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Purpose At least five years of adjuvant endocrine therapy (ET) is recommended for patients with hormone receptor-positive invasive breast cancer to reduce cancer recurrence risk. Up to half of patients prematurely discontinue ET, often due to musculoskeletal pain. Nociplastic pain is abnormal central nervous system pain processing without evidence of tissue or neuronal damage. This study aimed to evaluate the relationship between baseline nociplastic pain and ET discontinuation. Methods This was a retrospective, single center, cohort study. Included patients were female, had stage 0-III invasive breast cancer, did not receive neoadjuvant therapy, and completed quality of life questionnaires prior to breast surgery, including Fibromyalgia Survey for nociplastic pain. Clinical data including duration of ET were abstracted from the medical record. Patient characteristics were analyzed with t-tests and chi-squared tests, as appropriate. Univariate and multivariable regressions were performed with Cox proportional hazard models. Results 681 patients diagnosed between 2012–2019 met inclusion criteria; 480 initiated ET and were included in the analysis. Of these 480 patients, 203 (42.3%) prematurely discontinued initial ET therapy. On univariate analysis, tamoxifen use (hazard ratio [HR] 0.70, p = 0.021) and premenopausal status (HR 0.73, p = 0.04) were inversely associated with ET discontinuation, while Fibromyalgia Score was positively associated (HR 1.04, p = 0.043). On multivariable analysis, baseline Fibromyalgia Score remained associated with ET discontinuation. Conclusion Nociplastic pain present prior to surgery was associated with premature ET discontinuation. Fibromyalgia Score screening may be useful for evaluating ET discontinuation risk. Treatments targeting nociplastic pain may be more effective for treating ET-emergent pain.

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

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

Kinome-wide profiling data of UM-164 and dasatinib in MDA-MB 231 lysate

Supplementary Figure 2: Paclitaxel Exposure in Patients Who Did or Did Not Experience Peripheral Neuropathy-Induced Treatment Disruption. Patients who experienced PN-induced treatment disruption had greater median paclitaxel Tc>0.05 than patients who did not (11 hours (IQR 10-15) vs. 9.5 hours (IQR= 9-11), p=0.001) (left panel). The mean Cmax for patients who experienced treatment disruption was not statistically different from those who did not (2591.8 ng/mL (SD 897.9) vs. 2267.4 ng/mL (SD 521.2), p=0.18). The line in the box is the median. The lower and upper hinges correspond to the first and third quartiles and the lines extend 1.5 x IQR, representing an approximate 95% confidence interval.

Background: Endocrine therapy (ET) fails to induce a response in one half of patients with hormone receptor (HR)–positive metastatic breast cancer (MBC), and almost all will eventually become refractory to ET. Circulating tumor cells (CTC) are associated with worse prognosis in patients with MBC, but enumeration alone is insufficient to predict the absolute odds of benefit from any therapy, including ET. We developed a multiparameter CTC-Endocrine Therapy Index (CTC-ETI), which we hypothesize may predict resistance to ET in patients with HR-positive MBC.Methods: The CTC-ETI combines enumeration and CTC expression of four markers: estrogen receptor (ER), B-cell lymphoma 2 (BCL-2), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67. The CellSearch System and reagents were used to capture CTC and measure protein expression by immunofluorescent staining on CTC.Results: The feasibility of determining CTC-ETI was initially established in vitro and then in a prospective single-institution pilot study in patients with MBC. CTC-ETI was successfully determined in 44 of 50 (88%) patients. Eighteen (41%), 9 (20%), and 17 (39%) patients had low, intermediate, and high CTC-ETI scores, respectively. Interobserver concordance of CTC-ETI determination was from 94% to 95% (Kappa statistic, 0.90–0.91). Inter- and cell-to-cell intrapatient heterogeneity of expression of each of the CTC markers was observed. CTC biomarker expression was discordant from both primary and metastatic tissues.Conclusions: CTC expression of ER, BCL-2, HER2, and Ki67 can be reproducibly measured with high analytical validity using the CellSearch System. The clinical implications of CTC-ETI, and of the heterogeneity of CTC biomarker expression, are being evaluated in an ongoing prospective trial. Clin Cancer Res; 21(11); 2487–98. ©2014 AACR.See related commentary by Mathew et al., p. 2421

Legends associated with Supplementary Figures S1-S12.

Table S1. Antibodies used for CTC and tissue studies. Table S2. Stage 2 stopping rules for the cumulative number of successfully assayed patients. Table S3. A. CTC-Enumeration Points based on CTC Enumeration B. CTC-Bio-Pointsa Footnotes:aOnly aliquots with CTC {greater than or equal to}5/7.5 ml WB evaluated bLow or negative ER expression is weighed more than BCL-2, HER2, and Ki67 due to its fundamental role in endocrine responsiveness. C. Calculation of CTC-ETI Scores. D. CTC-ETI Categories. Footnote: Abbreviations: CTC= circulating tumor cells; ER = estrogen receptor; ET= Endocrine Therapy; MBC = metastatic breast cancer; ET= endocrine therapy. Table S4. CTC-ETI determination in cultured human breast cancer cell lines spiked into normal human blood and evaluated by the CellSearch® system. Table S5. Examples of low, intermediate, and high CTC-ETI from patient samples. A. LOW CTC-ETI Patient # 5 (Primary Tissue: ER 90% positive, HER2 negative by FISH; Metastatic tissue: ER positive, HER2 negative by FISH)* B. INTERMEDIATE CTC-ETI Patient #4 (Primary Tissue: ER {greater than or equal to}95% positive, HER2 0 by IHC; Metastatic tissue: insufficient tissue to evaluate ER and HER2)* C. HIGH CTC-ETI Patient # 3 (Primary Tissue: ER 60% positive, HER2 1+/2+ by IHC; Metastatic tissue: ER 75% positive; HER2 1+ by IHC)* Footnote: *ER and HER2 as per initial clinical laboratory using the laboratory's criteria for positivity or negativity. Table S6.< CTC-ETI for each patient. Footnote: aAF =Analytical Failure (CTCbTF=Technical Failure (Machine failure in at least one of 4 aliquots). Table S7. Concordance between biomarkers in primary and metastatic tissues and CTC. aKappa score for concordance between CTC and tissue biomarker for respective biomarker.

Purpose: Paclitaxel exposure, specifically the maximum concentration (Cmax) and amount of time the concentration remains above 0.05 μmol/L (Tc>0.05), has been associated with the occurrence of paclitaxel-induced peripheral neuropathy. The objective of this study was to validate the relationship between paclitaxel exposure and peripheral neuropathy.Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m2 × 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of and 16–26 hours after the first infusion to estimate Cmax and Tc>0.05. Patient-reported peripheral neuropathy was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with Tc>0.05. Secondary analyses were conducted using Cmax as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy–induced treatment disruption.Results: In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (P < 0.05), but neither Tc>0.05 (P = 0.27) nor Cmax (P = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18–1.80; P = 0.0008) and Tc>0.05 (OR = 1.79; 95% CI, 1.06–3.01; P = 0.029) or Cmax (OR = 2.74; 95% CI, 1.45–5.20; P = 0.002) were associated with peripheral neuropathy–induced treatment disruption.Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting peripheral neuropathy in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents peripheral neuropathy in these patients. Clin Cancer Res; 24(15); 3602–10. ©2018 AACR.

Supplementary Figure S1. Biochemical data for UM-164 and dasatinib. Supplementary Figure S2. Western blots showing the expression of P-Src, P-EGFR and P-p38MAPK in selected TNBC cell lines. Supplementary Figure S3. UM-164 is a dual c-Src/p38 kinase inhibitor in TNBC cell lysate. Supplementary Figure S4. Signaling pathway analysis of SUM 149 cells when treated with dasatinib or UM-164 at their IC50 values (630 nM and 230 nM, respectively). Supplementary Figure S5. Effect on cell invasion of dasatinib alone and dasatinib plus a p38MAPK inhibitor, BIRB-796. Supplementary Figure S6. Effect of dasatinib alone or in combination with p38MAPK inhibitors on the level of P-EGFR/Tyr1068 and P-p38MAPK. Supplementary Figure S7. UM-164 is cytostatic and does not induce apoptosis. Supplementary Figure S8. Histopathology of major organ systems from mice treated with 140 mg/kg UM-164 for 5 days and necropsied. Supplementary Figure S9. In vivo efficacy of UM-164 compared to dasatinib in MDA-MB 231 xenografts. Supplementary Figure S10. Inhibition of p-Src in MDA-MB 468 cells by UM-164 and dasatinib. Supplementary Figure S11. Effect of UM-164, dasatinib alone and in combination with BIRB-796 in spheroid culture. Supplementary Figure S12. Wetsern blot from the UM-164 treated tumor tissues showing expression of P-38MAPK, P-EGFR and P-Src.

Purpose: Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether EpCAM-based capture system (CellSearch) is effective in patients with triple-negative (TN) MBC, and whether CTC apoptosis and clustering enhances the prognostic role of CTC.Experimental Design: CTC enumeration and apoptosis were determined using the CXC CellSearch kit at baseline and days 15 and 29 in blood drawn from TN MBC patients who participated in a prospective randomized phase II trial of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without tigatuzumab. Association between levels of CTC and patient outcomes was assessed using logistic regression, Kaplan–Meier curves, and Cox proportional hazards modeling.Results: Nineteen of 52 (36.5%), 14 of 52 (26.9%), and 13 of 49 (26.5%) patients who were evaluable had elevated CTC (≥5 CTC/7.5 mL whole blood) at baseline and at days 15 and 29, respectively. Patients with elevated versus not elevated CTC at each time point had worse progression-free survival (PFS; P = 0.005, 0.0003, 0.0002, respectively). The odds of clinical benefit response for those who had elevated versus low CTC at baseline and days 15 and 29 were 0.25 (95% CI: 0.08–0.84; P = 0.024), 0.19 (95% CI: 0.05–0.17; P = 0.014), and 0.06 (95% CI: 0.01–0.33; P = 0.001), respectively. There was no apparent prognostic effect comparing CTC apoptosis versus non-apoptosis. Presence of CTC cluster at day 15 and day 29 was associated with shorter PFS.Conclusions: CTC were detected using CellSearch assay in approximately one-third of TN MBC patients. Elevated CTC at baseline and days 15 and 29 were prognostic, and reductions in CTC levels reflected response. Clin Cancer Res; 21(12); 2771–9. ©2015 AACR.See related article by Forero-Torres et al., p. 2722

Supplementary Figure 1-5. Supplementary Figure 1. Example of cluster image using the CellSearch® system. Supplementary Figure 2. REMARK diagram of the 19 patients who had elevated CTC (Group B/C) at baseline that were used to study "CTC-response". Supplementary Figure 3. PFS for TIG-treated patients versus the control group according to baseline CTC levels: CTC

Detailed experimental information for: Cell cycle analysis; Dose response studies; Western blot analyses; 3D cell culture; Bead motility assay; Cell invasion assays; General synthetic methods; Synthesis of UM-164.

Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.Experimental Design: We have analyzed the anti–triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts.Results: We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC. Clin Cancer Res; 22(20); 5087–96. ©2016 AACR.

Supplementary Figures. Figure S1. Clinical trial study design. Figure S2. Examples of biomarker staining of cultured human breast cancer cell lines after spike and capture from normal human blood using the CellSearch® system. A semi-quantitative scale was established based on relative expression of each biomarker: negative (0), weak (1+), intermediate (2+), and high (3+). Footnote: *hormone depleted condition. Figure S3. Demonstration of appropriate antibody staining of cultured human breast cancer cells with known positive and negative biomarker expression after spike and capture from normal human blood using the CellSearch® System. A: ER staining for MCF-7 and Sk-Br-3. B: BCL- 2 staining for MCF-7 and Sk-Br-3. C: HER2 staining for Sk-Br-3 and MCF-7. D: Ki-67 staining for MCF-7. Figure S4. Composite "CTC-Bio-Score" for different cell lines. A: Hormone depleted MCF-7 cells (Luminal-type). B: MDA-MB-231 (Basal-like type). C: Sk-Br-3 (HER2 positive). Figure S5. Heterogeneity of ER expression within the cultured MCF-7 human breast cancer cell line. Cells were cultured in hormone depleted media for 48 hours, harvested, and spiked into 7.5 ml of normal human blood. The blood was then processed using CellSearch® and stained for DAPI, CK, CD45, and ER. Examples of strong (2+, 3+), weak (1+), and no staining (0) are displayed. Apparent staining in the bottom panel is due to high gain analysis by the automated fluorescent microscopy, as indicated by very high background. Figure S6. Coefficient of variation of CTC-enumeration by mean CTC count. Figure S7. Heterogeneity between primary tissue and CTC for patient #4. The CTC galleries displayed were selected from over 1,000 images to illustrate CTC-ER heterogeneity.

Supplementary Table 1. Table illustrating the criteria with which a cell was considered viable, or apoptotic either due to positive M-30 staining and/or visual evidence of apoptosis (nucleic condensat). Legend: Y= Yes, N= No

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.

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

International audience; Abstract Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error ( p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections ( p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.; v2.5, 25 March 2021.

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

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 & AIMSAcute severe ulcerative colitis (ASUC) is a life-threatening presentation of ulcerative colitis requiring prompt treatment. Infliximab (IFX) rescue therapy can prevent colectomy in patients with ASUC.METHODSWe performed a cohort study of adult patients hospitalized with ASUC between 01/2014 – 02/2021 who received infliximab rescue therapy. Using multivariable logistic regression, baseline and longitudinal laboratory predictors of colectomy within 90 days of index hospitalization were identified and used to develop a risk prediction model and prognostic scoring system to identifying patients at risk for colectomy. Model performance was assessed using area under the receiver operator characteristic curve (AUC) analysis.RESULTS166 patients with ASUC who received infliximab rescue therapy were identified. Overall, 24.7% (n=41) underwent colectomy within 90 days. Multivariate analysis revealed that colectomy within 90 days could be predicted by having a calculated IFX clearance of >53L/d (OR 2.28, 95% CI 0.99, 5.22), a day 0 absolute C-reactive protein (CRP) > 91mg/L (OR 3.49, 95% CI 1.58 to 8.08), a decrease in CRP of < 43% from day 0 to day 3 (OR 4.13, 95% CI 1.84 to 9.94), and a decrease in CRP of < 9% from the day of IFX administration to one day post-IFX administration (OR 4.20, 95% CI 1.74 to 10.4). Using these predictors, two highly accurate prognostic scoring system were developed to identify patients at risk for requiring colectomy both prior to administering infliximab (AUC 0.76) and after administer infliximab rescue therapy (AUC 0.81).CONCLUSIONWe identified important baseline and longitudinal laboratory predictors of colectomy within 90-days among patients with ASUC receiving infliximab rescue therapy and developed accurate prognostic scores to determine risk of colectomy. These scores can be used risk-stratify patients and facilitate personalized management.

Clinical trials studying treatments for rare diseases are challenging to design and conduct due to the limited number of patients eligible for the trial. One design used to address this challenge is the small n, sequential, multiple assignment, randomized trial (snSMART). We propose a new snSMART design that investigates the response rates of a drug tested at a low and high dose compared with placebo. Patients are randomized to an initial treatment (stage 1). In stage 2, patients are rerandomized, depending on their initial treatment and their response to that treatment in stage 1, to either the same or a different dose of treatment. Data from both stages are used to determine the efficacy of the active treatment. We present a Bayesian approach where information is borrowed between stage 1 and stage 2. We compare our approach to standard methods using only stage 1 data and a log-linear Poisson model that uses data from both stages where parameters are estimated using generalized estimating equations. We observe that the Bayesian method has smaller root-mean-square-error and 95% credible interval widths than standard methods in the tested scenarios. We conclude that it is advantageous to utilize data from both stages for a primary efficacy analysis and that the specific snSMART design shown here can be used in the registration of a drug for the treatment of rare diseases.