bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Localization of non-receptor tyrosine kinase (nRTK) variants in solid tumor patients using next-generation sequencing (NGS).
Authors: Sareen Srishti , Stein Matthew , Morris Lindsay Kaye , Karri Saradasri , Patel Kruti , Shibata David , Vanderwalde Ari M. , Schwartzberg Lee Steven , Martin Michael Gary
Published: September 2018

1536

Background: Non-synonymous SNPs (nsSNPs) in nRTKs may serve as oncologic targets and predictive biomarkers, with significant lesions described in various nRTK regions including the tyrosine kinase domain (TKD). NGS allows the entire coding sequence to be evaluated, facilitating the identification of novel lesions. Methods: We searched all nsSNPs in 14 nRTKs in the tumors of patients (pts) at our institution that received NGS with Caris from 2013-2015 with a diagnosis of advanced breast, colon or lung cancer. Substitutions were classified as either within or extra-TKD; in the case of JAK1-3, pseudokinase domain lesions were also identified. In order to predict the pathogenicity of nsSNPs, in silico analysis with PolyPhen-2 (Harvard) was completed. Results: 356 pts (79 breast, 110 colon and 165 lung (156 NSCLC, 11 small cell)) were identified with a median age of 61 years (range 26-86); 58% female; 62% white, 35% black. 245 variants were found, with 200 nsSNPs and 45 known pathologic mutations (Pmut); Pmut were PIK3CA (21 breast, 13 colon, 5 NSCLC) and AKT1 (6 breast). 169/356 (47%) pts had ≥1 nRTK lesion (0-8). 52/200 (26%) nsSNPs were predicted-damaging (pnsSNPs) with in silico analysis among 49 pts (6 breast, 13 colon and 30 NSCLC). pnsSNPs were found in 14/14 nRTKs with median 3 (1-10). The most frequently mutated nRTKs in breast were SRC (2/2 variants were pnsSNPs) and ABL2 (1/5); in colon ABL1 (5/10), JAK3 (3/27) and CDK12 (2/8); and in NSCLC JAK3 (6/20), BTK (5/8), ABL1 (3/12), JAK2 (3/11), CDK12 (3/9) and JAK1 (3/3). Of 180 nsSNPs with in silico results, 68% were extra-TKD (29/122 variants were pnsSNPs), 23% within the TKD (13/42) and 9% in pseudokinase domains of JAK1-3 (10/16). Notably, 8/10 pseudokinase domain pnsSNPs were in NSCLC pts (3 JAK1, 2 JAK2 and 3 JAK3). Conclusions: > 13% solid tumors held an nRTK nsSNP that was predicted-damaging by in silico analysis, with 69% of these mutations occurring outside of the TKD-proper. Further work is needed to determine how these pnsSNPs affect function and if they are clinically actionable.
The relationship between statins and colorectal cancer stage in the Women's Health Initiative.
Authors: Rutledge Brian , Desai Pinkal M. , Abdel-Rasoul Mahmoud , Nassir Rami , Qi Lihong , Luo Juhua , Liu Simin , Arun Monica , Simon Michael S.
Published: September 2018

1540

Background: Statins are the most widely prescribed cholesterol-lowering drugs in the United States. The anti-carcinogenic effect of statins may reduce the metastatic potential of cancer cells leading to ‘stage migration’ with users more likely diagnosed with early rather than late stage cancer. We evaluated the relationship between prior statin use and colorectal cancer (CRC) stage at diagnosis in the Women’s Health Initiative (WHI). Methods: The study population included 132,322 post-menopausal women aged 50-79 years, among which there were 2,628 pathologically confirmed cases of insitu (3.3%), local (43.6%), regional (40.4%) and distant (12.7) stage CRC, after an average of 13.9 (SD = 4.7) years of follow-up. To reduce the possibility of detection bias among women more likely to be prescribed statins, we excluded women who did not report a mammogram within 5 years of study entry and who had no health insurance or medical care provider (n = 28,237). Stage was coded using criteria implemented in the Surveillance, Epidemiology and End Results (SEER) Program into early (in situ and local) vs. late (regional and distant) stage disease. Information on statin use prior to diagnosis was collected by self and interviewer-administered questionnaires at baseline and at one, three, six and nine years post-baseline. Self- and interviewer-administered questionnaires were used to collect risk factor information. Hazards ratios (HR) and 95% confidence intervals (CIs) evaluating the relationship between statin use at baseline only, and in a time-dependent manner, and diagnosis of late-stage CRC were computed from multivariable-adjusted Cox proportional hazards analyses. Statistical tests were two-sided. Results: Statins were used by 10,868 women (8%) at baseline. There was no significant relationship between statin use at baseline and late stage CRC cancer (HR = 1.03, 95% CI (0.82-1.30) and no significant association by type of statin or duration of use. In the multivariable-adjusted time-dependent model, use of statins was associated with a reduction in diagnosis of late-stage colorectal cancer (HR 0.79, 95% CI 0.67-0.94, p = 0.007). Conclusions: Prior statin use may have an influence on colorectal cancer stage at diagnosis.
Use of a marketing plan for recruitment to a lung cancer screening study.
Authors: Goffin John R. , Pond Gregory Russell , Tremblay Alain , Johnston Michael R. , Goss Glenwood D. , Nicholas Garth Andrew , Martel Simon , Bhatia Rick , Liu Geoffrey , Roberts Heidi , Tammemagi Martin , Atkar-Khattra Sukhinder , Tsao Ming Sound , Lam Stephen C. , Rudkowski Janice ,   Pan-Canadian Early Detection of Lung Cancer Study Research Team
Published: September 2018

1548

Background: Recruitment to clinic trials is typically poor. Among barriers to recruitment may be the limited knowledge of trialists with respect to marketing techniques. Improvements in marketing could decrease recruitment time and shorten the time to access new interventions. We hypothesized that a marketing plan would improve recruitment to a lung cancer screening study. Methods: The Pan-Canadian Early Detection of Lung Cancer Trial recruited subjects from 8 centres to a screening study of low-dose CT scan and autofluorescence bronchoscopy. Recruitment processes were undertaken independently at each centre. One centre (M) used marketing expertise and a marketing plan, including surveying study candidates for motivators, resulting in specific newsprint advertisements. Screened trial candidates provided demographic and tobacco use data and indicated how they had heard about the study (bus, friend/family, MD, mail, newsprint, radio, TV, other). No site paid for radio or TV time. We used regression analyses to assess whether newsprint advertisements were more effective for recruitment at site M compared with all other sites. Results: From 2008 to 2010, 7059 candidates contacted all centres for eligibility screening, including 779 at centre M. Overall, 50.2% were female; median age was 59 yrs. Compared with other centres, candidates at centre M had less education (p < 0.001), a higher median 3-year lung cancer risk (2.3 vs 2.0%, p < 0.001), but were more likely to have learned of the study by newsprint (58.8 vs 53.3%, chi-squared p = 0.004), and were more likely to be recruited (44.0 vs 34.9%, p < 0.001). It was more likely that newsprint was the driver for screening contact among candidates with higher education level (OR 1.05/level), higher age (OR 1.03 / yr) and contact at site M (OR 1.31) (all < 0.001). Recruitment after eligibility screening was higher when newsprint was the driver for contact on univariable but not multivariable analysis. Conclusions: The effectiveness of newsprint advertising in motivating study contact may be improved by the formal use of marketing expertise. Newsprint advertising may improve the likelihood of recruitment after study screening, possibly through improved initial self-screening by the candidate. Clinical trial information: NCT00751660.
Risk factors of colorectal adenoma recurrence among individuals under 50 years of age compared to those 50 years of age or older.
Authors: Molmenti Christine Louise Sardo , Yang Jingyan , Thomson Cynthia A , Hibler Elizabeth A , Ho Gloria , Neugut Alfred I. , Lance M Peter , Alberts David S. , Jacobs Elizabeth T
Published: September 2018

1554

Background: Colorectal cancer incidence and mortality are increasing among individuals < 50 years of age. Data are limited regarding the epidemiology of colorectal adenomas in this younger age group. This study investigated and compared risk factors associated with recurrence of adenomas in individuals under and over 50 years of age. Methods: Pooled analyses from the Wheat Bran Fiber and Ursodeoxycholic Acid phase III, randomized, controlled clinical trials included 1,623 participants, aged 40-80 years. Each completed baseline questionnaires related to family history and lifestyle habits, had one or more colorectal adenomas removed at baseline, and had a follow-up colonoscopy during the trial (mean follow up 36 months). Univariate and multivariate logistic regression modeling estimated the association between age and colorectal adenoma recurrence, and evaluate multiple risk factors, while controlling for confounding factors. Results: A statistically significant increased trend was found for colorectal adenoma recurrence with increasing age ( Ptrend= < 0.001). Multivariate logistic regression revealed that risk factors significantly associated with adenoma recurrence in the ≥50 age group (n = 1,523) included history of previous polyps, characteristics of adenomas removed at baseline (multiple adenomas and villous feature), current smoking, and an increased waist circumference. Although risk profile in the < 50 age group (n = 95) shared similarities with that in the ≥50 age group (e.g., current smoking), there were a few notable differences: history of previous polyps was a more prominent predictor for recurrence for the < 50 (OR< 50 = 4.76 and OR≥50 = 1.33, Pinteraction = 0.042), whereas baseline characteristics of adenomas were more important for the ≥50 (multiple adenomas: OR< 50 = 0.40 and OR≥50 = 2.28, Pinteraction = 0.043). Conclusions: Predisposition to colorectal adenoma is a more important risk factor for recurrence in the < 50 as compared to the ≥50. Future studies need to identify susceptibility factors contributing to the increasing incidence of colorectal cancer in this younger age group.
High accumulation of metformin in colonic tissue of subjects with diabetes or metabolic syndrome.
Authors: De Censi Andrea , Burhenne Juergen , Haefeli Walter E. , Weiß Johanna , Roth Wilfried , Parodi Andrea , Gnant Michael , Bachleitner-Hofmann Thomas , Scherer Dominique , Ulrich Neli , Štabuc Borut , Petrera Marilena , Puntoni Matteo , Coccia Gianni , Paleari Laura
Published: September 2018

1557

Background: Epidemiological studies consistently observed an association between metformin use in diabetic patients and decreased colon cancer incidence and mortality at clinical doses (1500-2250 mg day), corresponding to plasma levels of 0.003-0.045 mM. Preclinical models report much higher doses of metformin, ranging between 1 and 40 mM for in vitro and 0.006-0.145 mM for in vivo studies. A recent trial using a low dose of metformin (250 mg/day, Higurashi T et al. Lancet 2016;17:475) showed a 40% reduction of colorectal adenoma recurrence. We performed a pilot study to measure metformin in plasma and colonic tissue of subjects with diabetes or metabolic syndrome and to explore their correlation with different tissue biomarkers, including Ki-67, pS6k, a mTOR effector protein, and EGFR expression. Methods: We used LC-MS/MS to quantify metformin in plasma and colonic tissues from 13 volunteers with diabetes or metabolic syndrome undergoing screening colonoscopy. All patients had received metformin at 1000-1850 mg/day for a median of 6.5 yrs (range 2-15), except for one who served as untreated control. Tissue quantifications were performed on specimens derived from right and left colon biopsies with or without washing to exclude a potential contamination due to lumen accumulation by the drug. Biomarker assessment was performed by standard IHC assay. Results: The mean plasma metformin was 0.025 mM/L (range 5x10-5-0.017), whereas the colonic tissue was ~100 fold higher in right [0.39 mM/Kg (range 0.034-1.75)] and left colon [0.46 mM/Kg (range 5x10-3-1.86)]. There was no significant difference between washed and unwashed biopsies. No significant correlations were detected between metformin levels in plasma/tissue and tissue biomarkers. Conclusions: Metformin can attain ~100 fold higher colonic tissue levels than in plasma. These levels are in the range of a direct antitumor effect observed in in vivo preclinical models. A two-by-two clinical trial of metformin and aspirin in colon cancer patients is underway by our group to further elucidate independent and synergistic antitumor effects.
Breast cancer in male veterans: The Veterans Affairs (VA) informatics and computing infrastructure (VINCI) big data analysis.
Authors: Aggarwal Anita , Maron David , Krasnow Steven H.
Published: September 2018

1559

Background: Male breast cancer (MBC) management from diagnosis to treatment is generalized from female breast cancer (FBC) because of its rarity and paucity in literature. VINCI is a unique database for cross sectional and longitudinal analysis. The objective of this retrospective analysis was to compare characteristics and outcome of MBC with FBC in veterans. Methods: Detailed demographics, diagnosis, treatment and outcome of all patients diagnosed with breast cancer between 1998 and 2016 at 152 VA medical centers were obtained and analyzed with Chi-square and t-test univariate statistics. Results: In total 9765 patients' records were reviewed, 1613 MBC were compared with 8152 FBC. The mean age at diagnosis is 68.5 and 57.3 years for MBC and FBC, respectively (Table1). After a median follow up of 3.5 years, 48% MBC and 22% FBC died. Breast cancer mortality is 18% and 9% in MBC and FBC, respectively. A cox regression survival analysis indicates that males were 33% (Hazard Ratio 1.33, P=<0.0001) more likely to die from breast cancer than females. Conclusions: This is the largest comparison series of MBC with FBC to date in the Veteran population to author’s knowledge. Males have higher breast cancer specific mortality than females most likely because of older age and higher stage at the time of diagnosis. Differences in the biology and pathology may be contributing factors which needs further prospective studies. [Table: see text]
Socio-demographic variations in lung cancer screening before and after USPSTF recommendation: Results from national health interview surveys (NHIS).
Authors: Wang Qian , Jiang Changchuan , Deng Lei , Zhang Yaning , Sara Gabriel Albert
Published: September 2018

1563

Background: In 2013, USPSTF recommended low-dose CT screening (LCS) for lung cancer in high-risk adults. The change in real-world practice is largely unknown, as well as the association with socio-demographic factors. Methods: Data were extracted from the population-based 2010 and 2015 NHIS. LCS was defined as a chest CT to check for lung cancer within the past year. We included adults aged 55 to 80 years who 1) have 30+ pack-year smoking history; 2) are currently smokers or have quitted within the past 15 years. We excluded adults who 1) have lung cancer; 2) had not seen a physician in the past year. We used weighted analyses to estimate national lung cancer screening rates. Results: A total of 874 and 1041 high-risk smokers responded to the LCS questions for lung cancer in 2010 and 2015, respectively. The screening rate more than doubled from 4.1% to 9.1% (P < 0.01) in all respondents. The increase was greater in women (2.9% to 9.5%, p < 0.01) than men (5.2% to 8.8%, p = 0.03) and in age 65-80 (4.7% to 12.3%, p < 0.01) than age 55-64 (3.8% to 6.3%, p = 0.16). White saw the largest increase and highest rate in 2015 (4.0% to 9.3%, p = < 0.01). Those with some college or above education had the highest rate in 2010, but the lowest in 2015. Household income above 75,000 dollars was associated with the lowest rate in both 2010 and 2015. Conclusions: Since the recommendation of USPSTF, LCS rate for lung cancer has doubled but remains less than 10%. Higher education and household income are associated with lower screening rate, in contrast to studies of other cancers. [Table: see text]
Germline mutations in cancer predisposition genes among patients with thyroid cancer.
Authors: Kamihara Junne , LaDuca Holly , Dalton Emily , Speare Virginia , Garber Judy Ellen , Black Mary Helen
Published: September 2018

1581

Background: Thyroid cancers are known component tumors of both well-described and emerging hereditary cancer syndromes. To assess the contribution of germline variants in thyroid cancer predisposition, we examined the prevalence of germline mutations among individuals with a history of thyroid cancer, compared to those with thyroid and breast cancer or breast cancer alone. Methods: Clinical histories and molecular results were reviewed for individuals with a history of thyroid and/or breast cancer, ascertained from a cohort of > 140,000 patients who underwent hereditary cancer multigene panel testing at a single commercial laboratory. Clinical history information was obtained from test requisition forms completed by ordering clinicians and from pedigrees/clinic notes, if provided. Results: Among 2,678 thyroid cancer patients, the majority were Caucasian (66.9%), female (92.3%), and/or had an additional cancer primary (71.9%), with nearly half reporting an additional breast cancer primary (49.1%). Among those with available pathology information, 4.1% had medullary thyroid cancer. The median (IQR) age at diagnosis was 38 (26,48) years, and while 94.1% had a family history of cancer, 78.8% had at least one affected 1st degree relative. Overall, 11.1% were identified as mutation carriers, defined as ≥1 pathogenic or likely pathogenic variant. Among those with thyroid cancer alone, 9.7% had a mutation, similar to those with breast cancer alone (9.7%) and those with breast and thyroid cancer only (10.5%). Genes most frequently mutated in the thyroid only group included CHEK2 (3.1%), MUTYH (monoallelic) (2.4%), APC (2.0%), ATM (1.6%), and PALB2 (1.2%). CHEK2 was the most frequently mutated gene observed in all groups, with a higher frequency seen among those with thyroid and breast cancer (5.5%) compared to breast cancer (2.5%) or thyroid cancer (3.1%) alone (p < 0.001). Conclusions: A high rate of germline mutations is observed among individuals with thyroid cancer presenting for clinical genetic testing, even in the absence of other primary cancer diagnoses. Thyroid cancer may be an under-recognized component tumor of hereditary cancer predisposition syndromes suggesting the need for further investigation.
Are we still adjusting to multigene panel testing? An NCI-designated cancer center's 2-year experience.
Authors: Ramamurthy Chethan , Hitrik Mark A. , DeMora Lyudmila , Forman Andrea , Rainey Kim , Savage Michelle , Montgomery Susan , Masny Agnes , Schwartz Sharon , Hall Michael J. , Daly Mary Beryl , Obeid Elias
Published: September 2018

1585

Background: Genetic testing for hereditary cancer predisposition has rapidly changed over the past few years with the introduction of multigene panel testing. Multigene testing has evolved from disease-agnostic comprehensive (C) panels alone to include disease-specific but expanded (DSE) panels as well as guideline-based (GB) panels. We analyzed trends in utilization of genetic testing over a two-year period in one NCI-designated Cancer Center, hypothesizing that over time genetic testing usage would trend toward more disease-specific panels. Methods: We conducted a retrospective analysis of our program’s database for all germline genetic tests ordered from 9/1/2013 to 8/31/2015 (n = 619; 246 in year 1, and 373 in year 2). Tests were categorized into three groups based on specificity: GB (range: 2-12 genes tested), DSE (12-35 genes tested), and C (28-80 genes tested). The Chi-square test was used to analyze test types ordered in year 1 (9/1/2013-8/31/2014) and year 2 (9/1/2014 – 8/31/2015) and the proportions of resulting mutation types. Results: A total of 604 germline genetic tests met the inclusion criteria: 39 GB (20 year 1, 19 year 2), 171 DSE (43 year 1, 128 year 2), and 394 C (180 year 1, 214 year 2). Compared to year 1, a larger proportion of DSE tests (35% v. 18%, p < 0.001), and a smaller proportion of C tests (59% v. 74%, p < 0.001) and GB tests (5% vs. 8%, p = 0.146) were ordered. DSE panels revealed a pathogenic variant (PV) at a rate of 16% and a variant of unknown significance (VUS) at a rate of 24%. C tests revealed a PV and VUS at rates of 14% and 29%, respectively. GB tests revealed a PV and VUS at rates of 21% and 18%, respectively. No statistically significant differences in detection rates of mutation types (PV or VUS) were found between GB, DSE, or C tests. Conclusions: The rates of PV detection were not significantly different between test types, but the profile of tests ordered changed over time to favor DSE panels. Exploration of factors contributing to changing trends in genetic testing are warranted as counselors and clinicians adapt to the quickly expanding number of genes associated with hereditary cancer risks, many of them moderate-risk, and the evolving landscape of multigene panel testing.
Decision support for family history intake to determine eligibility for BRCA testing among multiethnic women.
Authors: McGuinness Julia E. , Trivedi Meghna S. , Vanegas Alejandro , Colbeth Hilary , Sandoval Rossy , Kukafka Rita , Crew Katherine D.
Published: September 2018

1586

Background: The U.S. Preventive Services Task Force (USPSTF) recommends that women who meet family history criteria for hereditary breast and ovarian cancer (HBOC) be referred for genetic counseling. However, HBOC genetic testing is under-utilized, particularly among racial/ethnic minorities. We evaluated different methods of family history intake, including a validated family history screener, documentation in the electronic health record (EHR), and a web-based decision aid (DA). Methods: Among women undergoing screening mammography, we administered a validated family history screener to determine eligibility for BRCA genetic testing based upon USPSTF guidelines. We developed a patient-centered DA ( RealRisks) which includes modules on breast cancer risk, collection of detailed family history, and information on HBOC genetic testing. Women who met high-risk criteria for breast cancer were enrolled in an intervention trial to determine whether exposure to RealRisks increases referrals for high-risk consultations. BRCA genetic counseling/testing uptake was assessed by self-report and EHR review. Results: From November 2014 to June 2016, 3077 women completed the family history screener. Median age was 59 years (range, 29-99), including 76% Hispanic, 4% Ashkenazi Jewish, and 60% with a high school education or less. 12% met family history criteria for BRCA genetic testing based upon the family history screener, of which only 5.9% had previously undergone genetic counseling or testing. Sixty high-risk women were enrolled to access RealRisks. When family histories based upon the screener, DA, and EHR were compared, 12 (20%) had discrepancies in number of affected relatives, type of cancer, and age at diagnosis which changed eligibility for BRCA testing. Follow-up is ongoing to determine whether the DA facilitates appropriate referrals for genetic counseling. Conclusions: In a population of predominantly Hispanic and less educated women, a large proportion met USPSTF family history criteria for BRCA testing, but uptake of genetic counseling was low. Developing decision support for accurate family history intake is critical to identifying appropriate candidates for genetic referrals.
Dissemination of universal genetic testing to three unique oncology care settings.
Authors: Bednar Erica , Muse Kimberly I. , Oakley Holly D. , Baker Ellen , Walsh Michael T. , Krukenberg Rebekah C. , Dresbold Cara S. , Morman Nichole A. , Bowdish Elizabeth C. , Cooper Julia N. , Wise Emaline E , Eppolito Amanda L. , Teed Kelly B. , Klein Molly H. , Chao Han , Method Michael W. , Grainger Andrew V. , Henson John W. , Lu Karen H.
Published: September 2018

1590

Background: Efforts are occurring across the United States to improve the rates of identification and standard of care genetic counseling (GC) and genetic testing (GT) of pts with breast and ovarian cancer. Following a successful quality improvement (QI) initiative to increase referrals and utilization of GC/GT among pts with breast and ovarian cancer to >80% at our host site (HS), we sought to disseminate the QI project to three unique oncology care settings (OCS). Methods: The OCS described in the Table are certified members of the HS network, were strategically identified, and agreed to participate in the QI project. Genetic counselors at the HS and OCS built teams to plan and initiate the project. A 130-item environmental scan was created by the HS team to assess OCS structure, resources, and GC/GT processes. OCS teams completed the environmental scan and a semi-structured interview with the HS; and from this, barriers to GC/GT were identified, then categorized using Ishikawa diagrams. Clinical interventions were designed to address these barriers. Resulting QI protocols follow the PDSA-cycle QI model. A database was built for retrospective and prospective data collection of eligible pts and rates of GC/GT referral and completion from 2015-2018. Results: Although unique barriers were identified at each OCS, all identified: pt referral/scheduling issues, technology and electronic medical record system inefficiencies, and inconsistent physician referral/GT practices. OCS interventions include: implementation of physician-coordinated GT, GC within chemo infusion suites, physician education sessions, GC scheduling improvements, creation of pt education documents, and development of referral tracking processes. Conclusions: Genetic counselors collaborated, planned, and initiated dissemination of a QI project to improve GC/GT utilization at three unique OCS. QI interventions were developed to address the unique environment and barriers at each OCS. [Table: see text]