bluuebunny/crossref_metadata_2025_split huggingface dataset:
A survey of thousands of tumor exomes and transcriptomes to expand clinical opportunities for crizotinib.
Authors: Bowden Emma , Eddy Sean , Williams Paul , Khazanov Nikolay , Bankhead Armand , Cyanam Dinesh , Wyngaard Peter , Rhodes Dan 
Published: March 2020

11017 Background: Cancer driver events occur as a result of chromosomal rearrangements. There are several examples where targeted inhibition of the resulting fusion produces dramatic clinical response. For example, the EML4-ALK fusion in non-small cell lung cancer (NSCLC). Other ALK fusions have been described in NSCLC and other diseases including the NPM-ALK fusion in anaplastic large cell lymphoma (ALCL). The efficacy of crizotinib and other ALK inhibitors are being investigated in these diseases. ALK is also subject to activation via mutation and sensitivity to crizotinib is reported in ALK mutation positive neuroblastoma. Finally, crizotinib has activity not only against ALK, but also against ROS1, MST1R and MET. ROS1 fusions have been found in NSCLC and glioblastoma, and MET amplification events in gastric adenocarcinoma identify additional settings that may benefit from crizotinib treatment. Methods: To further understand the full therapeutic potential of Crizotinib, we undertook a genomic survey of ALK, ROS1, MET and MST1R across 1,000’s of patients from the The Cancer Genome Atlas (TCGA) and Oncomine. Results: We confirmed the presence of EML4-ALK fusions in both lung and colorectal cancer (CRC), and also identified a novel ALK fusion in CRC. ALK hotspot mutations and focal amplifications were confined to neuroblastoma, as previously described. Our survey of ROS1 identified rare novel fusions in NSCLC and glioblastoma, and high-level amplifications in liposarcoma (2%) and rarely in breast cancer (0.2%). No fusions were identified for MET, however high-level amplifications were observed in 1-5% of papillary renal cell carcinoma, the intestinal subtype of gastric adenocarcinoma, oliogodendroglioma, glioblastoma and lung adenocarcinoma. Hotspot mutations were frequently observed in squamous head and neck (11%), and more rarely in hepatocellular carcinoma, small cell lung and ovarian cancers. Conclusions: These results leverage all available genomic profiling data to provide a broadened scope of therapeutic opportunity for inhibitors like crizotinib. With the growing availability of next-generation sequencing, such surveys can support hypothesis-driven development of targeted therapies.
Use of next-generation sequencing (NGS) to identify actionable genomic alterations (GA) in diverse solid tumor types: The Foundation Medicine (FMI) experience with 2,200+ clinical samples.
Authors: Miller Vincent A. , Ross Jeffrey S. , Wang Kai , Ali Siraj M. , Otto Geoff , Curran John , Palma Norma Alonzo , Yelensky Roman , Downing Sean , Stephens Phil , Lipson Doron , Palmer Gary A. 
Published: March 2020

11020 Background: ST oncology has been transformed by the linkage of GA with targeted therapeutics. Unfortunately, most STs still have no target detected by clinically available assays. More comprehensive testing platforms are needed to determine GA in ST and thus broaden treatment options. We developed a ST NGS diagnostic assay, optimized for routine clinical FFPE specimens including core and fine needle biopsies and malignant effusions, and analyzed > 2,200 patients’ tumors in a CLIA-certified lab (Foundation Medicine). Methods: Hybridization capture of 3,320 exons from 182 cancer-related genes and 37 introns of 14 genes commonly rearranged in cancer was applied to ≥ 50ng of DNA extracted from 2,200+ consecutive FFPE tumor specimens and sequenced to high unique coverage. GA (base substitutions, small indels, rearrangements, copy number alterations) were categorized as “actionable” if directly linked to a clinically available targeted treatment option or a mechanism-driven clinical trial. Results: 2,112/2,221 (95%) of specimens (most common 1° sites: lung 18%, breast 14%, colon 7%, other 34%) were successfully profiled (mean coverage 1134X). Alterations were reported in 155/182 (85%) of genes. Seventy-six percent of cases harbored ≥1 actionable GA, mean 1.6 (range 0-16); sixty-two percent harbored at least one actionable GA not assayed by available tumor-type specific tests or hotspot panels. This approach has led to novel insights into advanced cancer including: 13 novel, potentially druggable kinase gene fusions; alterations in known drug targets (e.g. ALK, EGFR, ERRB2, KIT, MET, PDGFR α and β, RAF1 and RET) in novel tumor types and new mechanisms of resistance to approved targeted therapies. Several patients demonstrated dramatic responses to treatment with targeted therapies directed against these alterations. Conclusions: Comprehensive NGS genomic profiling was successful in profiling >2,200 unselected clinical cases, identified actionable alterations in 76% of cases and provided additional treatment options for 62% of patients targeting alterations in genes not assayed by available hotspot panels.
BRCA1 like copy number profiles to predict benefit of intensified alkylating chemotherapy in breast cancer.
Authors: Schouten Philip C. , Linn Sabine C. , Aulmann Sebastian , Sinn Hans-Peter , Schneeweiss Andreas , Marme Frederik 
Published: March 2020

11023 Background: DNA copy number profiles can identify patients with a defect in BRCA1. We previously showed that patients with a BRCA1-like profile benefit from intensified alkylating chemotherapy (IA, 4 cycles 5-fluorouracyl, epirubicin, cyclophosphamide + 1 cycle carboplatin, thiotepa and cyclophosphamide with autologous stem cell transplantation (ASCT)). Presumably, this is because of the defect in error free homologous recombination DNA repair. Here we present an independent study of BRCA1-like profiles to predict benefit of IA chemotherapy (2 cycles induction chemotherapy consisting of 2500 mg/m2 ifosfamide and 40 mg/m2 epirubicin, followed by 12 g/m2 ifosfamide, 900 mg/m2 carboplatin, 180 mg/m2 epirubicin with ASCT) versus adriamycin-cyclophosphamide or cyclophosphamide-methotrexate-5-fluorouracyl regimens in high risk breast cancer. Methods: We isolated tumor DNA from 117 patients of a case-control study of high risk breast cancer patients to apply a marker by treatment interaction study design to assess overall survival. We generated copy number profiles and classified them to be BRCA1-like or non-BRCA1 like. We used Fisher Exact tests to calculate correlations and performed Kaplan-Meier and Cox regression analyses to investigate whether patients with a BRCA1-like tumor benefit from IA chemotherapy compared to an AC/CMF regimen. Results: 16 of 117 (14%) patients had a BRCA1-like profile. BRCA1-like status was associated with high tumor grade (p=0.03), triple negative status (p=0.0005) and high N stage (p=0.03). When corrected for hormone receptor and HER2 status, size, positive lymph nodes, and grade we found that BRCA1 like patients had a 6-fold decreased chance of death (HR: 0.15, 95% confidence interval: 0.03-0.80, p: 0.03) compared to non-BRCA1 like patients (HR: 0.94, 95% confidence interval: 0.53-1.67, p: 0.84). The interaction test between IA chemotherapy and marker status was significant (p: 0.04). Conclusions: We provide independent validation of the previous finding that breast cancer patients with a BRCA1 like copy number profile benefit highly from intensified alkylating chemotherapy.
Fibroblast growth factor receptor 1 (FGFR1) and SRY-related HMG-box (SOX2) amplification in squamous cell carcinoma (SCC) of the lung.
Authors: Gasco Amaya , Mendez Pedro , Ramirez Jose Luis , Viteri Ramirez Santiago , Moran Teresa , Carcereny Costa Enric , Costa Carlota , Gimenez Capitan Ana , Sansano Irene , Perez Maria , Tierno Montserrat , Botia Monica , Taron Miquel , Groen Harry J.M. , Rosell Rafael ,   Spanish Lung Cancer Group
Published: March 2020

11025 Background: SOX2 is a key transcription factor that is amplified in lung SCC. FGFR1 is a receptor tyrosine kinase that promotes cell proliferation, survival and apoptotic resistance through the PLCγ/PKC, RAS/MAPK and PI3K-AKT pathways, respectively. FGFR1 is amplified in 15-25% of lung SCC. Pre-clinical studies of targeted inhibitors showed a growth dependency on FGFR1 amplification both in vitro and in vivo. A European, multicenter clinical trial of second-line treatment with BIBF1120, an FGFR1 inhibitor, will be performed in p with lung SCC with FGFR1 amplification. Methods: We have examined FGFR1 and SOX2 gene copy number (GCN) in 76 lung SCC p by multiplex ligation-dependent probe amplification (MLPA). Genomic DNA (gDNA) was isolated from enriched tumor cells by laser capture microdissection from formalin-fixed paraffin embedded (FFPE) tumor tissue. 50-100 ng of gDNA was analyzed in each of three independent replicates per tumor sample. Two independent probe sets were used for each gene analyzed. For inter-patient GCN comparisons, the results from each patient were normalized against the GCN values derived from FFPE peripheral blood leukocytes. In order to study intra-tumor heterogeneity (TH), we examined FGFR1 and SOX2 GCN in different areas of 4 tumors. In 2 p, TH was examined in serial tumor biopsies and/or resections obtained at different points of disease progression. Results: High FGFR1 amplification was detected in 13/76 (17.10%) and low amplification in 7/76 (9.21%) p. High SOX2 amplification was observed in 38/63 (60.32%) and low amplification in 9/63 (14.28%) p. 46.15% of the FGFR1-amplified tumors were also co-amplified for SOX2. Intra-TH was observed in 2/4 tumors. Survival according to FGFR1 and SOX2 GCN will be presented. In addition, GCN changes in FGFR1, SOX2, PIK3CA, PDGFRA, KDR, EGFR and MET over 10 years of follow-up will be presented for one surgically resected SCC lung p. Conclusions: FGFR1 and SOX2 co-amplification could represent a novel therapeutic target and warrants further research.
Applicability of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial results in invasive lobular carcinoma.
Authors: Wang Jun , Mittendorf Elizabeth Ann , Sahin Aysegul A. , Yi Min , Caudle Abigail Suzanne , Hunt Kelly , Wu Yun 
Published: March 2020

1103 Background: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that, for patients with clinical T1-T2, N0 breast cancer and one or two positive sentinel lymph nodes undergoing breast conserving therapy, there was no difference in local-regional recurrence (LRR), disease-free survival or overall survival (OS) between patients who underwent sentinel lymph node dissection (SLND) alone or completion axillary lymph node dissection (ALND). However, there were a limited number of invasive lobular carcinoma (ILC) participants (7%) in the study. In addition, it is known that ILC has a different pattern of metastases, frequently presenting as small foci requiring immunohistochemistry for detection. Together, these considerations raise concern regarding the applicability of the ACOSOG Z0011 data to patients with ILC. Methods: Patients with ILC who met the ACOSOG Z0011 eligibility criteria were identified from the Surveillance, Epidemiology, and End Results database (1998-2009). Patients were evaluated based on the extent of axillary surgery: SLND alone or ALND. Clinicaloutcomes of the two groups were compared. Results: At a median follow-up of 71 months, there were no LRRs in the SLND arm, and only 4 (0.45%) in the ALND arm. There were no differences in OS or disease-specific survival between the two groups. Conclusions: Omission of completion ALND is appropriate in patients with ILC who fulfill the ACOSOG Z0011 eligibility criteria.
A loss of microRNA expression as a characterization of synchronous peritoneal secondary localizations of epithelial ovarian cancer as compared to primary tumors.
Authors: Mezzanzanica Delia , De Cecco Loris , Califano Daniela , Losito Simona , Bagnoli Marina , Franco Renato , Scognamiglio Giosuè , Chiappetta Gennaro , Lorusso Domenica , Raspagliesi Francesco , Canevari Silvana , Pignata Sandro 
Published: March 2020

11037 Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy and one of the most challenging areas of cancer research being a highly heterogeneous disease difficult to diagnose and treat. EOC has a peculiar dissemination process due to the sloughing-off of cells from primary tumors and their spread throughout the peritoneal cavity. A better characterization of the mechanism involved in tumor spreading might help in design new therapeutic intervention. Methods: Forty-four couples of chemo naïf primary tumors and synchronous secondary peritoneal localizations, obtained at primary surgery from MITO2 clinical trial, have been profiled for microRNA (miRNA) expression on an Agilent Platform. Total RNA was extracted from formalin-fixed paraffin embedded tissues. An independent validation set of samples with similar characteristics, has been collected at INT Milan. Results: By class comparison analysis, imposing a false discovery rate <10%,45 miRNAs were identified as differentially expressed: 32 down-modulated and 13 up-modulated in secondary localizations compared to primary tumors. Among the miRNAs down-modulated in the secondary localizations we detected most of the miRNA belonging to the Xq27.3 cluster, whose low expression we previously described to be associated with EOC early relapse, and a number of miRNAs related to epithelial/mesenchimal transition (EMT) whose modulation could be related to dissemination of the disease and response to drug treatment. In particularly loss of has-miR-506 resulted associated to platinum resistance since its ectopic expression in EOC cell lines increased their sensitivity to the drug. Furthermore preliminary data indicated that has-miR-506 regulated N-cadherin linking its modulation to EMT. Conclusions: To our knowledge, the present study is the first attempt to characterize a miRNA signature differentially expressed between EOC primary tumors and synchronous secondary peritoneal localizations. The validation of the miRNA profile as well as of target genes might help in elucidating EOC dissemination mechanisms and in defining possible new therapeutic targets.
Reliability of prognostic and predictive factors evaluated by needle core biopsy for breast cancer in large tumors.
Authors: Petrau Camille , Clatot Florian , Berghian Anca , Veresezan Liana , Cornic Marie , Baron Marc , Callonnec Francoise , Veyret Corinne , Laberge Sophie , Picquenot jean-Michel 
Published: March 2020

1104 Background: Preoperative needle core biopsy (NCB) in breast cancer allows both invasive carcinoma diagnosis and the assessment of the main prognostic/predictive markers. However, large tumors, which may be candidates for preoperative chemotherapy, are potentially more heterogeneous than small ones, and the reliability of these factors measurements by NCB in these cases has been less documented than in whole surgical specimens (SS). The aim of this study was to evaluate the correlation for the main histological and immunohistochemical (IHC) features between NCB and SS in large tumors (>2cm), and to assess major discordances that may impact the therapeutic decisions. Methods: All patients treated in our center for newly diagnosed early breast cancer between January 2008 and December 2011 were retrospectively screened. Large tumors for which both NCB and SS were available were included. Patients treated by preoperative chemotherapy were excluded. The assessed histological and IHC parameters were histological type, SBR grade, estrogen (ER) and progesterone receptors (PR) expression, HER2 status (completed by CISH if needed), intrinsic subtype, and proliferation markers (mitotic activity index (MAI), Ki67). All samples were independently read twice. Comparisons were performed using Kappa test. Results: 163 pairs of NCB-SS were analyzed. Average pathological tumor size was 3.2cm. Correlation was excellent for ER and HER2 (k=0.98 and 0.91 respectively), good for histological type (k=0.74), PR (k=0.79) and intrinsic subtype (k=0.73), but poor for Ki67 (k=0,60), SBR grade (k=0.29) and MAI (k=0.24). Among major discordances, 6 tumors were graded SBR I on NCB but SBR III on SS; 1 tumor was negative for ER on NCB but positive on SS. Importantly, 3 of the 21 HER2 positive cases (14%) were negative after CISH on NCB but positive on SS. Conclusions: Diagnostic NCB in large early breast tumors allows reliable determination of hormonal receptors expression, histological type and intrinsic subtype. SBR grade may however be deeply underestimated by this method, and false negative evaluation of the HER2 status in 14% of HER2 positive patients would have led to a detrimental lack of trastuzumab administration.
The usefulness of UGT1A1 polymorphism testing before starting irinotecan-based chemotherapy.
Authors: Harada Taishi , Saito Haruhiro , Sugiura Makiko , Murakami Shuji , Kondo Tetsuro , Oshita Fumihiro , Yamada Kouzo 
Published: March 2020

11055 Background: A few studies have revealed an association between UGT1A1 genotype and irinotecan-induced neutropenia. However, the usefulness of UGT1A1 polymorphism testing before starting irinotecan-based chemotherapy is controversial, even now. We assessed the clinical usefulness of UGT1A1 polymorphism testing before chemotherapy. Methods: 136 lung cancer patients were treated with nedaplatin and irinotecan combination chemotherapy as initial chemotherapy. Except for the patients with low enzyme activity of UGT1A1, 70 patients were treated after UGT1A1 polymorphism testing. (test group) 66 patients were treated without UGT1A1 polymorphism testing. (non-test group) We retrospectively analyzed adverse events and compared the test group with non-test group. Results: We could not confirm any reduction in hematologic or non-hematologic toxicity statistically in the test group. In 9 patients with non-hematologic toxicity of grade 4 and 5, 6 patients had febrile neutropenia (FN). All patients with FN were older than 70 years old. Adverse events in elderly patients were significantly more frequent than in the non-elderly. Conclusions: In patients treated with nedaplatin and irinotecan combination chemotherapy, UGT1A1 polymorphism testing before starting chemotherapy did not reduce adverse events. With UGT1A1 polymorphism testing only, it was difficult to predict the onset of severe adverse events. Therefore, it is more important to manage adverse events carefully, especially in elderly patients.
PIK3CA mutations in primary HER2-positive and triple negative breast cancer.
Authors: Loibl Sibylle , Denkert Carsten , Loi Sherene , Andre Fabrice , Mueller Berit , Schneeweiss Andreas , Blohmer Jens U. , Jackisch Christian , Sanxing Guo , Gade Stephan , Fasching Peter A. , Schem Christian , Sotiriou Christos , Untch Michael , Von Minckwitz Gunter 
Published: March 2020

11061 Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer (BC), PIK3CA mutations being the most common. Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20). Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2+ve BC. We therefore investigated the frequency and prognostic associations of PIK3CA mutations in HER2+ve and triple negative (TN) primary BC by treated with neoadjuvant therapy. Methods: We prospectively evaluated PIK3CA mutations in the 595 participants of the neoadjuvant Geparsixto study (NCT01426880). The study investigates the effect of adding carboplatin to a liposomal doxorubicin/taxane combination for the treatment of patients with HER2+ve and TN primary BC. All HER2+ve patients received trastuzumab and lapatinib, the TN patients received bevacizumab. HER2, hormone receptors (HR), and Ki67 were centrally assessed. PIK3CAwas genotyped in tumor material from formalin-fixed, paraffin embedded core biopsies taken before therapy using classical Sanger sequencing of exon 9 and 20. Results: From 09/2011 to 11/2012, 595 patients with HER2+ve or TN primary BC have been randomized in the Geparsixto study. Median age was 47 years (range 21-78); most tumors were cT2 (65%); cN0 (57%); ductal invasive (93%), grade 3 (65%); within the HER2+ve group 28% were HR positive. So far, PIK3CA genotype was evaluated in 395 randomized patients - 176 with HER2+ve and 219 with TN disease. Overall, 11.1% were found to have at least one mutation, in HER2+ve: 18.2% and TN BC: 5.5%. An exon 9 mutation was detected in 6.3% of the HER2+ve and 2.7% of the TNBC cases and an exon 20 mutation in 11.9% of the HER2+ve and 3.6% of the TN cases. A mutation in both exons was detected in 2 TN cases. PIK3CAmutations were more frequent in the HER2+ve/HR+ve compared to the HER2+ve/HR-ve group: 22.8% vs 10.6% respectively (p=0.047). Conclusions: PIK3CAmutations are more frequent in HER2+ve then in TN BC which is in line with previous reports. Results on all 595 patients and the correlation with response to therapy (pCR) will be presented at the meeting. The project has been funded within the EU-FP7 project RESPONSIFY No 278659. Clinical trial information: NCT01426880.
Correlation of ERCC1 mRNA expression with KRAS mutation status in colorectal, pancreatic, and lung adenocarcinoma.
Authors: Hanna Diana L. , Maus Martin K. H. , Stephens Craig , Grimminger Peter Philipp , Astrow Stephanie H. , Yang Dongyun , Loupakis Fotios , Hsiang Jack , Zeger Gary , Barzi Afsaneh , Lenz Heinz-Josef 
Published: March 2020

11062 Background: KRAS is mutated in about 40% of colorectal cancers; it is the only validated predictive marker used in patients with metastatic disease. ERCC1 is a critical enzyme in nucleotide excision repair and is associated with response, progression free and overall survival in patients with NSCLC, colorectal, and gastric cancer treated with platinum based chemotherapy. We tested whether ERCC1 mRNA expression correlates with KRAS and BRAF mutation status in patients with colorectal, pancreatic, and lung cancer. Methods: Formalin fixed paraffin embedded tumor specimens from 1,514 patients (573 colorectal; 91 pancreatic; 850 lung) were microdissected; DNA and RNA were extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codons 12 and 13 of KRAS and the V600E BRAF mutation. ERCC1 mRNA expression levels were measured by quantitative RT-PCR in a CLIA approved laboratory. Results: Mt KRAS tumors had significantly lower ERCC1 mRNA levels relative to wt KRAS tumors in both colorectal (0.89 vs. 1.06; p<0.001) and pancreatic (1.20 vs. 1.80; p=0.006) groups. While mt KRAS lung tumors showed decreased ERCC1 expression (1.25 vs. 1.39), the trend did not meet significance (p=0.069). Within the colorectal subset, mt BRAF cancers trended towards less ERCC1 expression than tumors harboring both wt KRAS/BRAF genes (0.96 vs. 1.06; p=0.25). Conclusions: This is one of the first reports linking KRAS mutation status with ERCC1 gene expression in colon, pancreatic and lung cancer. KRAS mutation status may predict sensitivity to platinum based therapy in colon and pancreatic cancer. Colorectal tumors with either the BRAF or KRAS mutation have decreased ERCC1 expression, relative to those that carry both wildtype genes. This may explain the poor sensitivity to oxaliplatin based regimens in these patients. Furthermore, this suggests that ERCC1 expression may be driven by MAPK activation given the uniform ERCC1 downregulation amongst mt KRAS and mt BRAF cancers. Thus, MEK inhibitors may improve the efficacy of oxaliplatin based chemotherapy. Prospective biomarker driven studies should validate these principles, guide clinical decision making and improve outcomes.