Citations

294 Background: CX-4945 is a first-in-class casein kinase-2 (CK2) threonine kinase small molecule inhibitor. CK2 is pleiotropic and regulates key cellular processes such as proliferation and DNA damage repair, and has been shown to enhance efficacy of gemcitabine (G) and cisplatin (C) in cell line and xenograft CCA model systems. A Phase IB study of G+C with CX-4945 was conducted in advanced cholangiocarcinoma (CCA) patients. Methods: A multi-center “3+3” dose escalation study was conducted in advanced CCA patients. Eligible patients had ECOG PS 0-1 and adequate hematologic, hepatic, and renal function. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints included pharmacokinetic (PK) analyses, overall toxicity evaluation and preliminary assessment of efficacy. Routine clinical dosing for G (1000 mg/m2) and C (25 mg/m2), both on days 1 and 8 every 21 days, was used. Dose escalation cohort were CX-4945 given twice daily on days 0,1,2 and 7,8,9 at 200 mg (DL1), 400mg (DL2), 600 mg (DL3), 800 mg (DL4) and 1000 (DL5) mg. NCI CTCAE v4.03 was used for toxicity assessment and RECIST v1.1 for efficacy evaluation. Results: Nineteen patients were enrolled (DL1:n = 3; DL2:n = 4 DL3:n = 3; DL4:n = 4; DL5:n = 5). No dose limiting toxicities were encountered. MTD and RP2D were ascertained to be DL5. No grade 3 or 4 toxicities at prevalence > 10% were encountered and the overall toxicity profile of the combination was reflective of standard G+C toxicity profile. At data cut-off, preliminary efficacy evaluation demonstrated disease control rate (CR+PR+SD) of 64% (PR:32%, SD:32% and CR:0%), along with median progression-free survival (PFS) of 5 months (range 0-14 months). PK analyses showed no evidence of drug-drug interactions between G, C and CX-4945. Conclusions: RP2D for G+C with CX-4945 is DL5 (CX-4945 dosed on days 0,1,2 and 7,8,9 at 1000 mg PO bid with standard G and C dosing). Preliminary clinical efficacy and tolerability of the regimen support planned controlled, randomized Phase 2 evaluation. Clinical trial information: NCT02128282.

Objectives Congenital absence of the pericardium (CAP) is often confused with other conditions presenting with right ventricular dilatation and usually warrants CT or cardiac MR (CMR) to confirm. It would be desirable to have more specific echocardiographic criteria to provide a conclusive diagnosis. Methods 11 patients who were diagnosed with CAP (four patients with total CAP) based on CT/CMR were consecutively enrolled. Thirteen patients with atrial septal defect (ASD) and 16 normal subjects served as controls. To investigate spatial changes of heart in the thoracic cavity in CAP, following echocardiographic measurements were made in the left and right decubitus positions: the angle between the ultrasound beam and the left ventricular posterior wall (Angle-PW) in end-diastole at the parasternal long axis, and the distance between the chest wall and the most distal part of the left ventricular posterior wall (Distance-PW) at the parasternal mid-ventricular short axis. Results Angle-PW in patients with CAP were significantly greater than in those with ASD (100.1±12.5° vs 74.5±8.6°, p<0.017) or in normal subjects (100.1±12.5° vs 69.9±7.6°, p<0.017) at the left decubitus, and the difference in Angle-PW according to posture (left vs right) was significantly greater in CAP compared with the other groups (CAP 20.7±12.7°, ASD 0.31±1.80°, normal 0.31±1.40°, all p<0.017). The differences in Distance-PW according to patient position (CAP 2.43±0.77°, ASD 0.42±0.45°, normal 0.26±0.55°) or cardiac cycle in each position (left: CAP 1.60±0.76°, ASD 0.41±0.27°, normal 0.17±0.12°; right: CAP 0.70±0.32°, ASD 0.22±0.19°, normal 0.22±0.13°) were significantly higher in the CAP group than in the other groups (all p<0.017). Conclusions Patients with CAP have dynamic alteration in cardiac position depending on posture, which is not observed in ASD or in normal controls. Hence, total or left-sided CAP can be reliably diagnosed with positional changes during routine echocardiography.

Abstract Background Diagnosis of rectal evacuation disorders ( RED ) is currently based on anorectal manometry ( ARM ) and evacuation tests in specialized laboratories; we recently showed higher rectal gas volume ( RGV ) and maximum rectal gas transaxial area ( MRGTA ) measured on abdominal and pelvic computed tomography ( CT ) in patients with documented RED .The aim of this study was to obtain cut‐off values of RGV , MRGTA , and rectal area on scout film ( RASF ) to differentiate constipated patients with RED from those without RED , based on ARM , balloon expulsion test ( BET ), and colon transit test. Methods We identified 118 constipated patients (65 with RED ) with prior record of CT . Using standard CT software, we used a variable region of interest ( ROI ) program to measure RGV , MRTGA , and RASF , as previously described. We constructed receiver operating characteristics curves based on different values, and we estimated AUC , specificity, and positive predictive value ( PPV ) to detect RED in patients with constipation. Key Results Receiver operating characteristics of the models to predict RED showed AUC 0.751 for RGV and 0.737 for MRGTA (both P <.001), and 0.623 for RASF ( P =.029). At specificity of 90%, RGV of 30 mL had a PPV 77.3%, MRGTA of 10 cm 2 had a PPV 75.0%, and RFAS of 9 cm 2 had a PPV of 68.8% for identifying constipated patients with RED . Conclusions & Inferences Rectal gas measurements on abdominal imaging may indicate RED in patients with constipation. At ~90% specificity for RED , RGV of 20 or 30 mL or MRGTA of 10 cm 2 on CT has PPV ~75%, and RASF of >9 cm 2 has PPV of ~69%.

Abstract Background: Despite the well-established survival benefit associated with adjuvant hormonal treatment, younger women with hormone receptor positive (HR+) breast cancer (BC) are less adherent to endocrine therapy (ET) as prescribed, compared to their older counterparts, and may have unique issues that contribute to ET non-adherence. In an effort to identify factors that can be targeted to improve ET uptake and adherence, we sought to evaluate ET initiation in young women with BC. Methods: As part of a multi-center, prospective cohort enrolling women with newly diagnosed BC at age ≤40 years between 2006-2016, we identified 657 women with HR+, Stage 0-III BC. Participants complete serial surveys that included questions about socio-demographics, fertility concerns, and treatment. Women who did not report taking tamoxifen or an aromatase inhibitor (AI) at least once in the 18 months after diagnosis (dx) were classified as non-initiators. Variables significant at p&lt;0.20 in univariable models were entered into a multivariable logistic regression model to identify independent (p&lt;0.05) predictors of non-initiation. Results: By 18 months post-dx, 15% (99/657) had not initiated ET; among women with Stage 0 BC, 77% (51/66) had not initiated vs 8% (48/591) with invasive BC (p&lt;0.0001). Among initiators (N=558), 93% were on tamoxifen, with 7% reporting AI alone or in addition to tamoxifen; 97% started ET within 12 months of dx. Among women with invasive BC (Table), non-initiation was associated with having less than a college degree (OR: 2.49 95% CI: 1.25-4.94), non-Caucasian race (OR: 2.58 95% CI: 1.18-5.64) and non-receipt of radiation (OR: 0.40 95% CI: 0.21-0.75).Age at dx, marital status, having children, employment, perceived financial comfort, fertility concern, stage, surgery, and chemotherapy were not significantly associated with non-initiation. Conclusion: Most young women with HR+ DCIS do not take adjuvant ET despite the potential benefits (substantially reduced risk of local recurrence and contralateral BC) and very low risk of serious toxicity. Among young women with invasive HR+ BC, a significant minority fails to start ET within 18 months of dx. Adjuvant ET non-initiation may contribute in part to the racial and SES outcomes disparities that have been observed. Further study is needed to elucidate barriers to initiation with the goal of developing targeted interventions that will enhance ET initiation and adherence in general. Table. Predictors of ET non-initiation in women with invasive BC (N=577*) Univariable Multivariable Median (range)OR (95% CI)pOR (95% CI)ppAge at dx (years)36 (17-40)1.08 (0.99-1.18)0.07 N (%) Financial comfort300 (51)0.88 (0.49-1.60)0.68 Non-white59 (10)2.68 (1.25-5.71)0.012.58 (1.18-5.64)0.02Full employment282 (48)0.76 (0.42-1.39)0.38 Less than college graduate95 (16)2.61 (1.36-5.02)0.0042.49 (1.25-4.94)0.009Married/living as married452 (77)0.79 (0.41-1.55)0.50 Children pre-diagnosis369 (62)1.11 (0.60-2.05)0.75 Fertility concern234 (40)0.92 (0.50-1.70)0.80 Stage (ref=3) 1244 (41)1.22 (0.47-3.15)0.68 2259 (44)1.27 (0.50-3.24)0.62 Mastectomy vs lumpectomy335 (57)1.16 (0.64-2.12)0.63 Radiation therapy331 (56)0.40 (0.21-0.73)0.0030.40 (0.21-0.75)0.004Chemotherapy411 (70)0.66 (0.36-1.22)0.18 *multivariable analytic cohort Citation Format: Rosenberg SM, Gelber S, Ruddy KJ, Tamimi RM, Schapira L, Borges VF, Come S, Meyer ME, Partridge AH. Drugs don't work if people don't take them: Non-initiation of endocrine therapy in young women [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 P2-09-07.

Abstract Introduction We sought to determine whether a systems biology approach may identify novel late‐onset Alzheimer's disease (LOAD) loci. Methods We performed gene‐wide association analyses and integrated results with human protein‐protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. Results We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1 , and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H , and APP were differentially expressed in the temporal cortex. Discussion Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

297 Background: Unlike acute lymphoblastic leukemia, no studies have examined the effect of race on survival among AML in AYA using national data. Methods: We studied patients in the US National Cancer Data Base aged 15-39 diagnosed with AML from 2001-2011 (excluding acute promyelocytic leukemia). AMLs harboring inv(16) or t(8;21) were defined as good-risk. We examined overall survival (OS) according to race/ethnicity and survival trends over three time-periods: 2001-2004, 2005-2008, and 2009-2011. Results: We identified 8,986 patients, with a mean follow-up of 37 months. The median OS according to race/ethnicity was 56, 49, 41, and 22 months for Asians/Pacific Islanders (A/PI), Hispanics, Whites, and Blacks respectively (P < 0.001). OS improved over time among Whites only, with respective median OS of 31, 43, and 49 months (P < 0.001). Multivariate analysis adjusting for socio-demographics, travel distance, and AML type, showed that, compared to Whites, Blacks had a significantly worse and Hispanics a significantly better OS (Table). Conclusions: We found significant disparities in OS among racial/ethnic subgroups in AYA with AML despite adjustment for socio-demographic factors. Blacks had the worse and Hispanics the best outcome. In the past decade, OS improved only among the Whites. Further studies should examine provider and patient care delivery factors that may contribute to these disparities. [Table: see text]

202 Background: Posttraumatic stress disorder (PTSD) is associated with morbidity and mortality in affected populations. Cancer survivors experience PTSD at a rate higher than the general population, with young age and female gender identified as risk factors. While young women with breast cancer experience greater psychosocial distress in general following diagnosis (dx), little is known about PTSD in this population. Methods: Women dx’d with Stage I-III breast cancer at age ≤ 40 were surveyed as a part of a multi-site cohort study. Demographic, treatment, psychosocial characteristics (including self-reported psychiatric conditions and use of psychiatric medications prior to dx), anxiety and depression (Hospital Anxiety and Depression Scale), fear of recurrence (Lasry Scale), and social support (Medical Outcomes Study) were assessed within 1 year after dx. PTSD was measured at 30 months post-dx using the PTSD Checklist – Civilian Version; a score ≥ 50 was considered positive for PTSD. Univariable and stepwise multivariable logistic regression were used to evaluate factors associated with PTSD. Results: 572 women were eligible for this analysis; median age at dx was 37 (range: 17-40); 87% had Stage I or II cancer. 37/572 women (6.5%) met criteria for PTSD at 30 months. Lower educational attainment, less financial comfort, less social support, stage 2 (vs. 1) disease, receipt of chemotherapy, fear of recurrence, anxiety and depression, and psychiatric comorbidities were associated (p ≤ 0.05) with PTSD in univariable analyses. Chemotherapy (OR = 3.48, 95% CI = 1.09-11.06), anxiety by HADS (OR = 20.29, 95% CI = 7.83-52.53), and psychiatric comorbidities (OR = 4.22, 95% CI = 1.40-12.74) were associated with increased likelihood of PTSD, whereas college education (OR = 0.25, 95% CI = 0.10-0.59) and greater social support (OR = 0.41, 95% CI = 0.17-0.99) appeared to be protective in multivariable analyses. Conclusions: PTSD affects a minority of young breast cancer survivors, with the prevalence in our cohort similar to that seen in other breast cancer populations. Early identification of those at risk for developing PTSD is essential for the adequate treatment of affected women and for the improvement of health outcomes and quality of life in cancer survivors.

175 Background: Inactivity is common in breast cancer survivors and has been linked to poor outcomes. Few trials have tested physical activity (PA) interventions in young women with breast cancer, who may face unique PA barriers due to demands of jobs and young families. Methods: Young and Strong was a cluster-randomized study evaluating the effect of education interventions for young breast cancer survivors.Sites were randomized 1:1 to a young women’s intervention (YWI), focused on fertility and other issues facing young women, or to a physical activity intervention (PAI). At PAI sites, providers were instructed to discuss PA with patients, and participants were given materials to encourage PA. PA was measured with the modified Godin Leisure Score Index at baseline, and 3, 6, and 12 months. Medical records were reviewed to assess provider attention to PA. Changes in weekly min of PA were compared between the PAI and YWI groups using general estimating equations to evaluate clustered binary and Gaussian data. Results: 467 patients enrolled between 7/12 -12/13 across 54 sites. Median age at dx was 40yrs (range 22-45). At baseline, participants were moderately active. PA increased in both groups over time (Table); there was no significant difference in PA between groups at any time (all p > 0.1). Provider attention to PA was documented in 74% of participants on PAI and 61% on YWI (p = 0.15), and correlated with PA at 12 months (median 100 min/wk of PA in participants with provider attention to PA vs. 60 min/wk in those without, p = 0.016). Participants who reported reading all or most the PAI materials reported higher levels of PA vs. those who read less (78% vs. 64%, p = 0.05) Conclusions: Young breast cancer survivors assigned to a PA intervention did not increase PA more than those assigned to an intervention focused on young women’s issues. However, the higher levels of PA among women who engaged with the PAI materials and those whose oncology providers addressed PA suggests the importance of enhancing patient and provider engagement with healthy lifestyle information and recommendations. Clinical trial information: NCT01647607. [Table: see text]

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.