Citations

Abstract BACKGROUND: Unique genes and pathways were identified for prognosis on tamoxifen (T, 5 yrs) and prediction on CAF-T vs T in S8814 using whole transcriptome RNA-Seq from archival FFPE tissue. (Albain, et al; Cherbavaz, et al; SABCS 2015) Discovery was robust for early DFS events but sparse for late. The aims of this new analysis were to 1) utilize a new endpoint BCSE for gene discovery of late events, prognosis and prediction and 2) add intronic counts to the previous exonic results to define whole genes impacting on late BCSE. METHODS: Charts of patients (pts) on CAF-T (212) vs T (142) were reviewed to define the BCSE endpoint (local/regional, contralateral, distant). Deaths without BC were treated as competing risks. BCSE models (including metagenes) of late prognosis and prediction used cumulative incidence functions. Consolidated intronic regions counts within genes were added to exonic regions counts. Using these “whole gene” (WG) counts, association of gene expression with time to BCSE was assessed by Cox regression. A multiple WG score (MWGS) for BCSE prognosis beyond 5 yrs (to 12.5 yrs) was constructed and evaluated for 1-3 and 4+ node (N) groups. False discovery rate was controlled at 10%. RESULTS: More exons and WG were discovered for prognosis on T alone over 12.5 yrs with the BCSE endpoint than DFS. For prognosis of late BCSE after 5 yrs, more genes were discovered using WG (n=111) than by exons (n=9). There were significantly fewer genes for late BCSE on CAF-T (8, WG; 0, exons). The functions of WG prognostic for late BCSE were: cell cycle/proliferation-26 genes, chromosome segregation/mitotic spindle-22, DNA repair/maintenance-10, transcriptional/translational control-5, cell adhesion/migration-4, immune-3, diverse/unknown-32 and growth factor/hormone receptor signaling-9 (this group was only found by WGs, not exons). Of these 111 WG, a MWGS prognostic for late BCSE on T used 57 previously discovered genes pre-specified for this analysis. Probability of BCSE beyond 5 yrs for low vs high MWGS was 8% vs 21% in N1-3+ and 17% vs 42% in N4+. Late prognosis on T differed by low vs high risk defined in a metagene model: cumulative BCSE at year 10 was 0% vs 47% (low vs high risk, p=0.001). Prediction of 10-yr incidence of BCSE varied by risk level by treatment in a metagene model: low risk- CAF-T=47%, T=0% (p=0.045); high risk- CAF-T=35%, T=45% (p=0.027). CONCLUSIONS: Gene discovery for prognosis of late BCSE is enhanced with a novel WG transcriptome expression approach. Use of chemotherapy (CT) before T significantly attenuated gene discovery, so that molecular tools for decisions on extending endocrine therapy (ET) may not be reliable in a setting of prior CT. Some pts on ET for 5 yrs may not require either longer ET or CT, given a N+ cohort was defined with no BCSE observed over 12.5 yrs. For prediction of CT benefit, CAF-T appeared to be inferior to T in a low risk metagene model for BCSE. In sum, these results add more evidence that ET alone may be sufficient (perhaps better) in select N+ settings. Validation in SWOG S1007 (RxPONDER) is planned. SUPPORT: NCI CA180888, 180819, 180821, 180820, 180863; in part, Genomic Health, Inc. Citation Format: Albain KS, Crager MR, Barlow WE, Baehner FL, Bergamaschi A, Rae JM, Ravdin PM, Tripathy D, Gralow JR, Livingston RB, Osborne CK, Ingle JN, Pritchard KI, Davidson NE, Carey LA, Cherbavaz DB, Sing AP, Shak S, Hortobagyi GN, Hayes DF. Discovery of molecular predictors of late breast cancer specific events (BCSE) in ER+, node+ breast cancer – new transcriptome expression whole gene analysis of the phase III adjuvant trial SWOG S8814 [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 PD7-07.

Abstract Background. We previously reported an alternative ESR1 somatic gain-of-function chromosomal translocation event in a patient presenting with aggressive, endocrine therapy resistant estrogen receptor (ER) positive disease, producing an in-frame fusion gene consisting of N-terminal ESR1 and the C-terminus of the Hippo pathway coactivator YAP1 (ESR1-YAP1). We recently identified another ESR1 fusion through RNA sequencing (RNA-seq) in advanced stage ER+ disease from a chest wall recurrence in a male patient that was refractory to multiple lines of treatment. Two examples of fusions discovered in primary breast cancer samples include ESR1 fused in-frame to C-terminal sequences from NOP2 (ESR1-NOP2), identified in a resistant cohort from a RNA-seq screen focused on 81 primary breast cancers from aromatase inhibitor clinical trials, and a second ESR1 fusion, fused in-frame to the entire coding sequence of POLH (ESR1-POLH), that was identified from RNA-seq analysis of 728 Cancer Genome Atlas breast samples. This current study extends our previous characterization of ESR1-YAP1 by comparing functional and pharmacological properties of these three additional ESR1 gene fusion events of both early stage and advanced breast cancers. Methods. In vitro and in vivo experiments were conducted to test ESR1 fusions to induce therapeutic resistance, and metastasis. The transcriptional and binding properties of each fusion was also examined. Pharmacological inhibition with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, was utilized to assess drug sensitivity in ESR1 fusion containing breast cancer cells and in a patient derived xenograft (PDX) model expressing ESR1-YAP1 (WHIM18). Results. The YAP1 and PCDH11x fusions conferred estrogen-independent and fulvestrant-resistant growth. Immunohistochemistry revealed significantly higher numbers of ER+ cells in lungs of mice xenografted with T47D cells expressing the YAP1 and PCDH11x fusions compared to YFP control, NOP2 and POLH fusions. Results from ChIP-seq and microarray studies suggest that these two fusions promote proliferation and metastasis through genomic action by binding estrogen response elements (ERE) and subsequent gene activation. We thereby define these fusions as “canonical” fusions compared to “non-canonical” NOP2 and POLH fusions, which demonstrated dramatically decreased genomic binding ability. The non-canonical fusions induced genes associated with basal-like breast cancer and promoted HER2, EGFR, and MAPK gene expression signatures in contrast to genes associated with cell cycle/proliferation induced by canonical fusions. The proliferative ability of canonical fusion-containing ER+ cells was inhibited by Palbociclib in a dose-dependent manner. In vivo WHIM18 tumors in mice fed with Palbociclib-containing chow demonstrated significantly reduced tumor volume, growth rate, and weight compared to tumors in mice on control chow. Conclusions. In-frame ERE activating canonical fusions occur in end-stage drug resistant advanced breast cancer and can be added to ESR1 point mutations as a class of recurrent somatic mutation that may cause acquired resistance. Growth induced by these fusions can be antagonized by Palbociclib and is potentially clinically helpful. Citation Format: Lei JT, Shao J, Zhang J, Iglesia M, Cao J, Chan DW, He X, Kosaka Y, Schmidt C, Matsunuma R, Haricharan S, Crowder R, Hoog J, Phommaly C, Goncalves R, Ramalho S, Lai W-C, Hampton O, Rogers A, Tobias E, Parikh P, Davies S, Ma C, Suman V, Hunt K, Watson M, Hoadley KA, Thompson A, Chen X, Perou CM, Creighton CJ, Maher C, Ellis MJ. Recurrent functionally diverse in-frame ESR1 gene fusions drive endocrine resistance in breast cancer [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 PD2-03.

42 Background: Methods of stratifying esophageal adenocarcinoma patients into prognostic groups are needed, as are new insights into genetic determinants of disease behaviour. Prognosis is likely to have non-negligible genetic influences, as mediated by host responses to tumor, resistance to therapeutic side-effects, and/or an influence on tumor development. Prior studies have used candidate-gene approaches. We took an alternative approach, using an unbiased, genome-wide approach, and novel analytic methods that may be better able to detect multi-gene interactions, which may contribute the majority of genetic effects for many clinical phenotypes. Methods: Germline DNA from a Toronto-based cohort of EAC patients (n=270) was analyzed by Omni1 Quad microarray as part of the BEAGESS initiative. Quality control and analysis was performed using PLINK, R, and GenABEL software packages. A Cox proportional hazards (CPH) model for progression-free survival tested each polymorphism for independent effects at a genome-wide significance level of P < 1E-07, adjusting for population stratification. While classical analysis has limited ability to detect gene-gene interactions, a Random Survival Forest algorithm was used to detect effects based on the complex interactions among top 1,000 polymorphisms by p-value ranking. Results: After data cleaning and standard GWAS quality control procedures, there were 735,309 SNPs and 245 patients remaining for analysis. The CPH model, adjusted for population stratification, produced a satisfactory Q-Q plot, and showed one SNP (rs7844673, Chr 8) that was significant at p=7.8E-8. In addition, Random Forest based variable selection produced a set of 20 polymorphisms that (1) reproduced 86% of the predictive ability of the full 1000 variables, and (2) also included the #3 ranked polymorphism by CPH modeling (rs9290822, Chr 3) upstream of the IGF2BP2 gene. Conclusions: A genome-wide approach has discovered two previously undescribed SNPs with a potential influence on EAC prognosis via a combination of independent and interactive effects. Validation in an independent cohort is currently being pursued.

PURPOSE: To determine the toxicity and response rate in children treated with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and l-asparaginase (DECAL) for recurrent non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD). PATIENTS AND METHODS: Ninety-seven children with recurrent NHL (n = 68) or HD (n = 29) were enrolled. Treatment consisted of two cycles of DECAL, then bone marrow transplantation or up to four cycles of ifosfamide, mesna, and etoposide alternating with DECAL maintenance therapy. RESULTS: After two cycles of DECAL induction therapy, complete response (CR) or partial response (PR) was reported in 19 (65.5%; 10 CRs and nine PRs) of 29 patients with HD and 29 (41.6%; 23 CRs and six PRs) of 68 patients with NHL. When only 24 patients with HD and 58 patients with NHL who were assessable for response were considered, the response rates were 79.2% (19 of 24 patients) and 50.0% (29 of 58 patients), respectively. Five-year event-free survival was 26% ± 9% and 23% ± 5% in patients with HD and NHL, respectively. Five-year survival was 31% ± 14% and 30% ± 6%, respectively. Although median time to treatment failure was significantly longer in patients with HD (EFS, P = .002; survival, P = .011), this difference did not translate into a higher long-term survival. Grade 3 or 4 toxic effects were observed during induction in 70 (72%) of 97 patients and during maintenance in 45 (70%) of 64 courses of DECAL therapy. Pancytopenia and systemic infections in particular were frequently observed. Other toxic effects were uncommon. Although not a formal part of the therapy or the study design, 42 patients who responded to therapy who underwent bone marrow transplant did not show any benefit from this approach. CONCLUSION: DECAL is an effective and tolerable salvage regimen for treating patients with recurrent NHL and HD.

We described physical activity measures and hourly patterns in patients with chronic obstructive pulmonary disease (COPD) after stratification for generic and COPD-specific characteristics and, based on multiple physical activity measures, we identified clusters of patients. In total, 1001 patients with COPD (65% men; age, 67 years; forced expiratory volume in the first second [FEV 1 ], 49% predicted) were studied cross-sectionally. Demographics, anthropometrics, lung function and clinical data were assessed. Daily physical activity measures and hourly patterns were analysed based on data from a multisensor armband. Principal component analysis (PCA) and cluster analysis were applied to physical activity measures to identify clusters. Age, body mass index (BMI), dyspnoea grade and ADO index (including age, dyspnoea and airflow obstruction) were associated with physical activity measures and hourly patterns. Five clusters were identified based on three PCA components, which accounted for 60% of variance of the data. Importantly, couch potatoes (i.e. the most inactive cluster) were characterised by higher BMI, lower FEV 1 , worse dyspnoea and higher ADO index compared to other clusters ( p < 0.05 for all). Daily physical activity measures and hourly patterns are heterogeneous in COPD. Clusters of patients were identified solely based on physical activity data. These findings may be useful to develop interventions aiming to promote physical activity in COPD.

Summary Objectives To evaluate obesity and overweight in children with congenital adrenal hyperplasia ( CAH ) and associations with glucocorticoids, fludrocortisone and disease control. Adjusting body mass index‐for‐height‐age ( BMI HA ) percentile is proposed to correct misclassification of obese/overweight status in CAH children with advanced bone age and tall‐for‐age stature. Design Longitudinal. Patients One hundred and ninety‐four children with CAH seen from 1970 to 2013: 124 salt wasting ( SW ); 70 simple virilizing ( SV ); 102 females. Measurements Body mass index (BMI) end‐points were overweight (85–94 percentile) and obese (≥95 percentile). Results Approximately 50% of the children had at least one BMI measurement ≥95 percentile and about 70% had at least one ≥85 percentile. Using BMI HA percentiles, obesity incidence decreased slightly in SW children (47–43%) and markedly in SV children (50–33%); however, overweight status was not reduced. Only 6% of SW and 1% of SV children were persistently obese (≥3 clinic visits) when BMI HA was applied, whereas overweight status persisted in 35% of SW and 33% of SV children. Most obesity or overweight when using BMI HA occurred before age 10 and there was no association with hydrocortisone (HC) or fludrocortisone dosing. Adiposity rebound for SW children occurred by 3·3 years and in SV females by age 3·8 years, over a year earlier than the adiposity rebound for healthy children. Conclusion Children with CAH are at higher risk for early onset obesity and overweight with or without using BMI HA but rates of persistent obesity were lower than previously reported. Careful HC dosing during early childhood is needed to prevent increased weight gain and an early adiposity rebound.

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.