bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liquid biopsy-based assays to monitor residual disease in cancer.
Authors: Mei Gangwu , Sebisanovic Dragan , Mir Alain , Gulzar Zulfiqar , Brooks James D. , Jeffrey Stefanie S. , Talasaz AmirAli 
Published: March 2020

11096 Background: One of the main challenges in cancer management is monitoring the non-organ-confined disease post metastasis. Recently analysis of circulating tumor nucleic acids has generated a new paradigm for monitoring the progression and molecular pathology of the residual disease through a non-invasive test. Methods: We have developed a new sequencing workflow, which increases the sensitivity and specificity of detecting and quantifying rare tumor-derived nucleic acids among healthy fragments by at least ten-fold. Unlike conventional sequencing library preparation protocols, the majority of extracted circulating DNA fragments are hybridized to sequencing flow cells with minimal modifications. The sequencing data are processed using our proprietary bioinformatics pipelines to search for rare genetic abnormalities within the heterogeneous circulating fragments. Results: To study the performance of our technology, we first evaluated its sensitivity in analytical samples. We spiked varying amounts of LNCaP cancer cell line gDNA into a background of normal gDNA and were able to successfully detect somatic mutations down to 0.1% sensitivity. Subsequently, we investigated the correlation of circulating DNA and tumor gDNA in human xenograft models in mice. In seven different mice models of two different human tumors, we found very strong correlation between somatic mutations detected in all pairs of tumor gDNA and mouse blood cfDNA. After preclinical studies, we initiated a pilot study on human samples across different cancer types. We found more than 90% correlation between tumor mutations in stage IIIb CRC cancer patients and the mutations detected in their circulation (n=7). In a pilot study in prostate cancer patients (n=3), we detected chromosomal abnormalities in multi locations in circulating DNA genome in both advanced and post-relapse stages of the disease. Conclusions: The present work indicates the potential of using circulating nucleic acids to facilitate the integration of real-time molecular pathology into routine cancer care. Our assay will be used to identify residual disease after neoadjuvant chemotherapy and/or surgery, but may also identify a subset of patients who may benefit from alternative therapies.
A community-based program for personalized cancer care using next-generation sequencing (NGS).
Authors: Liang Shile , Chandra Pranil , Ma Zeqiang , Haynes Debbie , Prescott James , Morrissey Lisa H. , Jones Suzanne Fields , Spigel David R. , Savona Michael R. , Hainsworth John D. , Infante Jeffrey R. , Burris Howard A. 
Published: March 2020

11102 Background: Despite growing interest and need, molecular profiling of tumor samples is largely unavailable in community cancer centers, where nearly 80% of cancer patients (pts) are treated. In 10/12, Sarah Cannon Research Institute (SCRI) launched a community-based molecular profiling program to: 1) better understand the molecular constituency of cancer patients, 2) identify appropriate pts for phase I and II clinical trials of targeted agents, and 3) identify pts with molecular abnormalities responsive to FDA-approved agents. Methods: Eligible pts consented to testing of available biospecimens, which were interrogated for alterations in 35 cancer-related genes using NGS (1000X average coverage) in a CLIA/CAP laboratory. Results were reported to the treating physician within 14 days and stored in a database to enable correlation with clinical outcomes. Results: As of 1/13, 209 pts had been enrolled with 84% having sufficient material for assay. At least 1 mutation was detected in 46% of tumors. Results in the 3 most commonly assayed tumor types are summarized (Table). Mutations for which there are FDA-approved targeted agents were found in 14 off-label tumors (EGFR 4, KIT 3, SMO 3, BRAF 2, HER2 2). 40 pts (27%) were subsequently enrolled in clinical trials; in 19 of these, assay results influenced clinical trial selection. Conclusions: This program provides molecular profiling data to community oncologists for clinical decision making. Experience to date indicates this information can be provided in a timely manner for incorporation into clinical practice. Profiling results will enable: 1) selection of pts with appropriate tumor targets for investigational targeted agents, 2) enhanced study enrollment, 3) evaluation of FDA approved targeted agents in off-label tumor types, and 4) correlation of treatment outcomes with patterns of tumor molecular abnormalities. [Table: see text]
Sentinel node biopsy in patients with microinvasive breast cancer: A systematic review and meta-analysis.
Authors: Gojon Helene , Fawunmi David , Valachis Antonis 
Published: March 2020

1119 Background: The aim of this meta-analysis is to evaluate the role of sentinel lymph node biopsy (SLNB) in patients with microinvasive breast cancer. Methods: We searched MEDLINE and ISI Web of Science to identify studies including patients with microinvasive breast cancer who underwent SLNB and reported the rate of sentinel-node positivity. We performed proportion meta-analysis using either fixed or random-effects model based on the between-study heterogeneity. Results: A total of 23 studies including 952 patients met the eligibility criteria. The summary estimate for the sentinel-node (SN) positivity rate was 3.1% (95% Confidence Interval (CI): 2.0%-4.4%), 4.1 % (95% CI 2.8%-5.6%), and 2.8% (95% CI : 1.6%-4.5%) for macrometastasis, micrometastasis and isolated tumor cells (ITC) respectively. Significant between-study heterogeneity was observed only in the meta-analysis of ITC positivity rate. Conclusions: The amount of positive sentinel node in patients with proven microinvasive breast cancer is relatively low. As a result, the indications for SLNB in these patients should be probably individualized.
Clinicopathologic features of multiple phyllodes tumors of the breast.
Authors: Yoshidaya Fumi , Hayashi Naoki , Yoshida Atsushi , Yagata Hiroshi , Tsunoda Hiroko , Suzuki Koyu , Nakamura Seigo , Yamauchi Hideko 
Published: March 2020

1126 Background: Phyllodes tumor of the breast is one of the rare neoplasm accounting for 0.3-0.5% of all breast tumors. It is difficult to diagnose the histological type of phyllodes tumors preoperatively by radiological and even pathological findings. The aim of this study is to clarify the clinicopathological features of phyllodes tumors. Methods: We retrospectively reviewed records from 116 patients with phyllodes tumors who underwent surgery between 2003 and 2011. We determined the clinicopathological characteristics, including the presense of multiple lesions and the type of surgical procedure, of each histological type of phyllodes tumors which were classified as benign, borderline, and malignant. Results: The median follow-up time was 23.3 months. Benign phyllodes tumors were presented in 91 patients (78.4 %), borderline were in 17 patients (14.6 %), and malignant were in 8 patients (6.9 %). Ten patients (8.6 %) had multiple phyllodes tumors; 9 for ipsilateral and one for bilateral breasts. One hundred two patients underwent lumpetcomy and 14 patients underwent mastectomy. No patients received chemotherapy or radiation therapy. Noteworthy, all multiple tumors were diagnosed histologically benign. The median age at operation were 41 years (range, 12-72 years) for benign tumors, 44 years (26-67 years) for borderline, and 47 years (39-60 years) for malignant. The size of malignant tumors was significantly large (a median, 11.3 cm; range, 6-27 cm) compared to benign (a median, 4.4 cm; range 1-21 cm) and borderline (a median, 4.7cm; range 1-16 cm) (p = 0.001, and 0.03, respectively). Local recurrence developed in 14 of the 91 patients (15.4 %) with benign, 2 of the 17 patients (11.8 %) with borderline, and 2 of the 8 patients (25 %) with malignant tumors. Four patients (50 %) with malignant tumors but none with benign and borderline developed distant metastasis. Of the 4 patients, 3 had undergone mastectomy and one had lumpetcomy for initial treatment. No benign and borderline tumor had malignant change when tumors recurred. Conclusions: Our new findings indicated that multiple phyllodes tumors may be histologically benign. Furthermore, patients with benign or borderline phyllodes tumors had good prognosis regardless of surgical procedure.
Efficacy of risk-reducing mastectomy (RRM) on overall survival (OS) in BRCA1/2-associated breast cancer (BC) patients.
Authors: Heemskerk-Gerritsen Bernadette Anna Maria , Hooning Maartje , van Asperen Christi J , Ausems Margreet GEM , Collée Margriet , Jansen Liesbeth , Kets Marleen , Keymeulen Kristien , Meijers-Heijboer Hanne EJ , van Os Theo AM , Vasen Hans FA , Koppert Linetta , Rookus Matti A. , Seynaeve Caroline 
Published: March 2020

1502 Background: RRM in BRCA1/2 mutation carriers with a history of unilateral BC significantly reduces the risk of developing contralateral BC (CBC). However, the outcome regarding OS is insufficiently known. Methods: The efficacy of RRM on CBC incidence and OS was studied in a Dutch multicenter cohort consisting of 515 BRCA-associated BC patients (399 BRCA1, 116 BRCA2) of whom 177 BRCA1 and 48 BRCA2 carriers underwent RRM. Data on patient, tumor and treatment characteristics were collected up to June 30, 2012. Women contributed person-years of observation (PYO) to the Non-RRM group from the date of primary BC (PBC) diagnosis or DNA diagnosis (whichever came last) to the date of death, RRM, or last contact. Contribution of PYO to the RRM group started at the date of RRM until similar endpoints as described for the Non-RRM group. Results: Regarding PBC, no significant differences in size, nodal status, differentiation grade, hormone and Her2Neu receptor, and endocrine therapy were observed between the Non-RRM and RRM group. Median age of PBC diagnosis was 42 years for Non-RRM and 38 for RRM women (p<0.001). Median time period between PBC and RRM was 2.3 years (range 0.02-20.1). PBC treatment included radiotherapy for 68% of Non-RRM versus 50% of RRM women (p< 0.001). Compared to Non-RRM, chemotherapy was more often given to RRM women (66% versus 49%; p<0.001), and more RRM women underwent risk-reducing salpingo-oophorectomy (81% versus 67%; p<0.001), while ovarian cancer incidence was not different. With a median FU of 11.7 years after PBC diagnosis, 58 CBC cases were observed in Non-RRM women, while 4 CBC cases occurred after RRM, yielding incidence rates (per 1000 PYO) of 30.6 and 2.5, respectively (adjusted HR 0.09, 95% CI 0.03-0.24). In the Non-RRM group 45 women died during 2408 PYO versus 17 women in the RRM group during 1756 PYO, yielding mortality rates (per 1000 PYO) of 18.9 and 9.7, respectively (adjusted HR 0.56, 95% CI 0.32-0.99). 10 year OS was 80% for the Non-RRM and 90% for the RRM group (p=0.008). Conclusions: RRM in BRCA mutation carriers with unilateral BC reduces CBC incidence and is associated with improved OS. Further research is needed to identify potential prognostic factors for this survival benefit.
The mutational spectrum of breast and ovarian tumors from BRCA1 and BRCA2 mutation carriers.
Authors: Maxwell Kara Noelle , De Sloover Daniel , Emery Lyndsey , Wubbenhorst Bradley , D'Andrea Kurt P , Long Jessica , Mueller Rebecca , Powers Jacqueline , Stopfer Jill , Feldman Michael D , Domchek Susan M. , Daber Robert , Nathanson Katherine L. 
Published: March 2020

1510 Background: Individuals who carry one mutated copy of the BRCA1 or BRCA2 genes have elevated lifetime risks of breast and ovarian cancer. A number of studies have investigated the somatic mutational spectra of breast and ovarian tumors; however, BRCA1/2mutated tumors are underrepresented. Methods: Sixty-eight formalin-fixed paraffin embedded samples from BRCA1/2patients have been identified. Massively parallel sequencing using 48 gene capture is in process, whole exome sequencing of tumor and matched germline DNA is planned. Data are analyzed using a custom bioinformatics pipeline. Results: In analysis of data from the first 26 breast (4 BRCA1, 6 BRCA2) and ovarian (8 BRCA1, 8 BRCA2) tumors, the majority (23/26, 88%) had 0-2 variants in 48 cancer genes. Known deleterious TP53 mutations were the only variants identified in 2/4 BRCA1 and 2/6 BRCA2 breast tumors. Of those remaining, 2 BRCA1 and 1 BRCA2 breast tumors had no identified deleterious mutations. Two BRCA2 breast tumors with no TP53 mutations had known deleterious mutations in a single gene each - FGFR2 and PI3KCA. One BRCA2 breast tumor with no TP53 mutation had a variant of uncertain significance in FLT3. Finally, one BRCA2 breast tumor had a very high mutational rate, with one deleterious TP53 mutation and 7 other small deletion and single nucleotide variants. For the ovarian tumors, 15/16 BRCA1 and BRCA2 tumors had known deleterious TP53 mutations; the ovarian tumor with no TP53 mutation had no other variants. TP53 mutations were the sole identified mutations in 8 ovarian tumors. One ovarian tumor carried a known JAK3 activating mutation and 4 ovarian tumors carried one variant of uncertain significance in a single gene - SMO, PDGFRA, GNA11 and NRAS. Finally, two ovarian tumors were found to have high mutational rates. Conclusions: Using a targeted resequencing panel, we confirmed the high rate of TP53 mutations in BRCA1/2 breast tumors and observed a higher than expected rate in BRCA1/2 ovarian tumors. Importantly, we have identified mutations in other known driver genes using FFPE samples, allowing generalizability to other sites. These analyses may uncover novel mutations that could be exploited in the development of targeted therapeutic agents for BRCA1/2 carriers.
Aspirin use in prostate cancer and the risk of death and metastasis.
Authors: Assayag Jonathan , Azoulay Laurent , Yin Hui , Pollak Michael N. , Suissa Samy 
Published: March 2020

1518 Background: There has been recent interest in the role of aspirin in preventing prostate cancer outcomes, but data remain limited. The objective was to determine whether the use of aspirin after prostate cancer diagnosis is associated with a decreased risk of prostate cancer mortality, distant metastasis and all-cause mortality in men newly-diagnosed with prostate cancer. Methods: A population-based cohort of men diagnosed with non-metastatic prostate cancer between 01/04/1998 and 31/12/2009 was identified using the UK Clinical Practice Research Datalink, including the Cancer Registry. All men were followed until death, distant metastasis, or 01/10/2012. A nested case-control analysis was performed where, for each case with an incident outcome event, up to 10 controls were matched on age, year of diagnosis and duration of follow-up. Exposure was defined as aspirin use during the matched follow-up period. Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression, adjusted for covariates and considering effect modification by aspirin use prior to prostate cancer diagnosis. Results: The cohort included 13,396 prostate cancer patients, followed for 3.9 (SD=2.4) years during which 4,425 deaths occurred, including 2,315 from prostate cancer, and 2,344 cases of distant metastasis. Aspirin use was associated with an increased risk of prostate cancer mortality (RR 1.36, 95% CI 1.18-1.55) and all-cause mortality (RR 1.33, 95% CI 1.21-1.47), but not distant metastasis (RR 1.09, 95% CI 0.94-1.27). The increased risks were limited to patients who did not use aspirin before diagnosis, for both prostate cancer mortality (RR 1.69, 95% CI 1.43-2.00) and all-cause mortality (RR 1.62, 95% CI 1.44-1.82), while those who used aspirin before diagnosis did not have increased risks (RR 0.93, 95% CI 0.76-1.15 and RR 0.98, 95% CI 0.85-1.13, respectively). Conclusions: The use of aspirin after prostate cancer diagnosis is not associated with a decreased risk of prostate cancer outcomes. Although increased risks were observed for all-cause and prostate cancer mortality, these effects were exclusively driven by new-users of aspirin, suggesting that aspirin use in these patients was likely related to disease progression.
Structural variations in mammary carcinomas and their detection in cell-free plasma DNA in a clinical dog model.
Authors: Hennecke Silvia , Bornemann-Kolatzki Kirsten , Urnovitz Howard B. , Neumann Stefan , Brenig Bertram , Schütz Ekkehard , Beck Julia 
Published: March 2020

1537 Background: Mammary tumors are the most frequent cancers in female dogs exhibiting a variety of histopathological differences to which a dearth of information about their genomic status exists. Massive parallel sequencing (MPS) of tumor, white blood cell and associated cell-free DNA from plasma revealed the utility of the dog in modeling the dynamics of cell-free cancer DNA. Methods: Five tumors of three different histological subtypes were evaluated. MPS of tumors was performed in comparison to the respective white blood cell DNA of each animal. Copy number and structural variations were evaluated and those only present in tumors were validated using digital droplet PCR (ddPCR). Results: Using mate-pair sequencing chromosomal aneuploidies were found in two tumors, frequent smaller deletions were found in one, inter-chromosomal fusions in one other, whereas noteworthy one tumor was devoid of any of these anomalies. The detected structural variations affect several known cancer associated genes such as BRCA1, cMYC, and KIT. One deletion of the proximal end of CFA27, harboring the tumor suppressor gene PFDN5 was detected in four of the five tumors. Using ddPCR, this deletion was validated and detected in 50% of tumors (N=20).One breakpoint specific ddPCRs was established for each of four tumors. In all cases tumor specific DNA was detected in the plasma prior to surgery and accounted for 1 to 24 % of the cfDNA. In one animal the ddPCR detected tumor specific DNA in cfDNA still present >1 year after surgery; subsequently a lung metastasis was found as cause. Furthermore, paired-end sequencing of extracted cfDNA and subsequent depth of coverage analysis proved that copy-number variations of the tumor are reflected by the cfDNA. Conclusions: The similarities of patterns of copy-number imbalances (e.g. chromosomal and segmental aneuploidy subtypes) of canine and human mammary cancers and their correlation in cfDNA supports the use of the dog as a model for using MPS for screening and discovery of individual cancer biomarkers. The ddPCR technology offers rapid, cost effective and sensitive confirmation and monitoring. The possibility exists that ddPCR can be expanded to screening for common cancer related variants.
Prospective correlation between clinical and pathologic criteria identification of Lynch syndrome (LS) in endometrial carcinoma (EC) patients and relapse.
Authors: Romero Ignacio , Garcia-Casado Zaida , Martinez Pedro , Illueca Carmen , Zorrero Cristina , Grau Montse , Bosch Jose Manuel , Fernandez-Serra Antonio , Lopez-Guerrero Jose Antonio , Poveda Andres 
Published: March 2020

1543 Background: Prospective comparison of different methods for recognition of LS associated EC is lacking. Microsatellite instability (MSI) has been observed to be inconsistent as a prognostic factor in EC. The aim of this study was to analyze the impact of MSI and Mismatch Repair (MMR)-deficiency on LS identification and prognosis in a prospective series of EC treated in one single institution. Methods: Consecutive and prospective EC patients were included. Clinical data, family history of cancer and criteria for LS were evaluated. MSI and MMR protein expression were performed. When loss of MMR proteins and/or high MSI (MSI-H) was observed, complete sequencing and large genomic rearrangement analysis of germline MLH1, MSH2, MSH6 or PMS2 was done once MLH1 methylation was excluded. Results: Seventy-seven women diagnosed with EC were enrolled from 2009 to 2012 with a median age of 62 (31-87), 84% histological type I, 16% type II and FIGO stages I 83%, II 2.8%, III-IVA 7% and IVB 7%. Among which, 6.6% fulfilled revised Bethesda criteria (rBC), 5.3% criteria defined by the Society Gynecologic Oncology (>20%-to-25% risk of LS) (SGO) and 5.3% Amsterdam II criteria (AII). Seventy-four underwent surgery with curative-intent. Tumor tissue was unavailable in 5 cases for molecular analysis. MSI-H was observed in16 cases (22%) and 18 (24%) had loss of expression of MLH1 (14), MSH2 (2), MSH6 (1) or PMS2 (1). Nine MLH1 hypermethylation, 10 K-RAS and no BRAF mutations were identified. Four (5.5%) pathogenic MMR germline mutations were recognized: 2 MSH2, one MSH6 and one PMS2. One patient (25%) with MSH6 mutation did not fulfil rBC, SGO nor AII criteria and was identified both by MSI-H and loss of MSH6 expression. Median follow-up was 23.4 (0.2-76.3) months. No correlation between MSI-H, MMR gene mutation and relapse was observed in stage I-IVA EC. Conclusions: Based on these results, rBC, AII and SGO criteria for identification of LS in EC do not identify 25% of germline MMR gene mutations. No correlation with relapse and MSI-H could be identified.
Lynch syndrome testing in ethnically diverse patients: Mutation spectrum and performance of prediction models.
Authors: You Y. Nancy , Vilar Sanchez Eduardo , Slack Rebecca , Chang George J. , Nguyen Sa Thi Nguyen , Cuddy Amanda , Khose Swapnil , Wisniewski William , Bannon Sarah A. , Mork Maureen M. , Lynch Patrick M. , Rodriguez-Bigas Miguel A. 
Published: March 2020

1546 Background: Lynch syndrome (LS) is characterized by deficiency in DNA mismatch repair (MMR). Several models can predict the probability of MMR gene mutations, but all were derived from populations in Northern Europe and America. We aimed to characterize MMR mutations and to evaluate the performance of 4 models (Leiden, MMRpredict, MMRpro, and PREMM1,2,6) in an ethnically diverse high-risk population. Methods: Mutation and pedigree data from 387 distinct probands tested for germline MMR mutations at a single center between 2003-2012 were analyzed. Mutation testing was triggered by suggestive tumor microsatellite results and/or clinical/family history. Race/ethnicity was self-reported: 84 (22%) were ethnically-diverse (African American, 19; Hispanic, 29; Asian/Arabic, 34; and other, 2) and 303 (78%) were white. Area under the receiver operating curve (AUC) for all 4 models was analyzed by logistic regression. Results: Pathogenic mutations were detected in 152 patients (39%; MLH1 in 37, MSH2/EPCAM in 84, MSH6 in 21, and PMS2 in 10). The detection rate was significantly lower in ethnically-diverse patients when compared to white patients (30 vs. 42%; p=0.04). The mutation frequency of the major MMR genes MLH1 and MSH2 differed, although the overall mutation distribution did not reach statistical significance (MLH1, 40 vs. 22%; MSH2: 36 vs. 59%; MSH6: 20 vs. 13%; and PMS2: 4 vs. 7%; p=0.10 vs. white). The Leiden, MMRpredict, MMRpro, and PREMM1,2,6 models trended toward inferior discrimination for the ethnically diverse patients, with AUCs of 0.63, 0.64, 0.63, and 0.66 respectively (vs. AUCs of 0.71, 0.69, 0.72, and 0.76 for white patients), but the difference was not statistically significant(p=0.11, 0.17, 0.09, and 0.08, respectively). Adjusting for family size did not significantly alter results. Conclusions: In ethnically-diverse patients, the overall detection rate for pathogenic MMR mutations is significantly lower, with associated differences in mutation frequencies and in predictive model performance. We caution against relying solely on predictive scores, as high-risk ethnically-diverse patients without an identified mutation may deserve to be followed as clinical LS patients.