Polypharmacy, over-the-counter medications, and aromatase inhibitor adherence in early-stage breast cancer.

PURPOSE: Polypharmacy is associated with negative health outcomes and decreased medication adherence. Polypharmacy is common in cancer populations, but few studies have evaluated the relationship between polypharmacy and aromatase inhibitor (AI) adherence. No studies have evaluated the relationship between over-the-counter (OTC) supplements and AI adherence. Our primary hypothesis was that polypharmacy would be associated with increased risk of premature AI discontinuation. METHODS: This exploratory analysis used data from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, a prospective, multicenter, randomized controlled trial that enrolled participants from 2005 to 2009. Included patients were female, postmenopausal, with stage 0-III breast cancer, who had completed indicated chemotherapy, surgery, and radiation. Participants were randomized to adjuvant exemestane or letrozole and completed serial clinical examinations and questionnaires for two years. Concomitant medication data were collected prospectively. Cox proportion models were used for statistical analysis of the relationship between polypharmacy, OTCs, medication class, and AI adherence. RESULTS: In the 490 analyzed participants, use of any prescription medications at baseline was associated with decreased risk of premature AI discontinuation (HR 0.56, p = 0.02). Use of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) at baseline was associated with decreased risk of premature AI discontinuation (HR 0.67, p = 0.04). Use of any OTCs was not associated with AI discontinuation. CONCLUSION: Baseline use of prescription medications but not OTCs was associated with increased AI persistence. Future research is needed to understand how this can be utilized to promote AI adherence.

Improving alcohol treatment engagement using integrated behavioral interventions in alcohol-associated liver disease: A randomized pilot trial.

INTRODUCTION: Alcohol cessation improves mortality in alcohol-associated liver disease (ALD), but few ALD patients will engage in treatment. We aimed to demonstrate the feasibility and acceptability of a mobile health intervention to increase alcohol use disorder (AUD) treatment among ALD patients. METHODS: We conducted a pilot randomized controlled trial (September 2020 to June 2022) at a single tertiary care center in adults with any stage of ALD, past 6-month drinking, and no past-month AUD treatment. Sixty participants were randomized 1:1 to a mobile health application designed to increase AUD treatment engagement through preference elicitation and matching to treatment and misconception correction. Controls received enhanced usual care. The primary outcomes were feasibility (recruitment and retention rates) and acceptability. Exploratory outcomes were AUD treatment engagement and alcohol use, measured by Timeline Followback. Outcomes were measured at 3 and 6 months. RESULTS: Baseline characteristics were balanced. The recruitment rate was 46%. Retention was 65% at 6 months. The intervention was highly acceptable to participants (91% were mostly/very satisfied; 95% felt that the intervention matched them well to AUD treatment). Secondary outcomes showed increased AUD treatment at 6 months in the intervention group (intent-to-treat: 27.3% vs. 13.3%, OR 2.3, 95% CI, 0.61-8.76). There was a trend toward a 1-level or greater reduction in World Health Organization (WHO) drinking risk levels in the intervention group (OR 2.25, 95% CI, 0.51-9.97). CONCLUSIONS: A mobile health intervention for AUD treatment engagement was highly feasible, acceptable, and produced promising early outcomes, with improved AUD treatment engagement and alcohol reduction in ALD patients.

Effects of CYP3A4 and CYP2C9 genotype on systemic anastrozole and fulvestrant concentrations in SWOG S0226.

Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes, SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e. CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (ß-coefficient = 10.03; 95% CI: 1.42, 18.6; p = 0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes.

Dynamic enrichment of Bayesian small-sample, sequential, multiple assignment randomized trial design using natural history data: a case study from Duchenne muscular dystrophy.

In Duchenne muscular dystrophy (DMD) and other rare diseases, recruiting patients into clinical trials is challenging. Additionally, assigning patients to long-term, multi-year placebo arms raises ethical and trial retention concerns. This poses a significant challenge to the traditional sequential drug development paradigm. In this paper, we propose a small-sample, sequential, multiple assignment, randomized trial (snSMART) design that combines dose selection and confirmatory assessment into a single trial. This multi-stage design evaluates the effects of multiple doses of a promising drug and re-randomizes patients to appropriate dose levels based on their Stage 1 dose and response. Our proposed approach increases the efficiency of treatment effect estimates by (i) enriching the placebo arm with external control data, and (ii) using data from all stages. Data from external control and different stages are combined using a robust meta-analytic combined (MAC) approach to consider the various sources of heterogeneity and potential selection bias. We reanalyze data from a DMD trial using the proposed method and external control data from the Duchenne Natural History Study (DNHS). Our method's estimators show improved efficiency compared to the original trial. Also, the robust MAC-snSMART method most often provides more accurate estimators than the traditional analytic method. Overall, the proposed methodology provides a promising candidate for efficient drug development in DMD and other rare diseases.

Reach Out Emergency Department: A Randomized Factorial Trial to Determine the Optimal Mobile Health Components to Reduce Blood Pressure.

BACKGROUND: Mobile health (mHealth) strategies initiated in safety-net Emergency Departments may be one approach to address the US hypertension epidemic, but the optimal mHealth components or dose are unknown. METHODS: Reach Out is an mHealth, health theory-based, 2×2×2 factorial trial among hypertensive patients evaluated in a safety-net Emergency Department in Flint, Michigan. Reach Out consisted of 3 mHealth components, each with 2 doses: (1) healthy behavior text messaging (yes versus no), (2) prompted self-measured blood pressure (BP) monitoring and feedback (weekly versus daily), and (3) facilitated primary care provider appointment scheduling and transportation (yes versus no). The primary outcome was a change in systolic BP from baseline to 12 months. In a complete case analysis, we fit a linear regression model and accounted for age, sex, race, and prior BP medications to explore the association between systolic BP and each mHealth component. RESULTS: Among 488 randomized participants, 211 (43%) completed follow-up. Mean age was 45.5 years, 61% were women, 54% were Black people, 22% did not have a primary care doctor, 21% lacked transportation, and 51% were not taking antihypertensive medications. Overall, systolic BP declined after 6 months (-9.2 mm Hg [95% CI, -12.2 to -6.3]) and 12 months (-6.6 mm Hg, -9.3 to -3.8), without a difference across the 8 treatment arms. The higher dose of mHealth components were not associated with a greater change in systolic BP; healthy behavior text messages (point estimate, mmHG=-0.5 [95% CI, -6.0 to 5]; P=0.86), daily self-measured BP monitoring (point estimate, mmHG=1.9 [95% CI, -3.7 to 7.5]; P=0.50), and facilitated primary care provider scheduling and transportation (point estimate, mmHG=0 [95% CI, -5.5 to 5.6]; P=0.99). CONCLUSIONS: Among participants with elevated BP recruited from an urban safety-net Emergency Department, BP declined over the 12-month intervention period. There was no difference in change in systolic BP among the 3 mHealth components. Reach Out demonstrated the feasibility of reaching medically underserved people with high BP cared for at a safety-net Emergency Departments, yet the efficacy of the Reach Out mHealth intervention components requires further study. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03422718.

Adaptive interventions for alcohol misuse and violent behaviors among adolescents and emerging adults in the emergency department: A sequential multiple assignment randomized controlled trial protocol.

Alcohol use and violent behaviors among youth are associated with morbidity and mortality. An emergency department (ED) visit provides an opportunity to initiate prevention efforts. Despite promising findings from our single session SafERteens brief intervention (BI), impact is limited by modest effect sizes, with data lacking on optimal boosters to enhance effects. This paper describes the protocol for a sequential, multiple assignment, randomized trial (SMART). Adolescents and emerging adults (ages 14-20) in the ED screening positive for alcohol use and violent behaviors (physical aggression) were randomly assigned to: 1) SafERteens BI + Text Messaging (TM), or 2) SafERteens BI + remote Health Coach (HC). Participants completed weekly surveys over 8 weeks after the ED visit to tailor intervention content and measure mechanisms of change. At one-month, intervention response/non-response is determined (e.g., binge drinking or violent behaviors). Responders are re-randomized to continued intervention condition (e.g., maintenance) or minimized condition (e.g., stepped down). Non-responders are re-randomized to continued condition (e.g., maintenance), or intensified condition (e.g., stepped up). Outcomes were measured at 4 and 8 months, including primary outcomes of alcohol consumption and violence, with secondary outcomes of alcohol consequences and violence consequences. Although the original goal was to enroll 700 participants, COVID-19 impacts on research diminished recruitment in this trial (enrolled n = 400). Nonetheless, the proposed SMART is highly innovative by blending real-time assessment methodologies with adaptive intervention delivery among teens with comorbid alcohol misuse and violent behaviors. Findings will inform the content and timing booster interventions to alter risk behavior trajectories. Trial Registration:ClinicalTrials.govNCT03344666. University of Michigan # HUM00109156.

Ovarian Function Suppression in Premenopausal Women With Concurrent Endocrine Therapy Use.

INTRODUCTION: Almost 20% of patients receiving ovarian function suppression (OFS) and endocrine therapy (ET) for breast cancer treatment had inadequate OFS within the first year of treatment. Few studies have explored the long-term effectiveness of OFS to maintain estrogen suppression. PATIENTS AND METHODS: This retrospective, single institution study examined premenopausal women with early-stage breast cancer undergoing treatment with OFS and ET. The primary endpoint was the percentage of patients with inadequate ovarian suppression (estradiol ≥10 pg/mL) during OFS cycle 2 or later. The secondary endpoint was the percentage of patients with inadequate ovarian suppression within the first cycle after OFS initiation. Differences in age, body mass index (BMI), and previous chemotherapy use were summarized via multivariable logistic regression. RESULTS: Of the 131 patients included in the analysis, 35 (26.7%) lacked adequate suppression during OFS cycle 2 or later cycles. Patients with adequate suppression throughout treatment were more likely to be older (odds ratio [OR] 1.12 [95% CI, 1.05-1.22], P = .02), have a lower BMI (OR 0.88 [95% CI, 0.82-0.94], P < .001), and have received chemotherapy (OR 6.30 [95% CI, 2.06-20.8], P = .002). A total of 20 of 83 patients (24.1%) had an inadequately suppressed estradiol level within 35 days of OFS initiation. CONCLUSION: This "real world" cohort demonstrates that estradiol concentrations above the postmenopausal range of the assay are frequently detected, including more than 1 year after the start of OFS. Additional research is needed to establish estradiol monitoring guidelines and optimal degree of ovarian suppression.

The Michigan Genetic Hereditary Testing (MiGHT) study's innovative approaches to promote uptake of clinical genetic testing among cancer patients: a study protocol for a 3-arm randomized controlled trial.

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).

Psychosocial factors impacting barriers and motivators to cancer genetic testing.

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.

Sequential, Multiple Assignment, Randomized Trial Designs.

This JAMA Guide to Statistics and Methods explains sequential, multiple assignment, randomized trial (SMART) study designs, in which some or all participants are randomized at 2 or more decision points depending on the participant's response to prior treatment.

An Interventional Response Phenotyping Study in Chronic Low Back Pain: Protocol for a Mechanistic Randomized Controlled Trial.

Evidence-based treatments for chronic low back pain (cLBP) typically work well in only a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients. Our central hypothesis is that an interventional response phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based treatments for cLBP. Thus, we will conduct a randomized controlled Sequential, Multiple Assessment, Randomized Trial (SMART) design study in cLBP with the following three aims. Aim 1: Perform an interventional response phenotyping study in a cohort of cLBP patients (n = 400), who will receive a sequence of interventions known to be effective in cLBP. For 4 weeks, all cLBP participants will receive a web-based pain self-management program as part of a run-in period, then individuals who report no or minimal improvement will be randomized to: a) mindfulness-based stress reduction, b) physical therapy and exercise, c) acupressure self-management, and d) duloxetine. After 8 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 8 weeks. Using those data, we will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically derived measures, can predict differential responsiveness to the treatments. In Aim 3, a subset of participants will receive deeper phenotyping (n = 160), to identify new experimental measures that predict differential responsiveness to the treatments, as well as to infer mechanisms of action. Deep phenotyping will include functional neuroimaging, quantitative sensory testing, measures of inflammation, and measures of autonomic tone.

Association between nociplastic pain and premature endocrine therapy discontinuation in breast cancer patients.

PURPOSE: At least 5 years of adjuvant endocrine therapy (ET) is recommended for patients with hormone receptor-positive invasive breast cancer to reduce cancer recurrence risk. Up to half of patients prematurely discontinue ET, often due to musculoskeletal pain. Nociplastic pain is abnormal central nervous system pain processing without evidence of tissue or neuronal damage. This study aimed to evaluate the relationship between baseline nociplastic pain and ET discontinuation. METHODS: This was a retrospective, single center, cohort study. Included patients were female, had stage 0-III invasive breast cancer, did not receive neoadjuvant therapy, and completed quality of life questionnaires prior to breast surgery, including Fibromyalgia Survey for nociplastic pain. Clinical data including duration of ET were abstracted from the medical record. Patient characteristics were analyzed with t-tests and Chi-squared tests, as appropriate. Univariate and multivariable regressions were performed with Cox proportional hazard models. RESULTS: Six hundred eighty-one patients diagnosed between 2012 and 2019 met inclusion criteria; 480 initiated ET and were included in the analysis. Of these 480 patients, 203 (42.3%) prematurely discontinued initial ET therapy. On univariate analysis, tamoxifen use (hazard ratio [HR] 0.70, p = 0.021) and premenopausal status (HR 0.73, p = 0.04) were inversely associated with ET discontinuation, while Fibromyalgia Score was positively associated (HR 1.04, p = 0.043). On multivariable analysis, baseline Fibromyalgia Score remained associated with ET discontinuation. CONCLUSION: Nociplastic pain present prior to surgery was associated with premature ET discontinuation. Fibromyalgia Score screening may be useful for evaluating ET discontinuation risk. Treatments targeting nociplastic pain may be more effective for treating ET-emergent pain.

Sleep to Reduce Incident Depression Effectively (STRIDE): study protocol for a randomized controlled trial comparing stepped-care cognitive-behavioral therapy for insomnia versus sleep education control to prevent major depression.

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.

Power prior models for estimating response rates in a small n, sequential, multiple assignment, randomized trial.

A small n, sequential, multiple assignment, randomized trial (snSMART) is a small sample, two-stage design where participants receive up to two treatments sequentially, but the second treatment depends on response to the first treatment. The parameters of interest in an snSMART are the first-stage response rates of the treatments, but outcomes from both stages can be used to obtain more information from a small sample. A novel way to incorporate the outcomes from both stages uses power prior models, in which first stage outcomes from an snSMART are regarded as the primary (internal) data and second stage outcomes are regarded as supplemental data (co-data). We apply existing power prior models to snSMART data, and we also develop new extensions of power prior models. All methods are compared to each other and to the Bayesian joint stage model (BJSM) via simulation studies. By comparing the biases and the efficiency of the response rate estimates among all proposed power prior methods, we suggest application of Fisher's Exact Test or the Bhattacharyya's overlap measure to an snSMART to estimate the response rates in an snSMART, which both have performance mostly as good or better than the BJSM. We describe the situations where each of these suggested approaches is preferred.

EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression.

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.

Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms.

OBJECTIVE: Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations. METHODS: In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk. RESULTS: Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10-8), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts. CONCLUSIONS: Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer.

Systematically higher Ki67 scores on core biopsy samples compared to corresponding resection specimen in breast cancer: a multi-operator and multi-institutional study.

Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error (p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections (p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.

Application of Bayesian methods to accelerate rare disease drug development: scopes and hurdles.

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.

Lack of association of CYP2B6 pharmacogenetics with cyclophosphamide toxicity in patients with cancer.

PURPOSE: Cyclophosphamide is a commonly used cancer agent that is metabolically activated by polymorphic enzymes. This study aims to investigate the association between predicted activity of candidate pharmacogenes with severe toxicity during cyclophosphamide treatment. METHODS: Genome-wide genetic data was collected from an institutional genetic data repository for CYP2B6, CYP3A4, CYP2C9, CYP2C19, GSTA1, GSTP1, ALDH1A1, ALDH3A1, ABCC1, ABCB1, and ERCC1. Treatment and toxicity data were retrospectively collected from the patient's medical record. The a priori selected primary hypothesis was that patients who have CYP2B6 reduced metabolizer activity (poor or intermediate (PM/IM) vs. normal (NM) metabolizer) have lower risk of severe toxicity or cyclophosphamide treatment modification due to toxicity. RESULTS: In the primary analysis of 510 cyclophosphamide-treated patients with available genetic data, there was no difference in the odds of severe toxicity or treatment modification due to toxicity in CYP2B6 PM/IM vs. NM (odds ratio = 0.97, 95% Confidence Interval: 0.62-1.50, p = 0.88). In an exploratory, statistically uncorrected secondary analysis, carriers of the ALDH1A1 rs8187996 variant had a lower risk of the primary toxicity endpoint compared with wild-type homozygous patients (odds ratio = 0.31, 95% Confidence Interval: 0.09-0.78, p = 0.028). None of the other tested phenotypes or genotypes was associated with the primary or secondary endpoints in unadjusted analysis (all p > 0.05). CONCLUSION: The finding that patients who carry ALDH1A1 rs8187996 may have a lower risk of cyclophosphamide toxicity than wild-type patients contradicts a prior finding for this variant and should be viewed with skepticism. We found weak evidence that any of these candidate pharmacogenetic predictors of cyclophosphamide toxicity may be useful to personalize cyclophosphamide dosing to optimize therapeutic outcomes in patients with cancer.

Development of a multicomponent implementation strategy to reduce upper gastrointestinal bleeding risk in patients using warfarin and antiplatelet therapy, and protocol for a pragmatic multilevel randomized factorial pilot implementation trial.

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.