Citations

1005 Background: Evidence-based treatments (tx) for metastatic, HER2+ BCBM are limited. We previously found a central nervous system (CNS) objective response rate (ORR) of 8% (95% CI 2-22%) for the irreversible, EGFR/HER2-targeted kinase inhibitor, neratinib. To enhance CNS activity, we evaluated the combination of neratinib + capecitabine in a subsequent cohort, and report results here. Methods: Pts with measurable BCBM (≥ 1 cm in longest dimension) and no prior lapatinib or capecitabine were eligible. All but 3 had CNS progression after local CNS tx. During 21 day cycles, pts received capecitabine 750 mg/m2 twice daily x 14 days followed by 7 days off + neratinib 240 mg orally once daily. Loperamide prophylaxis (16 mg total daily) was recommended during cycle 1. Brain MRI and non-CNS imaging were repeated every 2 cycles until 18 wks, then every 3 cycles. The primary endpoint was composite CNS ORR, requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions (central review, VORR), no progression of non-target or non-CNS lesions, no new lesions, no escalating steroids, and no progressive neurologic signs/symptoms. We used a two-stage design with hypotheses ORR 15% and 35% (error rates 5% and 20%), responses in ≥5/19 pts to enter 2ndstage; responses in ≥9/35 [26%] pts to be promising. Results: 39 pts enrolled between 4/2014-11/2016 (2 withdrew before tx, 37 analyzed); median age 51, median prior metastatic lines 2 (range 0-6), 65% had prior WBRT. As of 11/15/16, 23 (62%) patients are alive and 7 remain on protocol tx; median number of cycles initiated = 5 (range 1-26). 18 women (49%) had a VORR (95% CI 32-66%, neurologic exams not yet available on all pts). Overall 12-month survival is 63% (95% CI 43%-77%); 4/7 pts still on protocol therapy have not yet reached 6 cycles. No pts had grade 4 toxicity; 18 (49%) had grade 3 toxicity, with diarrhea most common (32%), and 6 pts discontinued tx for toxicity. Conclusions: The combination of neratinib and capecitabine is active for BCBM with VORR in nearly half of pts, supporting further development of the regimen for BCBM. Updated results will be presented at the meeting. Clinical trial information: NCT01494662.

502 Background: Pre-specified 5-year analyses of the phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial defined in Amendments 11&12. Methods: From June 2007 to July 2011, 8381 patients (pts) were randomised from 946 sites in 44 countries to receive either L+T, T→L, L, or T. In 2011, due to futility the L arm was closed and is not included in this analysis. The primary end point is disease-free survival (DFS). Secondary objectives include treatment comparisons with respect to overall survival (OS), time to recurrence (TTR), time to distant recurrence (TDR), cardiac and overall safety and tolerability. Primary analysis results of the study were published in JCO 2015 34:1034-1042. This updated analysis occurs at a 6.9 yrs median follow up (MFU). Results: All patients have reached 5-years of follow-up. 705 DFS events for L+T vs T have been observed. HR for DFS was 0.86 (95% CI, 0.74-1.00; 6-yr DFS%=85% vs 82%) for L+T vs T and 0.93 (95% CI, 0.81-1.08; 6-yr DFS%=84% vs 82%) for T→L vs. T. The 6-year OS was 93%, 92%, and 91% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T vs. T and 0.88 (95% CI, 0.71-1.08) for T→L vs. T. DFS differences for L+T vs. T were slightly higher for the hormone-receptor(ER)-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS%=84% vs. 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS%=83% vs.79%)] subgroups. There were no differences in sites of first DFS events according to treatment arm for CNS, loco-regional, or distant recurrences. There were more AEs related to study treatment (L+T 93% vs T 64%). The incidence of primary cardiac end points was low: 1% for L+T, 0.5% for T→L and 0.9% for T. Conclusions: The HRs for this updated analysis are similar to those from the Primary Analysis and the event rate remains lower than anticipated (705 vs 850 planned). Cardiac toxicity remains low. This analysis suggests that HER2+/ER- tumors may have a different biology than HER2+/ER+ and may benefit more from dual HER2 blockade. Long-term follow up continues. Clinical trial information: NCT00490139.

2068 Background: Pituitary carcinoma (PC) is a rare and aggressive neuroendocrine tumor diagnosed once a pituitary adenoma (PA) becomes metastatic. Although no standard treatment currently exists, surgery, radiation (XRT) and/or chemotherapy are most commonly used. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits accurate outcome assessment. Methods: We describe a single-center multidisciplinary team experience in managing PC patients over a 13-year period (Oct, 2003 to Jan, 2017). Results: A total of 17 patients (9 males) were seen. Median age at diagnosis of PC was 44 years (range 16-82 years) and the median time from PA to PC conversion was 6 years (range 1-29 years). Median follow-up time: 28 months (range 8-158 months) with 7 reported deaths. The majority of PC was hormone-secreting (HS) subtype (n = 12): ACTH (n = 5), PRL (n = 4), FSH/LH (n = 2), GH (n = 1). After PC diagnosis, all pituitary tumors were locally invasive, all underwent at least one resection (mean 2.3) and all received at least one course of XRT alone (IMRT = 76%, SRS = 29%, IMPT = 12%) or concurrent with chemotherapy (18%). Immunohistochemistry showed high Ki-67 labeling index ( > 3%) in 9 (53%) cases. Most cases (n = 14) had metastases to the CNS, 35% of those had combined CNS and systemic foci. Ten (59%) cases underwent focal treatment of metastases, 90% of which underwent XRT. The most common chemotherapy used was TMZ [n = 14 (82%): single agent (n = 10); TMZ+capecitabine (n = 5); concurrent TMZ+XRT (n = 3); concurrent TMZ+XRT with adjuvant TMZ (n = 1)]. The median longest progression-free survival (LPFS) was 18 months (range 4-45 months). TMZ was associated with the chemotherapy-related LPFS in 9 (75%) cases. The 2, 3 and 5 year survival rate was 65%, 53% and 35%, respectively. All patients surviving > 5 years were treated with TMZ (n = 5, 2 survived > 10 years). Two refractory cases are currently on PD-1 inhibitor agent. Eighty percent of non-functioning PC were alive at last follow-up (HS-PC, 58%). Recurrence occurred in 11 (65%) cases. Conclusions: Treatment of PC requires a multidisciplinary approach. Multimodality therapy with surgery, radiation and TMZ was associated with higher survival rates and longer PFS.

Background and ObjectivesA high proportion of persons in institutionalized settings such as the criminal justice system and psychiatric hospitals have substance use disorders (SUDs). We explored the association between substance use, demographics, and criminal justice involvement in a population of patients placed on involuntary 72‐h holds in a psychiatric facility.MethodsWe retrospectively identified patients aged 18 through 57 years who had been placed on 72‐h holds during an acute psychiatric hospitalization during a 1‐year period. Data were analyzed with standard descriptive statistics, and data collection was reviewed by 2 randomly assigned psychiatrists.ResultsWe identified 336 patients placed on 72‐h holds during an acute psychiatric stay. Of these, more than two‐thirds (68.5%; n = 230) had an SUD. Compared with patients not using substances, those with SUDs were significantly more likely to be younger (p = .003), male (p = .005), and unmarried (p < .001) and to have criminal justice involvement before (p < .001) and after hospitalization (p < .001). The rate of unemployment was similarly high in both users (67.4%) and nonusers (69.2%).Discussion and ConclusionsMost patients on involuntary psychiatric holds have comorbid SUDs. These patients are more likely to have interacted with the criminal justice system and less likely to have social support in the form of marriage. Unemployment was common among all patients.Scientific SignificanceWhen SUDs are not treated by the criminal justice or mental health system, rehospitalization and criminal recidivism may result. (Am J Addict 2018;27:574–577)

ABSTRACTBackground: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease (PD). Although recent validation studies suggest high accuracy, one unmet need is for highly specific criteria for clinical trials in early/de novo PD.Objectives: The objective of this study was to generate and test a PD diagnostic criteria termed “clinically established early PD.”Methods: We modified the Movement Disorder Society criteria to increase specificity for early PD by removing all disease duration components and changing red flags to absolute exclusions. We then estimated the sensitivity/specificity of clinically established early PD criteria in patients with disease duration <5 years, selected from a 626‐patient validation study.Results: After documentation of parkinsonism, 18 individual exclusion criteria are assessed that preclude the diagnosis of “clinically established early PD.” Among 212 PD and 152 non‐PD patients, the estimated specificity was 95.4%, with 69.8% sensitivity.Conclusions: We describe high‐specificity criteria for de novo PD, which are freely available for use in clinical trials. © 2018 International Parkinson and Movement Disorder Society

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Abstract Ewing sarcoma is the second most common sarcoma of the bone, afflicting predominantly the pediatric population. Although patients with localized disease exhibit favorable survival rates, patients with metastatic disease suffer a dismal 5-year rate of approximately 25%. Thus, there is a great need to develop treatments to combat the disseminated disease. Ubiquitin-specific protease 6 (USP6/TRE17) has been implicated as the key etiologic factor in several benign mesenchymal tumors, including nodular fasciitis and aneurysmal bone cyst (ABC). However, the role of USP6 in the biology of malignant entities remains unexplored. Previously, it was observed that USP6 is sufficient to drive formation of tumors mimicking ABC and nodular fasciitis, and that it functions through JAK1/STAT3 signaling. However, in the context of Ewing sarcoma, USP6 does not enhance the transformation, but rather triggers an IFN response signature, both in cultured Ewing sarcoma cells in vitro and in clinical specimens in vivo. Not only does USP6 independently induce activation of the IFN signaling mediators, JAK1 and STAT1, but it also renders Ewing sarcoma cells exquisitely responsive to exogenous IFNs, potentiating activation of STAT1 and STAT3. Furthermore, IFNβ (a type I IFN) induces apoptosis specifically in USP6-positive but not USP6-negative Ewing sarcoma cells. Finally, apoptosis is mediated through the proapoptotic ligand TRAIL, which is synergistically induced by type I IFN and USP6. Implications: These findings provide the first insights into USP6 functions in a clinically relevant malignant entity, and raise the possibility of using IFN for targeting USP6-positive Ewing sarcoma.

Abstract Background: A recent exploratory subgroup analysis pooling data from over 1000 patients (pts) in MONARCH 2 (final analysis) and MONARCH 3 (interim analysis) demonstrated that pts with clinical characteristics that predict for worse outcome (e.g. liver metastases, progesterone receptor [PgR]-negative status, high-grade tumors) received the largest benefit from the addition of abemaciclib to endocrine therapy (ET). There is also interest in determining the extent to which abemaciclib improves progression-free survival (PFS) in pts with favorable prognostic factors (e.g. bone-only disease, long treatment-free interval [TFI]). Here we present an update of the subgroup analyses of the MONARCH 3 study using data from the preplanned final PFS analysis. Methods: Enrollment criteria and study designs were previously described (Sledge et al. J Clin Oncol. 2017; Goetz et al. J Clin Oncol. 2017). An exploratory pooled analysis was conducted using data from MONARCH 2 (NCT02107703) and the MONARCH 3 (NCT02246621) preplanned final PFS analysis to identify significant prognostic factors regardless of therapy received. Using the updated MONARCH 3 data, PFS and objective response rate (ORR) (in pts with measurable disease) were examined within the prognostic subgroups that had been previously identified as being statistically significant. Additionally, subpopulation treatment effect pattern plot (STEPP) methodology was used to evaluate the association between TFI following adjuvant ET and outcomes of NSAI alone or with abemaciclib. Results: Assessment of clinical factors from MONARCH 2 and MONARCH 3 (final PFS data) confirmed that the following factors remained significantly prognostic regardless of treatment received: bone-only disease, liver metastases, tumor grade, PgR status, and ECOG performance status. In MONARCH 3, prognosis was poor in pts with liver metastases, PgR-negative tumors, and high-grade tumors. While all subpopulations benefited from the addition of abemaciclib to ET regardless of prognosis, pts with these three poor prognostic factors received substantial benefit from abemaciclib, with PFS hazard ratios (HR) ranging from 0.4 to 0.5 and with differential improvement in ORR typically &gt;30%. Furthermore, STEPP analysis of TFI (on the MONARCH 3 pts who had received adjuvant ET) demonstrated that pts who had a shorter TFI had a worse prognosis and received relatively greater benefit from abemaciclib plus NSAI than did pts with a longer TFI. Patients with bone-only disease or a long TFI also received benefit from abemaciclib, but to a relatively lesser extent (HR ranging from approximately 0.6 to 0.8). Conclusions: This exploratory analysis of the preplanned final PFS data from MONARCH 3 confirms previous findings that pts with poor prognostic factors may receive relatively greater benefit from the addition of abemaciclib to ET. Citation Format: Joyce O'Shaughnessy, Matthew P. Goetz, George W. Sledge, Miguel Martin, Yong Lin, Tammy Forrester, Ian C. Smith, Angelo Di Leo, Stephen Johnston. The benefit of abemaciclib in prognostic subgroups: An update to the pooled analysis of MONARCH 2 and 3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT099.

Abstract To assess cellular mechanisms that could contribute to muscle weakness in the context of cancer cachexia, we evaluated the effect of conditioned medium (CM) from highly tumorigenic Lewis lung carcinoma (LLC1) cells, CM from less tumorigenic MLE12 cells and non-CM on human skeletal muscle mitochondrial morphology and function. We assessed mitochondrial oxygen consumption, morphology, enzyme activity and gene expression in human skeletal muscle cells in the presence of tumor conditioned medium or control medium. We examined the secretome of LLC1 cells for mediators of skeletal muscle changes. We demonstrate that LLC1 CM inhibits cellular O2 consumption rate (OCR) and increases the proton production rate in human skeletal muscle cells. Mitochondrial fragmentation and the expression of the fission mediator, FIS1, are increased, whereas the expression of fusion mediators, OPA1 and MFN2 are reduced by LLC1 CM. LLC1 CM reduces pyruvate dehydrogenase (PDH) activity thereby limiting the production of acetyl CoA. Reduced PDH activity is associated with reduced PDHA1 sub-unit expression. The amount inactive phospho-PDH is increased in association with reduced PDP2 expression and increased PDK4 and SIRT4 expression in human skeletal muscle cells treated with LLC1 CM. The expression of several signaling pathways is altered by LLC1 CM in human skeletal muscle cells. When compared to MLE12 cells, LLC1 cells show increased expression of mRNAs encoding several potential mediators of altered muscle function such as Gdf15, TGFβ-induced protein, IL11, Il27, Il33, Il34, and PTH-like protein. We show that the active vitamin D metabolite, 1α,25(OH)2D3, that we previously demonstrated increases myoblast mitochondrial oxygen consumption and PDH activity, mitigates LLC1 CM effects on hSkMC OCR, mitochondrial fragmentation and mediators thereof. Mitochondrial oxygen consumption, morphology and enzyme activity in human skeletal muscle cells are inhibited or altered by tumor cell conditioned medium, and are reversed by 1α,25(OH)2D3, the active metabolite of vitamin D. Citation Format: Zachary C. Ryan, Theodore A. Craig, Xuewei Wang, Philippe Delmotte, Jeffrey L. Salisbury, Ian R. Lanza, Gary C. Sieck, Rajiv Kumar. 1,25-Dihydroxyvitamin D3 mitigates lung cancer cell mediated mitochondrial dysfunction in human skeletal muscle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5232.