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Aim: Determine the influence of SLCO1B3 polymorphisms on outcomes in kidney transplant recipients. Materials & methods: We retrospectively evaluated 181 adult kidney transplant recipients receiving mycophenolate. Outcomes included treated biopsy-proven acute rejection (tBPAR), de novo donor-specific antibody (dnDSA) formation, graft survival, patient survival and mycophenolate-related adverse effects among SLCO1B3 genotypes. Results: The presence of SLCO1B3 variants was not associated with increased risk of tBPAR (HR: 1.45, 95% CI: 0.76–2.74), dnDSA (HR: 0.46, 95% CI: 0.16–1.36) or composite of tBPAR or dnDSA (HR: 1.14, 95% CI: 0.64–2.03). Graft and patient survival were reduced among variant carriers; however, inconsistent findings with the primary analysis suggest these associations were not due to genotype. Adverse effects were similar between groups. Conclusion: Presence of SLCO1B3 polymorphisms were not predictive of rejection or dnDSA in kidney transplant recipients.

OBJECTIVE: Letrozole is a non-steroidal aromatase inhibitor (AI) used to treat hormone receptor positive (HR+) breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism including Cytochrome P450 2A6 (CYP2A6). The objective of this genome-wide association study (GWAS) was to identify polymorphisms associated with steady state letrozole concentrations. METHODS: The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized post-menopausal patients with HR+ non-metastatic breast cancer to letrozole or exemestane treatment. Germline DNA was collected pre-treatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole (and exemestane) plasma concentrations via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array (>650,000 variants) followed by imputation. The association of each germline variant with age- and body mass index-adjusted letrozole concentrations was tested in self-reported white patients via linear regression assuming an additive genetic model. RESULTS: There were 228 patients who met the study specific inclusion criteria and had both DNA and letrozole concentration data for this GWAS. The association for one genotyped polymorphism (rs7937) with letrozole concentration surpassed genome-wide significance (p=5.26x10(−10)), explaining 13% of the variability in untransformed steady-state letrozole concentrations. Imputation around rs7937 and in silico analyses identified rs56113850, a variant in the CYP2A6 intron that may affect CYP2A6 expression and activity. rs7937 was associated with age- and body mass index-adjusted letrozole levels even after adjusting for genotype-predicted CYP2A6 metabolic phenotype (p=3.86x10(−10)). CONCLUSIONS: Our GWAS findings confirm that steady-state letrozole plasma concentrations are partially determined by germline polymorphisms that affect CYP2A6 activity, including variants near rs7937 such as the intronic rs56113850 variant. Further research is needed to confirm whether rs56113850 directly affects CYP2A6 activity and to integrate non-exonic variants into CYP2A6 phenotypic activity prediction systems.

Study objective Outcomes of extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest depend on time to therapy initiation. We hypothesize that it would be feasible to select refractory out-of-hospital cardiac arrest patients for expedited transport based on real-time estimates of the 911 call to the emergency department (ED) arrival interval, and for emergency physicians to rapidly initiate ECPR in eligible patients. Methods In a 2-tiered emergency medical service with an ECPR-capable primary destination hospital, adults with refractory shockable or witnessed out-of-hospital cardiac arrest were randomized 4:1 to expedited transport or standard care if the predicted 911 call to ED arrival interval was less than or equal to 30 minutes. The primary outcomes were the proportion of subjects with 911 call to ED arrival less than or equal to 30 minutes and ED arrival to ECPR flow less than or equal to 30 minutes. Results Of 151 out-of-hospital cardiac arrest 911 calls, 15 subjects (10%) were enrolled. Five of 12 subjects randomized to expedited transport had an ED arrival time of less than or equal to 30 minutes (overall mean 32.5 minutes [SD 7.1]), and 5 were eligible for and treated with ECPR. Three of 5 ECPR-treated subjects had flow initiated in less than or equal to 30 minutes of ED arrival (overall mean 32.4 minutes [SD 10.9]). No subject in either group survived with a good neurologic outcome. Conclusion The Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest trial did not meet predefined feasibility outcomes for selecting out-of-hospital cardiac arrest patients for expedited transport and initiating ECPR in the ED. Additional research is needed to improve the accuracy of predicting the 911 call to ED arrival interval, optimize patient selection, and reduce the ED arrival to ECPR flow interval.

Background: Adjuvant aromatase inhibitors (AI) reduce recurrence and mortality after early stage hormone receptor-positive (HR+) breast cancer (BC). Treatment-related toxicities, including AI-induced musculoskeletal symptoms (AIMSS), are common during adjuvant AI therapy. Prior work suggests the risk of AIMSS is associated with inherited germline genetic polymorphisms in several genes, such as TCL1A, CYP19A1, OPG, and VDR. These pharmacogenetic associations require replication in independent cohorts prior to clinical translation to identify patients at risk for AIMSS. The objective of this retrospective pharmacogenetic analysis was to replicate previously reported associations for candidate germline genetic polymorphisms with AIMSS. Methods: Women with stage 0-III HR+ BC initiating adjuvant endocrine therapy (ET) with tamoxifen or an AI were enrolled in a prospective clinic-based observational cohort. The type of ET was selected by the provider. A baseline (BL) blood sample was collected for isolation of germline DNA for pharmacogenetic analysis. AIMSS were assessed by patient-reported outcomes (PRO). Participants completed PROMIS pain interference (PI), PROMIS physical function (PF) and Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) measures at BL and after 3, 6, 9, 12, 24, 48 and 60 months (mo). The FACT-ES includes one question about joint pain, rated on a 5-point scale (“not at all” to “very much”). This secondary retrospective pharmacogenetic analysis was conducted in participants receiving AI therapy for whom blood samples and PRO scores at BL and 3 and/or 6 mo were available. For the primary analysis, we defined AIMSS as a ≥4 point increase in PI T score from BL to 3 and/or 6 mo. For secondary analyses, we evaluated alternate definitions of AIMSS including a ≥4 point decrease in PF T score and a ≥1 category increase on the FACT-ES joint pain question from BL to 3 and/or 6 mo. The primary hypothesis was that TCL1A rs11849538 is associated with AIMSS. Twelve other germline variants in CYP19A1, VDR, PIRC66, OPG, ESR1, CYP27B1, CYP17A1, and RANKL previously reported to be associated with AIMSS were also analyzed. We assumed a dominant genetic effect and pre-specified the direction of effect on AIMSS for each variant. We conducted univariate logistic regression to evaluate associations between each definition of AIMSS and candidate polymorphism using an unadjusted α=0.05. Significant univariate associations in the expected direction were adjusted for age, race, body mass index (BMI), prior taxane and type of AI using multivariable logistic regression. Results: Of 182 participants on AI, 143 with PRO and genetic data available were included in this analysis. Median age was 67, 85% were white, median BMI was 27.8 and 27% had prior taxane. 78% received anastrozole, 20% letrozole and 2% exemestane. On primary analysis, participants carrying TCL1A rs11849538 were not more likely to develop AIMSS as defined by increase in PI T score by ≥4 (OR=1.29, 95% CI: 0.55-3.07, p=0.56). None of the other polymorphisms was associated with increase in PI T score by ≥4. On secondary analysis, OPG rs2073618 was associated with AIMSS, as defined by an increase on the FACT-ES joint pain question ≥1 (OR=3.33, 95% CI: 1.48-7.49, p=0.004) and this association maintained significance after covariate adjustment (OR=3.98, 95% CI: 1.61-9.84, p=0.003). Age, race, BMI, prior taxane and type of AI were not associated with AIMSS on multivariate analysis. No other polymorphisms were associated with AIMSS on secondary analyses. Conclusions: Carriers of OPG rs2073618 may be at increased risk of AIMSS. If confirmed in other cohorts, OPG genotyping may be able to identify individuals with HR+ early BC at increased risk for AIMSS during AI therapy. Alternate ET or interventions to reduce musculoskeletal symptoms may be needed for this population. Citation Format: Daniel L Hertz, Karen Lisa Smith, Yuhua Zong, Christina L Gersch, Andrea Pesch, Arti Patel, Jennifer Lehman, N. Lynn Henry, Kelley M Kidwell, James M Rae, Vered Stearns. Association of OPG rs2073618 and aromatase inhibitor induced musculoskeletal symptoms [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-25.

Aim: To evaluate toxicity risk in carriers of four DPYD variants using an institutional genetic repository. Materials & methods: Of over 65,000 patients in the repository, 582 were evaluated for the primary composite end point of grade 3 or higher toxicity or treatment modification due to toxicity. Results: The primary end point was more common in DPYD variant carriers (36.5 vs 18.1%, adjusted odds ratio 2.42, 95% CI: 1.05–5.55, p = 0.04), and in patients with decreased DPD activity (≤1 vs 2) (75.6 vs 17.0%, adjusted odds ratio 16.31, 95% CI: 2.64–100.68, p = 0.003). Conclusion: Patients carrying any of the four DPYD variants are at increased risk of severe toxicity or subsequent treatment modifications, suggesting such patients may benefit from genotype-informed treatment.

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.

PURPOSE: Scalp cooling therapy (SCT) is the most effective method to reduce chemotherapy-induced alopecia (CIA), a highly distressing side effect of cancer treatment. Despite data supporting SCT efficacy and safety, SCT use in the United States is not widespread. Oncologists' interactions with scalp cooling were examined to identify facilitators and barriers to SCT implementation. METHODS: A 33-question survey was distributed through the ASCO Research Survey Pool to a nationally representative, random sample of 600 oncology providers. Outcome measures included knowledge of SCT, frequency of initiating conversations about SCT with patients, degree of support, and barriers for SCT. Significance was defined as P < .001. RESULTS: Of 155 (25.8%) responding providers, 62% of providers were in favor of SCT always or most of the time, but only 26% reported initiating discussions about SCT always or most of the time. Providers who treat breast cancer ( P ≤ .0001), those who report being very familiar with SCT ( P ≤ .0001), those who report having read SCT literature in the past 2 years ( P ≤ .0001), and those who work at a facility with machine SCT ( P ≤ .0001) were significantly more likely to initiate conversations with patients about SCT. Financial concerns (58%) were the primary reason for not recommending SCT use; efficacy (31%), staff or facility (24%), and safety (15%) concerns were also noted. Although safety concerns have decreased markedly over time, 14% of providers report patients who continue to express these concerns and 17% of providers see safety issues as barriers to supporting SCT. CONCLUSION: Our findings suggest that oncology provider familiarity and experience with SCT lead to increased support for scalp cooling, which may ultimately result in greater availability and utilization of SCT when indicated.

Clinicians and researchers alike are increasingly interested in how best to personalize interventions. A dynamic treatment regimen (DTR) is a sequence of pre-specified decision rules which can be used to guide the delivery of a sequence of treatments or interventions that are tailored to the changing needs of the individual. The sequential multiple-assignment randomized trial (SMART) is a research tool which allows for the construction of effective DTRs. We derive easy-to-use formulae for computing the total sample size for three common two-stage SMART designs in which the primary aim is to compare mean end-of-study outcomes for two embedded DTRs which recommend different first-stage treatments. The formulae are derived in the context of a regression model which leverages information from a longitudinal outcome collected over the entire study. We show that the sample size formula for a SMART can be written as the product of the sample size formula for a standard two-arm randomized trial, a deflation factor that accounts for the increased statistical efficiency resulting from a longitudinal analysis, and an inflation factor that accounts for the design of a SMART. The SMART design inflation factor is typically a function of the anticipated probability of response to first-stage treatment. We review modeling and estimation for DTR effect analyses using a longitudinal outcome from a SMART, as well as the estimation of standard errors. We also present estimators for the covariance matrix for a variety of common working correlation structures. Methods are motivated using the ENGAGE study, a SMART aimed at developing a DTR for increasing motivation to attend treatments among alcohol- and cocaine-dependent patients., Supplementary material at https://osf.io/q7zv8/ This version updates funding information not previously included. Text remains the final accepted version of the manuscript in Statistical Methods in Medical Research

Aim: This study tested for associations between SLCO1B1 polymorphisms and circulating estrogen levels in women with breast cancer treated with letrozole or exemestane. Patients & methods: Postmenopausal women with hormone-receptor positive breast cancer were genotyped for SLCO1B1*5 (rs4149056) and rs10841753. Pretreatment and on-treatment plasma estrogens and aromatase inhibitor (AI) concentrations were measured. Regression analyses were performed to test for pharmacogenetic associations with estrogens and drug concentrations. Results: SLCO1B1*5 was associated with elevated pretreatment estrone sulfate and an increased risk of detectable estrone concentrations after 3 months of AI treatment. Conclusion: These findings suggest SLCO1B1 polymorphisms may have an effect on estrogenic response to AI treatment, and therefore may adversely impact the anticancer effectiveness of these agents.

Aim: This study evaluated the impact of CYP3A5 genotype and other patient characteristics on sublingual (SL) tacrolimus exposure and compared the relationship with oral administration. Patients & methods: Tacrolimus concentrations were retrospectively collected for adult lung transplant recipients, who were genotyped for CYP3A5*3, CYP3A4*22, CYP3A7*1C, and POR*28. Regression analyses were performed to determine covariates that impacted the SL and oral tacrolimus concentration/dose ratios. Results: An interaction of CYP3A5 genotype and CYP3A inhibitor increased the SL concentration/dose, while cystic fibrosis decreased the SL concentration/dose. The oral concentration/dose was independently associated with these covariates and was increased by serum creatinine and number of tacrolimus doses. Conclusion: This study suggests personalized dosing strategies for tacrolimus likely need to consider characteristics beyond CYP3A5 genotype.

PURPOSE: UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer. METHODS: Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 (BTM) and 24 (BMD) months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2. RESULTS: Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05). CONCLUSION: UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation.

CYP3A5 and CYP3A4 are the predominant enzymes responsible for tacrolimus metabolism; however only a proportion of the population expresses CYP3A5 secondary to genetic variation. CYP3A5 is expressed in both the intestine and the liver and has been shown to impact both the bioavailability and metabolism of orally administered tacrolimus. Increasing the initial tacrolimus dose by 50% to 100% is recommended in patients who are known CYP3A5 expressers; however, whether this dose adjustment is appropriate for i.v. tacrolimus administration is unclear. The objective of this study was to evaluate the impact of CYP3A5 genotype as well as other pharmacogenes on i.v. tacrolimus exposure to determine whether the current genotype-guided dosing recommendations are appropriate for this formulation. In addition, this study aimed to investigate dose conversion requirements among CYP3A5 genotypes when converting from i.v. to p.o. tacrolimus. This study is a retrospective chart review of all patients who underwent allogeneic stem cell transplantation at Michigan Medicine between June 1, 2014, and March 1, 2018, who received i.v. tacrolimus at the time of their transplantation. Secondary use samples were obtained for genotyping CYP3A5, CYP3A4, and ABCB1. Patient demographic information, tacrolimus dosing and trough levels, and concomitant medications received at the time of tacrolimus trough were collected retrospectively from the patients’ medical records. The i.v. dose-controlled concentration (C/D) and the i.v.:p.o. exposure ratio was calculated for all tacrolimus doses and patients, respectively. The impact of CYP3A5, CYP3A4, and ABCB1 genotypes on the i.v. C/D were evaluated with linear mixed modeling. The impact of CYP3A5 genotype on the i.v.:p.o. ratio was evaluated while controlling for age and concomitant use of an azole inhibitor. CYP3A5 and CYP3A4 genotypes were significantly associated with the i.v. C/D, with CYP3A5 expressers and CYP3A4 rapid metabolizers having 20% lower tacrolimus exposure. Neither genotype remained significant in the multivariable model, although age, hematocrit, and concomitant use of strong azole inhibitors were associated with increased i.v. C/D. When controlling for patient age and sex, CYP3A5 expressers had significantly higher i.v.:p.o. ratios than CYP3A5 nonexpressers (3.42 versus 2.78; P = .04). Post hoc analysis showed that the i.v.:p.o. ratio may differ among different CYP3A5 genotypes and azole inhibitor combinations. This study demonstrates that the current genotype-guided tacrolimus dose adjustment recommendations are inappropriate for CYP3A5 expressers receiving i.v. tacrolimus. Although CYP3A5 genotype is likely a minor contributor to i.v. tacrolimus exposure, genotype, in addition to capturing concomitant CYP3A inhibitors, would likely improve i.v.:p.o. dose conversion selection. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

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.

Importance Real-world surgical practice often lags behind the best scientific evidence. For example, although optimizing comorbidities such as smoking and morbid obesity before ventral and incisional hernia repair improves outcomes, as many as 25% of these patients have a high-risk characteristic at the time of surgery. Implementation strategies may effectively increase use of evidence-based practice. Objective To describe current trends in preoperative optimization among patients undergoing ventral hernia repair, identify barriers to optimization, develop interventions to address these barriers, and then pilot these interventions. Design, setting, and participants This quality improvement study used a retrospective medical record review to identify hospital-level trends in preoperative optimization among patients undergoing ventral and incisional hernia repair. Semistructured interviews with 21 practicing surgeons were conducted to elicit barriers to optimizing high-risk patients before surgery. Next, a task force of experts was convened to develop pragmatic interventions to increase surgeon use of preoperative optimization. Finally, these interventions were piloted at 2 sites to assess acceptability and feasibility. This study was performed from January 1, 2014, to December 31, 2019. Main outcomes and measures The main outcome was rate of referrals for preoperative patient optimization at the 2 pilot sites. Results Among 23 000 patients undergoing ventral hernia repair, the mean (SD) age was 53.9 (14.3) years, and 12 315 (53.5%) were men. Of these, 8786 patients (38.2%) had at least 1 high-risk characteristic at the time of surgery, including 7683 with 1, 1079 with 2, and 24 with 3. At the hospital level, the mean proportion of patients with at least 1 of 3 high-risk characteristics at the time of surgery was 38.2% (95% CI, 38.1%-38.3%). This proportion varied widely from 21.5% (95% CI, 17.6%-25.5%) to 52.8% (95% CI, 43.9%-61.8%) across hospitals. Interviews with surgeons identified 3 major barriers to improving this practice: lost financial opportunity by not offering a patient an operation, lack of surgeon awareness of available resources for optimization, and organizational barriers. A task force therefore developed 3 interventions: a financial incentive to optimize high-risk patients, an educational intervention to make surgeons aware of available optimization resources, and on-site facilitation. These strategies were piloted at 2 sites where preoperative risk optimization referrals increased 860%. Conclusions and relevance This study demonstrates a stepwise process of identifying a practice gap, eliciting barriers that contribute to this gap, using expert consensus and local resources to develop strategies to address these barriers, and piloting these strategies. This implementation strategy can be adopted to diverse settings given that it relies on developing and implementing strategies based on local practice patterns.

Aims Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce blood pressure without compensatory heart rate elevation, possibly by modulating sympathetic/parasympathetic activity. This may contribute to their cardiovascular benefits in type 2 diabetes (T2D). We evaluated the effects of dapagliflozin (DAPA) on measures of cardiovascular autonomic neuropathy (CAN), cardiac function, and glucose variability (GV) in T2D. Methods Pilot, randomized, two-period crossover trial comparing 12-week DAPA versus 12-week glimepiride treatment on CAN measures (cardiovascular autonomic reflex tests and heart rate variability), B-type natriuretic peptide (BNP), and GV (Abbott's Libre Pro devices) using signed rank tests and mixed models from baseline to 12 weeks within and between each period. Results Forty-five T2D participants on metformin monotherapy (mean age 57 ± 8 years, duration 7 ± 6 years, HbA1c 7.8 ± 1.3%) were enrolled with 41 completing the trial. There were no differences in CAN indices or BNP with each drug compared to baseline and each other. Participants on DAPA demonstrated greater weight loss, reduced time in hypoglycemia, and improved GV compared to glimepiride. Conclusions Short term treatment with DAPA did not affect CAN measures or BNP in uncomplicated and relatively healthy T2D participants. Longer prospective studies in patients with advanced disease are needed to better understand relationships between SGLT-2 inhibitors and CAN. Clinical trial registration: NCT02973477

Importance Cancer treatment delay has been reported to variably impact cancer-specific survival and coronavirus disease 2019 (COVID-19)-specific mortality during the severe acute respiratory syndrome coronavirus 2 pandemic. During the pandemic, treatment delay is being recommended in a nonquantitative, nonobjective, and nonpersonalized manner, and this approach may be associated with suboptimal outcomes. Quantitative integration of cancer mortality estimates and data on the consequences of treatment delay is needed to aid treatment decisions and improve patient outcomes. Objective To obtain quantitative integration of cancer-specific and COVID-19-specific mortality estimates that can be used to make optimal decisions for individual patients and optimize resource allocation. Design, setting, and participants In this decision analytical model, age-specific and stage-specific estimates of overall survival pre-COVID-19 were adjusted by the probability of COVID-19 (individualized by county, treatment-specific variables, hospital exposure frequency, and COVID-19 infectivity estimates), COVID-19 mortality (individualized by age-specific, comorbidity-specific, and treatment-specific variables), and delay of cancer treatment (impact and duration). These model estimates were integrated into a web application (OncCOVID) to calculate estimates of the cumulative overall survival and restricted mean survival time of patients who received immediate vs delayed cancer treatment. Using currently available information about COVID-19, a susceptible-infected-recovered model that accounted for the increased risk among patients at health care treatment centers was developed. This model integrated the data on cancer mortality and the consequences of treatment delay to aid treatment decisions. Age-specific and cancer stage-specific estimates of overall survival pre-COVID-19 were extracted from the Surveillance, Epidemiology, and End Results database for 691 854 individuals with 25 cancer types who received cancer diagnoses in 2005 to 2006. Data from 5 436 896 individuals in the National Cancer Database were used to estimate the independent impact of treatment delay by cancer type and stage. In addition, data from 275 patients in a nested case-control study were used to estimate the COVID-19 mortality rate by age group and number of comorbidities. Data were analyzed from March 17 to May 21, 2020. Exposures COVID-19 and cancer. Main outcomes and measures Estimates of restricted mean survival time after the receipt of immediate vs delayed cancer treatment. Results At the time of the study, the OncCOVID web application allowed for the selection of up to 47 individualized variables to assess net survival for an individual patient with cancer. Substantial heterogeneity was found regarding the association between delayed cancer treatment and net survival among patients with a given cancer type and stage, and these 2 variables were insufficient to discriminate the net impact of immediate vs delayed treatment. Individualized overall survival estimates were associated with patient age, number of comorbidities, treatment received, and specific local community estimates of COVID-19 risk. Conclusions and relevance This decision analytical modeling study found that the OncCOVID web-based application can quantitatively aid in the resource allocation of individualized treatment for patients with cancer during the COVID-19 global pandemic.

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) is promising but unproven. We developed a concept for a randomized Bayesian adaptive clinical trial to define the interval after arrest during which patients derive benefit. Hypotheses: We hypothesized that the simulated design characteristics of the adaptive design would efficiently confirm or refute the existence of a therapeutic window for ECPR in a future trial. Methods: Through iterative simulation and design modification, we developed a Bayesian adaptive trial of ECPR for adults with OHCA. The goals of the trial design were to address the uncertainty surrounding the OHCA-to-ECPR interval within which clinical benefit might be preserved and the difference in prognosis between patients with non-shockable vs shockable rhythms. The treatment effect was defined as the mean 90-day utility-weighted Modified Rankin Scale (uwmRS) for each rhythm subgroup and estimated CA-to-ECPR interval. The trial adaptively lengthens or contracts the estimated CA-to-ECPR eligibility window depending on the probability of benefit from ECPR. We simulated trial performance under six potential ECPR efficacy scenarios. We compared the adaptive design to a fixed design. Results: The trial had 91-100% power to detect a benefit from ECPR for non-shockable rhythms and 69-98% power for shockable rhythms under the scenarios simulated (figure). The design had a high probability of identifying the maximum CA-to-ECPR interval within which ECPR produces a clinically significant benefit of 0.2 on the uwMRS. In null scenarios, the 97-99% of the simulated trials ended early declaring futility. Conclusions: The adaptive trial design helps to ensure the patient population most likely to benefit from treatment—as defined by rhythm subgroup and estimated CA-to-ECPR interval—are enrolled. The design also promotes early termination of the trial if continuation is likely to be futile.

The small n, Sequential, Multiple Assignment, Randomized Trial (snSMART) is a two-stage clinical trial design for rare diseases motivated by the comparison of three active treatments for isolated skin vasculitis in the ongoing clinical trial ARAMIS (a randomized multicenter study for isolated skin vasculitis, NCT09239573). In Stage 1, all patients are randomized to one of three treatments. In Stage 2, patients who respond to their initial treatment receive the same treatment again, while those who fail to respond are re-randomized to one of the two remaining treatments. A Bayesian method for estimating the response rate of each individual treatment in a three-arm snSMART demonstrated efficiency gains for a given sample size relative to other existing frequentist approaches. However, these efficiency gains are dependent upon knowing how many subjects are required to determine a specific difference in the treatment response rates. Because few sample size calculation methods for snSMARTs exist, we propose a Bayesian sample size calculation for an snSMART designed to distinguish the best treatment from the second-best treatment. Although our methods are based on asymptotic approximations, we demonstrate via simulations that our proposed sample size calculation approach produces the desired statistical power, even in small samples. Moreover, our methods and applet produce sample sizes quickly, thereby saving time relative to using simulations to determine the appropriate sample size. We compare our proposed sample size to an existing frequentist method based upon a weighted

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.

This systematic review and meta-analysis was designed to determine the efficacy of mindfulness-based interventions (MBIs) in improving fatigue-related outcomes in adult cancer survivors. Randomized controlled trials (RCTs) were identified from PubMed, MEDLINE, PsycINFO, CINAHL, Web of Science, and EMBASE databases and reference lists of included studies. Separate random-effects meta-analyses were conducted for fatigue and vitality/vigor. Twenty-three studies reporting on 21 RCTs (N = 2239) met inclusion criteria. MBIs significantly reduced fatigue compared to controls at post-intervention (g = 0.60, 95 % CI [0.36, 0.83]) and first follow-up (g = 0.42, 95 % CI [0.20, 0.64]). Likewise, MBIs significantly improved vitality/vigor at post-intervention (g = 0.39, 95 % CI [0.25, 0.52]) and first follow-up (g = 0.35, 95 % CI [0.03, 0.67]). The evidence grade was low due to risk of bias, substantial heterogeneity, and publication bias among studies. MBIs show promise in improving fatigue and vitality/vigor in cancer survivors. More rigorous trials are needed to address current gaps in the evidence base.

Aim: This study explored whether inherited variants in genes causing the hereditary neuropathy condition Charcot–Marie–Tooth disease are associated with sensitivity to paclitaxel-induced peripheral neuropathy (PN). Patients & methods: Hereditary neuropathy genes previously associated with risk of paclitaxel-induced PN were sequenced in paclitaxel-treated patients. Eight putative genetic predictors in five hereditary neuropathy genes ( ARHGEF10, SBF2, FGD4, FZD3 and NXN) were tested for association with PN sensitivity after accounting for systemic exposure and clinical variables. Results: FZD3 rs7833751, a proxy for rs7001034, decreased PN sensitivity (additive model, β = -0.41; 95% CI: -0.66 to -0.17; p = 0.0011). None of the other genetic predictors were associated with PN sensitivity. Conclusion: Our results support prior evidence that FZD3 rs7001034 is protective of PN and may be useful for individualizing paclitaxel treatment to prevent PN.

BACKGROUND Extracorporeal cardiopulmonary resuscitation (ECPR) is a promising therapy for out-of-hospital cardiac arrest (OHCA) that is refractory to standard therapy, but no multicenter randomized clinical trials have been conducted to establish its efficacy. We report the design and operating characteristics of a proposed randomized Bayesian adaptive “enrichment” clinical trial designed to determine whether ECPR is effective for refractory OHCA and, if effective, to define the interval after arrest during which patients derive benefit. METHODS Through iterative trial simulation and trial design modification, we developed a Bayesian adaptive trial of ECPR for adults who experience non-traumatic out-of-hospital cardiac arrest. Our proposed trial design addresses the threats to trial success identified during the design process, which were (1) the uncertainty surrounding the cardiac arrest (CA)-to-ECPR interval within which clinical benefit might be preserved (2) the difference in prognosis between patients with an initial rhythm that is non-shockable vs. shockable. Trial subjects will be randomized 1:1 to receive either standard care or expedited transport to a hospital for potential ECPR. The CA-to-ECPR interval will be estimated in real time based on the sum of the estimated paramedic response time (911 call to scene arrival), paramedic scene time, and transport time to hospital. A Bayesian decreasing step function will be used to estimate the efficacy of the treatment with an outcome of the 90-day utility-weighted Modified Rankin Scale (uwmRS) for each rhythm subgroup and estimated CA-to-ECPR interval at pre-specified interims. The trial will adaptively lengthen the estimated CA-to-ECPR eligibility window if the treatment appears effective at the upper limit of initial eligibility window. If ECPR appears ineffective at longer estimated CA-to-ECPR intervals, the upper limit of the window for enrollment eligibility will be shortened. The analysis will be stratified by rhythm subgroup. RESULTS With a maximum total sample size of 400, and a cap on the maximum sample size of 300 for the non-shockable rhythm subgroup, the trial design has power ranging from 91–100% to detect a benefit from ECPR for non-shockable rhythms under the various efficacy scenarios simulated and power ranging from 69–98% for shockable rhythms under the same scenarios. The trial design also has a high probability of correctly identifying the maximum CA-to-ECPR interval within which ECPR produces a clinically significant benefit of 0.2 on the uwMRS. If ECPR is equivalent to standard CA care, the type I error is 2.5% with a 99% probability of stopping enrollment early for futility in the non-shockable subgroup and a 97% probability of stopping enrollment early for futility in the shockable subgroup. CONCLUSION This proposed adaptive trial design helps to ensure the population of patients who are most likely to benefit from treatment—as defined both by rhythm subgroup and estimated CA-to-ECPR interval—is enrolled. The design promotes early termination of the trial if continuation is likely to be futile.

Beneficial effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular outcomes in patients with type 2 diabetes (T2D) have been reported. We hypothesized that these benefits may be due to modulatory effects on the sympathetic/parasympathetic imbalance through blunting of the expected compensatory increase in heart rate associated with lowering blood pressure. We aimed to evaluate the effect of dapagliflozin (DAPA) on measures of cardiovascular autonomic neuropathy (CAN) in patients with T2D. We performed a pilot, randomized, 2-period crossover clinical trial comparing 12 weeks of glucose lowering intervention with DAPA versus glimepiride on measures of CAN [cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV)] assessed at baseline and end of each drug period. Signed rank tests and mixed models were used to evaluate the differences in CARTs and HRV indices from baseline to 12 weeks between each drug period. Preliminary data are presented for forty-one participants with T2D on metformin monotherapy (mean age 57±8 years, mean diabetes duration 7±6 years, mean HbA1c 7.8±1.3%) at baseline. Although there were no significant differences in indices of CAN in each drug period, there was a trend for higher expiration and inspiration ratio on DAPA compared to glimepiride (mean change 0.02±0.10; p=0.07). We found significant or near significant interactions between sex and treatment for the root mean square of the differences of successive RR intervals (rmsSD) (p=0.021) and Valsalva ratio (p=0.06) in women on DAPA versus glimepiride compared with men. In women, the mean 12-week change for both measures on DAPA was larger than the mean change on glimepiride, whereas in men, the mean 12-week change was larger on glimepiride than DAPA. These preliminary short-term data suggest that DAPA may have beneficial effects on measures of CAN particularly in women with T2D. These findings need to be confirmed in larger prospective studies with longer follow-up. Disclosure L. Ang: None. K.M. Kidwell: None. J. Reiss: None. B.R. Dillon: None. K.R. Mizokami-Stout: None. V.A. Leone: None. R. Pop-Busui: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Consultant; Self; Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association.

Aim: First, evaluate if patients carrying putatively diminished activity CYP2C8 genotype have longer paclitaxel exposure (e.g., time above threshold concentration of 0.05 μM [Tc >0.05]). Second, screen additional pharmacogenes for associations with Tc >0.05. Methods: Pharmacogene panel genotypes were translated into genetic phenotypes for associations with Tc >0.05 (n = 58). Results: Patients with predicted low-activity CYP2C8 had shorter Tc >0.05 after adjustment for age, body surface area and race (9.65 vs 11.03 hrs, β = 5.47, p = 0.02). This association was attributed to CYP2C8*3 (p = 0.006), not CYP2C8*4 (p = 0.58). Patients with predicted low-activity SLCO1B1 had longer Tc >0.05 (12.12 vs 10.15 hrs, β = 0.85, p = 0.012). Conclusion: Contrary to previous publications, CYP2C8*3 may confer increased paclitaxel metabolic activity. SLCO1B1 and CYP2C8 genotype may explain some paclitaxel pharmacokinetic variability.

Objective. Aromatase inhibitors (AI) are frequently prescribed in gynecologic oncology. We sought to define the frequency and duration of AI use, characterize AI side effects and determine the reasons for discontinuation in these patients. Methods. Uterine and ovarian cancer patients with AI use for gynecologic cancer therapy were identified retrospectively. Data were abstracted from the electronic medical record, including cancer type, stage, prior cancer treatments, body mass index, concurrent medications, prevalence of AI side effects before and during AI therapy, length of AI treatment and reason for AI discontinuation. Results. 146 women received AI therapy, with 68 for ovarian cancer (46.6%) and 78 for uterine cancer (53.4%). The majority (71.9%) had advanced stage disease at diagnosis. 54.1% noted AI-associated side effects within the first three visits after starting AI therapy. The most common side effects were arthralgias (29.5%), hot flashes (25.3%), new/worsening fatigue (16.4%), muscle or joint stiffness (8.2%) and myalgias (6.8%). The mean duration of therapy was 14.7 months. Gabapentin or selective serotonin reuptake inhibitor (SSRI) use was associated with decreased musculoskeletal side effects (gabapentin: p < .001, OR 0.88, 95% CI 0.83–0.94; SSRI: p < .001, OR 0.82, 95% CI 0.77–0.89). The most common reason for AI discontinuation was disease progression (87.9%), with 5.0% discontinuing due to side effects and 7.1% for other reasons. Conclusion. AI therapy for gynecologic cancers is frequently associated with musculoskeletal side effects, but rarely leads to treatment discontinuation. Thus, AI side effects should be assessed in gynecologic cancer patients to allow potential mitigation of symptoms through adjunct therapies.

Introduction Patients with cancer are increasingly using herbal supplements, unaware that supplements can interact with oncology treatment. Herb–drug interaction management is critical to ensure optimal treatment outcomes. Several screening tools exist to detect drug–drug interactions, but their performance to detect herb–drug interactions is not known. This study compared the performance of eight drug–drug interaction screening tools to detect herb–drug interaction with anti-cancer agents. Methods The herb–drug interaction detection performance of four subscription (Micromedex, Lexicomp, PEPID, Facts & Comparisons) and free (Drugs.com, Medscape, WebMD, RxList) drug–drug interaction tools was assessed. Clinical relevance of each herb–drug interaction was determined using Natural Medicine and each drug–drug interaction tool. Descriptive statistics were used to calculate sensitivity, specificity, positive predictive value, and negative predictive value. Linear regression was used to compare performance between subscription and free tools. Results All tools had poor sensitivity (Conclusion Lexicomp is the best available tool for screening herb–drug interaction, and Medscape is the best free alternative; however, the sensitivity and performance for detecting herb–drug interaction was far lower than for drug–drug interactions, and overall quite poor. Further research is needed to improve herb–drug interaction screening performance.

Aims Chemotherapy-induced peripheral neuropathy (PN) is a treatment limiting toxicity of paclitaxel. We evaluated if EPHA genetic variation (EPHA4, EPHA5, EPHA6, and EPHA8) is associated with PN sensitivity by accounting for variability in systemic paclitaxel exposure (time above threshold). Methods Germline DNA from 60 patients with breast cancer was sequenced. PN was measured using the 8-item sensory subscale (CIPN8) of the patient-reported CIPN20. Associations for 3 genetic models were tested by incorporating genetics into previously published PN prediction models integrating measured paclitaxel exposure and cumulative treatment. Significant associations were then tested for association with PN-related treatment disruption. Results EPHA5 rs7349683 (minor allele frequency = 0.32) was associated with increased PN sensitivity (β-coefficient = 0.39, 95% confidence interval 0.11-0.67, p = 0.007). Setting a maximum tolerable threshold of CIPN8 = 30, optimal paclitaxel exposure target is shorter for rs7349683 homozygous (11.6 h) than heterozygous (12.6 h) or wild-type (13.6 h) patients. Total number of missense variants (median = 0, range 0-2) was associated with decreased PN sensitivity (β-coefficient: -0.42, 95% confidence interval -0.72 to -0.12, P = .006). No association with treatment disruption was detected for the total number of missense variants or rs7349683. Conclusion Isolating toxicity sensitivity by accounting for exposure is a novel approach, and rs7349683 represents a promising marker for PN sensitivity that may be used to individualize paclitaxel treatment.

Background Delayed autologous breast reconstruction is commonly recommended in patients requiring postmastectomy radiation. This study examines gross and histologic changes in the breast skin of patients who have undergone postmastectomy radiation to help determine when radiation-induced skin changes begin to stabilize. Methods A prospective pilot study was conducted on eight patients with invasive breast cancer who required mastectomy and radiotherapy. At the time of mastectomy and 2, 4, 6, 8, and 12 months after completion of radiotherapy, a punch biopsy was taken from the radiated mastectomy skin of each patient. Serial standardized photographs were taken before and after radiotherapy to evaluate the degree of hyperpigmentation and graded by three blinded plastic surgeons. Skin biopsies were processed for histologic assessment of inflammation, elastin organization, and vascularity. Results Grading of patient photographs revealed an increase in hyperpigmentation after radiotherapy compared with baseline with a gradual improvement over time. SMAD3 immunostaining demonstrated a trend toward an increase in inflammation over 12 months. The elastin distribution within samples showed an increase in fiber disorganization, thickening, and clumping, with no improvement throughout the study period. The average number of vessels per high powered field decreased steadily through the duration of the study. Conclusion Histologic changes in dermal inflammation, elastin organization, and vascularity do not appear to correspond with the gradual improvement of hyperpigmentation, resulting from postmastectomy radiation. These histologic changes persist beyond the 12 month observation period and will require clinical correlation to determine the potential impact on postoperative outcomes.

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.

Purpose: Patients with cancer are an especially vulnerable population to potential drug-drug interactions (DDIs). This makes it important to adequately screen them for DDIs. The objective of this study was to compare the abilities of nine DDI screening tools to detect clinically relevant interactions with oral oncolytics. Methods: Subscription-based tools (ie, PEPID, Micromedex, Lexicomp, Facts & Comparisons) and free tools (ie, Epocrates Free, Medscape, Drugs.com, RxList, WebMD) were compared for their abilities to detect clinically relevant DDIs for 145 drug pairs including an oral oncology agent. Clinical relevance was determined by a pharmacist using Stockley’s Drug Interactions. Descriptive statistics were calculated for each tool, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and then compared grouped by free or subscription-based tools for the secondary analysis and analyzed via generalized estimating equations. Results: For individual metrics, PPV had overall higher values (0.88 to 0.97) relative to the low values included for sensitivity (0.65 to 0.96), specificity (0.53 to 0.93) and NPV (0.38 to 0.83). The top-performing subscription and free tools, Lexicomp and Drugs.com, had no statistically significant differences in performance. Overall, subscription tools had a significantly higher sensitivity (0.85 ± 0.017 v 0.78 ± 0.017; P = .0082) and NPV (0.57 ± 0.039 v 0.48 ± 0.032; P = .031) than free tools. No differences were observed between the specificity and PPV. Conclusion: Due to the low performance of some tools for sensitivity, specificity, and NPV, individual performance should be examined and prioritized on the basis of the intended use when selecting a DDI tool. If a strong-performing subscription-based tool is unavailable, a strong-performing free option, like Drugs.com, is available.

BACKGROUND Rising contralateral prophylactic mastectomy rates are a subject of national concern. This study assessed (1) factors critical to patients when deciding on contralateral prophylactic mastectomy and (2) patients' quality of life related to concerns about recurrence after unilateral or bilateral breast reconstruction. METHODS Patients with stage 0 to III breast cancer who underwent unilateral mastectomy or contralateral prophylactic mastectomy and breast reconstruction at a single institution between 2000 and 2012 were identified. Demographic and clinical data were extracted by chart review. Women's fears about breast cancer recurrence were assessed using the Concerns About Recurrence Scale, and motivational factors for contralateral prophylactic mastectomy were identified using the Decisions for Contralateral Prophylactic Mastectomy Survey. RESULTS Survey responses were received from 157 patients (59%) who underwent unilateral reconstruction and 109 (41%) who underwent bilateral reconstruction. The top 3 reasons for choosing contralateral prophylactic mastectomy were (1) decreasing the risk of contralateral breast disease (97%), (2) peace of mind (96%), and (3) improved survival (93%). Women who chose contralateral prophylactic mastectomy reported significantly greater overall fear and worry compared with the unilateral group, specifically, greater fears of dying and worries about adequately fulfilling roles of daily life (P < 0.05). CONCLUSIONS Despite no proven survival benefit, women chose contralateral prophylactic mastectomy primarily to optimize oncologic outcomes. Among breast reconstruction patients, women who underwent contralateral prophylactic mastectomy had greater anxiety and overall fear of breast cancer recurrence compared with those who chose unilateral mastectomy. These findings are important to consider when counseling women contemplating contralateral prophylactic mastectomy.

Background: Paclitaxel is commonly used in combination regimens in patients with early stage breast cancer, but its use is often limited by the development of severe paclitaxel-induced peripheral neuropathy (PIPN). Paclitaxel pharmacokinetics (PK), specifically the maximum paclitaxel concentration (Cmax) and amount of time the concentration remains above 0.05 µM (Tc>0.05), have been associated with occurrence of severe, clinician-documented (NCI CTCAE) neuropathy. Patient-reported outcomes are more reliable, sensitive, and responsive than clinician-documented neuropathy, particularly for subjective toxicities. The objective of this study was to confirm that paclitaxel PK predicts occurrence and progression of patient-reported PIPN. Methods: This observational trial enrolled patients with early stage breast cancer receiving adjuvant/neoadjuvant weekly 1-hour paclitaxel infusions (80 mg/m2 x 12 cycles) at the University of Michigan Comprehensive Cancer Center. Patients with existing neuropathy or previous neuropathic chemotherapy treatment were excluded. Paclitaxel concentration was measured via liquid chromatograph/mass spectrometry (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 treatment cycle. The 8-item sensory subscale of the CIPN20 (CIPN8, range 8-32) was estimated for each patient and cycle of treatment to calculate the change from baseline (ΔCIPN8, range 0-24). The analysis was conducted using two approaches. In the first analysis, the cohort was stratified into cases and controls by the median ΔCIPN8 and in the second, each patient was described by the rate of change of CIPN8 per treatment cycle. The association of Cmax and Tc>0.05 with case/control definition was tested using Wilcoxon rank sum and t-tests. Associations with rate of change of CIPN8 were tested using linear regression. Results: 60 patients were enrolled in this observational clinical study. The mean age was 52.4 years, 93% of patients were Caucasian, and 5% had diabetes diagnosis. At baseline there was very little patient-reported neuropathy (mean baseline CIPN8=8.3). The median ΔCIPN8 was 4. Patients with ΔCIPN8>4 had greater Cmax than patients with ΔCIPN8≤4 (p=0.010). In the regression modeling, there was a significant correlation between patient's Tc>0.05 and the rate of increase in ΔCIPN8 (r=0.28, p=0.03). Conclusions: Our preliminary findings suggest that a single PK sample collected at the end of the first cycle (Cmax) or 16-24 hours later (Tc>0.05) are indicative of a patient's risk of experiencing PIPN during paclitaxel treatment. Ongoing modeling that accounts for dosing decreases, delays, and discontinuations will further characterize the contribution of paclitaxel pharmacokinetics to PIPN development and enable identification of genetic and metabolomic biomarkers that predict which patients experienced more severe PIPN than would be anticipated based on their paclitaxel PK. Citation Format: Hertz DL, Kidwell KM, Vangipuram K, Sun D, Henry NL. Association of systemic paclitaxel concentrations with severity and progression of paclitaxel-induced peripheral neuropathy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-11-03.

Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti–CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti–PD-1 (programmed death-1), and anti–PD-L1 (PD-ligand 1) drugs by the FDA for numerous tumor types. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single-agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. There are questions about the use of combination immunotherapy or single-agent anti–PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In this article, we describe a novel use of sequential, multiple assignment, randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within an individual based on intermediate response and lead to the longest overall survival. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART. SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity. Clin Cancer Res; 24(4); 730–6. ©2017 AACR.

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.

A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95% confidence interval 1.00–2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.

Assess postoperative morbidity and patient-reported outcomes after unilateral and bilateral breast reconstruction in patients with unilateral breast cancer.Relatively little is known about the morbidity associated with and changes in quality of life experienced by patients who undergo contralateral prophylactic mastectomy (CPM) and breast reconstruction. This information would be valuable for decision making in patients with unilateral breast cancer.Women undergoing mastectomy and breast reconstruction for unilateral breast cancer were recruited for this prospective observational study. Postoperative complications after implant and autologous breast reconstruction in patients undergoing unilateral or bilateral mastectomy were recorded. Preoperative and 1 year patient-reported outcomes were measured. Univariate tests and logistic regression analyses were performed, studying the effects of reconstructive method, laterality, and risk factors on surgical complication rates, patient satisfaction, and anxiety.We identified 1144 women who underwent either unilateral (47.2%) or bilateral (52.8%) mastectomies with reconstruction. Bilateral autologous (odds ratio 1.73, 95% confidence interval 1.07-2.81) and implant reconstructions (odds ratio 1.73, 95% confidence interval 1.22-2.47) were associated with a higher risk of complications compared with unilateral reconstructions. Baseline anxiety was greater in women who chose bilateral compared with unilateral implant reconstructions (P = 0.001). There was no difference in anxiety levels between groups postoperatively. Postoperatively, women who chose CPM with implant reconstructions were more satisfied with their breasts than women with unilateral reconstructions (P = 0.034).Although higher postoperative complications were observed after CPM and reconstruction, these procedures were associated with decreased anxiety levels and improved satisfaction with breasts for women who underwent implant reconstructions.

The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42–63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

Aromatase inhibitors (AI), which decrease circulating estradiol concentrations in post-menopausal women, are associated with toxicities that limit adherence. Approximately one-third of patients will tolerate a different AI after not tolerating the first. We report the effect of crossover from exemestane to letrozole or vice versa on patient-reported outcomes (PROs) and whether the success of crossover is due to lack of estrogen suppression. Post-menopausal women enrolled on a prospective trial initiating AI therapy for early-stage breast cancer were randomized to exemestane or letrozole. Those that discontinued for intolerance were offered protocol-directed crossover to the other AI after a washout period. Changes in PROs, including pain [Visual Analog Scale (VAS)] and functional status [Health Assessment Questionnaire (HAQ)], were compared after 3 months on the first versus the second AI. Estradiol and drug concentrations were measured. Eighty-three patients participated in the crossover protocol, of whom 91.3% reported improvement in symptoms prior to starting the second AI. Functional status worsened less after 3 months with the second AI (HAQ mean change AI #1: 0.2 [SD 0.41] vs. AI #2: −0.05 [SD 0.36]; p = 0.001); change in pain scores was similar between the first and second AI (VAS mean change AI #1: 0.8 [SD 2.7] vs. AI #2: −0.2 [SD 2.8]; p = 0.19). No statistical differences in estradiol or drug concentrations were found between those that continued or discontinued AI after crossover. Although all AIs act via the same mechanism, a subset of patients intolerant to one AI report improved PROs with a different one. The mechanism of this tolerance remains unknown, but does not appear to be due to non-adherence to, or insufficient estrogen suppression by, the second AI.

Background: S100A8 and S100A9 are members of a family of calcium binding proteins that regulate inflammatory response, and are biomarkers of inflammatory diseases, S100A8/A9 preferentially form heterodimers that interact with their receptor, RAGE, to activate signaling pathways (ERK1/2 MAPK, JNK, and NF-κB) and stimulate tumor cells. Elevated expression of S100A8/A9 has been observed in cancers of the bladder, esophagus, colon, ovary, and breast. S100A8/A9 are expressed intratumorally by cancer cells and in the stroma by infiltrating immune and myeloid cells as well. We investigated the associations of elevated expression of intratumoral and stromal S100A8 with survival outcomes in breast cancer. Methods: Tissue microarrays (TMA) were constructed from breast cancer specimens from patients with stage I-III breast cancer treated at the University of Michigan Comprehensive Cancer Center between 2004-2006, ensuring a minimum of 10-year follow-up. Each patient was represented on the TMA by representative regions of non-necrotic tumor and distant normal tissue. Automative Quantitative Immunofluorescence (AQUA) was performed for S100A8 protein, and samples were scored for intratumoral and stromal S100A8 expression. S100A8 staining was assessed as a continuous value and by exploratory dichotomous cutoffs. Associations with disease-free survival (DFS) or overall survival (OS) and S100A8 expression, either as continuous value or based on the exploratory cutoffs, were determined using the Kaplan-Meier method and Cox proportional hazards models. Results: In the entire patient cohort, high intratumoral S100A8 expression, as a continuous measure, was a significant prognostic factor for OS (univariable hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.02-1.56, p=0.036), and for DFS (multivariable HR [95%CI] = 1.24 [1.01-1.53], p = 0.043). Exploratory analyses demonstrated optimal cutoffs of intratumoral and intrastromal staining that greatly separated survival curves. We evaluated whether the prognostic significance of S100A8 expression is different in breast cancer patients based on hormone receptor status and determined that neither intratumoral nor stromal S100A8 expression were significantly associated with outcomes. Conclusions: Elevated intratumoral and stromal expression of S100A8 are significant indicators of poor outcome in breast cancer patients. These data further support a biological role for S100A8 signaling in mammary carcinogenesis and aggressive tumor behavior. Evaluation of S100A8 protein expression might provide additional prognostic information beyond traditional breast cancer prognostic biomarkers. Further validation is necessary to investigate these findings. Citation Format: Miller P, Kidwell K, Thomas D, Sabel M, Rae J, Hayes DF, Lippman ME, El-Ashry D. High intratumoral and stromal S100A8 expression is prognostic of poor outcome in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-13.

Background: Exemestane is a third generation steroidal aromatase inhibitor (AI) used for the treatment of estrogen receptor (ER) positive breast cancer in postmenopausal women. Differences in AI treatment efficacy and side effects may be due, in part, to variability in drug exposure. We previously reported that patients who self-report as white and those who carry the low-activity CYP3A4*22 single nucleotide polymorphism (SNP) have increased exemestane steady-state concentrations. Additional SNPs in CYP3A may contribute to pharmacokinetic variability and explain this inter-race difference. CYP3A5*3 (rs776746) is a non-expresser genotype that is far more common in European (minor allele frequency (MAF)∼0.94) than African (MAF∼0.18) individuals. CYP3A7*1C (rs45446698) is believed to tag adult expression of the fetal CYP3A7 enzyme and is relatively uncommon in tested cohorts (European MAF=0.04, African MAF Methods: 500 patients were randomly assigned to either drug on the Exemestane and Letrozole Pharmacogenetics (ELPh) Study. Clinical data and DNA were collected at baseline and blood samples were collected after 1 or 3 months of treatment to measure steady-state exemestane concentration via HPLC/MS. Genotyping for CYP3A5*3 and CYP3A7*1C was performed via Taqman Allelic Discrimination. Pharmacogenetic association with log-transformed concentrations were tested for each variant by inclusion in a multivariable model with CYP3A4*22 and self-reported race, assuming additive genetic effect, using Tobit regression to censor concentrations below the lower limit of quantification. SNPs with suggestive p-values 40, body mass index (BMI), and prior chemotherapy) to assess their independent contribution. Results: In 231 evaluable patients there was a suggestive trend toward lower steady-state exemestane concentrations for CYP3A7*1C carriers (6.3 vs. 8.0 ng/mL) in the model including CYP3A4*22 and race (p=0.083). In the final multivariable model each CYP3A7*1C allele decreased exemestane concentration 31.5% (p=0.035, Table 1). CYP3A5*3 was not associated with exemestane concentration (p>0.2). Multivariable Model of Exemestane Concentration % change in concentration (95% CI)p-valueCYP3A4*22 (rs35599367)64.5% (23%, 120%)0.0008CYP3A7*1C (rs45446698)-31.5% (-52%, -2.6%)0.035Self-Reported White47.2% (9.0%, 99%)0.012AST or ALT>4041.3% (1.0%, 98%)0.044BMI-0.9% (-2.4%, 0.55%)0.22Prior Chemotherapy-23.5% (-37%, -7.6%)0.006CI: Confidence Interval Conclusions: Patients with breast cancer who carry CYP3A7*1C have lower steady-state exemestane concentrations but this association does not explain the greater concentrations in self-reported white patients. Ongoing analyses will determine whether exemestane concentration predicts treatment efficacy or toxicity, and if so, whether genetic and clinical factors can be useful for individualizing dosing to optimize outcomes. CYP3A7*1C should be prioritized for analyses of pharmacokinetic variability of other CYP3A substrates. Citation Format: Hertz DL, Kidwell KM, Gersch CL, Desta Z, Storniolo AM, Stearns V, Skaar TC, Hayes DF, Henry NL, Rae JM. Genetic variation in CYP3A affects steady-state exemestane concentrations but does not explain inter-race difference [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-11.

Background: AIs are commonly used for treatment of postmenopausal women with hormone receptor-positive breast cancer for 5-10 years. However, women often experience side effects including musculoskeletal pain and sleep disturbances that lead to treatment discontinuation and worse healthcare-related outcomes. There is a need to understand the impact of adjuvant AI therapy on sleep and activity patterns in treated patients and associations with treatment adherence. This study examines objective and subjective changes in sleep patterns and daytime function in patients starting AI therapy using actigraphy and questionnaires. Methods: 49 postmenopausal women with hormone receptor-positive breast cancer who completed local surgery and chemotherapy and were planning to start AI therapy were enrolled. Patients completed 10 consecutive days of actigraphy and validated questionnaires to assess pain, sleep quality, fatigue and physical function at baseline and after three months of AI therapy. Changes in actigraphy parameters after 3 months of AI therapy were examined using paired T-tests and associations between actigraphy measures and patient-reported outcomes were examined using Pearson's correlations. Results: 42 patients completed the baseline assessment and 22 patients completed the 3 month assessment. 20 patients were excluded due to incomplete actigraphy data (n=3), discontinuation of AI therapy (n=5) or withdrawal from the study per patient preference (n=12) prior to the 3 month assessment. Total 24 hour activity, average activity per minute and maximum activity over a 24 hour period worsened after 3 months of AI therapy (all p-values Changes in actigraphy variables and questionnaires after 3 months of AI therapyMean actigraphy sleep and activity variablesBaseline assessment3 month assessmentP-value*24 hour total activity2125901881040.01924 hour average activity per minute (AC)157.6141.00.03724 hour maximum activity (AC)10359030.012Total sleep time (min)456.1469.10.17Sleep efficiency (%)77.274.60.068Wake after sleep onset (min)72.982.00.52Total activity at night (AC)595367050.13PROMIS Physical Function52.148.30.001Brief Pain Inventory Severity0.601.10.10*p-value from t-test Conclusions: Daytime activity and sleep patterns are negatively affected by AI therapy and are associated with worsening fatigue. Future research is needed to better understand the relationship between fatigue and daytime activity, which may lead to interventions to improve tolerance and adherence to AI therapy. Citation Format: Bhave MA, Kidwell K, Lyden AK, Alsamarraie C, Henry NL. Effect of aromatase inhibitor (AI) therapy on sleep and activity patterns in early stage breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-13-05.

PURPOSE: Approximately 25% of patients receiving weekly paclitaxel for breast cancer require treatment disruptions to avoid severe, irreversible peripheral neuropathy (PN). Vitamin insufficiencies are PN risk factors in many diseases, but their relevance to chemotherapy-induced PN is unknown. METHODS: We investigated whether baseline insufficiency of vitamin D, vitamin B12, folate, or homocysteine increased PN in patients with breast cancer receiving weekly paclitaxel in a retrospective analysis of a prospective observational study. Patient-reported PN was collected at baseline and during treatment on the Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy(CIPN20). The primary analysis tested associations between vitamin deficiency and the maximum increase from baseline in the CIPN20 sensory subscale (ΔCIPN8). Secondary analyses tested for association with PN-induced treatment disruptions and adjusted associations for treatment and clinical variables. RESULTS: 25-hydroxy-vitamin D was the only nutrient with sufficient deficiency (< 20 ng/mL) for analysis (15/37=41%). Vitamin D deficient patients had a greater mean PN increase than non-deficient patients (ΔCIPN8±SD, 36±23 vs. 16±16, p=0.003) and a non-significant, approximately 3-fold increase in risk of treatment disruption (OR = 2.98, 95% CI [0.72, 12.34], p=0.16). In multivariable models adjusted for clinical and treatment variables, baseline vitamin D level was inversely associated with PN (β = −0.04, p = 0.02). CONCLUSIONS: Pre-treatment vitamin D deficiency was associated with PN in women receiving weekly paclitaxel for breast cancer. Vitamin D deficiency may be an easily detected PN risk factor that could be resolved prior to treatment to prevent PN, avoid treatment disruptions, and improve treatment outcomes.

12068 Background: Aromatase inhibitors (AI) are recommended for at least five years to reduce risk of breast cancer recurrence in postmenopausal women with hormone receptor-positive disease. Despite the potential benefit, up to 50% of patients discontinue AI early, primarily because of musculoskeletal side effects. Some patients, including those with fibromyalgia and other chronic pain conditions, have preexisting pain that arises from altered nociception without clear evidence of tissue or peripheral nerve damage, called nociplastic or centralized pain. We hypothesized that preexisting nociplastic pain is associated with early discontinuation of AI therapy due to toxicity. Methods: Patients diagnosed with breast cancer between 2012-19 and who enrolled in the Michigan Genomics Initiative (MGI) were identified. Patients who were female, had hormone receptor-positive breast cancer, had not received neoadjuvant therapy, and who initiated adjuvant AI therapy were included in the analysis. Prior to breast cancer surgery patients completed surveys about pain in the affected breast and overall worst pain (Brief Pain Inventory [BPI]), nociplastic pain (2011 Fibromyalgia Survey [FS], which assesses widespread pain plus somatic symptom severity), and anxiety (PROMIS Anxiety 4a v.1). Demographics, cancer characteristics, and treatment history, including date and reason for discontinuation of AI therapy, were abstracted from the medical record. Patients were censored at date of last oncology follow-up. Univariate and multivariable analyses were conducted to assess relationship between age, BMI, surgical site pain, overall worst pain, FS score, anxiety, and time to discontinuation of initial AI medication. Results: Of 207 analyzed patients, the average age was 61 years, average BMI was 30.3 kg/m2, 181 (87%) were postmenopausal at the time of breast cancer diagnosis, and 31% received chemotherapy. The majority were prescribed anastrozole (n=196); 6 took letrozole and 5 took exemestane. Average scores prior to surgery were 1.5/10 for worst pain, 0.2/10 for surgical site pain, 4.2/31 for FS score, and 54.1/100 for anxiety. On univariate analysis, only use of exemestane (HR 5.55, p

BackgroundNRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical complications after surgery in patients who did or did not receive bev.MethodsA total of 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15mg/kg every 3weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24months following study entry.ResultsEarly surgical complications were significantly more frequent in the bev group (25.4 vs. 18.9%; trend test p = 0.008), but most were grade 1-2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4 vs. 3.1%; trend test p = 0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8 vs. 5.1%; trend test p = 0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (

Objectives: To evaluate use of sentinel lymph node (SLN) frozen section (FS) before and after publication of the Z0011 trial. Methods: We identified 116 pre-Z0011 and 134 post-Z0011 patients from 18 months before and after Z0011-initiated changes. Clinicopathologic features were assessed by chart review. Results: Post-Z0011 SLN FS use markedly declined when performed with breast-conserving therapy (BCT) ( P

AIMS In the SWOG S0226 trial the combination of anastrozole plus fulvestrant (n = 349) was superior to anastrozole alone (n = 345) in hormone receptor (HR)-positive metastatic breast cancer. Here we report a pharmacokinetic subset analysis investigating a possible drug interaction between anastrozole and fulvestrant. METHODS Post-menopausal patients with HR-positive metastatic breast cancer were randomized to anastrozole with or without concurrent fulvestrant. Blood samples were collected at 2, 4, 6 and 8 months, just prior to receiving the next dose of anastrozole and fulvestrant. Drug concentrations were measured via LC/MS-MS. Anastrozole concentration was compared in patients on anastrozole alone vs. patients on concomitant fulvestrant. Comparisons were made at each time point using parametric tests and over time using a linear mixed effects model. RESULTS A total of 483 anastrozole concentration measurements were included, 224 samples from 64 patients on the anastrozole alone arm and 259 from 73 patients on the combination arm. The mean anastrozole concentration in the combination arm was significantly lower than that in the anastrozole alone arm at each sample collection time (all P

In the prospective Exemestane and Letrozole Pharmacogenetics trial of adjuvant aromatase inhibitor (AI) therapy for early-stage breast cancer, worsening of multiple treatment-related symptoms during AI therapy predicted AI early discontinuation. If these findings are confirmed in independent trials, early detection of changes in PRO measures could be used clinically to target interventions in patients at high risk for early discontinuation., Background. Early discontinuation of aromatase inhibitors (AIs) is common and leads to poor outcomes but is challenging to predict. In the Exemestane and Letrozole Pharmacogenetics trial, a high rate of early discontinuation due to intolerance was observed. We hypothesized that early changes in patient-reported outcomes (PROs) predict AI discontinuation and that biochemical factors are associated with changes in PROs. Patients and Methods. Postmenopausal women with early-stage breast cancer enrolled in a prospective randomized trial of exemestane versus letrozole completed questionnaires at baseline and serially over 24 months to assess overall quality of life (EuroQOL Visual Analog Scale [VAS]); mood; and multiple symptoms, including a musculoskeletal symptom cluster. A joint mixed-effects/survival model was used to estimate the effect of the change in PROs on AI discontinuation. Associations between biochemical factors and change in PROs were examined. Results. A total of 490 patients were analyzed. Worsening of EuroQOL VAS and the musculoskeletal cluster were associated with the highest risk for early discontinuation (hazard ratio [HR], 2.77 [95% confidence interval (CI), 2.72–2.81; p = .015]; HR, 4.39 [95% CI, 2.40–8.02; p < .0001], respectively). Pharmacokinetics and estrogen metabolism were not consistently associated with change in PRO measures. No clinically significant differences in any PRO between AIs were observed. Conclusion. Changes in PROs early during AI therapy were associated with treatment discontinuation. Identification of these changes could be used to target interventions in patients at high risk for early discontinuation. Implications for Practice: Early changes in patient-reported outcomes (PROs) can predict nonpersistence to aromatase inhibitor therapy. If used in clinical practice, PROs might identify women at highest risk for early discontinuation and allow for interventions to improve tolerance before significant toxicities develop. Further research is needed to improve capturing PROs in routine clinical practice.

Osteoarthritis (OA) of the lower extremities is a prevalent cause of disability in which symptoms interfere with mobility and activity participation. Behavioral self-management for OA symptomatology is commonly recommended; but these interventions are underutilized, unstandardized in application, and at times, unavailable in the context of clinical care. For people with chronic pain, rehabilitation professionals may select to apply activity pacing instruction as one behavioral strategy to manage symptoms. Activity pacing is widely used in combination with other pharmacological and behavioral interventions but has not been studied as a singular behavioral intervention for people with OA. The purpose of this study was to evaluate the effectiveness of an occupational therapist-delivered, time-based activity pacing program for treatment of pain, fatigue, and physical function in people with symptomatic knee or hip OA. A 3-arm randomized controlled trial was conducted in which 193 people were randomized into tailored activity pacing, general activity pacing, or usual care arms. Assessments were done at 10 weeks and 6 months after baseline. Using linear mixed models, Western Ontario and McMaster Universities Osteoarthritis Index pain scores changed over time, decreasing the most in the general and usual care groups; only the usual care group had decreased pain over 6 months. The tailored and general activity pacing groups reported higher frequency of pacing behaviors than the usual care group at 10 weeks, but pacing was not sustained at 6 months. This trial does not support the use of time-based pacing as a singular behavioral strategy for people with knee or hip OA.

We evaluated the impact of a comprehensive pediatric asthma management program (the Children's Asthma Wellness Program, CAWP) on the frequency of emergency department (ED) visits and hospital admissions. The CAWP generally consisted of 4 clinic sessions over a 1-year period, but some patients attended fewer clinic sessions, and some required additional clinic sessions due to incomplete asthma control. Patients were evaluated and treated by pediatric pulmonologists, nurse asthma care coordinator/educator, and social worker. We retrospectively reviewed program results over an 8-year period (2005–2013). We compared ED visits and hospital admissions before and after participation in the CAWP. There were 254 children referred to the CAWP; 172 children were enrolled. Fifty-four children (31%) received >6 sessions due to incomplete asthma control. On average, children requiring additional clinic sessions were older and more likely to be African American, hold Medicaid insurance, and have severe asthma. We obtain...