bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Genomic alterations in matching primary tumors and metastasis in breast cancer.
Authors: Jiang Tingting , Szekely Borbala , Szasz Attila Marcell , Kluger Yuval , Kulka Janina , Pusztai Lajos
Published: March 2020

1549

Background: We examined DNA sequence alterations in matching normal tissues, primary breast cancers and metastatic lesions to study the genomic evolution of breast cancer. We also assessed technical reproducibility. Methods: DNA was extracted from formalin fixed paraffin embedded tissues obtained during autopsies from 3 patients including 12 specimens. We performed paired-end whole exome sequencing with SOliD V4 Genome Analyzer using the Agilent Sure Select All Exon Kit including technical replicates. Nucleotide variants (NV) were detected by Varscan V2.2 and functional impact was predicted by ANNOVAR. Results: After 4 QC steps (duplicate and strand bias removal, base quality and minor allele frequency filters) that removed 98.81% of variants per sample (range 96.50%-99.99%). We observed on average 2648 new NVs per cancer sample (range 10-5541) at a mean coverage of 72 (range 19-283) and mean library size of 48270660 base (range 7764034 base - 60752085 base). Concordance for high quality NVs reached 95% (range 92%-98%) in replicates. Mutation rate in the primary cancer differed from patient to patient (range 10.41per Mb to 18.29 per Mb) with more mutations seen in patients with longer disease history and extensive prior therapy. We also observed more differences in mutations between primary tumors and metastasis than expected by technical nose alone. On average, 234(83.53%) mutations were shared between a primary tumor and a metastasis (range 4 – 947; 62.5%-97.63%) and the number of site-specific mutations ranged from 0 to 251. An index for assessing mutational heterogeneity was greater in primary cancers compared to their metastasis. Mapping of variants with predicted functional impact yielded different targetable anomalies for different tumor sites. Conclusions: Mutation rates differed among patients according to their disease history. Difference of mutation between primary tumor and metastatic lesion were larger than technical noise and the heterogeneity of primary cancers was larger than that of metastasis. Metastasis often differed from the primary tumor in the spectrum of potentially targetable anomalies.
Plasma adiponectin to predict incident cancer in a large multiethnic population-based cohort study.
Authors: Beg Muhammad Shaalan , Saleem Sadia , Turer Aslan , Ayers Colby , Zhang Song , Scherer Philipp , Lakoski Susan
Published: March 2020

1560

Background: Previous retrospective studies have suggested an inverse relationship between cancer and markers of insulin resistance, including adiponectin. Whether circulating levels of adiponectin are associated with future cancer incidence has not been well demonstrated. As such, we examined the association of adiponectin on the risk of future cancer development in a large population based cohort study. Methods: The Dallas Heart Study (DHS) is a multiethnic population based study of 3,531 Dallas County residents with an intentional oversampling of minorities which are underrepresented in other population studies. Incident and prevalent cancer cases were identified in the DHS by the Texas Cancer Registry. Cases were defined as ‘incident’ if they were diagnosed 24 months after enrollment into DHS. Fasting blood samples were obtained from DHS participants between 2000 and 2002, and used for biomarker analysis. Univariate and multivariate analysis was performed to test the association of incident cancer and adiponectin after adjusting for age, diabetes status, gender, ethnicity and body mass index (BMI). Results: Of 3,531 individuals, 150 incident cancer cases were diagnosed. The study population comprised 55.8% females, 51.5% were black and 39.6% had a BMI above 30 kg/m2. Mean adiponectin was 8.12 μg/ml in incident cancer group and 7.46 μg/ml in non-cancer group (p=0.129). In multivariable analysis, adiponectin was not an independent predictor of cancer incidence after adjusting for age, diabetes status, gender, ethnicity and BMI (p=0.167) Conclusions: Previous population based studies have demonstrated conflicting results on the association of markers insulin resistance, including adiponectin, and cancer incidence. In this study of a predominant ethnic minority population, an association between adiponectin and cancer incidence was not seen. Further prospective studies are needed to understand the association between markers of insulin resistance and risk of future cancer risk.
Public awareness of the HPV vaccine: A national population-based study.
Authors: Shrader Abigail , Niccolai Linda , Mayne Susan T , DiMaio Daniel , Chagpar Anees B.
Published: March 2020

1574

Background: Human papilloma virus (HPV) is associated with a number of malignancies. While national guidelines exist for the use of HPV vaccines in men and women up to the age of 26, data are lacking regarding public awareness of these vaccines. Methods: The National Health Interview Survey is conducted annually by the CDC, and is designed to be representative of the US population. Questions regarding the HPV vaccine were fielded in 2010, and formed the basis of this analysis. Results: 9120 men and 10946 women between the ages of 18 and 64 were surveyed. More women than men had heard about the HPV vaccine (68.1% vs. 34.0%, p<0.001), and young people (aged 18-26) were more likely to have heard about the vaccine than their older counterparts (54.3% vs. 50.5%, p=0.002). Factors associated with awareness of HPV vaccines amongst the younger cohort (eligible for the vaccine) are shown below. On multivariate analysis, race, insurance, and education were significant predictors of HPV vaccine awareness. Conclusions: While over half of young people aged 18-26 are aware of the HPV vaccine, racial/ethnic minorities, along with less educated and uninsured populations lag behind their majority counterparts in their awareness of the HPV vaccine. These data should be useful in directing public health educational programs. [Table: see text]
Individual insulin use and the risk of breast cancer: An international clinical epidemiology study.
Authors: Grimaldi-Bensouda Lamiae , Cameron David A. , Marty Michel , Barnett Anthony H , Penault-Llorca Frederique , Pollak Michael N. , Charbonnel Bernard , Riddle Matthew , Mignot Laurent , Boivin Jean-Francois , Khachatryan Artak , Rossignol Michel , Benichou Jacques , Alperovitch Annick , Abenhaim Lucien ,   ISICA Group
Published: March 2020

1578

Background: The association between individual insulin use and cancer risk has been previously considered with studies reporting higher breast cancer incidence for insulin glargine. Objective: To assess the relative risk of breast cancer associated with individual insulin use (glargine, human insulin, insulin analogs aspart and lispro). Methods: Systematic case-control study of incident breast cancer occurring in women with diabetes from across the United Kingdom, Canada and France. Participants and Settings: 775 case-patients with diabetes and primary invasive or in situ carcinoma of the breast (diagnosed between 1 January, 2008 and 30 June, 2009) selected from 39,958 incident breast cancer patients from 92 large oncology clinics; and 3,050 control-patients with diabetes selected from 580 general practices and matched on country, age, date, type of diabetes (1 or 2), and management by diabetologist or general practitioner. Data on exposure: Data was collected from physicians and patients. Statistical analysis: The main risk model was a multivariable conditional logistic regression including individual insulin use, 8 years preceding the index date, and controlling for past use of any insulin, oral antidiabetic drug use, reproductive factors, lifestyle, education, hormone replacement therapies and contraceptive use, body mass index, comorbidities, diabetes duration, and annual number of physician visits. Results: Adjusted odds ratios of breast cancer were: 1.04 [95% Confidence Interval: 0.76-1.44] for glargine; 1.23 [0.79-1.92] for lispro; 0.95 [0.64-1.40] for aspart; 0.81 [0.55-1.20] for human insulin. Similar results were observed in new insulin users. No effect of dose or duration of use was observed for glargine on the risk of breast cancer. Conclusions: This first international case-controlled study found no difference in the risk of developing breast cancer among patients according to individual insulin use.
Abnormal bone marrow signal on MRI heralding oncologic diagnoses: A single institution review.
Authors: Shah Gunjan L. , Jarboe Jamie Michelle Bunch , Rosenberg Aaron Seth , Klein Andreas Kirschmer , Cossor Furha Iram
Published: March 2020

1580

Background: The increased use of magnetic resonance imaging (MRI) has resulted in increased numbers of incidental findings. Oncologists often receive consults for workup of "abnormal marrow signal." As there is no standard evaluation for such findings and the yield of additional evaluation is unclear, we performed a retrospective study of patients evaluated with MRI at Tufts Medical Center (TMC). Methods: With IRB approval, TMC radiology reports were searched from 5/9/05-12/31/08 with GE Centricity Radiology Information System 2.2. Included patients had MRI reports containing the phrases “abnormal bone marrow” or “heterogeneous bone marrow”, but no clear etiology stated. Further workup, including referral to a subspecialist, laboratory, radiographic, or pathologic evaluations, final diagnosis, and last follow up were collected. Results: 29,508 MRIs were performed and 77 patients met search criteria. Median age was 58 years with a median follow-up of 41 months at TMC after qualifying MRI. 40/77 (52%) of patients had either an MRI of the lumbar spine or hip with 21/77 (27%) undergoing work-up for the marrow findings. Evaluations included CBC (38%), SPEP (24%), quantitative immunoglobulins (14%), free light chains (10%), peripheral blood flow cytometry (5%), bone marrow biopsy (19%), skeletal survey (14%), bone scan (48%), CT scan (24%), biopsy of other site (24%), and subspecialty referal (48%, 29% to oncology). Definitive diagnosis was assigned in 11/21 (52%) cases, with 5 being malignancies (1 follicular lymphoma, 2 multiple myeloma, 2 lung cancer). Three patients were later diagnosed with malignancy (breast cancer, myelodysplastic syndrome, merkel cell carcinoma) at a median of 19 months. Overall, 10% of patients with abnormal marrow on MRI were diagnosed with a malignancy. Conclusions: Incidentally noted abnormal or heterogeneous bone marrow signal on MRI was not inconsequential. Of those patients who underwent evaluation for the finding, 24% were diagnosed with a malignancy. We conclude that abnormal bone marrow findings on MRI should not be ignored, and given the rates of malignancy in our series, oncologists are ideally suited for this task.
Association of PIK3CA mutations and age with the occurence of second primary lung cancer (SPLC).
Authors: Bos Marc Christiaan Allardt , Gardizi Masyar , Scheffler Matthias , Nogova Lucia , Zander Thomas , Heukamp Lukas Carl , Schildhaus Hans-Ulrich , Merkelbach-Bruse Sabine , Fassunke Jana , Binot Elke , Schlesinger Andreas , Geist Thomas , Kambartel Kato , Schnell Roland , Schulz Holger , Behringer Dirk M. , Serke Monika , Schmitz Stephan H. , Randerath Winfried , Wolf Juergen
Published: March 2020

1589

Background: The incidence of SPLC in Germany was reported to be 1.2 per 100,000 inhabitants in 2007 and the prevalence of second primary cancers reported by the US International Cancer Institute's Surveillance, Epidemiology and End Results Program has more than doubled over the last 25 years. Recently there has been tremendous progress in the ability to detect driver mutations in lung cancer and large studies presented the frequencies of driver mutations in unselected patient populations. We conducted an association study of known genetic driver events and clinical characteristics with the occurence of SPLC. Methods: Within the Network Genomic Medicine Lung Cancer, a local molecular screening network encompassing hospitals and office-based oncologists in the catchment area of the Center for Integrated Oncology Köln Bonn, we retrospectively reviewed the medical records of 375 molecularly annotated NSCLC patients for their SPLC status and clinical characteristics (age at diagnosis, histology, sex, smoking status). Molecular analysis for lung adenocarcinoma included the EGFR, ALK, BRAF, KRAS and PIK3CA status and for squamous cell lung cancer the FGFR1 and PIK3CA status. Results: 84 of 375 (22,4%) patients were SPLCs. The median age of SPLC diagnosis was 70 yrs. (Range 53 - 85 yrs.) and differed significantly from the rest of the population with a median age of 65 yrs. (Range 28 - 86 yrs.). The frequency of SPLCs was not significantly different between males and females (p = 0,259). In univariate logistic regression analysis active and former smoking, positive PIK3CA mutation and FGFR1 amplification status as well as age were significantly associated with the occurrence of SPLC. In a multivariate logistic regression analysis including the variables mentioned above only PIK3CA mutations (OR 9,48 95% CI 1,83 - 49,1) (p = 0,007) and age (OR 1,06 95% CI 1,03 - 1,1) (p = 0,015) could be confirmed to be independent prognosticators for the occurrence of SPLCs. Conclusions: The occurrence of SPLC was associated with age and PIK3CA mutations in our study population. Further comprehensive investigations on this topic are needed to confirm our findings and to further understand the association between mutation status and SPLCs.
Neurologic, vascular, and endocrine morbidity following childhood exposure to low and moderate doses of ionizing radiation.
Authors: Sadetzki Siegal , Chetrit Angela , Boursi Ben , Sikron Fabienne
Published: March 2020

1599

Background: While the association between exposure to ionizing radiation and cancer is well known, its possible role in the development of other diseases e.g. in the vascular, neurologic and endocrine systems is limited and inconsistent. The aim of this study was to assess the effect of childhood exposure to low and moderate doses of radiation on the development of chronic diseases (other than cancer) based on a large cohort followed for 55 years. Methods: The study population included an exposed group of 13,158 individuals treated with ionizing radiation for tinea capitis and a comparison group of 16,225 unexposed subjects. The mean dose to the head and the thyroid gland were 1.5 Gy and 0.094 Gy respectively and the mean age at exposure was 7.1±3.1y. Data on the outcome variables was obtained through computer linkage of the study database with the largest health care provider registry in Israel. Results: Of the study population, 64% were found to be insured in this heath provider (66.8% among the irradiated and 63.6% among the unexposed group). The two study groups did not differ in current age (mean 62.1+4.5 y), gender, marital status, smoking and BMI. Compared to the unexposed group, the irradiated group demonstrated a significantly (p<0.001 ) increased prevalence of epilepsy (1.8% vs. 2.8%), CVA (6.4% vs. 8%), diabetes (26.5 % vs. 28.2%), hyperthyroidism (8.1% vs. 9.4%), hyper/hypo-parathyroidism (0.6% vs. 1.2%) and depression (8.1% vs. 9.4%), respectively. There was no statistical difference between the groups in the prevalence of dementia and Parkinson's disease. Multivariate models accounting for different variables of interest (e.g. age at exposure, gender, SES) will be presented. Conclusions: These results have practical implications for primary prevention and early detection of therapeutic and diagnostic radiation associated morbidity.
Prevalence and patterns of cancer in patients with congenital disease: A national-based cohort study.
Authors: Lin Po-Han , Muo Chih-Hsin , Li Long-Yuan , Yang Hwai-I , Chiu Chang-Fang , Tsai Fuu-Jen
Published: March 2020

1600

Background: Association of congenital disease (CD) and malignancy was noted in some studies. However, the cancer risk and patterns of different CD was unclear. In this study, we aimed to assess and quantify the relationships between CD and cancers. Methods: In the National Health System of Taiwan, 2.9 million children were born between 1998 and 2010. Patients with CD were identified using ICD-9-CM 740-759. Cox’s proportional hazards regression analysis was used to assess the cancer risk of CD. Results: A total of 32358 CD patients were identified and 87 of them developed malignancy. The cancer diagnostic age was significantly younger in patients with CD (2.44 ± 2.28 years) than patients without CD (3.97 ± 3.04 years; p<0.001). The hazard ratio (HR) of cancer incidence was 2.70 (95% confidential interval (CI) 2.12-3.44). Subgroup analysis showed that significantly increased risk of cancer development was noted among patients with cardiac anomalies (N=26, HR=1.91, 95% CI 1.28-2.86), digestive anomalies (N=8, HR=3.32, 95% CI 1.64-6.70), cutaneous anomalies (N=2, HR=21.5, 95% CI 5.35-86.40) and chromosomal anomalies (N=29, HR=17.5, 95% CI 12.00-25.70); other congenital diseases did not. Considering cancer types, patients with cardiac anomalies had higher rate of hematological cancers (N=12, HR=2.09, 95% CI. 1.15-3.79), especially acute myeloid leukemia (AML; N=9, HR=12.2, 95% CI. 5.36-28.0). Patients with digestive anomalies also had higher rate of hematological cancers (N=4, HR=3.95, 95% CI. 1.46-10.70), and the dominant type was non-Hodgkin lymphoma (N=2, HR=14.70, 95% CI. 3.38-64.0). Patients with chromosomal anomalies had superior rate to have retroperitoneal sarcoma (N=1, HR=8.54, 95% CI. 1.14-63.90), anterior mediastinal tumor (N=1, HR=8.54, 95% CI. 1.14-63.90), and hematological cancers (N=23, HR=33.20, 95% CI. 21.20-51.80), especially the AML (N=21, HR=231, 95% CI. 119-448). Down syndrome patients had extremely high risk of AML (N=8, HR=388, 95% CI. 164-918). Conclusions: Patients with cardiac, digestive, cutaneous and chromosomal CD were at increased risk and younger age to develop cancer. Hematological malignancies, especially AML, were the most common cancer type among these patients.
A randomized phase II study of bevacizumab versus bevacizumab plus lomustine versus lomustine single agent in recurrent glioblastoma: The Dutch BELOB study.
Authors: Taal Walter , Oosterkamp Hendrika M , Walenkamp Annemiek M.E. , Beerepoot Laurens Victor , Hanse Monique , Buter J. , Honkoop Aafke , Boerman Dolf , De Vos Filip Yves Francine Leon , Jansen Rob L. , van den Berkmortel Franchette W.P.J. , Brandsma Dieta , Kros Johan M , Bromberg Jacoline E , van Heuvel Irene , Smits Marion , van der Holt Bronno , Vernhout Rene , Van Den Bent Martin J. ,   Landelijke Werkgroep voor NeuroOncologie
Published: March 2020

2001

Background: Bevacizumab (BEV) is widely used in recurrent glioblastoma, alone or in combination with other agents. There is however no well-controlled trial to support the use for this indication. Methods: In a three-arm Dutch multicenter randomized phase II study (NTR 1929) patients were assigned to either BEV 10 mg/kg iv every 2 weeks, BEV 10 mg/kg iv every 2 weeks and 110 mg/m2 lomustine every 6 weeks, or lomustine 110 mg/m2every 6 weeks. Eligible were patients with histologically proven glioblastoma, with a first recurrence after chemo-irradiation with temozolomide, having concluded radiotherapy more than 3 months ago, with adequate bone marrow, renal and hepatic function, and WHO performance status (PS) 0-2. Primary endpoint was 9 months overall survival (OS); P0 was set at 35% and P1 at 55%. Progression was defined using RANO criteria. A safety review after the first 10 patients in the combination arm was preplanned. Results: Between December 2009 and November 2011, 153 patients were enrolled of whom 148 were considered eligible. Median age was 57 years (range, 24-77) and median WHO PS was 1. With respect to prognostic factors groups were well balanced. After review of the safety cohort the dosage lomustine in the combination arm was lowered to 90 mg/m2 because of hematological toxicity (predominantly thrombocytopenia without symptoms). At this lower lomustine dose level the combination treatment was in general well tolerated. Outcome: see Table. Conclusions: In this first well-controlled study on BEV in recurrent glioblastoma with a primary OS endpoint, combination treatment with bevacizumab and lomustine met the prespecified criterion for further investigation in clinical trials, whereas both drugs given as single agent failed to meet this criterion. Clinical trial information: NTR1929. [Table: see text]
Tumor response based on adapted Macdonald criteria and assessment of pseudoprogression (PsPD) in the phase III AVAglio trial of bevacizumab (Bv) plus temozolomide (T) plus radiotherapy (RT) in newly diagnosed glioblastoma (GBM).
Authors: Wick Wolfgang , Cloughesy Timothy Francis , Nishikawa Ryo , Mason Warren , Saran Frank , Henriksson Roger , Hilton Magalie , Kerloeguen Yannick , Chinot Oliver L.
Published: March 2020

2002^

Background: Until recently the primary criteria for assessing response to GBM therapy were those by Macdonald et al. (JCO 1990;8:1277–80). Advances in imaging technology/targeted therapies exposed limitations, addressed in 2010 by Response Assessment in Neuro-Oncology Working Group. Prior to this, the AVAglio study similarly adapted Macdonald criteria to address anti-angiogenic therapy/corticosteroid use by incorporating non-contrast-enhancing components and integrating a strict algorithm to standardize assessment of possible PsPD. Methods: Randomisedpts (n=921) received: T/RT + Bv or placebo (P), 6 wks; 28-d break; maintenance T + Bv or P (6 cycles); monotherapy Bv or P until PD/unacceptable toxicity. Tumor response was investigator (inv)-assessed by MRI (adapted Macdonald criteria) at baseline (BL), end of break, every 2nd maintenance cycle, every 9 wks during monotherapy, at PD and 9 wks post-PD. PsPD was inv-assessed at the end of the break. A ≥25% increase in index lesions and/or unequivocal progression of existing non-index lesions relative to BL and in the absence of clinical deterioration was assessed as PsPD. Confirmatory PsPD assessment: end of the 2nd maintenance cycle. If progression was confirmed, PsPD was retrospectively designated as PD. If PsPD was confirmed, pts remained on treatment and the 1st post-RT MRI was used as a new BL. Best ORR was evaluated in pts with lesions at BL, excluding pts with confirmed PsPD. Results: Co-primary endpoint of inv-assessed PFS was longer for pts receiving Bv+RT/T compared with P+RT/T (HR 0.64, 95% CI 0.55–0.74; p<0.0001). Best ORR and PsPD are shown (Table). Conclusions: Addition of Bv to 1st-line T/RT significantly improves ORR. The rate of confirmed PsPD was low in both arms. Clinical trial information: NCT00943826. [Table: see text]
Neurocognitive function (NCF) outcomes in patients with glioblastoma (GBM) enrolled in RTOG 0825.
Authors: Wefel Jeffrey Scott , Pugh Stephanie L. , Armstrong Terri S. , Gilbert Mark R. , Won Minhee , Wendland Merideth M , Brachman David , Komaki Ritsuko , Crocker Ian R. , Robins H. Ian , Lee R. Jeffrey , Mehta Minesh P.
Published: March 2020

2004

Background: RTOG 0825 evaluated overall survival (OS) and progression-free survival (PFS) differences in patients with newly diagnosed GBM treated with standard chemoradiation, maintenance temozolomide and placebo (Arm 1) or bevacizumab (Arm 2). While OS was equivalent, PFS was longer in Arm 2. Longitudinal NCF testing was performed to evaluate clinical benefit. Methods: NCF was evaluatedat baseline and while on study and progression free with the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT) and Controlled Oral Word Association (COWA). Change in NCF from baseline was categorized using the reliable change index. Differences between treatment arms were compared at follow-up evaluations. Additionally, baseline (B) and early changes (EC) (B to week 10) in NCF were examined as prognostic factors. Results: 542 patients consented and 507 randomized patients participated, with test completion rates at weeks 0 (B), 10, 22, and 34 of 94-97, 69-73, 59-64, and 53-58%, respectively. Mean test performance at B was equivalent between arms and ranged from -0.8 to -4.8 SDs below healthy population norms with global NCF on a composite variable at -2.0 SDs. There were no statistically significant between arm differences in frequency of improvement through week 34. Decline on COWA (verbal measure of executive function) at week 34 relative to baseline was more common (16.1 vs 5.7%) in patients in Arm 1 (p<0.05); whereas, there were trends for more decline in Arm 2 on a visuomotor measure of executive function (TMT B, p< 0.06; 22.2 vs 35.4%). B performance and EC in global NCF, memory, executive function and processing speed were prognostic for OS. At B, global NCF was prognostic for PFS. EC in global NCF, memory and executive function were prognostic for PFS. Conclusions: There was a statistically significant difference in the frequency of decline on a verbal test of executive function at week 34 favoring Arm 2. However, this was not found at earlier time points and was not found on a visuomotor test of executive function. B and EC in NCF were prognostic for OS and PFS. Longitudinal modeling is ongoing to further evaluate the impact of treatment on patients’ NCF. Support: U10 CA21661, U10 CA37422 and Genentech, Inc. Clinical trial information: NCI-2009-01670.