Citations

New Findings What is the central question of this study? What is the role of β2‐adrenergic receptor (β2AR) vasodilatation in older postmenopausal women as compared to premenopausal women and the role of nitric oxide (NO) in β2AR‐mediated vasodilatation in both groups of women? What is the main finding and its importance? β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women. Additionally, NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women. Abstractβ2‐Adrenergic receptor (β2AR)‐mediated vasodilatation, which is partially dependent on nitric oxide (NO) formation, is blunted in men at risk for developing hypertension. However, the role of β2AR vasodilatation in hypertension pathophysiology in ageing postmenopausal women is unclear. Therefore, the goals of this study were to determine if forearm vasodilatation to the selective β2AR agonist terbutaline is blunted in older postmenopausal women (59 ± 4 years) compared to young premenopausal women (27 ± 3 years) and to assess NO contribution to β2AR‐mediated vasodilatation in both groups of women. Forearm blood flow (FBF) and forearm vascular conductance (FVC) were measured using venous occlusion plethysmography at baseline and during intra‐arterial infusions of terbutaline at 0.1–2.0 µg (100 ml tissue)−1 min−1 with and without the NO synthase inhibitor l‐NG‐monomethylarginine (l‐NMMA). Mean arterial pressure was significantly greater in postmenopausal women than in young women at baseline (P = 0.01). Baseline FBF and FVC did not differ between young and postmenopausal women (P > 0.05) and rose significantly within each group during terbutaline infusion (P < 0.05). There were significant group × dose interactions for FBF (P = 0.01) and FVC (P = 0.001), indicating vasodilator responses were lower in postmenopausal women. In young women, FVC response to the highest dose of terbutaline tended to be lower with l‐NMMA co‐infusion vs. without l‐NMMA (P = 0.05). There were no significant decreases in FBF or FVC responses to terbutaline in postmenopausal women with l‐NMMA co‐infusion (P > 0.05 for all). These data suggest that β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women, and that NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women.

e20608 Background: The American Society of Clinical Oncology recommends that physicians (MDs) assess the treatment goals and preferences of patients (pts) with advanced stage cancer. Available data, however, shows that pts’ values are not always well prioritized when making a treatment plan. Therefore, we iteratively developed a values tool containing 16 belief domains to inform MDs during conversations with their pts about the pts’ current priorities as they plan the next step in care. The purpose of this study was to determine the feasibility of using this values tool (defined as half of the tools having at least one value checked and half of the MDs discussing at least one value) in a phase I clinic setting. Methods: We audio-taped initial MD-pt conversations about potential enrollment in a phase I clinical trial at two academic medical centers (Emory and Mayo). The pts completed the values tool by selecting the 4 most important considerations for their next stage of care and were instructed to give the completed tool to the MD. The MDs were informed through the consent process but not specifically coached on use of the tool. The recorded conversations were coded using standard qualitative methodology to determine if a value from the tool was discussed. Results: There were 23 recorded encounters. All of the completed tools had at least one value checked and 19 of 23 (83%) completed tools were delivered to the MDs by the pts, as instructed. Of those who received the tool, 12 (63%) MDs discussed one or more of the values. The average satisfaction scores on a 5-point Likert scale were 3.9, 4.0, and 4.0, respectively, for tool clarity, ease of understanding, and benefit for pts who are offered a phase 1 trial (22/23 pts completed the evaluation). Average satisfaction scores from the 19 MDs who completed evaluations were 4.2 and 4.6, respectively, for influence of the tool on their treatment recommendation and accurate reflection of pts’ desires. Conclusions: The study met the predefined feasibility threshold and provides a strong rationale for future efficacy testing, including coaching of MDs. The tool was well accepted by both MDs and pts, and failure to deliver the completed tool by the pt was identified as a potential barrier to its effectiveness.

9515 Background: CC 49907 showed superiority of standard therapy (cyclophosphamide/doxorubicin [AC] or cyclophosphamide/methotrexate/5-fluorouracil [CMF]) over capecitabine[C]. Dose adjustments made for renal insufficiency (RI) for methotrexate and C; ideal body weight used. Purpose was to analyze the relationship between RF at baseline and 5 endpoints: toxicity, dose modification, therapy completion, relapse-free survival [RFS] and overall survival [OS]. Methods: Pre-treatment RF was calculated (Cockcroft-Gault). Endpoints assessed by regimen. RF was tested as a dichotomous and continuous variable of stages 1,2 vs. 3,4 kidney disease (National Kidney Foundation). Logistic regression modeled the relationship between renal stage and the first three endpoints of toxicity, dose modification and therapy completion. Toxicity divided by hematologic or not. The relationship of RFS and OS with RF was assessed with the logrank test and as a continuous variable with Wald chi square. Results: 619 patients; incidence of stage 3/4 RI(<60 ml/min) was: CMF=72%; AC=64%; C=75%. With AC the incidence of toxicity differed by renal function. 31% of patients with poorer function >grade 3 non-hematologic toxicity vs. 14% with better function(p=0.011). There was a suggestion of effect of RF on OS and RFS for C-treated patients. RF was not associated with dose modification, premature therapy termination, RFS or OS for the CMF-treated patients. Conclusions: 1) AC: declining RF was associated with increased non-hematologic toxicity. 2)Patients with RI who received dose modifications were not at increased risk for complications in comparison to those who did not have renal insufficiency and received full dose. 3)Declining RF did not affect therapy completion. 4)C: suggestion that worse RF was related to poorer RFS or OS. 5)Exclusion of patients from clinical trials with RI based on concern of excessive hematologic toxicity may not be justified with appropriate modification. 6)Results should be considered in the design of clinical trials for older patients.

1024 Background: The combination of platinum agents and PARP inhibitors may benefit patients (pts) with BRCA-associated metastatic breast cancer (MBC). We report on the response and clinical benefit rates when combining the PARP inhibitor veliparib (V) and carboplatin (carb) in a phase I trial. Methods: BRCA carriers with MBC were eligible. Carb starting at an AUC of 6 was given IV in 21-day cycles (C) and V was given orally twice daily (BID) at dose levels (L) L1 through L5. Results: Twenty-eight pts (26 eligible) carrying BRCA1 (12) or BRCA2 (15), or both (1) mutations were accrued between June 2010 and June 2012. The median age (32-66) was 45 years. The number (#) of prior chemotherapy regimens given for MBC was 1 (0-5); 70% of BCs were ER+, and 7% were HER2+. The schema, dose limiting toxicities (DLT) during C 1, median # of Cs on trial, and maximum tolerated dose (MTD) are shown. There were 3 (12%) complete and 9 (35%) partial responses (PR). Unconfirmed PR or stable MBC (median duration: 8 months [6-10+]) were seen in 7 pts (27%); the clinical benefit rate was74%. The median progression-free survival (PFS) is 7.8 months (95% CI 7.3-9.5). The pt with Fallopian tube cancer had a CR. DLTs with C 1 were seen in 2/6 evaluable pts at L1 (1 pt w/grade 3 hyponatremia and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to de-escalation of carb. At L2, 1 pt had grade 4 PLT. At L5, 1 pt had grade 4 PLT, and 2 pts grade 3 PLT (1 pt also experienced grade 4 granulocytopenia [ANC]), defining the MTD at carb AUC 5 and V 150 mg BID (L4). Dose delays and/or dose adjustments due to grade ≥ 2 toxicities for ANC or PLT were seen during the first 3 Cs at L1 (100%), L2 (50 %), L3 (67%), L4 (83 %), and at L5 (67%). Conclusions: The combination of carb and V is active, and is associated with substantial clinical benefit rate and managable hematologic toxicities in BRCA carriers with MBC. Further definition of the role of V is warranted. [Table: see text]

6624 Background: RUX is a JAK1/JAK2 inhibitor that demonstrated significant clinical benefit in patients (pts) with MF in COMFORT-I (NCT00952289), a phase 3, randomized (1:1), double-blind, placebo (PBO)-controlled study (N=309). Methods: Pts assessed MF-related symptoms daily using the modified Myelofibrosis Symptom Assessment Form v2.0; Total Symptom Score (TSS) was calculated from individual scores for abdominal discomfort, pain under left ribs, early satiety, night sweats, itching, and bone/muscle pain. Therapy was interrupted if platelet or absolute neutrophil count fell below 50,000/µL or 500/µL, respectively. AEs were evaluated during treatment interruption or discontinuation. The protocol suggested an optional tapering strategy and possible addition of steroids if RUX therapy was discontinued for reasons other than thrombocytopenia. Results: In RUX-treated patients with treatment interruption, TSS gradually returned to baseline levels over approximately 1 week. The most common AE leading to treatment interruption or discontinuation in each group was thrombocytopenia (n=11, RUX) and abdominal pain (n=4, PBO). Of these, only 1 RUX pt discontinued for thrombocytopenia. A summary of new onset/worsening AE data after treatment interruption or discontinuation is presented (Table). Of 58 pts who discontinued study treatment, 23 (n=10, RUX; n=13, PBO) experienced a total of 43 SAEs (19, RUX; 24, PBO) that showed no specific pattern or difference between treatment groups. Four of 21 RUX-treated pts had dose tapering following study drug discontinuation. Conclusions: Apart from the expected return of MF-related symptoms, there was no pattern of AEs to suggest that RUX interruption or discontinuation is associated with a specific withdrawal syndrome. [Table: see text]

6015 Background: Comorbidity increases with age. We evaluated how comorbidity was associated with toxicity and clinical outcomes among older women with BC who received adjuvant chemotherapy. Methods: Cancer and Leukemia Group B (CALGB 49907) enrolled 633 women ≥65 years with early stage BC and randomized them to standard adjuvant chemotherapy (AC or CMF) or capecitabine (N Eng J Med 360:2055, 2009). 329 women on the Quality of Life companion study completed a pre-treatment health survey (Older American Resources and Services Questionnaire, physical health subscale). The survey evaluates 14 conditions and the degree to which each interferes with daily activities (rated from 1 “not at all” to 3 “a great deal”). Comorbidity was analyzed as follows: 1) total number 2) comorbidity burden score (summed conditions multiplied by interference rating); and 3) individual diseases. Primary outcomes were: 1) grade 3-5 toxicity (incident and cumulative); 2) time to relapse (TTR), and 3) overall survival (OS). Contingency table methods were used to evaluate the association between comorbidity and toxicity. Cox proportional hazards models were used to evaluate TTR and survival outcomes. Results: Among 329 women [median age 71 years (range 65-89), 86% white, 98% ECOG performance score 0-1, 75% stage 1-2] the median number of comorbidities was 2 (0-10), median comorbidity burden score was 3 (0-25), and most common conditions were arthritis (58%) and hypertension (54%). Few patients had diabetes (17%), heart disease (16%), and pulmonary disease (9%). No comorbidity measure was associated with toxicity or TTR. With a median follow-up of 5.4 years, increasing comorbidity was associated with shorter OS. For each additional comorbid condition the hazard of death increased by 18% (HR 1.18 [95% CI; 1.06-1.33]) after adjusting for age, tumor size, treatment, node status and receptor status. Comorbidity burden score was similarly associated with OS (HR 1.08 [95% CI; 1.03-1.14]), while no specific condition was independently associated. Conclusions: Among older women with good functional status, comorbidity was not associated with toxicity or BC relapse. However, comorbidity burden was associated with shorter OS.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Abstract Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93–0.98; P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92–0.97; P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03–1.08; P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01–1.07; P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01–1.06; P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

Objective We surveyed the American Headache Society (AHS) New Investigators and Trainees Section (NITS), and International Headache Academy (IHA) attendees to better understand what they perceive as the most pressing issues for themselves as new investigators and trainees in the field of headache medicine. Background The NITS and IHA are intended as platforms for mentorship, leadership training, and professional development in the field of headache medicine. Identifying and addressing pressing issues among new investigators and trainees based on their perceived needs is critical to encouraging their development and success as headache medicine clinicians and researchers. Methods Paper surveys were administered at the NITS meeting at the November 2018 Scottsdale Headache Symposium and the January 2019 IHA. Additionally an online version was sent to the NIT listserv in November of 2018. The survey queried demographic information (gender, race, age, profession, training status, and years in practice) and asked participants to identify their top 3 most pressing issues/questions among a list of options. Results Fifty‐three responses were submitted (53/255; total response rate 20.7%). Among the surveys, 18 in‐person responses were from the NITS meeting (18/20; response rate 90.0%), 23 in‐person responses were from the IHA (23/45; response rate 51.1%), and 12 responses were from the online survey (12/190; response rate 6.3%). No duplicate responses were submitted based on comparison of demographics. One respondent identified as a researcher exclusively and was excluded from further analyses; the rest identified as clinicians at various levels of medical training. Fifteen respondents were not members of the NITS (28.8%); the most common reason for nonmembership was lack of awareness of the section (92.8%). Overall the most pressing issues/questions included (% of respondents who ranked issue/question among top 3): Career planning (51.9%), Logistics of running a headache clinic (40.4%), and Opportunities for involvement (38.5%). Most pressing issues/questions differed depending on level of training. Working with industry was the most pressing issue/question identified by early career physicians (55.0%). Career planning was the most pressing issue/question among fellows (72.2%) and residents (64.3%). Conclusion Many of the most pressing issues identified by respondents are topics that are not formally addressed in medical and research training.