bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenic variants in DNA damage response (DDR) genes in patients with advanced solid tumors.
Authors: Ileana Dumbrava Ecaterina Elena , Brusco Lauren , Daniels Molly S , Wathoo Chetna , Shaw Kenna Rael , Lu Karen H. , Zheng Xiaofeng , Strong Louise C. , Litton Jennifer Keating , Arun Banu , Eterovic Agda Karina , Piha-Paul Sarina Anne , Subbiah Vivek , Hong David S. , Woodman Scott Eric , Mendelsohn John , Yap Timothy Anthony , Mills Gordon B. , Chen Ken , Meric-Bernstam Funda 
Published: September 2018

11567 Background: Deleterious mutations in DDR genes are frequently associated with response to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum chemotherapy. However, much remains unknown about their association with specific molecular signaling pathways. We report the prevalence of pathogenic variants in DDR genes and their co-alteration with other somatic variants. Methods: Targeted exome sequencing of 201 genes was performed in 1,189 patients (pts) with advanced solid tumors enrolled in a molecular testing protocol (NCT01772771), using matched normal and tumor DNA. We assessed germline and somatic alterations in 15 cancer-related DDR genes, their co-occuring genomic alterations and the tumor mutation burden (TMB), defined as number of somatic non-synonymous mutations. Results: A total of 124 pathogenic or likely pathogenic variants in DDR genes were identified in 111/1189 (9%) pts with 57% of these alterations being somatic. These variants were found in the following genes: ATM 17 pts (1.4%); BAP1 5 pts (0.4%); BRCA1 18 pts (1.5%); BRCA2 17pts (1.4%); CHEK1 8 pts (0.7%); CHEK2 16 pts (1.3%); ERCC3 4 pts (0.3%); ERCC4 2 pts (0.2%); ERCC5 3 pts (0.2%); MLH1 4pts (0.3%); MSH2 8 pts (0.7%); MSH6 6 pts (0.5%); PALB2 3 pts (0.2%) and RAD51 1pt (0.1%). DDR alterations were found more frequently in the following tumor types tested: breast 14%, colorectal 12%, melanoma 8%, glioblastoma 6% and ovarian 6%. The most relevant somatic co-alterations with DDR mutations were activation of the PI3K/AKT/mTOR pathway through mutations or copy-number variations in AKT1, MTOR, NF1, PIK3CA, PIK3R1, PTEN, TSC1 and TSC2 (p = 0.008). Patients with deleterious variants in mismatch excision repair genes (MLH1, MSH2 or MSH6) had a significantly higher TMB than all other patients enrolled (median TMB = 62 vs 5, p = 0.002). Patients with somatic pathogenic DDR variants had a significantly higher TMB (median = 13) compared to patients with germline DDR variants (median = 5) (p = 0.004). Conclusions: The association of DNA repair mutations with alterations in signaling pathways provide rationale for novel therapeutic combinations. Variations in TMB based on distinct types of DDR gene alterations may have implications for immunotherapy.
Molecular profiling comparison of breast cancer subtypes in young women and older women.
Authors: Tan Antoinette R. , Feldman Rebecca , Symanowski James Thomas , Fisher Julie Gottlieb , Hadzikadic-Gusic Lejla , White Richard L. , Kim Edward S. 
Published: September 2018

11581 Background: Young women with breast cancer (YWBC; ≤40 years) have a more aggressive clinical course and is associated with a poorer prognosis. In this analysis, we explore molecular features in tumors of YWBC and older women with breast cancer (OWBC; ≥65 years) by subtype. Methods: Somatic genomic profiles of 1879 breast tumors collected from 2013-2017 were assessed retrospectively and included in a de-identified data analysis if ER, PR and HER2 (immunohistochemistry [IHC] and/or in situ hybridization [ISH]) were available. Testing included IHC, ISH and massively parallel sequencing assays (next-generation sequencing [NGS]) at a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). Pearson’s chi-square was utilized for comparisons and significance defined as p < 0.05. Results: Frequency of subtypes in YWBC (n = 536) and OWBC (n = 1343) were 45% and 55% HR+HER2-, 38% and 36% triple-negative (TN), 7% and 5% HER2+HR-, and 10% and 4% in HER2+HR+, respectively. Specimens tested were breast (53%, 43%) and a metastatic site (43%, 57%) in YWBC and OWBC, respectively. HR+HER2- YWBC exhibited higher rates of pathogenic mutations in TP53 (34%, 24.4%; n = 748; p = 0.008), BRCA1 (9%, 4.5%; n = 503; p = 0.047), BRCA2 (14.8%, 8.4%; n = 501; p = 0.032), gene amplifications in FGF3 (26.7%, 10.4%; n = 107; p = 0.034), FGF4 (26.7%, 9.1%; n = 107; p = 0.019), FGF19 (29.6%, 11.6%; n = 96; p = 0.033), CCND1 (36.7%, 18.2%; n = 107; p = 0.042), and overexpression of EGFR (18.6%, 8%; n = 364; p = 0.004). TN YWBC had higher rates of alterations in TP53 (80.2%, 67.4%; n = 577; p = 0.002) and BRCA1 (13.3%, 5.9%, n = 375; p = 0.015). YWBC that was HER2+HR+ exhibited a higher rate of APC mutations (10%, 0%; n = 84; p = 0.03). In OWBC, there were higher rates of PD-L1 expression in HER2+HR- (22.7%, 0%; n = 70; p = 0.009) and TN (13%, 6.3%; n = 458; p = 0.035). There were also higher PIK3CA mutations in HER2+HR+ (43.4%, 18.8%; n = 101; p = 0.008) and CDH1 mutations (12.8%, 0%; n = 85; p = 0.022) in TN. Conclusions: There were distinct molecular aberrations and significantly different frequency of alterations in subtypes of YWBC compared to OWBC. These molecular changes may contribute to increased understanding of breast cancer tumor biology and refinement of treatment strategies in YWBC and OWBC.
Alterations in the Β-catenin pathway in non-small cell lung cancer to define a distinct molecular subtype with prognostic and therapeutic implications.
Authors: Bhattacharya Saveri , Somasundaram Aswin , Ding Fei , Gaither-Davis Autumn , Pennathur Arjun , LaFramboise William A , Dacic Sanja , Kurland Brenda F , Stabile Laura P. , Burns Timothy Francis 
Published: September 2018

11584 Background: The treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the development of targeted therapy for distinct molecular subsets. Activation of the β-catenin pathway is essential for colorectal carcinoma tumorigenesis and has been implicated in hepatocellular, thyroid and ovarian cancer. The β-catenin pathway is involved in the cell adhesion complex and Wnt signaling. While mutations in this pathway have been reported in NSCLC and β-catenin overexpression correlates with worse survival, its role in lung tumorigenesis is poorly understood. Methods: We performed targeted next generation sequencing using the Ion Torrent Hotspot Cancer Panel v.2 on tumor tissue from 244 NSCLC patients in which we have defined key demographic and clinical parameters including stage and survival. This cohort contained 91 Stage I cases with mRNA expression data using an Illumina platform. Co-occurrence of genes in the β-catenin pathway and 27 other genes in the panel were assessed by Fisher’s exact test, with Benjamini-Hochberg adjustment for multiple comparisons. Results: Seventeen of 244 tumors had mutations in the β-catenin pathway (APC, CTNNB1, and NOTCH1): 10/170 non-squamous NSCLC (6%, 95% CI 3%-10%), and 7/70 squamous NSCLC (10%, 95% CI 5%-19%). The rate of EGFR and RB1 mutations was higher in tumors with b-catenin pathway mutation (5/17 and 2/17) than in those without (13/227 and 0/227, adjusted p = 0.06 for both). The presence of an APC mutation was also associated with higher mRNA expression of the pro-survival protein, BCL2 (n = 91; 5/41 vs. 0/50, unadjusted p = 0.022, adjusted p = 0.3). Furthermore, APC mutations were more frequently observed in tumors with higher levels of EMT markers (high VIM 8% vs. low VIM 0%, unadjusted p = 0.16) and EMT transcription factors (10% vs. low expression 2%, unadjusted p = 0.16). Finally, we observed a trend toward worse overall survival in non-squamous tumors with mutations in the β-catenin pathway (n = 170, log rank test p = 0.07). Conclusions: These studies suggest that tumors with b-catenin pathway alterations are defined by a more mesenchymal and potentially drug resistant subtype which portends a poor prognosis.
Induction of a BRCAness state by oncometabolites and exploitation by PARP inhibitors.
Authors: Bindra Ranjit , Sulkowski Parker L , Corso Christopher D. , Glazer Peter , Shuch Brian M. 
Published: September 2018

11586 Background: 2-Hydroxyglutarate (2HG) exists as two enantiomers, R-2HG and S-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (aKG)-dependent dioxygenases. The former is an oncometabolite induced by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, while the latter is produced under pathologic processes such as hypoxia. Recurring IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML). Methods: Our group recently reported that IDH1/2 mutations induce a homologous recombination (HR) defect which renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. Remarkably, this “BRCAness” phenotype can be completely reversed by mutant IDH1/2 inhibitors, and it can be entirely recapitulated by treatment with either 2HG enantiomer in cells with intact IDH1/2. We performed a comprehensive series of studies that directly implicate two aKG-dependent dioxygenases, KDM4A and KDM4B, as key mediators of the observed phenotype. Results: Using the methodology and preliminary data obtained above as a basis for further inquiry, here we have extended these findings to several related gene mutations, which similarly induce profound synthetic lethality with PARP inhibitors in these tumors, and our data suggest a similar mechanism of action via which HR is suppressed. Finally, we provide additional evidence that suppression of 2HG production with small molecule inhibitors of mutant IDH1/2 function does not lead to any detectable decreases in cell growth or viability in several unique models. Conclusions: Small molecule inhibition of oncogenic kinases is a pillar of precision medicine in modern oncology, and this approach has been extrapolated to treat IDH1/2-mutant and other oncometabolite-producing cancers with inhibitors blocking the neomorphic activity of the mutant proteins. The findings present here directly challenge this therapeutic strategy, and they instead provide a novel approach to treat these tumors with DNA repair inhibitors. Based on these findings, we are planning a multi-center Phase II trial testing the efficacy of olaparib for the treatment of recurrent IDH1/2-mutant tumors later this year.
Phosphopeptide mapping of DLC1 in ER+ breast cancer reveals AMOTL2, a key hippo pathway component, as an important target.
Authors: Gokmen-Polar Yesim , True Jason D , Vieth Edyta , Qi Guihong D , Mosley Amber L , Badve Sunil S. 
Published: September 2018

11592 Background: Metastases suppressor genes are believed to control tumor progression and metastases. Deleted in Liver Cancer 1 (DLC1) acts as a gatekeeper for tumor and metastasis suppression. Low expression of DLC1 correlates with poor prognosis in patients with ER+ breast cancer. It is essential to understand the impact of DLC1 and its functional network in preventing tumor and metastasis suppression. Methods: T47D cells with stable DLC1-Full-Length (DLC1-FL) were generated using mammalian expression cloning vector, pcDNA3.1+/C-(K)-DYK, and CloneEZ™ technology. Growth rate of control and DLC1-FL knock-in cells was assessed for 2 weeks using clonogenic assay. Proteomic and phosphopeptide enrichment assays (Pierce TiO2 enrichment kit) were performed in triplicates to examine the basis of altered growth phenotype. The PeakJuggler node in Proteome Discoverer was utilized for label-free quantitation of both protein and peptide MS peak areas. In addition, GO term enrichment analysis was performed in DAVID for the significantly changed phosphopeptides. Results: Stable knock-in of T47D-DLC1-FL inhibits cell growth significantly in vitro compared to T47D-control in clonogenic assay. The phosphopeptide enrichment proteomic analyses showed 199 phosphopeptides were identified only in T47D-DLC1-FL and 182 peptides were identified only in T47D-control cells. Pathway analysis using DAVID showed 3 main clusters of significantly differently identified phosphopeptides (p-values ≤ 0.01) involving cadherin binding (p = 4.9e-12), cell-cell adherens junction (p = 3.9e-10), and cell-cell adhesion (p = 9.4e-7). Analysis of specific phosphopeptides showed canonical pathways such as CTNNB1 (Thr552), and BCL2L13 (370-385). More importantly, phosphorylation of HIPPO-pathway component AMOTL2 at S766, critical for promoting YAP signaling and invasion was only identified in T47D-control but not T47D-DLC1-FL (p = 5.78e-5). Conclusions: This data suggest that the absence of DLC1 promotes phosphorylation of AMOTL2, and thereby activating YAP-TAZ signaling leading to invasiveness. This data provides mechanistic basis for targeting this pathway to prevent recurrence in ER+ breast cancer.
Programmed cell death ligands expression in pheochromocytomas (PCC) and paragangliomas (PGL): Relationship with the hypoxic response and malignant behaviour.
Authors: Pinato David James , Black James M , Trousil Sebastian , Dina Roberto , Trivedi Pritesh , Mauri Francesco A , Sharma Rohini 
Published: September 2018

11597 Background: The hypoxic response underlies the pathogenesis and malignant behaviour of PCC/PGL. Regulation of PD-1 receptor-ligand signalling, a therapeutically actionable driver of the anti-tumour immune response, is a hypoxic-driven trait across malignancies. We evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with PCC/PGL. Methods: Tissue microarrays sections including consecutive cases of PCC/PGL diagnosed between 1983-2011 were stained for PD-L1 & 2, Ki-67, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A). Candidate biomarkers were assessed for correlation with clinical variables including overall survival. Results: In total, 100 patients, 10% malignant, 64% PCC, 29% familial with a median tumour size of 4.7 cm (range 1-14) were included. Median follow-up was 4.7 years. PD-L1 expression was observed in 18% of cases and was independent of adverse pathological features including capsular (CI), vascular invasion (VI), necrosis (N) and expression of biomarkers of hypoxia. We observed a trend towards association with malignancy (p = 0.08). PD-L2 expression was found in 16% of tumors. PD-L2 overexpression strongly correlated with CI, VI, N (p < 0.01) and malignant behaviour (p = 0.009) and was associated with stronger Hif-1a and CaIX immunolabeling (p < 0.01). PD-L2 but not PD-L1 expression was predictive of shorter survival (162 versus 309 months, HR 3.1 95%CI 1.1-9.2, Log-rank p = 0.03). Gene set enrichment analysis on the TGCA PCC/PGL RNA-seq dataset (n = 184) revealed a positive correlation between PD-L2 and a number of transcripts involved in angiogenesis and immunity including Interleukin-6 (Pearson R = 0.57) and CD-8a (R = 0.56). Conclusions: We report for the first time PD-1 ligands expression in PCC/PGL with a distinctive prognostic and clinicopathologic role. These findings support a potential therapeutic role for PD-1/PD-L1 targeted checkpoint inhibitors in these tumors.
Selecting patients with metastatic colorectal cancer for treatment with temozolomide using proteomic analysis of MGMT.
Authors: Schwartz Sarit , Cecchi Fabiola , Tian Yuan , Scott Kerry , Di Bartolomeo Maria , Morano Federica , Fucà Giovanni , Martinetti Antonia , De Braud Filippo G. , Dominoni Francesca , Milione Massimo , Calegari Maria Alessandra , Orlandi Armando , Barone Carlo , Pietrantonio Filippo , Hembrough Todd A. 
Published: September 2018

11601 Background: Temozolomide (TMZ) is a standard treatment for melanoma and glioblastoma and it has shown limited but encouraging activity in patients with metastatic colorectal cancer (mCRC). In multiple cancer types, the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a resistance marker for TMZ; MGMT promoter methylation is associated with loss of MGMT expression and response to TMZ. We hypothesized that mCRC patients whose tumors expressed quantities of MGMT protein below a pre-defined cutoff would have better outcomes on TMZ than patients with MGMT expression above the cutoff. To test our hypothesis, we assessed MGMT by mass spectrometry in the tumor samples of patients with refractory mCRC and MGMT promoter methylation receiving TMZ. Methods: Archived formalin-fixed, paraffin-embedded tissue sections were obtained from 24 patients from two phase 2 trials. A pathologist marked the tumor areas, which were microdissected and solubilized. In each tumor sample, multiple protein biomarkers including MGMT were quantified with selected reaction monitoring mass spectrometry. An MGMT cutoff of 200 amol/ug was based on the limit of quantitation from a concentration curve. The Mantel-Cox log-rank and the Fisher’s exact tests were used for survival comparisons. Results: MGMT protein was detected in 13 of 24 (54.2%) colorectal tumor samples (range: 229.3-784.8 amol/µg). The overall response rate was 29%. Patients with MGMT protein levels below a cutoff of 200 amol/ug (n = 11) had a notably higher response rate than patients with MGMT levels above the cutoff (64% vs. 0%; p = 0.001 Fisher’s test). Also a longer progression-free survival was observed (4.3 vs. 1.6 months, HR = 0.36, 95% CI = 0.13-1.10, p = 0.054). Results for overall survival were consistent but not statistically significant (8.9 vs 6.9 months, HR = 0.55, p = 0.221). Conclusions: Patients with mCRC whose tumors expressed low or undetectable levels of MGMT protein had a better outcomes following TMZ treatment than their counterparts. Quantitative proteomic analysis of MGMT could potentially be used to select CRC patients for TMZ treatment. The results of validation studies are forthcoming.
Preliminary correlative analysis of PD-L1 expression from the SUNRISE study.
Authors: Kallinteris Nikoletta Lea , Sanborn Rachel E. , Horn Leora , Gerber David E. , Natale Ronald B. , Tang Min , Downing Sean , Clement Amanda , Guennel Tobias , Shan Joseph , Hoyt Cliff 
Published: September 2018

11603 Background: SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer, demonstrated similar overall survival (OS) in both treatment arms. Biomarkers including pre-treatment PD-L1 expression are being retrospectively assessed in on-going exploratory analyses. Methods: Archival tissue obtained at the time of diagnosis was requested but not required in the SUNRISE trial. FFPE slides were stained with a panel of lymphoid cell markers: CD3+, CD8+, FoxP3+, PD-L1+, CD163+, CK+ and DAPI using a 6-plex quantitative immunohistochemistry (IHC) assay (OPAL, PerkinElmer, Hopkinton, MA, USA). Baseline PD-L1 expression was retrospectively scored on tumor cells (TC) as a percentage of PD-L1 expressing tumor cells: TC3≥50%, TC2≥5% and < 50%, TC1≥1% and < 5%, and TC0 < 1%. Cox regression models for PD-L1 IHC subgroup populations were used for correlation with OS. Results: In the subset of patients with available diagnostic biopsies (110 out of 597 randomized patients), the prevalence of PD-L1 expression was 5% for TC3, 18% for TC2/3, 35% for TC1/2/3, 65% for TC0. Median OS (mOS) of the D+B arm is 11.5 months (TC0, < 1%) and 6.0 months (TC1/2/3, ≥1%) with HR 0.38 (95% CI, 0.19-0.76); p-value = 0.004. mOS of the D+P arm is 11.1 months (TC0, < 1%) and 10.4 months (TC1/2/3, ≥1%) with HR 0.93 (95% CI, 0.47-1.87); p value = 0.844. Conclusions: Baseline PD-L1 expression in a subset of SUNRISE patients demonstrated that PD-L1 expression (TC0) was associated with a significantly prolonged OS compared to positive PD-L1 expression (TC1/2/3) in patients receiving D+B. No difference in OS was observed in the D+P group by PD-L1 expression. These observations are consistent with the hypothesis that bavituximab may demonstrate more effect in PD-L1 negative or low expressing “immune cold” tumors. Clinical trial information: NCT01999673.
Comprehensive analysis of potential immunotherapy genomic biomarkers by profiling paired tumor/normal exome of 1,000 Chinese cancer patients.
Authors: Xu Qiang , Wang Guan , Dai Chun , Xu Xiaoman , Wei Jinwang , Xu Jiayue , Wu Angela , Wang Jiping 
Published: September 2018

11605 Background: With the broadening landscape of immunotherapy use, it is important to identify patients who are likely to benefit from the therapy. We reported the comprehensive analyses of potential predictive biomarkers for PD1/PD-L1 inhibitors based on Chinese patients’ exome profiling data. Methods: Over 1,000 cancer patients from 70 hospitals across 20 provinces in China were recruited and the whole exome of tumor/normal samples of each patient were sequenced. Four potential genomic biomarkers: tumor mutation burden (TMB), mismatch repair deficiency (MMR), microsatellite instability (MSI), and PD-L1 (CD274) amplification (PD-L1 AMP) were analyzed in this Chinese cohort and compared with the mainly Caucasian cohort in TCGA database. Results: At least one of the four preselected genomic biomarkers was identified in 40.8% of this Chinese cancer patient cohort by clinical whole exome sequencing (CWES) analysis. Similar to TCGA cohort, the top 3 high TMB tumor types are lung, esophagus and colorectal cancer. Chinese hepatocellular carcinoma (HCC) patients showed higher TMB than the TCGA cohort (Median: 106 vs. 65 non-synonymous mutations per tumor NMT), which might be due to different etiologies. Five late stage cancer patients (3 lung, 1 melanoma and 1 gallbladder) using PD1/PD-L1 blockade with high TMB showed durable clinical benefit (SD≥6months/PR/CR). Comparing with TCGA data, Chinese colorectal cancer cohort (252 patients) had relative lower MSI-high or MMR related mutations (8.33% vs. 12.5%, and 3.97% vs. 10.0% respectively). PD-L1 AMP most frequently occurred in lung squamous (14.3% VS 9.8% TCGA), HER2-positive breast cancer (8.8% VS 6.8% TCGA with unknown HER2 status) and sarcoma (6.0% VS 9.4%TCGA). One Chinese renal cell carcinoma patient with PD-L1 AMP received anti-PD-1 treatment and on-going PFS is 7 months by far. Conclusions: Our CWES analysis and limited clinical follow-up observations suggested that about 40% Chinese cancer patients had at least one of the 4 potential immunotherapy predictive biomarker mutations. Long-term follow-up is needed to verify the validity of those markers.