bluuebunny/crossref_metadata_2025_split huggingface dataset:
Online biomarker validation of survival-associated biomarkers in breast and ovarian cancer using microarray data of 3,862 patients.
Authors: Gyorffy Balazs , Lanczky Andras , Szallasi Zoltan 
Published: March 2020

10571 Background: The pre-clinical validation of prognostic gene candidates in large independent patient cohorts is a pre-requisite for the development of robust biomarkers. Today, curated microarray cohorts combined with appropriate clinical data offer a cost effective tool to prescreen potential new biomarkers. In present study we expanded our online Kaplan-Meier plotter tool to assess the effect of genes on ovarian cancer prognosis. Methods: Gene expression data and survival information of breast and ovarian cancer patients were downloaded from GEO and TCGA. To analyze the prognostic value of the selected gene in the various cohorts the patients are divided into two groups according to the quantile expression of the gene. Filtering is implemented for stage, grade, and histology subtypes. Follow-up threshold is implemented to exclude long-term effects. A Kaplan-Meier survival plot is generated and significance is computed in the R statistical environment using Bioconductor packages. The combination of several probe sets can be employed to assess the mean of their expression as a multigene predictor of survival. Results: All together 1,390 ovarian cancer patients and 2,472 breast cancer patients were entered into the database. These groups can be compared using relapse free survival (n=2,324 in breast cancer and 1,090 in ovarian cancer) or overall survival (n=464 and n=1,287). We used this integrative data analysis tool to validate the prognostic power of 37 ovarian cancer associated biomarkers identified in the literature. Of these, CA125 (p=3.7e-5, HR=1.4), CDKN1B (p=5.4e-5, HR=1.4), KLK6 (p=0.002, HR=0.79), IFNG (p=0.004, HR=0.81), P16 (p=0.02, HR=0.66) and BIRC5 (p=0.00017, HR=0.75) were associated with survival. Conclusions: We set up a global online biomarker validation platform to mine all available microarray data to assess the prognostic power of 22,277 genes in 2,472 breast and 1,390 ovarian cancer patients. Registration-free online access at: http://www.kmplot.com/.
A gene expression profile test that distinguishes ovarian from endometrial cancers.
Authors: Lal Anita , Panos Rebecca , Marjanovic Mira , Walker Michael , Fuentes Eloisa , Kapp Daniel Stuart , Henner William David , Buturovic Ljubomir J , Miller Meredith Halks 
Published: March 2020

10576 Background: The differential diagnosis between primary epithelial ovarian and endometrial cancers is often unresolved because the histologic subtypes of these two tumor types can have very similar histology and immunohistochemical appearance. Here we report the development and validation of a gene expression profile (GEP) diagnostic test (Pathwork Tissue of Origin Endometrial Test) that distinguishes ovarian and endometrial cancers in formalin-fixed, paraffin-embedded (FFPE) specimens using a 316–gene classification model. Methods: The test was clinically validated in a blinded study using a pre-specified algorithm and microarray data files for 75 metastatic, poorly differentiated or undifferentiated primary FFPE tumor specimens that had either a known clinical diagnosis of ovarian or endometrial cancer and belonged to one of the 14 ovarian and endometrial WHO histologic subtypes on the test panel. Results: Classification biomarkers, empirically selected by machine learning, included several genes such as homeobox transcription factors and kallikrein peptidases with known function in the biology of ovarian and endometrial cancers. The Tissue of Origin Endometrial Test accurately identified the primary site for 94.7% (95% CI, 87% to 99%) of ovarian and endometrial cancers. Other measures of test performance include an area under the ROC curve of 0.997 and a diagnostic odds ratio of 406. Test performance did not change significantly when stratified by specimens from metastases (90.5%) or by poorly differentiated and undifferentiated primary tumors (96.3%). All stages of ovarian and endometrial cancers were included in the validation study and had agreements of 85% to 100% with the clinical diagnosis. In a precision study, concordance in test results was 100%. Reproducibility in test results between three laboratories had a concordance of 94.3%. Conclusions: The GEP test identified specific ovarian and endometrial cancer morphologies even when a clear distinction could not be made by histologic criteria. The GEP test can aid in resolving an important differential diagnostic question in gynecologic oncology and may impact clinical management of these patients as well as entry opportunities into clinical trials.
Specific and sensitive detection of BRAF and KRAS mutations in clinical samples.
Authors: Kelchner Vanessa , Chupreta Sergey , Mishra Anjali , Beaubien Ron , Kurihara Laurie , Laliberte Julie , Mikheykin Andrey , Beer David G. , Makarov Vladimir 
Published: March 2020

10587 Background: The development of highly sensitive and specific genotyping assays that are suitable for clinical research and molecular diagnostics opens new opportunities for the detection, assessment, and research of cancer. Swift Biosciences has developed myT Primer qPCR technology which has unique structural and thermodynamic properties that enables highly sensitive mismatch discrimination. The myT Primer reagents can detect 1% mutant BRAF or KRAS present in a background of 103 wild-type genomic DNA copies with no background signal from wild-type. A separate ultrasensitive BRAF format has been developed which enables the detection of a single mutant BRAF copy in > 104 wild-type genomic DNA copies, representing 0.01% detection. Methods: To evaluate the performance on clinical samples, DNA was prepared from 26 melanoma, 40 colorectal, and 49 lung tumor fresh frozen and FFPE samples, and their corresponding normal adjacent samples. qPCR was performed using standard cycling conditions in single tube format with allele-specific myT primers to assess two BRAF alleles or seven KRAS alleles. Performance of the assay was evaluated on the ABI 7500, CFX96, and Roche LightCycler. A subset of samples were selected for validation by Sanger sequencing. Results: Mutations of BRAF in melanoma, colorectal, and lung tumors were observed to be 46%, 5%, and 2%, in concordance with published data for the frequency of BRAF mutations. Mutations of KRAS in colorectal cancer were observed to be in 17/40, or 42% of samples, consistent with published reports of KRAS in colorectal cancer. 34% of lung cancer samples had a KRAS mutation, also consistent with available statistics. Mutation status was confirmed with Sanger sequencing in the subset of selected samples. Conclusions: The extreme selectivity of the myT BRAF Primers makes them well suited for genotyping of conventional FFPE and frozen tissue samples, whereas the ultrasensitive format is ideal for use with difficult samples such as needle biopsies, CTCs, and serum. The extreme selectivity of these primers results in a definitive Yes/No answer and eliminates the need to use a delta Ct method.
Activation of angiogenic pathway in the prediction of pathologic response to bevacizumab-based neoadjuvant therapy in breast cancer.
Authors: Lopez-Vega Jose Manuel , Calvo Elena Galve , Plazaola Arrate , Morales Serafin , Hernando Blanca , Gomez Rosa Maria Sanchez , Alvarez Isabel , Anton Antonio , Illarramendi Jose J. , De Juan Ana , Martinez Purificación , Lahuerta Ainhara , Llombart Cussac Antonio , Garcia Gonzalez Maria , Lao Juan , Boni Valentina , Puertolas Teresa , Sherer Stefan , Sabariz Luis , Garcia-Foncillas Jesus 
Published: March 2020

10595 Background: To evaluate potential biomarkers of pathological response to bevacizumab-based neoadjuvant therapy in untreated breast cancers (BC) patients recruited in a phase II, multicenter clinical trial. Methods: Patients received a single infusion of bevacizumab (15 mg/ kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy (NAC) consisting in 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/ kg) every 21 days (C2-C5) following by surgery. Biomarker expression was assessed by immunohistochemistry (Ki67, CD31, CD31/Ki67, VEGFR2, pVEGFR2 [Y951]) before and after bevacizumab infusion (C1). Gene expression was analyzed using Affimetrix Human Gene ST 1.0. Results: This analysis was performed on 73 patients (49 yr, range 29-70). Twenty (27%) patients obtained best response (G4-G5) whether 50 (68%) were considered as no responder (G1-G2-G3). Response was associated with negative estrogen receptors expression (p=0.02) and high Ki67 basal and after C1 expression (p=0.009 and p=0.01). Six (54%) of the triple negative tumors were responders (p=0.05). Interestingly, change in pVEGFR2 [Y951] staining induced by bevacizumab administration was found significantly associated with response (p=0.0). Decrease in the phosphorilation status of VEGFR2 (Y951) >70% yielded a receiver operating characteristic (ROC) curve area of 0.681 (95% CI: 0.536 - 0.825) with 84% sensitivity and 95% specificity. The positive and negative predictive values for this marker were 60% and 64%, respectively. The change in phosphorilation status of VEGFR2p remains a significant predictor biomarker of response in multivariate analysis (OR=0.9, IC%95 0.96-0.99, p=0.04) after adjusting for clinical-pathological characteristics. Conclusions: These findings suggest the role of the phosphorilation status of VEGFR2 as predictive biomarkers of pathological response to bevacizumab in neoadjuvant setting in breast cancer.
Response and long-term outcomes after neoadjuvant chemotherapy: Pooled dataset of patients stratified by molecular subtyping by MammaPrint and BluePrint.
Authors: Gluck Stefan , De Snoo Femke , Peeters Justine , Somlo George , Van T Veer Laura 
Published: March 2020

10597 Background: Classification of breast cancers into molecular subtypes may be important for the proper selection of therapy for patients with early breast cancer. Previous analyses had shown that breast cancer subtypes have distinct clinical outcome (Sorlie, PNAS, 2001; Esserman, BCRT, 2011). Herein, we analyze using MammaPrint together with an 80-gene molecular subtyping profile (BluePrint) the response to neo-adjuvant chemotherapy and long term outcomes. Methods: This study was carried out on data from 144 patients from the I-SPY I trial; 232 patients from biomarker discovery program at MD Anderson (133 and 99 respectively; Hess, 2006, JCO; Iwamoto, 2011, BCRT); and 68 patients from City of Hope (Somlo, ASCO, 2010). All patients were treated in the neo-adjuvant setting with standard chemotherapy. MammaPrint and BluePrint were determined on 44K Agilent arrays run at Agendia or available through the I-SPY 1 data portal, or from Affymetrix U133A arrays. MammaPrint and BluePrint resulted in 4 distinct molecular groups: Luminal A (MammaPrint Low-risk/Luminal-type), Luminal B (MammaPrint High-risk/Luminal-type), Basal-type and HER2-type. Results: The overall pCR of this patient cohort was 22% but differed substantially among the subgroups. pCR was observed in 5% of the Luminal-A samples and 10% of Luminal-B, in 39% of the HER2-type samples and in 33% of the Basal-type samples. Patients with Basal-type tumors had a 5-year DFS of 71%; HER2-type had a 5-year DFS of 67%(n=71); 69% in HER2-type subgroup not treated with HER2-targeted therapy (n=45); Luminal-B type had a 5-year DFS of 77% and Luminal-A type showed 5-year DFS of 95%. Conclusions: We observed marked differences in response and DFS to neo-adjuvant treatment in groups stratified by MammaPrint and BluePrint. These findings confirm differences in chemotherapy response among molecular subgroups and indicate that the BluePrint and MP profile used for this analysis helps to further establish a clinical correlation between molecular subtyping and treatment outcomes.
Correlation between in vitro chemotherapy sensitivity and PARP-1 expression in patients with breast cancer.
Authors: Liedtke Cornelia , Packeisen Jens , Denkert Carsten , Kiesel Ludwig , Vogt Ulf , Mueller Berit , Hess Kenneth R. , Buerger Horst 
Published: March 2020

10627 Background: Based on its potential use as a therapeutic target through PARP inhibitors expression of Poly-A-Ribose-Polymerase-1 (PARP-1) has come into scientific focus. Furthermore, it could be demonstrated that cytoplasmic PARP-1 expression varies depending on molecular breast cancer subtypes and that it correlates with an increased response to neoadjuvant taxane-anthrazykline containing chemotherapy (von Minckwitz et al., J Clin Oncol 2011). In-vitro-chemotherapy sensitivity and resistance assays (CSRAs) are a means to directly measure chemotherapy sensitivity in a given tumor uninfluenced by host factors. Methods: We conducted a systematic immunohistochemical tissue-microarray (TMA)-based analysis of 550 samples of invasive breast cancers to evaluate the expression of a set of molecular markers including estrogen receptor (ER), progesterone receptor (PR) and HER2 as well as PARP-1. Triple negative breast cancers (TNBC) were identified through lack of (over-)expression of ER, PR and HER2. All carcinomas were analyzed in an in vitro CSRA protocol for epirubicin/docetaxel (ED) and epirubicin/cyclophosphamide (EC). In-vitro-chemotherapy sensitivity was analyzed using an adenosine triphosphate (ATP) bioluminescence assay. Results: Moderate/high expression of PARP-1 was found in 48 and 33% of cases with TNBC and non-TNBC, respectively (p=0.015). No correlation between TNBC phenotype and cytoplasmic expression was observed. However, increased expression of both cytoplasmic and nuclear PARP-1 was correlated with an increased in-vitro sensitivity against ED (p=0.012 and 0.025, respectively) but not EC (p=0.27 and 0.62, respectively). Conclusions: Our results support previous observations demonstrating a significant correlation between expression of PARP-1 and an increased sensitivity against taxane-anthracycline chemotherapy independent of tumor phenotype.
Chemotherapy of methioninase-synchronized S/G2 phase-blocked cancer cells identified by cell cycle-specific fluorescent reporters.
Authors: Yano Shuya , Li Shukuan , Han Qinghong , Tan Yuying , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: March 2020

1063 Background: Cancer cells of all types have a generally elevated requirement for methionine compared to normal cells. This phenomenon is termed methionine-dependence and may be due to excessive methylation reactions in cancer cells, since methionine is the global source of cellular methyl groups (Biochim. Biophys. Acta, Reviews on Cancer 738, 49-87, 1984). Deprivation of methionine selectively arrests cancer cells during late S-phase (Proc. Natl. Acad. Sci. USA 77, 7306-7310, 1980), where they are highly sensitive to chemotherapy drugs which damage DNA (J. Natl. Cancer Inst. 76, 629-639, 1986). Methods: Cancer cells, transformed to express different color fluorescent reporters during specific phases of the cell cycle (Cell 132, 487-498, 2008), were used to monitor the onset of the S/G2-phase block due to methionine deprivation effected by recombinant methioninase (rMETase). The S/G2-phase blocked cancer cells fluoresced yellow or green in contrast to cancer cells in G1 which fluoresced red. Cancer cells, including MKN45 stromal cancer and MCF-7 breast cancer, synchronously blocked in S/G2-phase by rMETase, were identified by their yellow-green fluorescence and allowed to accumulate to the maximum extent. At the point of maximum yellow/green cells in the culture, the cells were administered chemotherapy drugs which interact with DNA or block DNA synthesis such as doxorubicin, cisplatin or 5-fluorouracil. We termed this procedure color-coded chemotherapy (CCC). Results: CCC was highly effective against the cancer cells (90% cell kill). In contrast, treatment of cancer cells with drugs only, and without rMETase-effected S/G2-phase synchrony, led to the majority of the cancer cell population being blocked in G1 phase (red fluorescent) where they were resistant to the drugs (40% cell kill). Conclusions: CCC, which identifies, by fluorescent color, when cancer cells are blocked in S/G2-phase by a unique cell-cycle-blocking agent, rMETase, demonstrates the potential of cell-synchronization-based chemotherapy.
Analysis according to prognostic factors in patients (pts) treated with first-line bevacizumab (BEV) combined with paclitaxel (PAC) for HER2-negative metastatic breast cancer (mBC) in a routine oncology practice study.
Authors: Schrader Iris , Foerster Frank Gerhard , Schneeweiss Andreas , Geberth Matthias , Hahn Lars , Schumacher Claudia , Hertz-Eichenrode Martin Michael , Schoenegg Winfried , Wolfgarten Matthias Kim , Kutscheidt Andreas , Schmidt Marcus , Aktas Bahriye 
Published: March 2020

1077 Background: 1st-line BEV combined with weekly PAC significantly improves progression-free survival (PFS) and response rate (RR) vs PAC alone in HER2-negative mBC, as shown in E2100. We analyzed data from a German routine oncology practice study of 1st-line BEV–PAC according to prognostic factors. Methods: Pts who had received no prior chemotherapy for mBC received BEV–PAC according to the European label. Efficacy and safety were documented for up to 1 y (or until progression, death, or BEV discontinuation if earlier) with additional long-term follow-up. Efficacy was analyzed in clinically important subgroups. Results: Efficacy data were available for 818 pts. The median duration of follow-up was 11.4 mo. The composition of the pt population with respect to the subgroups below was generally similar to the population treated in E2100, except for a higher proportion of pts with visceral disease or metastases in <3 organs. RR was very similar across all subgroups analyzed. Differences in median PFS and OS were generally in line with the differing prognoses according to clinical characteristics. Conclusions: These data suggest that 1st-line BEV–PAC is typically associated with median PFS >9 mo in the real-life setting, irrespective of baseline characteristics. [Table: see text]
Trends in the use of breast-conserving surgery and adjuvant radiation therapy in patients with DCIS: A U.S. population-based analysis from 1996 to 2007.
Authors: Nishimura Jennifer , Choi Audrey , Kim Sharon , Kim Julian 
Published: March 2020

1031 Background: The treatment for patients with DCIS remains controversial. Current guidelines based upon best available evidence suggest that breast conserving surgery (BCS) followed by adjuvant radiation therapy (RT) result in acceptable local control and breast cancer specific survival. The purpose of this study was to analyze trends in patterns of care as well as identify factors associated with surgery type and use of adjuvant radiation therapy in a select cohort of patients enrolled into the SEER database. Methods: The study included females 18 years and older with focal DCIS and known tumor size of 5 cm or less diagnosed between 1996 and 2007. The Cochran-Armitage trend test was applied to identify trends in the use of BCS and RT over time. Multivariate logistic regression analyses were used to determine factors associated with receiving BCS vs. mastectomy and BCS plus RT vs. BCS alone. Cox proportional hazard model was used to determine associations with breast cancer-specific mortality. Results: Of the 34,233 women with DCIS, 76.59% were treated with BCS. 66.36% of BCS patients received adjuvant RT over the study period. The proportion of women receiving BCS increased from 71.5% in 1996 to 76.9% in 2007 (p<0.0001). Additionally, the proportion of women who underwent BCS and received adjuvant radiation therapy over the same time period increased from 55.3% to 69.7% (p<0.0001). Multivariate analysis demonstrated that year of diagnosis, race, marital status, geographic region, tumor size, tumor grade and comedo necrosis all were significantly associated with the use of adjuvant radiation therapy, but age was not. Cox proportional hazards models did not associate either surgery type or use of adjuvant radiation in patients undergoing BCS with breast cancer-specific mortality. Conclusions: Based upon reporting within the SEER database, the proportion of DCIS patients undergoing BCS and the BCS patients receiving adjuvant radiation increased over the study time period. Surgery type and use of adjuvant radiation therapy in patients with BCS was not associated with decreased risk of breast-cancer specific death in this cohort.
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) as early imaging biomarker of axillary sentinel lymph node (SLN) status in locally advanced node-positive breast cancer (NPBC) patients (pts) receiving neoadjuvant chemotherapy (NACT).
Authors: Dockx Yanina , Huizing Manon Thirza , Van Den Wyngaert Tim , Altintas Sevilay , Huyghe Ivan , Geboers Inge , Vervliet Johan , Molderez Christoph , van Goethem Mireille , van Marck Veerle , Sonnemans Hetty , Tjalma Wiebren 
Published: March 2020

1129 Background: Use of FDG-PET in the early evaluation of NACT for NPBC is currently under investigation. The aim of this study is to assess FDG-PET in NPBC pts receiving NACT in order to identify a subset of pts that can be spared axillary lymph node dissection (ALND) in case of response. Methods: All pts (period 2009-2011) had [cT2 (≥3cm)-T4, pN1-3], and no prior BC treatment. All pts received 8 cycles (cy) of NACT +/- trastuzumab. FDG-PET was performed at baseline and after 2 cy. After NACT, mastectomy with SLN and ALND was peformed. As primary endpoint, the change in maximum standardized uptake value (SUVmax) in the primary tumor (PT) and ALNs was compared with pathological response (Jonckheere-Terpstra test). Logistic regression was used to determine the predictive value of a 50% reduction in SUVmax on pathological response and SLN status. Results: Forty-one pts were evaluable for the primary endpoint and 31 pts had successful SN procedures. The median age was 49.8 years (range 27-75). Overall, 9.8% (4/41; 95% CI 2.7 – 23.1) of pts had progressive disease (PD), 7.3% (3/41 ; 95% CI 1.5 – 19.9 ) stable disease (SD), 53.7% (22/41; 95% CI 37.4 – 69.3) partial response (PR), and 21.9% (9/41; 95% CI 10.6 – 37.6) a complete pathological response (pCR). A linear trend existed between pCR and higher decreases in SUVmax of the PT site (p=0.008), but not with lymph node SUVmax (p=0.294). The odds of achieving a pCR, increased significantly when SUVmax of the PT decreased with >50% (OR 10.7; 95% CI 1.2 - 98.0; p=0.03), but not lymph node SUVmax (OR 4.75; 95% CI 0.82 - 27.5; p=0.08). Achieving a true negative SLN status was more likely with >50% reductions in PT SUVmax (OR 41.2; 95% CI 4.0 - 421.9; p= 0.002). A reduction of >50% in nodal SUVmax was not predictive of negative SLN status (OR 3.33; 95% CI 0.66 - 16.8; p=0.1). Conclusions: Early changes in PT metabolism imaged with FDG-PET after only 2 cy of NACT is a promising biomarker in the management of the axilla in NPBC. Molecular imaging of PT biology and to a lesser extent of axillary lymph nodes using FDG-PET warrants further study.