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PURPOSE In patients with diffuse large B-cell lymphoma (DLBCL), most relapses occur within the first 2 years of diagnosis. We sought to define the rate and outcome of late relapses that occurred after achieving event-free survival at 24 months (EFS24). METHODS We prospectively followed 1,324 patients with newly diagnosed DLBCL from 2002 to 2015 and treated with immunochemotherapy. Cumulative incidences of late DLBCL and indolent lymphoma relapses were analyzed as competing events. Postrelapse survival was defined as time from first relapse to death from any cause. RESULTS In 847 patients who achieved EFS24, the cumulative incidence of late relapse was 6.9% at 3 years, 9.3% at 5 years, and 10.3% at 8 years after EFS24. The incidence of DLBCL relapse was similar in patients with DLBCL alone at diagnosis (6.3% at 5 years), compared with patients with concurrent indolent lymphoma at diagnosis (5.2%; P = .46). However, the rate of indolent lymphoma relapse was higher in patients with concurrent indolent lymphoma (7.4% v 2.1% at 5 years; P < .01). In patients with DLBCL alone, the rate of DLBCL relapse was similar in the germinal center B-cell–like (GCB) (4.1% at 5 years) and non-GCB (4.0%; P = .71) subtypes, whereas the rate of indolent lymphoma relapse was higher in patients with the GCB subtype (3.9% v 0.0% at 5 years; P = .02). Postrelapse survival was inferior for patients who relapsed with DLBCL than for those who relapsed with indolent lymphoma (median 29.9 months v unreached; P < .01). CONCLUSION Patients with DLBCL with a concurrent indolent lymphoma and those with the GCB subtype had a higher rate of late relapse, owing to increased relapses with indolent lymphoma. Patients who relapsed with DLBCL had a worse prognosis than those who relapsed with indolent lymphoma.

e23108 Background: ASCO antiemetic guidelines recommend upfront triple prophylaxis (NK1 receptor antagonist (RA) + 5HT3 RA + dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC). Physicians exhibit high variation in HEC guideline adherence, principally involving inclusion of NK1 RA. Whether adherence is associated with selection of the specific 5HT3 RA agent remains inadequately studied. Methods: In the IBM Explorys electronic health record database, we used procedure and diagnosis codes to identify HEC courses and related nausea/vomiting (NV) from 2012 to 2018. We defined HEC guideline adherence as triple prophylaxis at chemotherapy initiation. We assigned HEC courses for ≥ 7 day cycles of cisplatin or anthracycline + cyclophosphamide (AC), or carboplatin (≥ 14 day cycles as a proxy for AUC ≥ 4) to prescribing oncologists based on encounter frequency. We categorized 5HT3 RA use of each physician treating ≥ 5 HEC courses based on their most commonly used 5HT3 and performed descriptive statistics. Results: Of 12,262 HEC courses, 57% involved physicians having greater use of ondansetron (OND) (mean OND to palonosetron (PALO) ratio of 3.9:1). These courses had lower guideline adherence (due to NK1 RA omission) and higher rates of NV for combined HEC, AC, and carboplatin. NV rates for cisplatin did not vary by 5HT3 agent used. Courses involving physicians with greater PALO use (mean OND:PALO ratio of 0.2:1) had superior adherence and NV rates, despite involving a slightly higher risk population (younger and/or female). Conclusions: According to HEC antiemetic guidelines, NK1 RA use should occur independent of 5HT3 RA agent selection. However, we observed less NK1 RA use where OND was preferred, which may have caused the observed higher rates of NV with OND. Further evaluation should assess whether pharmacy cost minimization is a driver of both OND preference and NK1 omission in HEC. [Table: see text]

5078 Background: Strategies integrating androgen targeted and locoregional therapies are being increasingly used in PCa with regional spread, but are rarely curative. Angiogenesis inhibitors delay progression in castration resistant PCa and may synergize with ADT through endothelial cell apoptosis in hormone naïve patients (pts). We hypothesized that the frontline combination of ADT with the potent VEGF inhibitor Axi would improve PCa control relative to ADT alone and allow for meaningful time off systemic therapy after surgical consolidation. Methods: Pts with either clinically detected LN+ (TxN1M0 or TxNxM1a) or very high risk for LN PCa were treated with ADT for 2 mos and then randomized 2:1 to respectively add open label Axi (5 mg PO bid) vs. continue ADT alone for 4 mos until surgery. Those responding with PSA ≤5 ng/mL were offered prostatectomy and extended pelvic lymphadenectomy (RP). ADT +/- Axi was withheld postoperatively and PSA measured q3 mos until 1 y. Primary objective: proportion of pts progression free (FFP) 12 mos after RP, defined as PSA ≤1.0 ng/mL and no radiation or ADT, aiming to detect a 35% difference favoring ADT+Axi. Results: 72 pts completed accrual. We report on the 54 pts with LN+ disease: median age 62 y (range 42-76), pretreatment PSA 22.9 ng/mL (range 3.6 - 404.4), 38 N1 / 16 M1a. Table shows presurgical therapy outcomes. Path responses in the prostate were similar between arms, but in 5 ADT+Axi vs. 0 ADT LN+ pts there was no residual nodal disease. Testosterone recovery: 24/26 ADT+Axi and 9/9 ADT RP pts by 6 mos. 21/36 ADT+Axi and 15/18 ADT pts have failed; 1 y FFP estimates 48.0% (SE 8.6%) and 16.7% (SE 8.3%), respectively (p = 0.02). 1 y undetectable PSA 9 pts (6 ADT+Axi). No grade 4 toxicities or unexpected side-effects were observed. Conclusions: 1 year after RP, ADT+Axi resulted in proportionally greater number of LN+ PCa pts off treatment and progression free than ADT alone. Tissue analysis is evaluating predictors of benefit to further develop angiogenesis inhibition as part of combination strategies for hormone naïve PCa. Clinical trial information: NCT01409200. [Table: see text]

4521 Background: The MTAP gene encodes an essential enzyme for the salvage pathway of nucleotide synthesis and is frequently deleted in UBC. Anti-folate agents such as pemetrexed can effectively inhibit the de novo pathway of nucleotide synthesis and as a result, create a synthetic lethality in MTAP deficient UBC. We hypothesize that MTAP gene loss correlates with enhanced response to pemetrexed in UBC. Methods: We investigated MTAP gene deletion rates in the TCGA database and determined MTAP protein loss rates by immunohistochemistry (IHC) using a UBC tissue microarray (TMA) from 151 patients (pts). We then performed in vitro and in vivo studies using MTAP proficient and MTAP deficient bladder cancer cell lines. At the clinical level, we performed a retrospective analysis based on MTAP status of pts treated with pemetrexed as 2nd line at our institution between 2014 and 2018. We are now enrolling pts in a single-arm, open-label, phase II clinical trial (NCT02693717) with pemetrexed in pts with MTAP deficient UBC. Results: Per our TCGA and TMA IHC analyses, MTAP deficiency rate was 25.9% and 27.8%, respectively. MTAP deficient UBC cell lines were at least 40 times more sensitive to pemetrexed than MTAP proficient lines. Knockdown of the MTAP gene increased apoptosis rate by pemetrexed from approximately 20% to 60%. Additionally, pemetrexed significantly inhibited the growth of MTAP deficient or knockdown xenograft tumors but not MTAP proficient tumors. Retrospective analysis of 12 pts using RECIST criteria indicated that all 4 MTAP deficient UBC pts responded to pemetrexed whereas only 1 of 8 (12.5%) MTAP proficient UBC pts responded. Of the 6 pts enrolled on the clinical trial, 3 (50%) had complete or partial response, 1 had stable disease, 1 was not evaluable and 1 had disease progression. Combined analysis of the entire experience demonstrates a higher response rate in MTAP deficient UBC (70%) as compared to MTAP proficient UBC (12.5%). Conclusions: Our preclinical and clinical data demonstrate that MTAP loss in UBC leads to a state of synthetic lethality when treated with pemetrexed and should be further investigated as a novel biomarker to predict response to anti-folate agents.

4070 Background: Esophageal cancer (EC) is a lethal malignancy with limited treatment options. Genomic analyses have led to the elucidation of numerous dysregulated genes in esophageal adenocarcinoma (AC) and squamous cell carcinoma (SCC), and the potential for advancement of targeted therapies in this disease. Data regarding circulating tumor DNA (ctDNA) plasma analysis in EC in real-world clinical practice is limited. Methods: We performed ctDNA next-generation sequencing (NGS) analysis in patients (pts) with EC (January 2015- February 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA) which detects single nucleotide variants and insertion/deletion mutations, and specific amplifications and fusions, in up to 73 different genes. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance was defined as alterations within OncoKB levels 1-3B and R1. Results: Among 450 pts, 487 total samples were analyzed (77% AC, 31% SCC). ctDNA NGS revealed at least one genomic alteration (excluding variants of uncertain significance and synonymous mutations) in 81% of pts (90% AC, 88% SCC). Median number of alterations per AC patient was 4 [range, 1-59] and a median MAF of 0.84% (range, 0.02% - 83.7%); SCC was 5 [range, 1-26], with a median MAF of 0.99% (range, 0.01% - 85.2%). The total number of unique alterations was 1,162. The most commonly altered genes in AC: TP53 (70%), KRAS (20%), ERBB2 (18%), EGFR (16%), PIK3CA (16%); in SCC: TP53 (88%), PIK3CA (24%), CCND1 (23%), KRAS (21%), EGFR 15%). Therapeutically relevant alterations will be described. Conclusions: ctDNA plasma profiling of pts with EC is a feasible alternative and non-invasive method to gather comprehensive genomic data. Further large comparison studies to assess landscape of genomic alterations observed through ctDNA versus tissue-based assays, in addition to studies of targeted therapy outcomes based on ctDNA-detected alterations, are needed.

Abstract Background Women may benefit from radial artery access (RAA) for percutaneous coronary interventions (PCI) due to a higher risk of bleeding compared to men; however, RAA may be underutilized in women. We sought to determine the frequency and predictors of RAA use in patients undergoing PCI. Methods We studied 21,123 (29.0% female) participants in the Mayo Clinic PCI Registry from January 1, 2006–December 31, 2016. Data were analyzed as a cohort and by time tertiles. Frequency of RAA versus femoral access and bleeding events were recorded. Logistic regression was used to identify predictors of RAA. Results In the overall cohort, women compared to men were older (69.6 ± 12.6 vs. 65.6 ± 11.9; p < .001), more likely to present with acute coronary syndrome (82.0% in women vs. 80.0% in men; p = .0008) and had more comorbidities. RAA increased from tertile one (3.5% for women vs. 4.0% for men; p = .3) through tertile three (46.8% for women vs. 50.3% for men; p = .01), but remained lower in women. In multivariable analysis, female sex is associated with 22% less RAA use (OR 0.78, 95% CI 0.72–0.84; p < .0001). Women compared to men experienced more bleeding (6.3 vs. 3.0%; p < .0001) but bleeding was less likely in RAA (OR 0.45, 95% CI 0.36–0.56; p < .0001). Conclusion Women undergoing PCI are less likely to receive RAA compared to men despite having a higher risk of bleeding. This trend persists despite increase in RAA use. Given the potential benefit of RAA in women, sex should be considered in patient selection for RAA.

AbstractAnaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK−, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSCE116K, exclusively in ALK− ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSCE116K for ALK− ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin–bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation–sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30–IRF4–MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSCE116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30–IRF4–MYC axis and cell cycle progression in a unique subset of ALCLs.

Abstract Introduction Flight surgeons play a vital role in U.S. Air Force aviation operations by ensuring that pilots are medically prepared to meet the demands of military aviation. However, there is natural tension between pilots and flight surgeons. A pilot may be reluctant to share medical information with a flight surgeon who could negatively impact the pilot’s career or flight status. In this preliminary study, we sought to identify pilot-perceived strengths and weaknesses in the relationship between U.S. Air Force aviators and their flight surgeons. Materials and Methods An online survey regarding pilot–flight surgeon confidence and perceived values was distributed electronically to a convenience sample of U.S. Air Force aviators. Participants included U.S. Air Force active duty and Air Reserve Component (Air Force Reserve and Air National Guard) military aviators in addition to U.S. Air Force Academy aviation cadets. Results One hundred and seventy-three aviators participated in the survey. Respondents reported variable comfort in approaching flight surgeons with medical concerns and suggested that they believed other pilots might be withholding medical information from flight surgeons or seeking care from civilian physicians for career protection. Conclusions We sought to examine the pilot–flight surgeon relationship and its impact on daily flying operations. While limited, results suggest that there may be gaps in trust between pilots and their flight surgeons. These findings could present an opportunity to improve the pilot–flight surgeon relationship by identifying factors that contribute to closer pilot–flight surgeon relationships.

Abstract Background: Aromatase inhibitors are a mainstay hormone receptor-positive breast cancer treatment. AIA occur in up to 50% of patients (pts), adversely affecting quality of life and treatment compliance. A small phase II clinical trial of oral testosterone unedeconate appeared to improve AIA over placebo (P), with no significant androgenic side effects. The current study was performed to confirm these findings. Methods: This randomized P-controlled trial enrolled postmenopausal women on adjuvant anastrozole or letrozole and experiencing moderate-to-severe AIA (≥5 on 0-10 scale). Pts were initially randomized to receive a subcutaneous pellet containing T 120 mg + anastrozole 8 mg (T+AIpellet) or P at the end of the first week on study (after obtaining baseline hot flash data) and at 3 months (mo). Due to slow accrual, the protocol was amended to change the route of delivery to topical T or P applied to the skin once daily for 6 mo. Baseline and monthly questionnaires were administered, including: Modified Brief Pain Inventory for aromatase arthralgia (BPI-AIA), prolife of mood states (POMS), the menopause specific quality of life questionnaire (MENQOL), a hot flash diary, the hot flash related daily interference scale (HFRDIS) and a symptom experience questionnaire. The primary endpoint was intra-patient change in joint pain at 3 mo, compared using a two-sample t-test. Results: 227 pts were accrued between 9/1/2013-11/29/2017. 55 pts were randomized prior to the protocol amendment and received T+AIpellet or P. Baseline characteristics were balanced between arms, with the exceptions of median weight, BMI, hemoglobin (all higher in T arm), and breast tenderness, dissatisfaction with personal life/depression, and skin changes (all higher in P arm). Compared to baseline, there were no significant differences between T and P in average pain or joint stiffness at 3 (p=0.483) or 6 mo (p=0.573). Average pain was significantly lower each month compared to baseline, irrespective of treatment arm. There were no significant differences in any other items evaluated by BPI-AIA, POMS, MENQOL, hot flash diary or HFRDIS. Similarly, there were no substantial differences in toxicity. A subset analysis of the 55 pts randomized to receive T+AIpellet or P identified significant reductions in average pain scores with T+AIpellet during the first month (p=0.038), but not thereafter. T+AIpellet pts had significantly more reduction in reported % of baseline hot flash frequency (p=0.034) and score (p=0.031), nausea (p=0.019), fatigue (p=0.042), mood swings (p=0.026), hand/feet swelling (p=0.009), stress urinary incontinence (p=0.039) and changes in appearance, texture or tone of their skin (p=0.0083), than pts on P. Conclusions: Overall, T did not improve AIA or menopausal symptoms compared to P. While there was significant improvement in AIA over the study period, T did not facilitate this process. However, T+AIpellet was associated with improvement in short-term AIA and several menopausal symptoms compared to P, suggesting that subcutaneous T combined with anastrozole may be superior to transdermal T alone. Support: UG1CA189823, U10CA180820, U10CA189809; ClinicalTrials.gov Identifier: NCT01573442 Citation Format: Leon-Ferre RA, Le-Rademacher J, Terstriep S, Glaser R, Novotni P, Giuliano A, Copur MS, Jones C, Page S, Mitchell W, Birrell SN, Loprinzi CL. A randomized, double-blind, placebo-controlled trial of testosterone (T) for aromatase inhibitor-induced arthralgias (AIA) in postmenopausal women: Alliance A221102 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-01.