bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of TP53 p.R337H mutation in children with cancer from a public hospital in southern Brazil.
Authors: Giacomazzi Juliana , Rossi Cristina , Selistre Simone Geiger , Alemar Barbara , Roth Daniela , Brunetto Algemir Lunardi , Netto Cristina , Goldim Jose Roberto , Hainaut Pierre , Camey Suzi Alves , Ashton-Prolla Patricia 
Published: March 2020

10593 Background: Childhood cancers are a common feature in Li-Fraumeni/Li Fraumeni-Like Syndromes (LFS/LFL), associated with the inheritance of a germline TP53 mutation. Recently, a specific germline mutation in exon 10 of the TP53 gene, p.R337H, has been reported at a high prevalence in Southeastern Brazil. Initial studies on this mutation claimed that the main, if not exclusive, cancer risk in carriers is childhood adrenocortical carcinoma (ADR). However, others recent reports identified p.R377H carriers among LFL families and among a larger spectrum of tumors, such as choroid plexus carcinoma (CPC) and osteosarcoma. The aim of this study was to assess the frequency of the p.R337H mutation in children diagnosed with tumors of the LFS/LFL spectrum: ADR, sarcoma, central nervous system tumors, leukemia, germline cell tumors and Wilm’s tumor) at the Children’s Cancer Institute of Rio Grande do Sul (Brazil) between 1998 and 2011. Methods: Family history (FH) was recorded in pedigrees, and DNA was extracted from peripheral blood and FFPE samples by standard methods. Screening for the p.R337H mutation was performed by allelic discrimination (TaqMan assay) and by TP53 exon 10 sequencing. Results: Analysis of 295 children diagnosed with tumors of the LFS/LFL spectrum identified the p.R337H mutation in 9/11 (81,8%) children with ADR (including a homozygous p.R337H individual) and in 2/2 (100%) children with CPC. All individuals had loss of heterozygosity in the tumor and in all cases the mutant allele occurred on the same founder haplotype. One hundred fourth-six (49,5%) patients had a cancer FH in first or second degree relatives, 47 (16,0%) had a FH of breast cancer and 49 (16,6%) had FH of LFL consistent with Chompret and/or Birch criteria. Conclusions: These results confirm the strong association of p.R337H with ADR and CPC. A FH consistent with LFL syndrome is present in a high proportion of children diagnosed with tumors of the LFS/LFL spectrum in Southern Brazil. Financial support: FIPE-HCPA, CAPES, FAPERGS and Glaxo Smith Kline.
Prognostic value of “angiogenic” risk score in early-stage NSCLC.
Authors: Sanmartin Elena , Jantus-Lewintre Eloisa , Sirera Rafael , Sanchez Jose Javier , Usó Marta , Gallach Sandra , Blasco Ana , Hernando Cristina , Martinez Nieves , Figueroa Santiago , Rolfo Christian Diego , Guijarro Ricardo , Martorell Miguel , Camps Carlos 
Published: March 2020

10594 Background: Angiogenesis is a key mechanism in tumor growth and dissemination mainly regulated by VEGF family members. We analyze the expression of 11 angiogenic genes in a cohort of resectable NSCLC patients and correlate them with clinico-pathological variables and prognosis. Methods: RNA was obtained from tumor and normal lung specimens from 175 NSCLC patients. RT-PCR was performed to assess the expression of HIF1-A, PIGF, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, NRP1 and NRP2. Relative expression was normalized by an endogenous gene (GUS) using the Pfaffl formulae. Differences were considered statistically significant at p<0.05. Results: We found that tumor samples had a significant higher expression of PIGF and lower expression of VEGFD, VEGFR2, and VEGFR3 compared with normal tissue (2.76X, 0.035X, 0.417X and 0.426X, respectively). The group of patients with higher expression levels of VEGFA or PlGF had a significantly reduced TTP (p=0.024 and p=0.027, respectively) and OS (p=0.055 and p=0.048, respectively) whereas those patients with values of VEGFB or VEGFD below the median had reduced TTP (p=0.020 and p=0.135, respectively) and OS (p=0.003 and p=0.089, respectively). The multivariate Cox regression analysis revealed that VEGFA, VEGFB and PlGF were independent prognostic markers for TTP and OS and based on these results we generated an “angiogenic” risk score model. TTP and OS were significantly different among the low, medium and high risk score patients (Table). Conclusions: VEGF family members are master control genes of the angiogenic process and have a crucial role in the prognostic of the disease. We found differences in the expression of four genes between tumor and normal lung samples. An “angiogenic” risk score (based on the expression of PlGF, VEGF-A and VEGF-B) significantly predicts OS and TTP in our cohort of early-stage NSCLC patients. Validation in an independent cohort is needed. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII. [Table: see text]
The efficacy of targeted next-generation sequencing for detection of clinically actionable mutations in cancer.
Authors: Wen Yu-Ye , Fang Erica , Li Yanchun , Carmack Condie Edwin , Li Marilyn M. 
Published: March 2020

10598 Background: The emergence of next-generation sequencing (NGS) technologies has significantly accelerated the identification of cancer-causing mutations and the development of personalized cancer care. However, the clinical application of these technologies to detect cancer gene mutations has been extremely limited due to the long turn around time, the high cost, and large amount of input DNA required by existing NGS-based tests. Methods: We have assessed the performance of a novel NGS technology that merges multiplex PCR with ion semiconductor sequencing (AmpliSeq, Life Technologies, Inc.) in our clinical diagnostic laboratory. The test interrogates 739 common mutations in 46 cancer genes including many clinically actionable mutations concurrently. First, we studied 12 tumor samples including 4 archived FFPE, 4 blood/bone marrow, and 4 cell line samples with known mutations to evaluate the sensitivity and specificity of the test. We then studied 34 de-identified, archived FFPE tumor samples of unknown genotype to further evaluate the efficacy of the test. Results: We successfully identified all known mutations previously detected by Pyposequencing or Sanger sequencing technologies. Multiple serial dilution studies showed that the test could detect mutations at frequencies as low as 5% with 99% confidence. For the samples of unknown genotype, we detected 23 COSMIC mutations in 16 samples including HRAS, BRAF, MET, TP53 mutations in lung cancer, KRAS, PIK3CA, TP53, APC, BRAF, ERBB2 mutations in colon cancer, TP53 and KRAS mutations in breast cancer, and KIT and PDGFRA mutations in GIST. Analysis of the variant call data showed that a minimum of 100X coverage is required in order to detect mutations at 10% frequency or above; a minimum 300K final library reads are necessary in order to minimize/eliminate amplicon dropout. Conclusions: The targeted NGS test can effectively detect cancer gene mutation with input DNA as low as a few nanograms, turn around time can be as short as two days, and can significantly lower cost compared to traditional Sanger sequencing. Our experience demonstrates that this technology holds great potential for clinical use, including diagnostic and therapeutic applications.
Evaluation of the clinical utility of kallikrein-related peptidase 6 gene (KLK6) downregulation in breast cancer.
Authors: Michaelidou Kleita , Tzovaras Alexandros , Tsoukalas Nikolaos , Mavridis Konstantinos , Tsoukalas Grecory , Tsapralis Nikos , Stamatopoulou Sofia , Zylis Dimosthenis , Misitzis Ioannis , Ardavanis Alexandros , Scorilas Andreas 
Published: March 2020

10606 Background: Breast cancer (BC), the most common malignancy among the female population, remains a crucial public health problem. The identification and exploitation of novel molecular biomarkers can contribute in the multidimensional approach which is required for optimal management of BC patients. The abnormal expression of several KLK members has been documented for breast cancer. Interestingly, many of these genes are found to be potential prognostic markers for this malignancy. KLK6 expression is positively associated with tumor progression in various human malignancies; however in breast cancer, it can restrain tumor progression. We therefore sought to investigate the possible clinical value of KLK6 as a breast cancer biomarker. Methods: Total RNA was isolated from 107 breast tumors and their matched normal compartments. After testing the quality of the extracted RNA, cDNA was prepared by reverse transcription. Quantitative Real-time PCR was performed, for KLK6 mRNA quantification, using the SYBR Green chemistry. Relative quantification analysis was made using the comparative Ct (2-ΔΔCT) method. HPRT1 was used as an endogenous control gene and BT-474 breast cancer cell line served as a calibrator. Results: KLK6 mRNA levels were significantly downregulated in the cancerous breast tissue specimens compared to their normal counterparts (p<0.001). Additionally, a negative association was observed between KLK6 expression status and tumor stage, given the fact that 54.2% of less advanced breast tumors (TNM stage≤ T2a) were KLK6-positive compared to the 34.6% of more advanced-stage tumors (TNM >T2a) (p=0.034). Moreover, a statistically significant negative correlation was documented between KLK6 mRNA levels and estrogen (p<0.001) and progesterone receptor (p=0.003) statuses. Conclusions: The downregulation of KLK6 in cancerous compared to normal sections of breast tissue samples reflects the reported tumor suppressor properties of KLK6 gene in breast malignancies. Furthermore, the negative association of KLK6 mRNA expression with tumor stage, ER and PR statuses reveals the putative role of KLK6 as a promising prognostic breast cancer biomarker.
Cytokeratin 19 fragment (CYFRA21-1) to predict the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small cell lung cancer (NSCLC) harboring EGFR mutation.
Authors: Tanaka Kosuke , Hata Akito , Kaji Reiko , Fujita Shiro , Takeshita Jumpei , Matsumoto Takeshi , Monden Kazuya , Nagata Kazuma , Otsuka Kyoko , Nanjo Shigeki , Tachikawa Ryo , Otsuka Kojiro , Hayashi Michio , Tomii Keisuke , Katakami Nobuyuki 
Published: March 2020

10610 Background: EGFR mutation is independently associated with a favorable response in NSCLC patients receiving EGFR-TKIs, regardless of gender or smoking history. However, recent reports have indicated that squamous cell carcinoma patients harboring EGFR mutations show a worse response to EGFR-TKIs than adenocarcinoma patients. We hypothesized that serum CYFRA21-1 is a predictive marker in EGFR mutated patients treated with EGFR-TKIs. Methods: We retrospectively screened 160 NSCLC patients harboring EGFR mutations (exon 19 deletions, L858R in exon 21, or other minor mutations) who received either gefitinib or erlotinib between 1992 and 2011. Patients were screened for histology, sex, age, smoking status, efficacy of EGFR-TKI and tumor markers (CEA/CYFRA21-1) at initial diagnosis. Results: Out of 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA21-1 level (>2 ng/ml) showed statistically shorter progression-free survival (PFS) than 83 patients with normal CYFRA21-1 level (median PFS 7.5 vs 14.0 months, p=0.006). No significant difference in PFS was observed between high CEA group (>5 ng/ml) and normal CEA group (median PFS 8.6 vs 11.2 months, p=0.2423). Multivariate analysis revealed that high CYFRA21-1 level is independently associated with PFS (HR 1.35; p=0.002) as well as squamous cell carcinoma (HR 1.40; p=0.020) and performance status 2-4 (HR 2.63; p=0.003). No statistically significant difference in overall survival (OS) was observed between high CYFRA21-1 group and normal group (median OS 24.8 vs 39.1 months, p=0.104). Conclusions: High CYFRA level patients have significantly shorter PFS, which may indicate that this subgroup has a larger squamous component and thus less response to EGFR-TKIs. Serum CYFRA21-1 level is a predictive marker of EGFR-TKIs efficacy and EGFR mutated patients can be divided into two subgroups according to CYFRA21-1 level at initial diagnosis.
Evaluation of EZH2 SNPs in cholangiocarcinoma patients.
Authors: Paolicchi Elisa , Pacetti Paola , Giovannetti Elisa , Mambrini Andrea , Orlandi Massimo , Crea Francesco , Tartarini Roberta , Vasile Enrico , Danesi Romano , Peters Godefridus J , Cantore Maurizio 
Published: March 2020

10611 Background: Cholangiocarcinoma (CCA) is an aggressive tumor arising from biliary tract epithelium.CCA is the second most common primary hepatic malignancy, with a progressive increasing incidence in western countries. Polycomb group protein Enhancer of Zeste homolog 2 (EZH2) is overexpressed in several human carcinomas, including CCA, where EZH2 overexpression is associated with tumor progression. The aim of this study is to evaluate the correlation between candidate EZH2 Single Nucleotide Polymorphisms (SNPs) with clinical outcome in CCA patients. Methods: Genomic DNA was extracted from blood samples of 75 patients [44 male and 31 female, with average age of 62.3 (range, 26-80 years)] affected by hystologically confirmed advanced CCA, treated with the epirubicin-cisplatin-xeloda (ECX) regimen. We performed an in silico characterization to select EZH2 SNPs (rs2302427 C/G, rs6464926 C/T, rs17171119 T/G and rs887569 C/T) from 26 EZH2 SNPs described previously. Genotyping was performed through Taqman PCR. Prognostic value of selected EZH2 SNPs was assesses by correlation with time to progression (TTP) and overall survival (OS). OS and TTP curves were obtained through Kaplan-Meier method, and comparison with survival distribution was evaluated with logrank test. Results: Through specific software (PROMO 3.0, MicroSNiper and Gene Card) we performed an in silico analysis based on functional characterization criteria (transcription factor binding-TFB, miRNA binding and missense mutations). We selected 4 EZH2 SNP alleles showing specific relevance in CCA because of their differential TFB affinity (PPARα/RXRα, E2F-1, Pax-5 and p53). The rs887569 C/T SNP was significantly associated with clinical outcome. The TT genotype predicted a significantly longer OS in CCA patients (TT vs CT-CC p=0.026). Moreover, the TT genotype showed a trend-like association with reduced risk of death (HR=0.59, 95%CI=0.33-1.05, p=0.075), at multivariate analysis. Conclusions: These results suggest the role of rs887569 EZH2 SNP as a possible predictive marker of OS in advanced CCA patients treated with ECX regimen, and offer a potential new tool for treatment optimization.
Effect of everolimus on angiogenic biomarkers in patients with tuberous sclerosis complex (TSC): Results from EXIST-1 and EXIST-2.
Authors: Franz David Neal , Kingswood Christopher , Jozwiak Sergiusz , Budde Klemens , Belousova Elena , Sparagana Steven , Zonnenberg B. A. , Frost Michael , Shah Gaurav D. , Lebrec Jeremie , Ford James , Kalfoglou Creton , Chen David , Bissler John 
Published: March 2020

10619 Background: The efficacy and safety of everolimus, an oral mTOR inhibitor, was assessed in two randomized, double-blind, placebo-controlled, phase 3 trials: EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400). EXIST-1 examined everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) associated with TSC and EXIST-2 for the treatment of renal angiomyolipoma (AML) associated with either TSC or sporadic lymphangioleiomyomatosis. In each instance, everolimus was superior to placebo for the primary endpoints, SEGA and renal AML response rates. Inhibitors of mTOR have antiangiogenic effects on tumor growth in vitro and in vivo. Methods: Patients were randomized to receive everolimus (n=78) starting at 4.5 mg/m2/day (target trough, 5-15 ng/mL) or placebo (n=39) in EXIST-1 and 10 mg/day everolimus (n=79) or placebo (n=39) in EXIST-2. Plasma samples were taken at baseline and pre-dosing on day 1 of weeks 4, 12, 24, 36, and 48 of treatment. Angiogenic markers of interest were vascular endothelial growth factor (VEGF)-A and -D, placental growth factor (PlGF), soluble VEGF receptor-1 (sVEGFR1), soluble VEGF receptor 2 (sVEGFR2), c-Kit, and collagen type IV. Results: Compared with placebo, a sustained ~30% and ~60% increase in VEGF-A was observed in the everolimus arm of EXIST-1 and EXIST-2, respectively. A concomitant decrease in collagen type IV (~25% EXIST-1; ~45% EXIST-2) and sVEGFR2 (~25% both trials) was also observed in the everolimus arm. A sustained decrease (~60%) in VEGF-D was observed in the everolimus arm of EXIST-2, but not EXIST-1. In both studies, no change was observed in PlGF, sVEGFR1, or c-Kit plasma concentrations in the everolimus arm or any biomarkers evaluated in the placebo arm. Baseline sVEGFR2 and VEGF-D were ~40% and ~4-fold higher, respectively, while VEGF-A was ~50% lower in EXIST-2 compared with EXIST-1. A similar baseline plasma concentration for the other biomarkers was noted in both studies. Conclusions: Patients presenting with SEGA or renal AML associated with TSC had a reduction in plasma concentrations of sVEGFR2, collagen type IV, and VEGF-D (AML only) and an increase in VEGF-A. Everolimus may have antiangiogenic properties in TSC patients.
Cost-effectiveness analysis using a Markov model assessing the addition of bevacizumab to paclitaxel in HER2-negative metastatic breast cancer patients.
Authors: Refaat Tamer , Choi Mehee , Gaber Germaine , Small William , Kiel Krystyna D. 
Published: March 2020

1069 Background: Metastatic breast cancer (MBC) remains an incurable disease despite advances in treatment modalities. In 2008, Eastern Cooperative Oncology Group 2100 trial (E2100) results led to FDA approval for bevacizumab with paclitaxel in the initial treatment of HER2-negative MBC. The addition of bevacizumab to paclitaxel led to a gain of around 2.5 months of progression-free survival (PFS), no significant benefit on overall survival (OS), and increased toxicity. In November 2011, the FDA officially revoked approval of bevacizumab for HER2-negative MBC. However, both the European Medicines Agency (EMEA) and NCCN still endorse bevacizumab for this indication. One of the greatest challenges facing healthcare worldwide is reconciling incremental clinical benefits with exponentially rising costs. This study aimed to assess the cost-effectiveness of bevacizumab with paclitaxel for HER2-negative MBC. Methods: A Markov decision tree using Data 3.5 (TreeAge Software, Inc.) was created to do decision and cost-effectiveness analyses of using bevacizumab in combination with paclitaxel versus paclitaxel alone as first-line chemotherapy in HER2-negative MBC using efficacy and toxicity data from the E2100 study. Costs were obtained from the Center for Medicare Services Drug Payment Table and Physician Fee Schedule. The model was designed from the patient and payer perspectives and sensitivity analyses were run. Results: The marginal cost between paclitaxel alone versus bevacizumab and paclitaxel was 86K with a marginal efficacy of 0.369 quality-adjusted life-years and marginal cost effectiveness of 232,720.72 USD. The expected outcome value was 1.86 for bevacizumab and paclitaxel and 1.67 for paclitaxel alone. However, the combination was not cost effective and only a marginal survival advantage that was not significant was observed. Conclusions: This study demonstrates that, despite a significant PFS advantage, the addition of bevacizumab to paclitaxel is not cost-effective for patients with HER2-negative MBC. Such data could be informative to policymakers who consider the health economics and incremental cost-effectiveness of medical therapies.
Phase I trial of ixabepilone and vorinostat in metastatic breast cancer.
Authors: Luu Thehang H. , Blanchard Suzette , Beumer Jan Hendrik , Anyang Bean N. , Somlo George , Mortimer Joanne E. , Hurria Arti , Yang Lixin , Yen Yun 
Published: March 2020

1070 Background: VOR, an HDAC inhibitor, induces acetylation of tubulin, and decreases resistance by attenuating downstream activation of AKT, c-Raf and HER-2. Patients (pts) with MBC treated with VOR had a TTP of 8.5 months (range 4-14) and stable disease in 29% (Luu et al., 2008). Our preclinical data showed synergistic effect of IXA and VOR in MDA-MB-231 and MCF7. Methods: The primary aims were to: 1) define the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT), and 2) describe the pharmacokinetics (PK) of 2 schedules of VOR and IXA. Secondary aims were to describe: 1) response rate (RR) and 2) clinical benefit rate (CBR). The study included: 1) pts with MBC; 2) ECOG PS 0-2; 3) adequate marrow and organ functions; 4) no prior IXA or VOR; and 5) < grade (gr) 1 neuropathy. Stable brain metastasis were allowed. Pts were randomized to schedule A: VOR (QDx14) + IXA (D2) Q21D; or B: VOR (D1-7 and 15-21) + IXA (D2, 9, 16) Q28D. A modified toxicity probability interval design (target toxicity rate= 0.2 and equivalence range +/- 0.05) (Ji et al, 2010) determined dose escalation guidelines. PK were assessed with LC-MS/MS assays. Results: Among 37 pts randomized, 36 were evaluable [median age (55 yrs); median prior chemotherapy regimens (3); ER and/or PR + (64%); HER2 + (19%)]. In cohort A, 16 pts were treated (1 inevaluable). The MTD was: VOR 300mg (QDx14) + IXA (32mg/m2 D2) Q21D (dose level 1). DLT was experienced by 27% (4/15) pts [gr 4 neutropenia, gr 3 fatigue/AST, hyponatremia and allergic reaction to IXA]. In cohort B, 21 pts were treated (dose level 1, n=15; dose level 2, n=6). The MTD was VOR 300mg QD (D1-7 and 15-21) + IXA 16mg/m2 (D2, 9, 16) Q28D (dose level 1), no DLTs were observed. Dose level 2 was closed with 50% (3/6) of pts experiencing DLTs [gr 3 neutropenia, hypertension, and hypokalemia]. Median cycles treated (cohort A: 6, cohort B: 4). Response in cohort A and B respectively was: 1 CR, 2 PR, 7 SD (RR: 20%, CBR: 67%) and 1 CR, 4 PR, 9 SD (RR: 33%, CBR: 93%). VOR and IXA PK were not influenced by the presence of the other drug, clearance values= 220 L/h and 20 L/h/m2, respectively. Conclusions: We established the MTD of VOR and IXA in pts with MBC. The combination demonstrated clinical activity in these heavily pretreated pts. Further studies are recommended.
Impact of the delivery of adjuvant anthracycline-based nontaxane chemotherapy schedules on the outcome of breast cancer patients: Results from a retrospective database analysis.
Authors: Chirivella Isabel , Bermejo Begona , Insa Amelia , Perez-Fidalgo Jose Alejandro , Magro Ana , Rosello Keranen Susana , Martin Paloma , Bosch Ana , Lluch Ana 
Published: March 2020

1074 Background: A dose-response effect has previously been observed with CMF and anthracycline-based schedules. The objective of this post-hoc analysis was to give additional information on the impact of chemotherapy delivery on patients’ outcome. Methods: Selection criteria were to have early breast cancer (stage I-IIIA) from Jan 1980 to Dec 2000, to undergo surgery as primary treatment and to receive an anthracycline-based non-taxane schedule in the adjuvant setting. G-CSF support was not given to any patient. Chemotherapy delivery was assessed based on ≥ 2 vs. < 2 delayed cycles, ≥ 15 vs. <15 delayed days and < 85% vs. ≥ 85% of the relative dose intensity (RDI) given. Patients’ outcomes were assessed based on 5- and 10-year disease-free survival (DFS) and overall survival (OS) rates. Results: 793 breast cancer patients with a median age of 51 years (21-79) were analyzed of whom 27% had stage IIIA and 23% had stage I disease. As shown in the table, 5- and 10-year rates of DFS and OS significantly improved when adjuvant chemotherapy was optimally delivered. Conclusions: The dose-response effect is a key factor that should be taken into account when an anthracycline-based non-taxane chemotherapy is administered in the adjuvant setting. Delays and/or reductions of chemotherapy should be avoided in order to achieve the maximal benefit for the patient. This study was partially funded by Amgen SA. [Table: see text]