bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case-control study of PD-1, PD-L1 and B7-H3 expression in lung cancer (CA) patients (pts) with and without human immunodeficiency virus (HIV) infection.
Authors: Scilla Katherine Ann , Zandberg Dan Paul , Bentzen Soren , Heath Jonathon , Ioffe Olga B. , Cellini Ashley L , Mainor Candace Barette , Edelman Martin J. , Riedel David , Feliciano Josephine Louella 
Published: September 2018

11606 Background: PD-1, PD-L1 and B7-H3 are co-signaling molecules involved in CA immunology. There are limited data on expression of these molecules in HIV-infected (HIV+) lung CA pts and these pts are routinely excluded from immunotherapy trials. Methods: We reviewed archived lung CA tissue samples from HIV+ cases (n = 13) and HIV-uninfected controls (n = 13) from 2001-2015. Cases and controls were matched by histology and stage. Baseline demographics were collected for all pts. CD4 count and HIV RNA viral load (VL) were collected for HIV+ pts. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 and B7-H3 (Abcam), and percent of tumor-infiltrating lymphocytes (TIL) expressing PD-1 and PD-L1 (Abcam). Positive expression was defined as > 5%. Statistical analysis was performed using the non-parametric Mann-Whitney test and the chi-square test. Proportions are specified as percentage with 95% confidence limits in parentheses. Results: Lung CA HIV+ case pts were predominantly male (62%), black race (100%), adenocarcinoma histology (77%), stage 4 disease (62%), and had a median age of 48 years. Of case pts with available data, mean CD4 count was 307 (range 37-617) and mean HIV VL was 29,400 (range 0-100,000). PD-L1 expression on tumor cells was positive in 23% (8%, 50%) of cases and 46% (23%, 71%) of controls. B7-H3 expression on tumor cells was positive in 92% (67%, 99%) of cases and 69% (42%, 87%) of controls. PD-1 expression on TIL was positive in 69% (42%, 87%) of cases and 54% (29%, 77%) of controls. PD-L1 expression on TIL was positive in 31% (13%, 58%) of cases and 69% (42%, 87%) of controls (p = 0.05). B7-H3 percent expression on tumor cells was significantly higher in cases vs controls (median 90% vs 20%, p = 0.005), but there were no significant differences in percent expression of PD-L1 on tumor cells, PD-1 on TIL or PD-L1 on TIL. Conclusions: HIV+ lung CA pts had significantly higher B7-H3 tumor percent expression compared to HIV-uninfected controls, with similar rates of PD-L1 tumor percent expression, PD-1 TIL percent expression and PD-L1 TIL percent expression. These results support inclusion of HIV+ lung CA pts in future immunotherapy trials.
Development of a pan-cancer 15 gene expression signature to detect a subgroup driven by EMT/MAPK signalling.
Authors: McCabe Nuala , Knight Laura A , Price Bethanie , McCavigan Andrena , El-Helali Aya , Harkin Denis P , Gourley Charlie , Kennedy Richard D. 
Published: September 2018

11616 Background: Epithelial–mesenchymal transition (EMT) is the conversion of epithelial cells to mesenchymal cells and involves loss of cell–cell adhesion and cell polarity and increased motility, invasiveness and metastases. The EMT process has therefore been under investigation as a new target for anticancer drug discovery. The aim of this work was to develop an EMT biomarker suitable for formalin-fixed paraffin embedded (FFPE) tissue that could be used for patient treatment selection. Methods: Unsupervised hierarchical clustering of ovarian cancer gene expression data (TCGA. 2011) previously identified an EMT subgroup. We confirmed this EMT subgroup in FFPE tissue using 265 high grade serous ovarian cancer (HGSOC) FFPE samples. The analysis was extended to show existence of an EMT subgroup across a range of solid tumours including colon, lung, melanoma and prostate cancer. Further to this, a common gene list was generated to include only transcripts with high variability and expression across diseases, and used as a starting list for development of a 15 transcript assay which can be used to prospectively identify the EMT subgroup from archived tissue. Results: The 15 gene expression assay was a poor prognostic marker in Colorectal, (Relapse free survival: HR = 1.46 [95% CI:1.07-1.98]); Lung, (Relapse free survival: HR = 2.18 [95% CI:1.33-3.56]); Prostate cancer, (Biochemical recurrence: HR 2.49 CI: 1.43-4.34) and was associated with activated MAPK (phospho-MAPK) in preclinical models and clinical samples (p < 0.05). The assay score was reduced by MEK inhibition (p < 0.05) and elevated by KRAS, NRAS and MEK1 overexpression (p < 0.05). The assay predicted response to the MEK inhibitors Trametinib and Selumetinib in cell line models (p < 0.001). Conclusions: A 15 gene expression assay has been developed from FFPE samples across multiple diseases to detect an EMT molecular subgroup associated with MAPK signalling. The assay predicted sensitivity to MEK inhibitors in pre-clinical model systems. Further work aims to validate the assay as a predictive biomarker in clinical samples from patients treated with EMT or MEK targeted therapies.
Parallel VENTANA IHC and RT-PCR of ALK status in non-small cell lung cancer and response to crizotinib.
Authors: Xu Chunwei , Wang Wen-xian , Fang Meiyu , Chen Yan-ping , Chen Yu , Zhong Li-hua , Chen Fang-fang , Zhuang Wu , Lin Gen , Chen Xiao-hui , Xu Hai-peng , Huang Yun-jian , Guan Yan-Fang , Yi Xin , Lv Tangfeng , Wang Xiao-jiang , Shi Yi , Lin Xian-dong , Chen Gang , Song Yong 
Published: September 2018

11623 Background: Advanced NSCLC patients who harbor (ALK) rearrangement were sensitive to crizotinib. However, not all ALK-positive patients benefit equally from crizotinib. A method for determining ALK rearrangement is RT-PCR, the Chinese FDA has approved RT-PCR to detect ALK rearrangement. In this regard, VENTANA IHC is a standard method to identify ALK protein overexpression in NSCLC. However, up to now, it is still largely unknown about the response to crizotinib for Chinese NSCLC patients having ALK overexpress detected by VENTANA IHC. To better clarify the clinical implication of VENTANA IHC to detect ALK rearrangement, we compared the curative effect and survival by the two methods in advanced NSCLC patients and analysis VENTNA IHC and RT-PCR inconsistent cases. Methods: A total of 1720 patients with NSCLC who had their ALK rearrangement detected by IHC and/or RT-PCR were included in this analysis. And we compared the efficacy and survival of patients with ALK positive detected by IHC and RT-PCR. We used next-generation sequencing (NGS) to detect patients whom two methods were not consistent. Results: 187/1720 patients were identified as ALK-positive by IHC and/or RT-PCR and 66 patient received crizotinib. We identified 172/1674 patients had ALK positive by IHC method, 41/322 patients had ALK rearrangements by RT-PCR method. And 29/276 patients with ALK positive were simultaneously analyzed by IHC and RT-PCR. The overall response rates (ORR) were 65.90% by IHC and 55.88% by RT-PCR, respectively. And the disease control rates (DCR) were 86.36% by IHC and 76.47% by RT-PCR. The median PFS of IHC was 8.5 months and RT-PCR was 9.2 months Targeted next-generation sequencing in the special type: Among 6 cases of 17 cases ALK positive patients were inconsistent by IHC and RT-PCR performed with NGS, 4 cases were identified to have EML4-ALK fusions, and 2 cases were KCL1-ALK(ND) and FBXO36-ALK (PFS 21.2 months). Conclusions: VENTANA IHC is a reliable and rapid screening tool in routine pathologic laboratories for the identification of suitable candidates for targeted therapy. It has a moderate sensitivity and a slightly higher curative effect, and some VENTANA IHC positive but RT-PCR negative cases may benefit from crizotinib.
KRAS in non-small cell lung cancer: Single institution experience—What factors are involved?
Authors: Amanam Idoroenyi Usua , Gupta Rohan , Mambetsariev Isa , Koczywas Marianna , Cristea Mihaela C. , Massarelli Erminia , Reckamp Karen L. , Salgia Ravi 
Published: September 2018

11624 Background: Disease heterogeneity with variable molecular mutations is one of the main contributory factors in non-small cell lung cancer (NSCLC). The goal of this study was to better understand the KRAS patients with co-occurring mutations. Methods: We identified 60 patients with a diagnosis of NSCLC and a KRAS mutation in the COH Cancer Registry from 2009 to 2016. Next generation sequencing was performed. Results: Of the 60 patients identified, 42 (70%) were Stage IV at diagnosis, 7 (12%) Stage I and 7 (12%) stage II and 4 (6%) Stage III. 47 (78) patients were smokers. Caucasian was the most common (n = 44, 73%) racial group, followed by Asians (n = 9, 15%), African-Americans (n = 3, 5%), other (n = 3, 5%) and Pacific Islander (n = 1, 1.7%). The average age at diagnosis was 67 (median 69.50) years; 30 patients (50%) were over 70 years, 23 (38%) patients were 51-69 years, and 7 (12%) 50 years or below. Majority of the patients had metastatic disease (n = 52, 87%) with 20% (n = 12) having brain metastasis with average metastatic sites 1.6. An average of 1.97 (range = 0-5) lines of therapy including chemotherapy, biologic agents or immunotherapy were received. 12 (20%) patients received immunotherapy, radiation in 28 (47%) and surgery in 22 (37%) with a median overall survival at 15 months. The most frequent molecular alteration was codon 12 mutation (n = 47, 78%), followed by codon 13 (n = 7, 12%) and codon 61 (n = 6, 10%) mutations. The most common co-occurring mutations in this cohort were TP53 (n = 15, 25%), ATM (n = 9, 15%), LRP1B (n = 9, 15%), ARID1A (n = 8, 13%), STK11 (n = 8, 13%), ARID1B (n = 7, 12%), TERT (n = 7, 12%), EGFR (n = 6, 10%), RBM10 (n = 6, 10%), SPTA1 (n = 6, 10%). We are currently evaluating the relevance of the Circos plot analysis for these mutations, clinical response to immunotherapy and potential biomarkers. Conclusions: KRAS mutations are among the most common molecular alterations identified in NSCLC. Effective treatments targeting KRAS mutations have represented a challenge so far. Understanding the significance of co-mutations and their therapeutic implications, especially in response to immunotherapy and other agents represents an important step to develop better treatment options for KRAS mutated lung cancers.
High risk genetic screening program in a community hospital breast imaging center.
Authors: Kushwaha Anne C. , Sweeney Lilian E , Ghosh Madhumita , Arun Banu 
Published: September 2018

1507 Background: The NCCN has published guidelines for screening and testing of Hereditary Breast and Ovarian Cancer (HBOC) that is typically used by the primary physician or oncologist. Little data exists on the value of genetic screening at a major health care access point: the breast imaging center (BIC). Using BICs as potential clinics to identify high risk women could increase the number of appropriate referrals for genetic risk assessment. Therefore, at our hospital-based BIC serving mostly low to middle income patients in a major metropolitan center, we developed a practical screening tool based on the HBOC guidelines and prospectively screened women receiving screening and diagnostic mammography. Methods: A questionnaire based on the NCCN HBOC genetic referral guidelines was added to the intake forms of all patients (pts) obtaining breast imaging at our BIC from 2012 to 2015. Forms were reviewed by the radiologists and flagged if the patient met the guidelines of the tool. Identified pts were contacted by letter and/or telephone and a nurse navigator or genetic counselor verified data, and provided information about genetic counseling to the patient prior to scheduling genetic counseling appointments. Results: Almost 35, 000 pts were seen during the study period. 1214 pts (3.5%) were flagged as possibly high risk, of which 189 pts. had received prior genetic testing. Of the 1025 remaining pts identified as candidates for genetic counseling, 258 (25%) made a genetic counseling appointment and 163 (16%) received genetic counseling. 106 pts. were tested for BRCA1/2. 9 pts (8.5%) tested positive for a BRCA1/2 pathogenic mutation and 8 pts (7.5%) had a Variant of Unknown Significance. Conclusions: Screening for HBOC syndromes at the time of annual breast imaging in a community-based middle to low income metropolitan breast imaging center is practical. Our screening tool identified women with BRCA mutations who would have been otherwise missed. This will have immediate implications for the patient and their family members in regards to increased surveillance and risk reductive surgery discussions.
Multi-gene panel testing of patients with multiple primary malignancies suspected with hereditary cancer syndrome.
Authors: Chan Gloria HJ , Ong Pei Yi , Low Jeffrey JH , Kong Hwai L. , Ow Samuel Guan Wei , Tan David SP , Lim Yi Wan , Eng Lim Siew , Lee Soo Chin 
Published: September 2018

1512 Background: Developing multiple primary cancers is an indicator of underlying hereditary cancer predisposition, but there is a paucity of data regarding the characteristics and clinical genetic testing outcome of these patients. Methods: We compared cancer index patients with 1 vs > 1 primary malignancy who underwent evaluation and clinical testing with multi-gene panels comprising up to 49 genes in a cancer genetics clinic in a tertiary cancer centre in Asia from 1998-2016. Results: Among 1191 cancer index patients, 960 (80.6%), 205 (17.2%), and 26 (2.2%) respectively had 1, 2, and ≥3 primary malignancies. Among patients with > 1 primary cancers (n = 231), the most common cancer pairs were breast-breast (35.4%), breast-ovary (12.1%), endometrium-ovary (8.2%), colon-colon (2.4%) and, colon-endometrium (2.4%). The mean age at diagnosis of the first, second and third cancers were 46.0 (21 to 87), 52.1 (21 to 89) and 57.7 (41 to 83) respectively. The mean duration between first and second cancers is 6.0 years (0 to 32). The most commonly suspected syndromes in patients with 1 vs > 1 primary cancer were hereditary breast and ovarian cancer 63.8% vs 53.6%, Lynch 24.8% vs 31.1%, Li-Fraumeni syndromes 1.8% vs 1.7%, and others 9.3% vs 13.4% (p = 0.03). Patients with > 1 primary cancer were more likely to have > 20% a priori risk of suspected hereditary cancer syndrome (42.8% vs. 26.5%; p < 0.001). 504/1191 (42.3%) patients underwent gene testing, including 394/960 (41.0%) and 110/231 (47.6%) patients with 1 vs > 1 cancer. Deleterious mutations were more likely to be identified in patients with > 1 vs 1 cancer (34.5% vs. 25.8%; p = 0.073), with causative genes being BRCA1 38.5%, BRCA2 17.9%, MLH1/MSH2/MSH6 20.5%, TP53 7.7%, and others (ATM [n = 2], MUTYH, APC, PALB2, RAD51 [n = 1 each]) for patients with > 1 cancer. VUS rates were 31.7% vs.31.8% in patients with 1 vs > 1 cancer, and were identified in genes including BRIP1, CHEK2, PALLD, POLE, PTEN, STK11, SMARCA4, and VHL. Conclusions: Patients with > 1 primary cancer comprised one-fifth of cancer index patients evaluated at a cancer genetics clinic, and were more likely to be found with deleterious mutations than patients with only 1 cancer on multi-gene panel testing.
Optimizing somatic genomic reporting and physician interpretation with web-based, interactive technologies.
Authors: Gray Stacy W. , Cronin Angel M. , Sholl Lynette M. , Cerami Ethan , Gagan Jeffrey , Uno Hajime , Oliver Nelly , Lowenstein Carol , Lederman Ruth , Revette Anna , Suarez Aaron , Lee Charlotte , Byran Jordan , Van Allen Eliezer Mendel 
Published: September 2018

1517 Background: The increased availability of tumor genomic profiling is revolutionizing oncology. However, the promise of precision care will not be realized if providers misinterpret complex genomic data. Methods: We created web-based, interactive reports with enhanced data visualization elements and embedded decision support for > 300 gene panels. We conducted a randomized vignette-based survey study to determine whether exposure to the interactive reports, as compared to static reports, improves physicians’ genomic understanding and report-based satisfaction. Overall comprehension and satisfaction scores were calculated across three vignettes (possible range 0-18 and 1-4 respectively, higher score correspond to improved endpoints). Results: 105 physicians at a major cancer center participated (29% participation rate); 67% medical, 20% pediatric, 7% radiation and 7% surgical oncology; 37% female. Prior to viewing the case-based vignette reports, 34% of physicians reported that they found it difficult to make treatment recommendations based on the standard report in their routine practice. After viewing the case-based vignettes, physicians’ overall comprehension scores did not differ significantly by report type (mean score interactive 11.6 vs. static 10.5, difference = 1.1, 95% CI -0.3, 2.5, p = 0.13). However, physicians who viewed the interactive report were more likely to correctly assess sequencing quality (p < 0.001) and understand when reports needed to be interpreted with caution (e.g., if low tumor purity, p = 0.02). Overall satisfaction scores were significantly higher in the interactive group than the static group (mean score 2.5 vs. 2.1, difference = 0.4, 95% CI 0.2, 0.7, p = 0.001). Of the 92 physicians who endorsed the need for additional genomic support for providers, 66% reported that interactive genomic reports would be helpful. Conclusions: Interactive, genomic reports may improve physicians’ ability to accurately assess genomic data and increase physician satisfaction. To advance the field, further research in representative provider populations is warranted and efforts to integrate interactive genomic reports into electronic health records are needed.
Pathogenicity of mutation analyzer (PathoMAN): A fast automation of germline genomic variant curation in clinical sequencing.
Authors: Joseph Vijai , Ravichandran Vignesh , Offit Kenneth 
Published: September 2018

1529 Background: A challenge in clinical oncology is interpretation of multiplexed gene sequencing of patients at risk. The plethora of variants to be curated for pathogenicity or actionability poses a growing burden for cancer care professionals. Current guidelines by the ACMG requires the aggregation of multiple lines of genomic data evidences from diverse resources. A computational tool that automates, provide uniformity and significantly speed the interpretive process is thus necessary. Methods: The Pathogenicity of Mutation Analyzer (PathoMAN), is a tool that automates germline genomic variant curation from clinical sequencing based on ACMG guidelines. PathoMAN aggregates multiple tracks of genomic, protein and disease specific information from public sources such as ClinVar, ExAC, UniProt, 1000 genomes, dbNSFP and locus specific databases. Variant specific and gene specific annotations are used to classify variants to model the ACMG rubric. We analyzed 2500 manually curated and classified, high quality variants in 180 genes from 3 large, published studies to quantify the performance of PathoMAN; analyzing 242 pathogenic/likely pathogenic (P/LP), 1272 benign/likely benign (B/LB) and 1261 variants of uncertain significance (VUS). We report the summary of PathoMAN classifications in four categories contrasted against the manual curation. Results: PathoMan achieves an average of 75% concordance and 1.5% discordance for P/LP mutations and 60% and 0.1% for B/LB variants. PathoMAN is able to resolve 12% of reported VUS as either P/LP or B/LB. It loses resolution to classify 25% of P/LP and B/LB variants due to lack of information and due to inconsistencies in available data from public resources. Conclusions: PathoMAN provides a breakthrough in rapid classification of genetic variants by generation of robust models using a knowledgebase of diverse genetic data. It is easily accessible, web-based resource that allows the community to rapidly test a large number of variants for pathogenicity. Such bioinformatic tools are essential to reduce manual workload of a domain level experts. We propose, a new nosology for the 5 ACMG classes to facilitate better reporting to ClinVar.
Multi-gene hereditary cancer testing among men with breast cancer.
Authors: Brown Krystal , Calip Gregory Sampang , Bernhisel Ryan , Evans Brent , Rosenthal Eric Thomas , Saam Jennifer , Lancaster Johnathan , Hoskins Kent 
Published: September 2018

1532 Background: All men with a personal diagnosis of breast cancer (BC) are candidates for BRCA1/2 genetic testing, as pathogenic variants (PVs) in these genes have a known association with BC risk in both men and women. As additional genes with known BC risk in women are now routinely included in multi-gene panel testing, we evaluated the outcomes of multi-gene panel testing in a large cohort of men with BC. Methods: This analysis includes the results of commercial genetic testing for 1,358 men with BC usinga multi-gene pan-cancer panel between September 2013 and January 2017. Clinical information was obtained from provider-completed test request forms. Age at diagnosis, personal, and family history were compared for men with PVs in BRCA1/2 versus non- BRCA1/2 genes. Results: Overall, 207 (15.2%) men with BC were found to carry a PV, where 147 (10.8%) men had a PV in BRCA1/2 ( BRCA1, 0.7%; BRCA2, 10.2%) and 60 (4.4%) men had a PV in a non- BRCA1/2 gene ( CHEK2, 2.0%; ATM, 1.0%; PALB2, 1.0%; BARD1, 0.2%; NBN, 0.2%; MSH6, 0.1%; BRIP1, 0.1%; CDH1, 0.1%; CDKN2A, 0.1%; MLH1, 0.1%, TP53, 0.1%). There were no substantial differences in the median age-at-diagnosis for men without a PV (65) compared to those with a BRCA1/2 PV (66) or a non- BRCA1/2 PV (63). Prostate cancer was the most common additional malignancy among all men with BC (9.0%), with a similar incidence among men with a BRCA1/2 PV (9.2%) and a non- BRCA1/2 PV (8.3%). In addition, 1.4% of men with a BRCA1/2 PV and 3.3% of men with a non- BRCA1/2 PV had a second BC. A family history of breast and/or ovarian cancer was present in 44.4% of the testing cohort, 66.7% of men with a BRCA1/2 PV, and 48.3% of men with a non- BRCA1/2 PV. This is consistent with the relative penetrance of BRCA1/2 and other genes included here. There were no other substantial differences in family history among BRCA1/2 PV carriers versus non- BRCA1/2 PV carriers. Conclusions: Close to a third of all PVs identified here in men with BC were in a gene other than BRCA1/2. There were no obvious differences in the clinical presentation of men with a BRCA1/2 PV compared to men with a PV in another gene or no PV at all. Collectively, this suggests that multi-gene panel testing is appropriate for all men with BC, regardless of other personal or family history.