bluuebunny/crossref_metadata_2025_split huggingface dataset:
FGFR2: A pan-genomic target.
Authors: Madison Russell , Sokol Ethan , Schrock Alexa Betzig , Johnson Adrienne , Pavlick Dean , Elvin Julia Andrea , Vergilio Jo-Anne , Ngo Nhu , Killian Jonathan Keith , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Duncan Daniel , Ali Siraj Mahamed , Reddy Prasanth , McGregor Kimberly , Alexander Brian , Miller Vincent A. , Ross Jeffrey S. 
Published: May 2019

3099 Background: FGFR2 genomic alterations (GA) have been described in a variety of solid tumors and emerged as biomarkers for investigational agents undergoing clinical trials. Methods: 201,766 primarily relapsed/refractory malignancies were evaluated with a hybrid-capture based sequencing assay Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and reported as mut/Mb. Microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3 antibody). Results: FGFR2 GA were detected in 2,993 (1.5%) cases featuring short variant (SV) mut (42%), copy number changes (27%), rearrangements/fusions (28%) and multiple GA (3%). The most frequent SV GA were S252W, N549K, C382R, P253R, Y375C, K659E and R664W. A small cohort (2%) of tumors featured the V564I and V564L GA that are associated with resistance to TKI drugs. The FGFR2-altered cases were 69% female/31% male with median age of 61 yrs. Most frequent GA in FGFR2 altered cancers: TP53 (47%), PIK3CA (22%), PTEN (20%), ARID1A (18%), CDKN2A/2B (18/14%) and MYC (12%). FGFR2 SVs most common in endometrial, breast carcinomas (ca) and CUP. FGFR2 amplification most common in breast, gastroesophageal and lung ca. FGFR rearrangement/fusions most common in cholangioca (37%), CUP (15%), pancreatobiliary (12%) and breast ca (6%). The FGFR2- BICC1 was the most frequent fusion followed by fusions with TACC2, AHCYL1, CCDC6, VCL, and KIAA1217. MSI-High status present in 6.8% of evaluable FGFR2 altered cases (63% in endometrial ca). Median TMB was 3.5 mut/Mb with 21.8% featuring ≥ 10 mut/Mb and 12.0% featuring ≥ 20 mut/Mb. Only 63% of MSI-High FGFR2 mut tumors had TMB ≥ 20 mut/Mb. 12.7% FGFR2 mut+ had > 1% PD-L1 staining with 3.4% > 50% staining. 29% of PD-L1 IHC+ cases in NSCLC. FGFR mut ca’s responding to anti-FGFR2 therapies will be presented. Conclusions: FGFR2 GA are most frequent in cholangioca, breast, GI tract, lung ca and CUP, with enrichment of FGFR2 fusions in biliary tract ca. Cases with FGFR2 GA typically do not feature other kinase driver GA and are associated with mut in the MTOR/PIK3CA/AKT pathways. Finally, in contrast with RTK driver GA in EGFR (5.7%) and ERBB2 (7.9%), at 12.0%, across all tumor types, FGFR2 mut cancers may have higher frequency of TMB ≥ 20 mut/Mb suggesting potential immunotherapy responsiveness.
Molecular biology and treatment strategies for non-V600 BRAF-mutant NSCLC.
Authors: Negrao Marcelo Vailati , Raymond Victoria M. , Lanman Richard B. , Ng Patrick Kwok Shing , Nagy Rebecca , Banks Kimberly , Zhu Viola Weijia , Amador Bianca E , Roarty Emily , Chae Young Kwang , Clarke Jeffrey Melson , Crawford Jeffrey , Ou Sai-Hong Ignatius , Gandara David R. , Heymach John , Bivona Trever Grant , McCoach Caroline Elizabeth 
Published: May 2019

3102 Background: BRAF alterations (alts) account for ~4% of non-small cell lung cancers (NSCLC) with 50% being non-V600 alts. Because these alts are functionally heterogeneous and have a poorly characterized genomic landscape, determining appropriate treatment strategies is a challenge. Methods: The Guardant360 clinical database was queried for NSCLC patients (pts) with BRAF alts. Alts were categorized by clonality, type and class (1 and 2: BRAF monomer and dimer signaling; 3: requires co-occurring upstream RAS-mediated signaling). Functionality and drug screen assays were performed in Ba/F3 cells. Pts with non-V600 mutations were analyzed for sensitivity to MEK +/- BRAF inhibitors (M+Bi). Results: 306 unique BRAF alts were identified and the majority were observed once (233/306; 76%). Amplifications (806/1663; 48.5%) and missense alts (795/1663; 47.8%) were the most common occurrences. Missense alts were predominantly clonal (58%), and of known functionality (428/795; 54%). All class 1-2 alts were activating in Ba/F3 cells, while class 3 alts were found to have variable functionality (activating: 4/9). Functionality was correlated with clonality as demonstrated by class 1-3 alts having higher clonality compared to variants of unknown significance (VUS) (1: 56%; 2: 54%; 3: 45%; VUS: 38%; P<0.01). Drug screens for G469V and L597R alts showed resistance to first generation BRAF inhibitors (IC50 ≥100nM), but sensitivity to M+Bi (IC50 0.02-36nM). Growth inhibition was more pronounced for dabrafenib + trametinib (D+T) (IC50 <0.1nM) compared to encorafenib + binimetinib (IC50 8-35nM) and vemurafenib + cobimetinib (IC50 2-36nM). BRAF D594G mutation (class 3) was not activating in Ba/F3 cells. Three pts with non-V600 alts were treated with M+Bi. G469V and D594G had rapid disease progression (PFS 2 and 4 mos respectively), while pt with L597R has ongoing partial response (PFS 8+ mos). Conclusions: BRAF alts show correlation between clonality and functionality, which provides important clinical information given the numerous VUS in the BRAF non-V600 setting. Drug screens reveal non-V600 alts may be sensitive to M+Bi and suggest D+T is the most active combination. Clinical data supports that some non-V600 BRAF mutations may be sensitive to M+Bi.
The Circulating Cell-free Genome Atlas (CCGA) Study: Size selection of cell-free DNA (cfDNA) fragments.
Authors: Filippova Darya , Larson Matthew H. , Maher M. Cyrus , Calef Robert , Pimentel Monica , Zhou Yiqi , Newman Joshua , Gross Samuel , Nicula Virgil , Liu Ting-Chun , Yakym Christopher , Berman Jennifer , Aravanis Alex , Jamshidi Arash 
Published: May 2019

3103 Background: Detection of somatic copy number aberrations in individuals with cancer via cfDNA whole-genome sequencing (WGS) is challenging at low tumor fractions. Given that tumor-derived cfDNA fragments are shorter than those from healthy tissues, this exploratory analysis evaluated the potential effect of size selection on the ability to detect cancer. Methods: CCGA WGS libraries were in silico and in vitro size selected to estimate the change in tumor fraction by tumor types (breast, lung, and colorectal [CRC]) and stage (I-III vs IV). In silico analyses used clinically evaluable training set samples with WGS assay results (n = 1422: 560 non-cancer [NC], 862 cancer [C] stages I-IV); classification (cancer/non-cancer) performance was estimated using fragments within the 90-150 bp range. In vitro analyses used a subset of samples (n = 93: 28 NC, 65 C stages I-IV), including C cases sampled within a range of tumor fractions; tumor fraction was also measured at each progressive removal of maximum-length fragments (intervals of 10 bp: 150 bp down to 50 bp). Results: In silico and in vitro analyses, respectively, resulted in median 2.00±0.58-fold (at 6.91±2.64X depth) and 2.00±0.52-fold (at 23±4.45X depth) increases, in overall tumor fraction (compared to non-size-selected 36X depth). This was consistent across tumor types ( in silico: 1.78±0.73 breast, 2.00±0.58 CRC, 2.00±0.41 lung; in vitro: 2.00±0.82 breast, 2.51±0.52 CRC, 2.53±0.94 lung) and stages ( in silico: 2.00±0.74 I-III, 1.78±0.52 IV; in vitro: 2.00±0.55 I-III, 1.68±0.29 IV). Tumor fraction increased with initial fragment length titrations, but not following size selection to shorter lengths ( < 140 bp). Classifier trained on in silico size-selected data had increased sensitivity at 98% specificity compared to those trained on non-size-selected data (p < 1e-5). Conclusions: In silico and in vitro size selection consistently increased tumor fraction across cancer types and stages, and this increase was maximized by tuning the length range of size selection. Relative to full-depth data, classification performance improved significantly. These data suggest that size selection targeting cfDNA under 140 bp may enhance cfDNA-based cancer detection. Clinical trial information: NCT02889978.
Targeting the p300/CBP interactome through blockage of the CH1-domain triggers tumor regression in AR-positive and AR-negative xenograft models of castration-resistant prostate cancer (CRPC).
Authors: Cattori Valentino , Hentsch Bernd , Kessler Ulrich 
Published: May 2019

3105 Background: In advanced prostate cancer, the paralog transcription co-activators p300/CBP are often highly expressed and have been associated with disease progression and poor prognosis. While several inhibitors of the bromo- and histone acetyltransferase domains of p300/CBP have been described, past efforts to develop drug-like ligands of other regions of this attractive target have been unsuccessful. Methods: A rationally designed small molecule modulator of the CH1-domain of p300/CBP was tested in a panel of prostate cancer cell lines, followed by cell cycle analysis and beta-galactosidase staining. Inhibition of the p300-dependent androgen receptor (AR) related transcriptional response was determined in a luciferase reporter assay and by qPCR analysis of expression of downstream genes like prostate-specific antigen (PSA), transmembrane protease-serine 2 (TMPRSS2) and prostein (SLC45A3). In vivo effects were evaluated in cell line- and patient-derived xenograft models of CRPC. Results: Selective blockage of the CH1 domain of p300/CBP results in sustainable anti-proliferative effects in AR-positive and AR-negative prostate cancer cells inducing apoptosis and/or senescence. Transcriptome and gene expression analyses revealed the downregulation of various drivers of cell cycle progression as well as decreased expression of hormone-induced, AR-regulated genes. In enzalutamide-resistant xenograft models of CRPC, oral administration of the compound triggered tumor regression/eradication at well tolerated doses. Serum PSA levels were strongly decreased in treated animals. Conclusions: Simultaneous inhibition of both, AR-signaling and downregulation of p300/CBP activity, may cause profound and long lasting antitumoral effects in patients with advanced prostate cancer. Future clinical investigation of this novel oral small molecule agent is warranted.
Prediction of olaparib sensitivity for variants of unknown significance in homologous repair genes.
Authors: Chevrier Sandy , Desmoulins Isabelle , Favier Laure , Ghiringhelli François , Bengrine Leila , Arnould Laurent , Boidot Romain 
Published: May 2019

3108 Background: the recent use of PARP inhibitors in clinical practice gives very interesting outcome for ovary tumors with BRCA1 or BRCA2 mutation but also in other tumors with homologous repair deficiency. Nevertheless, no hotspot mutations are present, consequently, more than 85% of observed variants have unknown significance, blocking the use of PARP inhibitor. Methods: Exome analysis was performed on a cohort of 27 patients treated with olaparib. After bioinformatics analyses, variant interpretation was performed by interrogating different databases. For variants of unknown significance (VUS), PROVEAN software and allelic frequency normalized with tumor cellular content were used to classify VUS as potentially benign or potentially deleterious. Results: Among the 27 patients analyzed, 16 harbored already classified variants (3 benign and 13 pathogen variants) and 11 had VUS. The first Progression Free Survival (PFS) analysis showed that benign variants did not respond to olaparib with a median survival of 62 days, whereas pathogenic variants had a median of 109 days. Surprisingly, VUS had a median of 136 days, suggesting that some of them could be classified as potentially deleterious. On the subset of 11 patients with VUS, we applied PROVEAN prediction classifying 5 variants as benign and 6 variants as deleterious, with a median PFS of 54 days and 140 days ( p=0.3235), respectively. With the second prediction, based on variant allelic frequency, we obtained PFS of 73.5 months for benign variants and 210 days for deleterious ones ( p=0.29). By combining both predictions, we classified as benign, VUS predicted benign with both predictions, and as deleterious, VUS predicted as deleterious with at least one prediction. Consequently, we perfectly discriminated benign from deleterious variants with a median PFS of 36 days for predicted benign and 177 days for predicted deleterious ( p=0.0084). From all patients, PFS were significantly different ( p=0.0003) between benign (n=6, 56 days) and deleterious variants (n=21, 140 months). Conclusions: Our work tends to show that VUS of homologous repair genes could be predicted as benign or deleterious, and could increase the number of patients eligible for a treatment by PARP inhibitors. The number of patients needs to be increased in order to validate our prediction algorithm.
Long-term follow-up of pharmacokinetics (PK) and immunogenicity of the anti–PD-1 antibodies nivolumab (Nivo) and pembrolizumab (Pembro) in real-world practice.
Authors: Fukudo Masahide , Mishima Kazuto , Kimura Norihisa , Shinden Yuichiro , Sasaki Takaaki , Okumura Shunsuke , Ohsaki Yoshinobu , Uehara Jiro , Yamamoto Akemi , Tamaki Gaku , Kakizaki Hidehiro , Kishibe Kan , Takahara Miki , Hayashi Tatsuya , Harabuchi Yasuaki , Shonaka Tatsuya , Hasegawa Kimiharu , Ono Takashi , Tasaki Yoshikazu 
Published: May 2019

3120 Background: The PD-1 blockers Nivo and Pembro are widely used to treat patients (pts) with various types of cancer, but their PK and immunogenicity have not been adequately characterized in clinical practice. Here we report the first long-term follow-up of PK and anti-drug antibodies (ADAs) of Nivo and Pembro, correlated with efficacy and safety. Methods: We included 147 pts receiving Nivo (n = 98) or Pembro (n = 49) between May 2016 and Jan 2019. Plasma samples were longitudinally collected before each infusion and after discontinuation for as long as samples were obtainable. Drug concentrations were measured by ELISA (LLOQ: 0.0125 µg/mL), and ADAs were evaluated by bridging ELISA. Results: Median (range) follow-up was 6.0 (0.1-38.7) mo, and 1718 samples were analyzed. ADAs were confirmed at baseline or at last sample for both Nivo (2 [2.2%] and 4 [4.5%] pts, respectively) and Pembro (2 [4.2%] and 3 [6.7%] pts). Of the 4 baseline ADA-positive pts, 3 experienced drug-induced fever after initial infusion. Pts developing ADAs at last sample had earlier progression than ADA-negative pts (median PFS: 46 vs. 119 days, log-rank P = 0.0827). Persistent drug exposure until ~1 y beyond discontinuation was observed for both drugs. In 1 Nivo-treated pt with delayed adrenal insufficiency 8.6 mo after discontinuation, Nivo was still detectable (0.2 µg/mL). In 71 and 41 efficacy-evaluable pts receiving Nivo and Pembro, respectively, mean trough levels in the early period (~cycle 6) were significantly higher in pts achieving response than in pts with progressive disease at first assessment (Nivo: 43.5 vs. 31.0 µg/mL, P = 0.0107; Pembro: 30.6 vs. 22.1 µg/mL, P = 0.0174). Conclusions: Our findings provide insight into the etiological mechanism of late-onset adverse events associated with PD-1 blockers. Moreover, ADA may potentially influence clinical outcomes, and it may be possible to optimize dose in certain pts with lower drug exposure for improved efficacy, warranting further investigation. Clinical trial information: UMIN000033036. [Table: see text]
A phase I study of a novel IAP inhibitor APG-1387 as a monotherapy or in combination with pembrolizumab in treatments of patients with advanced solid tumors.
Authors: Rasco Drew W. , Li Yufeng , Tang Yuefen , Men Lichuang , Wang Hengbang , Ji Jiao , Liang Zhiyan , Sun Joan , Amaya Alex , Huang Yingjie , Yang Dajun , Zhai Yifan 
Published: May 2019

3125 Background: APG-1387 is a novel, bivalent small molecule IAP (inhibitor of apoptosis proteins) inhibitor. It has shown strong antitumor activities in multiple human xenograft cancer models. APG-1387 also acts as host immune modulator, supporting the notion that APG-1387 in combination with anti-PD1 antibody for cancer therapy. Methods: This study consists of two parts (NCT03386526). Part 1 is the dose escalation study of APG-1387 including a mPC (metastatic pancreatic cancer) cohort expansion. Part 2 is the dose escalation and cohort expansion study of APG-1387 in combination with pembrolizumab. APG-1387 is administrated IV for 30 minutes once weekly in a 21-day-cycle. Pembrolizumab is administrated at 200mg IV on day1 of a 21-day-cycle. The study objectives are to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed per RECIST v1.1 every 6 weeks). Results: Through Jan 4, 2019, total 23 patients had been treated in 4 cohorts of APG-1387 (20mg, 30mg, 45mg, 60mg). Two DLTs were observed at 60mg including lipase increase and Bell’s palsy, MTD was determined as 45mg. Nineteen of 23 patients experienced at least 1 TEAE. The most common TEAEs were nausea (21.7%), fatigue (17.4%), decreased appetite (13.0%), and abdominal pain (13.0%). Three grade 3 TEAEs including elevated bilirubin, lipase increase, and shortness of breath were documented at 45mg and 60mg. Three out of six mPC patients (one at 60mg, two at 45mg) achieved SD, one of them at 45mg has been treated > 5 cycles with confirmed SD (-18%). Two patients, who were treated with APG-1387 at 20mg in combination with pembrolizumab, had no DLT observed during the first cycle. Preliminary PK data of APG-1387 showed a dose proportionality in exposure (Cmax and AUC) over the dose range of 20-60 mg. Conclusions: APG-1387 was well tolerated and had manageable adverse events. The potential effects of APG-1387 alone or in combination with pembrolizumab deserve further exploration in patients with advanced solid tumors, especially in the mPC patients. Clinical trial information: NCT03386526.
A phase I study of a novel MDM2 antagonist APG-115 in patients with advanced solid tumors.
Authors: Rasco Drew W. , Lakhani Nehal J. , Li Yufeng , Men Lichuang , Wang Hengbang , Ji Jiao , Tang Yuefen , Liang Zhiyan , Amaya Alex , Estkowski Kathy , Sun Joan , Huang Yingjie , Yang Dajun , Zhai Yifan 
Published: May 2019

3126 Background: APG-115 is a potent and orally active small-molecule MDM2 protein inhibitor. Binding to MDM2 protein, APG-115 restores p53 tumor suppressive function via induction of apoptosis in tumor cells retaining wild-type p53. In addition, enhanced antitumor activity was demonstrated in the syngeneic tumor models after APG-115 combined with PD-1 blockade. Methods: This Phase I study (APG-115-US-001) was designed to enroll the patients with advanced solid tumors in US (NCT02935907). Study objectives included to assess safety, dose limited toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity (assessed every 8 weeks per RECIST v1.1). The patients received APG-115 orally every other day (QOD) at the designated dose (ranging from 10 to 300 mg) for first 21 days of a 28-day cycle, until disease progression. Results: Up until Jan 4 2019, total 28 patients were treated with APG-115 at various doses (one patient at 10mg, 20mg and 50mg, respectively; 14 patients at 100mg, 6 patients at 200mg, and 5 patients at 300mg). The median number of prior systemic anticancer therapies was 4 (range 0-15). The DLTs were observed during cycle 1, including one grade 2 thrombocytopenia at 200mg, one grade 3 thrombocytopenia at 300mg, and one grade 3 fatigue at 100mg and 300mg respectively. The most common AEs (reported in ≥10% of pts) included: fatigue, nausea, vomiting, diarrhea, decreased appetite, dehydration, neutrophil count decreased, white blood cell count decreased, pain in extremity, thrombocytopenia. The most common Grade 3 or 4 treatment related AEs were fatigue (10.7%), and thrombocytopenia (10.7%). Six patients had stable disease (SD) after two cycle treatments, two of them are continuing in this study. PK analyses indicated that exposure (Cmax and AUC) generally increases with the increase of dose level from 20 mg to 300 mg. Conclusions: APG-115 was well tolerated and had manageable adverse events. The MTD/RP2D of APG-115 monotherapy with oral administration, QOD for 21 days of a 28-day cycle for treatment of patients with advanced solid tumors was determined as 100 mg. Further evaluation of APG-115 in combination with pembrolizumab in patients with advanced solid tumors is ongoing. Clinical trial information: NCT02935907.
Molecular differences between lymph nodes (LNs) and distant metastases (mets) in colorectal cancer (CRC).
Authors: Puccini Alberto , Xiu Joanne , Goldberg Richard M. , Grothey Axel , Shields Anthony Frank , Salem Mohamed E. , Seeber Andreas , Battaglin Francesca , Berger Martin D. , El-Deiry Wafik S. , Tokunaga Ryuma , Naseem Madiha , Zhang Wu , Arora Sukeshi Patel , Khushman Moh'd M. , Hall Michael J. , Philip Philip Agop , Marshall John , Korn Wolfgang Michael , Lenz Heinz-Josef 
Published: May 2019

3130 Background: LNs mets are thought to occur before distant mets. However, lymphatic and distant mets arise from independent subclones of the primary tumor, suggesting that LNs are not essential intermediaries for distant mets. We aimed to comprehensively characterize the molecular profile of LN mets and to explore the differences between LN vs distant mets and primary tumors. Methods: Tumor samples from primary CRCs, LNs, and distant mets were analyzed using NGS (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Results: In total, 11871 tumors samples were examined, comprising primaries (N = 5862), distant (N = 5605) and LNs mets (N = 404). The most frequently mutated genes in LNs were TP53 (72%), APC (61%), KRAS (39%), ARID1A (20%), and PIK3CA (12%). LNs showed a higher mean TMB (13 mut/MB) vs distant mets (9, P < .0001). TMB-high (17mut/MB) was more frequent in primaries and LNs vs distant mets (9.5% and 8.8% vs 4.2%, P < .001 and P = .001, respectively), as well as MSI-H (8.8% and 6.9% vs 3.7%, P < .001 and P = .017, respectively). TMB-high is significantly higher in LNs vs distant mets and primaries (P < .0001), independent of MSI-H status. Analyzing distant mets by location, LNs showed higher TMB compared to lung, liver and peritoneum mets (P < .0001). Overall, LNs showed significantly different rates of mutations in APC, KRAS, PI3KCA, KDM6A, and BRIP1 (P < .01 for all comparisons) vs primaries; while presenting a distinct molecular profile compared to distant mets ( TP53 72 vs 67%; KRAS 39 vs 50%; RNF43 7 vs 4%; ATM 5 vs 3%; KDM6A 4 vs 1%; BRCA2 4 vs 2%; MSH6 3 vs 2%; PTCH1 4 vs 1%; BRCA1 2 vs 1%; GNAS 2 vs 5%; P < .05 for all comparisons). Our cohort of 30 paired samples confirmed the molecular heterogeneity between primaries, LNs, and distant mets. Conclusions: This is the largest study to investigate the molecular differences between LNs mets, distant mets and primary tumors in CRC patients. Our data support the hypothesis that lymphatic and distants mets harbor different mutation profiles which suggests that they may arise from distinct subclones.