bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous molecular alterations in solid tumors with IDH1 or IDH2 mutations.
Authors: Janku Filip , De Groot John Frederick , Javle Milind M. , Penas-Prado Marta , Shroff Rachna T. , Luthra Rajyalakshmi , Banks Kimberly , Lanman Richard B. , Conley Anthony Paul , Broaddus Russell , Davies Michael A. , Kopetz Scott , Yung W. K. Alfred , Heymach John , Fu Siqing , Shaw Kenna Rael , Meric-Bernstam Funda 
Published: September 2018

11609 Background: Somatic mutations in IDH1 or IDH2 genes are prevalent in diverse solid tumors and implicated in tumorigenesis. Therapeutic responses to IDH inhibitors are infrequent plausibly due to presence of simultaneous alterations activating compensatory molecular pathways. Methods: We retrospectively reviewed results from clinical genomic profiling with targeted next-generation sequencing in two independent data sets of archival formalin-fixed paraffin-embedded (FFPE) tumor samples (Ion Torrent < 50 genes, 300; FoundationOne < 343 genes, 30; Oncomine 128 genes, 4) and plasma liquid biopsies (Guardant360 < 73 genes panel, 337 samples) from patients with solid tumors of all stages. Results: In 334 FFPE samples the most represented cancers were gliomas (50%), melanomas (14%), cholangiocarcinomas (11%), and non-small cell lung cancer (NSCLC, 6%). In 296 IDH1-mutated FFPE samples the most frequent simultaneous alterations were in TP53 (45%), BRAF (11%), KRAS (9%), and PIK3CA (26, 9%). In the most represented IDH1-mutated tumor types commonly altered genes were TP53 (66%) in gliomas, BRAF (53% [V600K/R 30%, V600E 19%]) in melanomas, PIK3CA (13%), CDKN2A (13%) in cholangiocarcinomas and KRAS (65%) in NSCLC. In 38 IDH2-mutated FFPE samples the most frequent simultaneous alterations were in TP53 (32%), and KRAS (16%). In 337 plasma samples the most represented cancers were NSCLC (39%), cholangiocarcinoma (13%), and breast cancer (8%). In 172 IDH1-mutated plasma samples the most frequent simultaneous alterations were in TP53 (40%), KRAS (23%), EGFR (16%) and BRAF (16%). In the most represented IDH1-mutated tumors commonly altered genes were TP53 (48%), KRAS (37%) in NSCLC and TP53 (37%), KRAS (24%), BRAF (18%) in cholangiocarcinoma. In 161 IDH2-mutated plasma samples the most frequent simultaneous alterations were in TP53 (43%), EGFR (20%), and KRAS (19%). In the most represented IDH2-mutated tumors commonly altered genes were TP53 (43%), EGFR (32%), KRAS (18%) in NSCLC and TP53 (18%), ESR1 (18%), KRAS (18%) in breast cancer. There were 4 tumors with IDH1 and IDH2mutations. Conclusions: IDH1 and IDH2 mutations often coexist with simultaneous oncogenic alterations including these in potentially druggable molecular targets.
Deficient necroptosis pathway as a negative prognostic factor in acute myeloid leukemia.
Authors: Lo Monaco Silvia , Marconi Giovanni , Fontana Maria Chiara , Papayannidis Cristina , Fonzi Eugenio , Baldazzi Carmen , Testoni Nicoletta , Ottaviani Emanuela , Franchini Eugenia , Ferrari Anna , Simonetti Giorgia , Padella Antonella , Ghelli Luserna di Rorà Andrea , Robustelli Valentina , Paolini Stefania , Abbenante Maria Chiara , Parisi Sarah , Nanni Jacopo , Bertamini Luca , Martinelli Giovanni 
Published: September 2018

11611 Background: Necroptosis is a type of necrotic cell death involving several genes transcription and activation of molecular mechanisms as death receptors, interferon, toll-like receptors, intracellular RNA and DNA sensors.The process is leading by the family of receptor-interacting protein kinase ( RIPK3, RIPK2, RIPK1) and the MLKL substrate. Losses of RIPK3 or MLKL, as well as deficiency in apoptosis, could allow tumor cells to escape the immunomediated cells death (ICD). Methods: We performed SNP Arrays (Cytoscan HD and SNP 6.0, Affymetrix) on a cohort of 300 non-M3 AML patients at diagnosis and we analyzed the Overall Survival (OS) of our patients with deficiency on necroptosis pathways. Survival was analyzed with Kaplan-Mayer method and Log-Rank test. We further analyze the relevance of different prognostic factors by the use of COX-Hazard Ratio statistical analysis. Results: We find that 18 patients presented a loss of RIPK1 or MLKL (nobody presented losses in RIPK3/RIPK2) and 13/18 patients were older than 65 years old. The Overall Survival (OS) of patients with alterations in these genes is significantly lower than control group, with a median OS of 3 vs 6 month respectively (p<.0.001). With Fisher Exact Test we further demonstrate that copy number loss of RIPK1 or MLKL are associate to loss of TP53 or FANCAgenes, complex karyotype and advanced age. COXHR model with RIPK1 or MLKL loss, BRACA1 loss, TP53 mutation, FANCA loss, secondary disease and diagnosis karyotype considered as categorical variable shows that necroptosis deficiency (HR 1.98, CI 95% 1.04-3.78), TP53mutation , and secondary AML are independent negative prognostic factors in an optimal model. Conclusions: Our study shows that losses in necroptosis pathways are an uncommon alteration in AML, prevalent in old population. Moreover, we hypothesize that the loss of genes involved in necroptosis could be a real mechanism of tumor immune-escape and could be a rational to select patients that have high probability to be resistant at chemotherapy promoting ICD mechanism. Acknowledgment: ELN,AIL,AIRC, progetto Regione-Università 2010-12, FP7 NGS-PTL project,HARMONY.
PD-L1 assessment in FNA (EBUS) dervied samples.
Authors: Lerner Andrew , Yarmus Lonny , Feller-Kopman David , Lee Hans , Oswiecimka Jesi , Forde Patrick M. , Illei Peter B. 
Published: September 2018

11615 Background: Pembrolizumab therapy for non-small cell lung cancer requires PD-L1 immunohistochemistry (IHC). FDA approval was based on staining of resections or core biopsies. Little is known about PD-L1 expression in fine needle aspiration (FNA) specimens including EBUS of mediastinal lymph nodes. Methods: IHC was performed using the PD-L1 IHC 22C3 pharmDx test on formalin fixed paraffin embedded FNA cell blocks of 8 squamous cell carcinomas and 15 adenocarcinomas (ACA) (age: 42-84, mean: 63, median: 63; 11 female and 12 male). Mutation data (50 gene NGS panel, and ALK, ROS1, RET and MET FISH) was available for 14 ACA. Membranous PD-L1 staining of any intensity and extent was recorded in at least 100 tumor cells (tumor proportion score). The tumors were grouped as: no staining (<1%), low expression (1-49%) and high expression (50% or more). Results: Six (26%) tumors showed no staining, 6 (26%) low expression and 11 (48%) high expression (table 1). High PD-L1 expression was seen in 1 ALK, 1 braf, 1 EGFR, 1 Her2 exon20, 2 kras mutated tumors and 2 tumors with no or unknown mutation status, low PD-L1 expression in 1 braf and 1 EGFR mutated case and 1 tumor without mutation. No expression was seen in 1 ROS1, 1 kras mutated tumor and 1 tumor without mutation. One EBUS biopsy also had PD-L1 assessed on a transbronchial biopsy of the primary tumor showing similar staining (30% versus 20%). Conclusions: PD-L1 immunohistochemistry appears to be feasible using cell blocks of fine needle aspirates containing adeqaute number of viable tumor cells. The majority of ACA were also adequate for NGS mutation and FISH analysis. High PD-L1 expression was seen in approximately half the tumors, which is greater than has been observed in resections/core biopsies, this finding merits further study. High expression of PD-L1 was seen in both squamous cell carcinoma and adenocarcinoma, and tumors with and without common driver mutations. [Table: see text]
Androgen receptor (AR) activation in breast cancer (BC) liver metastases.
Authors: Ramos Corinne , Hoke Nicholas N , Wilks Tom , Levin Maren K. , Hippely Sarah , Pierobon Mariaelena , Petricoin Emanuel , O'Shaughnessy Joyce 
Published: September 2018

11619 Background: AR is expressed in the majority of BCs and its signaling may contribute to the development of BC metastases (mets). The expression pattern of AR, its phosphorylated form, p-AR S650, and correlations with other BC growth and survival pathways were evaluated in BC mets by reverse phase protein array (RPPA). Methods: RPPA was performed on 93 FFPE primary BCs and mets at a CLIA-certified laboratory. Immunostaining with 24 antibodies was directed against AR, p-AR S650, p-MET, and total and p-HER1/2/3 pathway proteins. Clinical and genomic data were obtained from pt chart review. Analysis of variance (ANOVA) was used to assess any statistically significant differences between the groups. Results: 35 tissues were primary BCs (38%); 58 were mets (62%). Sites of mets: liver (n = 41); lung (n = 8); chest wall (n = 9). Of the 41 liver mets, 2 were triple negative (TN), 32 were ER+/HER2-, and 7 were HER2+. AR expression was increased in chest wall (1.7-fold; p = 0.038) compared to primary BCs. p-AR was increased in liver (2.0-fold; p = 0.039) and chest wall (1.8-fold; p = 0.026) compared to primary BCs. ER+ liver mets especially showed strong liver-specific activation of AR along with overexpression of HER1, HER3, VEGFR, and activation of mTOR, S6 Ribo, 4EBP1, and STAT3. MEK/ERK pathway was not activated in ER+ liver mets. HER2+ liver mets had pan-HER1/2/3 activation along with MET, SRC, S6 Ribo, 4EBP1, and JAK2/STAT3. In the 2 TN liver mets, EGFR, VEGFR, mTOR, S6 Ribo, 4EBP1, and JAK2/STAT3 were activated while AR and MEK/ERK were not. The ER+ liver mets showed higher expression of p-AR (p = 0.079), p-HER3 (p = 0.002), p-HER2 (p = 0.010) and p-Jak2 (p = 0.002) compared to primary ER+ BCs whereas the HER2+ liver mets showed lower level of p-IGFR (p = 0.049) and p-MET (p = 0.010) compared to primary HER2+ BCs. Interestingly, TN chest wall mets had higher levels of AR and p-AR (p = 0.008 and 0.044 respectively) compared to TN BCs. Conclusions: ER+ liver mets have strong expression of AR and p-AR, and all liver met subtypes showed accumulation of S6 Ribo/4EBP1 and activation of JAK2/STAT3, but not the MAPK pathway. HER1/3 and HER1/2/3 were activated in ER+ and HER2+ liver mets, respectively. These data suggest that targeting AR, HER1/3, and mTOR in ER+ liver met would be of interest.
Phosphoproteomic analysis of matched primary breast cancer (BC) and lymph node (LN) metastases.
Authors: Ramos Corinne , Hoke Nicholas N , Levin Maren K. , Grant Michael D , Hippely Sarah , Thamby Rohan , Pierobon Mariaelena , Baldelli Elisa , Snipes George J , Petricoin Emanuel , O'Shaughnessy Joyce 
Published: September 2018

11620 Background: Therapeutic recommendations are often based on molecular markers expressed in primary BCs. However, LN metastases (mets) may more accurately reflect the lethal potential of the disease (Ries 2007). Whether activated oncogenic pathways in axillary LN mets can be reliably identified in the associated primary BCs is unknown. We evaluated the activation of key signaling pathways in pts’ matched primary BC and axillary LN mets using reverse phase protein array (RPPA). Methods: 60 pts’ matched FFPE primary BC and axillary LN mets (20 TN, 20 ER+/HER2-, 20 HER2+) are to be evaluated by RPPA at a CLIA-certified laboratory. The first 20 matched BC/LN (3 TN, 14 ER+/HER2-, 3 HER2+) and 7 unmatched (1 TN LN, 1 ER+/HER2- BC, 5 ER+/HER2- LN) results are reported here. Immunostaining of 14 HER1/2/3 and downstream pathway proteins was performed. Mann-Whitney U tests (p value) were utilized to compare BC vs LN mets protein level. Results: Increased expression of HER1 (6-fold) and p-Akt (2-fold) was observed in TN compared to Luminal (Lum) and HER2+ primary BCs. AR expression was upregulated in TN and HER2+ (2-fold) compared to Lum primary BCs. The LN mets showed higher expression of HER1 (p = 0.004), p-HER3 (p = 0.040), p-IGFR (p = 0.009), p-S6 (p = 0.033), p-4EBP1 (p = 0.027) and p-MEK1/2 (p = 0.023) compared to primary BCs. TN had higher level of p-Akt T308 (p = 0.077) in the LN mets compared to the primary BCs while HER2+ showed a downregulation of p-Akt T308 (p = 0.049) in the LN mets. HER2+ also had higher level of HER1 (p = 0.049), p-HER3 (p = 0.049), p-FGFR (p = 0.083), and p-4EBP1 (p = 0.049) in the LN mets compared to primary BCs. Higher levels of HER1 (p = 0.043) and p-MEK1/2 (p = 0.027) were observed in Lum B LN mets compared to p-IGFR (p = 0.041), p-Akt S473 (p = 0.088), p-S6 (p = 0.063) and p-4EBP1 (p = 0.097) in Lum A LN mets. Conclusions: In TNBC, preliminary results show that p-Akt is differentially upregulated in LN mets while HER1, p-HER3 and p-4EBP1 are overexpressed in HER2+ LN mets. Lum A LN mets showed higher levels of p-IGFR, p-Akt, p-S6 and p-4EBP1 vs Lum B LN mets which had higher levels of HER1 and p-MEK1/2. These data suggest different signaling pathways in BC LN mets compared to primary BCs. Analyses of 60 pts’ matched primary BC/LN samples will be presented.
Genetic counseling and testing in endometrial cancer: Are we capturing high-risk women?
Authors: Lee Jessica , Gubernick Lindsay , Chern Jing-Yi , Gerber Deanna , Blank Stephanie V. , Pothuri Bhavana 
Published: September 2018

1503 Background: Lynch syndrome accounts for the majority of inherited endometrial cancers and the identification of probands presents a unique opportunity to treat and prevent multiple cancers. This is now even more relevant with the potential of novel immunotherapy agents for women with germline mutations. The diagnosis of endometrial cancer (EC) can provide the indication for women with specific risk factors to undergo genetic testing (GT). We sought to evaluate genetic counseling referrals (GCR) and subsequent GT rates. Methods: All women with EC between 2012 and 2015 were identified. Statistical analyses were performed to evaluate risk factors including age, body mass index (BMI), positive family history defined as two or more family members with Lynch-related cancers, and tumor mismatch repair (MMR) protein expression loss. Results: A total of 447 women were diagnosed with EC and of these, 107 (24%) were given GCR by their gynecologic oncologist based on their discretion. Compared to non-GCR, GCR women were significantly younger (median 54 vs 65, p < 0.0001) and had lower BMI (median 28.2 vs 30.8, p= 0.007). Of the 107 GCR women, 71 (66%) underwent GT. Of the 71 GT women, 8 (11%) were found to have a germline mutation in one of the MMR genes. Table 1 lists GCR, GT and positive germline mutations among specific high-risk cohorts. Of these cohorts, 56% under 50 years of age, 28% with family history, and 61% with loss of tumor MMR proteins had GCR. Conclusions: Many young, thin EC women with a family history or a tumor MMR deficiency are not given GCR. Among GCR women, 66% underwent GT, despite there being a high rate of germline mutations among these women. It is imperative that high-risk women receive GCR with subsequent GT to capture the maximum number with Lynch syndrome to screen and prevent additional cancers as well as enable cascade testing in family members. Facilitated pathways may be helpful in increasing GCR, as well as GT in EC women. [Table: see text]
Effects of lifestyle and diet as modifiers of risk of breast cancer (BC) in BRCA1 and BRCA2 carriers.
Authors: Pollan Marina , Torres Asunción , Ramon Y Cajal Teresa , Llort Gemma , Castello Adela , Fisas David , Yague Carmen , Lopez Consol , Leon Maria Teresa , Pollan Marina 
Published: September 2018

1505 Background: Mutations in the BRCA1/2 genes confer a high lifetime risk of BC. Penetrance varies among populations and individuals suggesting that non-genetic factors may modify the inherited risk. Knowledge of modifiable factors will help to develop preventive strategies. Methods: Information on physical activity (PA) (current PA and in the adolescence) and smoking was collected in 892 women (W) with a BRCA1/BRCA2 germ-line mutation (582 with BC, 45,62% BRCA2) from 279 families, followed at three Spanish Genetic Counseling Units, 481of these W also answered a food frequency questionnaire. Participants gave their consent and the study was approved by the ethics committee. The association between BC, lifestyle factors and dietary patterns (Mediterranean and Western) associated with BC were studied using logistic regression. Huber-White robust estimators of variance were employed to take into account correlations between family members. Age, menopausal status, specific mutated gene, BMI, parity and oral contraception were included as co-variables. BC was classified as HR+/+,- or HR-. Results: W who did PA daily had half the risk of BC than sedentary W (OR:0,53;p=0,043 for current PA;OR:0,40;p=0,007 for PA in the adolescent) and no differences were observed between BRCA1 and BRCA2 carriers. Also, W who daily exercised in both periods had a reduction of their BC risk (OR:0,22;p<0,001). The effect of PA was particularly important among premenopausal W (p-het<0,05). PA in the adolescent decreased the risk of all type of tumors. Nevertheless, alcohol intake, smoking habit and type of diet, did not significantly modify BC risk in this BRCA W. Conclusions: Our preliminary data suggest a clear reduction in BC risk among BRCA1/2 carriers who exercise regularly, mainly during the adolescence, and could be considered as potential modifiable factor for BC prevention in these group of W.
Incidence, persistence and determinants of human papillomavirus: A prospective cohort study of 10,000 HIV-negative Nigerian women.
Authors: Adebamowo Sally Nneoma , Odutola Michael Kolawole , Famooto Ayo , Dareng Eileen , Adebayo Amos , Achara Peter , Alabi Bunmi , Bakare Rasheed , Obende Kayode , Offiong Richard , Olaniyan Olayinka , Ologun Sanni , Adebamowo Clement Adebayo ,   ACCME Research Group
Published: September 2018

1510 Background: Cervical cancer is the second commonest cancer in Africa. Persistent High-risk HPV (HRHPV) infection is a necessary cause but little is known about the persistence and associated risk factors of HRHPV infection in African women. The aim of this study was to determine risk factors and incidence of HPV infection in Nigerian women. Methods: ACCME is a multicenter prospective cohort study of host germline, cervical somatic and HRHPV genomics, epigenomics, and vaginal microenvironment; and their association with HPV. From February/2014 to January/2016, 10,000 HIV-negative women were enrolled into the cohort and are being followed up every 6 months. We used SPF25/LiPA10to characterize HPV infection and defined persistent infection as 2 consecutive positive tests done at least 12 months apart. Logistic regression models were used to estimate the associations between risk factors and persistent HPV. Results: The mean (SD) age of the study participants at baseline was 40 (10) years and the mean (SD) vaginal pH was 5.2 (0.6). About 42% of the participants were positive for any HPV positive and 21% had persistence of any HPV infections. Some, 35% of the participants had multiple infections with any HPV. About 54% of those with persistent any HPV infections had HRHPV; HPV types 52 (25%) and 18 (15%) were the most prevalent and persistent HRHPV types. The incidence of any HPV infection was 6.6/1,000 person-months while that of HRHPV was 2.6/1,000 person-months. Age, body mass index, level of education, marital and socio-economic status and total number of lifetime sexual partners were associated with HPV infection in these women. Conclusions: We defined the incidence, risk factors and commonest types of HRHPV in a large cohort of women in West Africa.
Effects of gene penetrance on adherence to breast cancer screening recommendations (BCSR) among high-risk women.
Authors: Desjardin Jacqueline Talea , Dhawan Mallika Sachdev , Blanco Amie , Munster Pamela N. 
Published: September 2018

1515 Background: Adherence to cancer screening depends on the interplay between risk perception and convenience. For instance, high perceived risk is likely what motivates high-risk mutation carriers (HRMC) to adhere well to rather inconvenient BCSR. While the NCCN offers BCSR for moderate-risk genes, adherence in moderate-risk mutation carriers (MRMC) and non-carriers with negative multigene panels (NC) is unknown. Methods: Screening behavior was examined in 120 women (15 HRMC, 20 MRMC, 85 NC) 20-65 years old (y) without cancer who received genetic testing and counseling. The groups did not differ in age or family history (fhx). Medical records were reviewed pre- and post-testing to determine adherence. Average follow up was 15 months. Data were analyzed by Chi-squared test. Results: Prior to genetic testing, 93% of women were adherent to general population BCSR, and 58% were already screening in accordance with post-test counseled BCSR. Testing altered adherence to counseled BCSR for HRMC (p<0.01), but not for MRMC (p=0.21) or NC (p=0.86). HRMC had better post-test adherence than MRMC (p<0.05). Conclusions: MRMC are often told to follow similar BCSR to HRMC, namely annual mammogram and MRI, but MRMC may be less motivated to adhere to these BCSR due to lower risk perception. We found adherence was high in HRMC, likely due to high risk perception; intermediate in NC, likely due to manageable BCSR; and comparably low in MRMC, possibly because their risk perception was insufficient to motivate biannual imaging studies. Understanding how genetic testing influences adherence is essential to ensuring proper surveillance in high-risk women. [Table: see text]
Expanded yield of multiplex panel testing in fully accrued prospective trial.
Authors: Idos Gregory , Kurian Allison W. , Ricker Charite Nicolette , Sturgeon Duveen , Culver Julie , Kingham Kerry , Koff Rachel , Chun Nicolette M. , Rowe-Teeter Courtney , Lowstuter Katrina , Hartman Anne-Renee , Allen Brian , Kidd John , Mills Meredith , Ma Cindy , Hong Christine , McDonnell Kevin , Ladabaum Uri , Ford James M. , Gruber Stephen B. 
Published: September 2018

1525 Background: Genetic testing is a powerful tool for stratifying cancer risk. Multiplex gene panel (MGP) testing allows simultaneous analysis of multiple high- and moderate- penetrance genes. However, the diagnostic yield and clinical utility of panels remain to be further delineated. Methods: A report of a fully accrued trial (N = 2000) of patients undergoing cancer-risk assessment. Patients were enrolled in a multicenter prospective cohort study where diagnostic yield and off-target mutation detection was evaluated of a 25 gene MGP comprised of APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were enrolled if they met standard testing guidelines or were predicted to have a ≥2.5% mutation probability by validated models. Differential diagnoses (DDx) were generated after expert clinical genetics assessment, formulating up to 8 inherited cancer syndromes ranked by estimated likelihood. Results: 1998/2000 patients had reported MGP test results. Women constituted 81% of the sample, and 40% were Hispanic; 241 tested positive for at least 1 pathogenic mutation (12.1%) and 689 (34.5%) patients carried at least 1 variant of uncertain significance. The most frequently identified mutations were in BRCA1 (17%, n = 41), BRCA2 (15%, n = 36), APC (8%, n = 19), CHEK2 (7%, n = 17), ATM (7%, n = 16). 39 patients (16%) had at least 1 pathogenic mutation in a mismatch repair (MMR) gene ( MLH1, n = 10; MSH2, n = 10; MSH6, n = 8; PMS2, n = 11). 43 individuals (18%) had MUTYH mutations – 41 were monoallelic. Among 19 patients who had mutations in APC – 16 were APC I1307K. Only 65% (n = 159) of PV results were included in the DDx, with 35% (n = 86) of mutations not clinically suspected. Conclusions: In a diverse cohort, multiplex panel use increased genetic testing yield substantially: 35% carried pathogenic mutations in unsuspected genes, suggesting a significant contribution of expanded multiplex testing to clinical cancer risk assessment. The identification of off-target mutations broadens our understanding of cancer risk and genotype-phenotype correlations. Follow-up is ongoing to assess the clinical utility of multiplex gene panel testing. Clinical trial information: NCT02324062.