of resistance to fulvestrant, including insufficient dosage, ESR1 mutation, or conversion to dependence on non‐ER pathways. CTC enumeration, phenotyping, and genotyping might identify patients who would benefit from fulvestrant dose escalation versus switching to alternative therapies.

OBJECTIVES/SPECIFIC AIMS: Peripheral neuropathy is the dose limiting toxicity of paclitaxel treatment. Paclitaxel pharmacokinetics (PK), specifically the Cmax and amount of time the concentration remains above 0.05 µM (Tc>0.05), have been associated with occurrence of severe, clinician-documented neuropathy. The objective of this study was to confirm that paclitaxel PK predicts progression of patient-reported neuropathy. METHODS/STUDY POPULATION: This observational trial enrolled breast cancer patients receiving weekly 1-hour paclitaxel infusions (80 mg/m2×12 cycles) at the University of Michigan Comprehensive Cancer Center. Paclitaxel concentration was measured via LC/MS in plasma samples collected at the end of (Cmax) and 16–24 hours after (Tc>0.05) first infusion. Patient-reported neuropathy was collected (EORTC CIPN20) at baseline and each cycle. The rate of neuropathy severity increase per treatment cycle is being modeled for each patient. Cmax and Tc>0.05 values will be introduced into the model to confirm that PK independently contributes to neuropathy progression. RESULTS/ANTICIPATED RESULTS: PK and neuropathy data have been collected from 60 patients for ongoing analysis. Our initial model will characterize the expected severity of neuropathy after each cycle of paclitaxel treatment. The PK-neuropathy model will include either PK parameter to validate their contribution to the progression of neuropathy severity during treatment. We anticipate, based on our preliminary analysis of the first 16 patients, that both PK parameters will significantly contribute to the model but Tc>0.05 will be more strongly associated with neuropathy progression. DISCUSSION/SIGNIFICANCE OF IMPACT: This project will generate a model that can be used to predict a patient’s neuropathy severity throughout treatment using a single, conveniently collected and easily measured PK sample during their first cycle. The next steps of this project include identifying genetic and metabolomic biomarkers that predict which patients experienced more severe neuropathy than would be anticipated based on their paclitaxel PK, and a planned interventional trial of personalized paclitaxel dosing to enhance efficacy and/or prevent neuropathy.

Background: The aim of this study was to identify risk factors that may predispose breast cancer patients to the development of CNS metastases. Materials & methods: We conducted a matched case–control study of breast cancer patients treated with surgery with curative intent. A total of 71 cases and 71 controls were analyzed, matched by year of surgery. Results: In our multivariable model, positive lymph node status (odds ratio [OR]: 5.08; CI: 2.04–12.65), the use of neoadjuvant chemotherapy (OR: 6.02; CI: 2.06–17.57) and triple-negative breast cancer (OR: 5.44; CI: 1.99–14.90) were statistically significant predictors of the development of CNS metastases. Conclusion: Women with certain risk factors have an increased odds of developing CNS metastases and evaluation of utility in brain metastases screening should be considered.

Pulmonary infections with Mycobacterium abscessus (M. abscessus) are increasingly prevalent in patients with lung diseases such as cystic fibrosis. M. abscessus exists in two morphotypes, smooth and rough, but the impact of morphotype on virulence is unclear. We developed an immune competent mouse model of pulmonary M. abscessus infection and tested the differences in host inflammatory response between the morphotypes of M. abscessus. Smooth and rough morphotypes of M. abscessus were isolated from the same American Type Culture Collection strain. Wild type and cystic fibrosis mice were intratracheally inoculated with known quantities of M. abscessus suspended in fibrin plugs. At the time of sacrifice lung and splenic tissues and bronchoalveolar lavage fluid were collected and cultured. Bronchoalveolar lavage fluid was analyzed for leukocyte count, differential and cytokine expression. Pulmonary infection with M. abscessus was present at both 3 days and 14 days post-inoculation in all groups at greater levels than systemic infection. Inoculation with M. abscessus rough morphotype resulted in more bronchoalveolar lavage fluid neutrophils compared to smooth morphotype at 14 days post-inoculation in both wild type (p = 0.01) and cystic fibrosis (p

Purpose: Many survivors of breast cancer experience an array of chronic symptoms, including pain, insomnia, and fatigue. Few effective therapies have been identified. Behavioral management programs to address similar symptom clusters in other chronic conditions have been effective. The objective of this study was to determine the effect of an Internet-based lifestyle and behavioral self-management program on cancer-related symptoms., Patients and Methods: Women with stage 0 to 3 breast cancer who reported insomnia, pain, or fatigue as their primary symptom of concern during the 7 days before enrollment were enrolled. Local therapies and/or chemotherapy were completed at least 3 months before enrollment. Patients were assessed at baseline and after 8 weeks, and they completed the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Profile and Patient Global Impression of Change (PGIC) questionnaire electronically. Change in each of the eight symptom domains was assessed., Results: Fifty patients enrolled. In the 45 patients with both baseline and 8-week PROMIS data, statistically significant improvements in anxiety, sleep, fatigue, activity level, and pain severity were reported. Of the 35 patients who responded to the PGIC, 62.9% reported improvement in their primary symptom. Those who reported fatigue as their primary symptom reported greatest overall benefit in multiple symptom improvement, including improvements in fatigue, anxiety, pain severity, pain interference, and participation in social activities., Conclusions: These findings suggest that this lifestyle and behavioral management program may improve multiple symptoms in breast cancer survivors when delivered via the Internet. Randomized studies are warranted to evaluate the efficacy of the online intervention compared with standard symptom management approaches and to identify patients most likely to benefit.