bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Knowledge outcomes in a randomized trial of telephone vs. in-person disclosure of genetic testing: The COGENT study.
Authors: Beri Nina , Patrick-Miller Linda J. , Egleston Brian L. , Olopade Olufunmilayo I. , Hall Michael J. , Daly Mary Beryl , Fleisher Linda , Grana Generosa , Ganschow Pamela , Fetzer Dominique , Domchek Susan M. , Bradbury Angela R. ,   The COGENT Research Team
Published: September 2018

1534

Background: Telephone disclosure (TD) of genetic testing is non-inferior to in-person disclosure (IPD) for most outcomes but did not meet non-inferiority for knowledge change. We sought to understand which concepts patients don’t understand and factors associated with lower knowledge. Methods: Patients were recruited to a multi-center, randomized trial (NCT01736345) comparing TD to IPD of genetic test results. 819 patients were randomized (IPD = 418; TD = 401); 165 declined randomization and requested IPD. Knowledge was assessed after pre-test counseling (V1) and test disclosure (V2). Results: There were no significant differences in genetic or multi-gene (MG) knowledge between disclosure groups after V1 and V2. On average, patients answered 73% (SD 1.19) of genetic knowledge and 57% (SD 1.78) of mg knowledge items correctly.After V1, most understood implications of a positive result (87%), that results are not deterministic (84%) and risks for their children (91%). Understanding of uninformative negative, true negative and variant of uncertain significance (VUS) results was lower (post-V1: 33%, 65%, 29%; post-V2 : 37%, 65%, 25%). In multivariable analyses, lower genetic knowledge after V1 was associated with study site, being older (p < 0.01), single (p < 0.01), non-white (p < 0.01), not Ashkenazi Jewish (p = 0.01), and not having a mutation in the family (p = 0.03), having more relatives with cancer (p < 0.01) and not graduating college (p < 0.01). Lower mg knowledge after V1 was associated with site and being non-white (p = 0.01). Lower genetic knowledge after V2 was not associated with disclosure method but associated with study site, being older (p < 0.01), not graduating college (p < 0.01) and being non-white (p < 0.01). Lower mg knowledge after V2 was only associated with not graduating college (p = 0.02). Conclusions: While there were no significant differences in genetic knowledge by disclosure method, understanding of several concepts (e.g. VUS and negative results) were lower regardless of arm. Several factors, including age, education and race/ethnicity were associated with lower knowledge. Interventions to improve genetic knowledge in real-world and diverse populations are needed. Clinical trial information: NCT07136345.
The scientific impact and value of large, NCI-sponsored randomized phase III cancer prevention trials.
Authors: Unger Joseph M. , Barlow William E. , Tangen Catherine M. , Ramsey Scott David , Thompson Ian Murchie , Klein Eric A. , LeBlanc Michael Leo , Blanke Charles David , Goodman Phyllis J. , Minasian Lori M. , Hershman Dawn L.
Published: September 2018

1541

Background: The cooperative cancer research groups of the National Cancer Institute’s National Clinical Trials Network have a history of successful conduct of large randomized phase III trials of prevention for cancer. An important question for funding agencies is whether the conduct of large prevention trials provides strong scientific return on investment. Methods: We used study data from a single NCI-sponsored cooperative group (SWOG) over a 20-year period (1990-2009, inclusive). During this time, SWOG conducted two large prevention trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin E Cancer Prevention Trial) and numerous treatment trials. Scientific impact for prevention and treatment trials was examined using citation analysis. Average annual citation counts were compared using t-tests. Scientific impact was also assessed as a function of trial costs. Results: Twenty-six treatment trials with 16,391 patients and two prevention trials with 54,415 patients were examined. The mean annual citation rate for primary articles was higher for prevention trials compared to treatment trials (173.6 vs. 41.7, p = .003). For both primary and secondary article publications, mean annual citations for articles associated with prevention trials were also higher (557.2 vs. 67.6, p < .0001). Large prevention trials were estimated to provide 70% greater scientific impact on a cost-adjusted basis. Conclusions: Based on these criteria, the scientific impact of large phase III cancer prevention trials was very high in absolute terms and after accounting for trial costs. For appropriate scientific questions, large prevention trials provide a strong scientific return on investment for federal funding agencies.
Immune profiling of oral pre-malignant lesions (OPLs): An Erlotinib Prevention of Oral Cancer (EPOC) study biobank analysis.
Authors: William William Nassib , Uraoka Naohiro , Peng S. Andrew , Lee J. Jack , El-Naggar Adel K. , Parra Cuentas Edwin Roger , Rodriguez-Canales Jaime , Gillenwater Ann M. , Lin Heather Y. , Wistuba Ignacio Ivan , Myers Jeffrey , Gold Kathryn A. , Hwu Patrick , Heymach John , Papadimitrakopoulou Vassiliki , Lippman Scott Michael
Published: September 2018

1545

Background: We previously demonstrated that high-risk loss of heterozygosity (LOH) profiles (i.e., 3p14/9p21 LOH) and EGFR gene copy number gain (CNG) in OPLs were associated with inferior oral cancer-free survival (OCFS) in patients enrolled in the randomized EPOC trial. Herein, we performed comprehensive immune profiling of OPLs and correlated the findings with molecular features and outcomes, using the prospectively collected and clinically annotated EPOC biobank. Methods: We evaluated OPL specimens by multiplex immunofluorescence using the Opal 7-color fIHC Kit and the Vectra multispectral microscope / inForm Cell Analysis software. Markers included AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD8, and CD68. Wilcoxon rank-sum and Fisher’s exact tests were used to assess the associations between binary markers and continuous and categorical variables, respectively. Cox model was used to investigate associations of markers with OCFS. Results: The cohort included 188 OPL patients with hyperkeratosis/hyperplasia (18%), mild/moderate (44%), or severe dysplasia (5%); 65% had high-risk LOH profiles. The 5-year OCFS was 72.3% (median follow-up of 50 months). PD-L1 expression in > 1% of epithelial cells occurred in 28% of OPLs. Intraepithelial CD3+, CD3+/CD8+, CD68+, and CD68+/PD-L1+ cells were detected in 100%, 88%, 88%, and 54% of the samples, respectively. OPLs with high-risk LOH profiles had increased epithelial PD-L1 expression (P = 0.007), intraepithelial CD68+/PD-L1+ cells (P = 0.002), and a trend towards more CD3+/CD8+ cells in the stroma (P = 0.06) but not in the epithelium (P = 0.97), compared with low-risk LOH OPLs. Increased epithelial PD-L1 expression was associated with inferior OCFS on univariate (P = 0.023), and multivariate analysis including LOH status and EGFR CNG as co-variates (P = 0.018). Conclusions: High-risk OPLs defined by LOH profiles had increased PD-L1 expression in epithelial cells and intraepithelial macrophages, as well as stromal CD3+/CD8+ immune infiltration. Higher PD-L1 expression was associated with increased oral cancer risk. The findings may support evaluation of (PD-1-targeted) immunoprevention strategies in high-risk OPLs.
Ten year experience of an integrated cancer prevention center screening for multiple cancer types.
Authors: Wolf Ido , Leshno Ari , Liberman Eliezer , Gur Eyal , Elran Hanoch , Sror Miri , Harlap-Gat Amira , Jean Maayan , Steiner Moran , Galazan Lior , Av Galit , Blachar Arye , Kessler Ada , Golan Orit , Shapira Shiran , Geva Ravit , Arber Nadir
Published: September 2018

1549

Background: Cancer is the leading cause of mortality worldwide. Prevention and early detection are pivotal tools for reducing cancer burden. Methods: We describe the 10 year experience (2006-2016) of an integrated cancer prevention center that provides screening for prevention and early detection of 11 most common cancer types. Healthy individuals (20-80 yr) were included. Extensive clinical and epidemiological data was obtained. DNA was extracted from all participants and genotyped for APC I1307K and E1317Q. Patients were examined by specialists in internal medicine, surgery, plastic surgery, OBGYN, urology, oncology, oral surgery, gastroenterology, and others. Women underwent vaginal US and pap smear and (40yr) mammography and US/MRI with a clinical indication. PSA and free PSA for Men ( > 40yr). LDCT for heavy smokers. Colonoscopy was recommended to all subjects ( > 40yr). Results: A total of 6258 (49%) men and 6461 (51%) women mean age 47.0±11.5 year were screened. New malignant lesions were detected in 389 (1.75%) of screeners. The most common cancers were of skin (74, 0.6%), prostate (62, 0.5%), thyroid (51, 0.4%), breast (36, 0.3%), colorectal (22, 0.2%), ovarian (19, 0.1%), uterus (14, 0.1%), testis (12, 0.09%) urinary (9, 0.07%) and lung (10, 0.08%). In 28 patients (0.22%) more than one cancer was detected. Twenty eight of the cancer patients (7.2%) died after 32.4±28.1 months at a mean age of 69.4±14.2 years. Significantly, better than the expected cancer mortality. The APC I1307K and E1317Q variants were detected in 572 (4.8%) and 182 (1.5%) subjects respectively. First degree family member with cancer (OR = 2.02), I1307K carrier ship (OR = 1.53), female gender (OR = 1.23) and advanced age (OR = 1.06) were all associated with statistically significant (P < 0.05) increased cancer risk. Advanced age and first degree family history were also associated with detection of more than one cancer types. Conclusions: One stop shop screening, in the setting of a multidisciplinary outpatient clinic, is feasible and can prevent and detect cancer at an early stage. It significantly improve morbidity and mortality. Impressively the APC I1307K carries an overall increase cancer risk.
Risk of breast or ovarian cancer in family members who do not carry the BRCA1 or BRCA2 family mutation: Findings from the EMBRACE study.
Authors: Girardi Fabio , Barnes Daniel R. , Barrowdale Daniel , Frost Debra , Easton Douglas F. , Antoniou Antonis C. ,   EMBRACE Collaborators
Published: September 2018

1558

Background: BRCA1/BRCA2 true-negatives are proven non-carriers of the BRCA mutation segregating within their family. Currently, there is no conclusive evidence on the risk of developing breast or ovarian cancer in these individuals, potentially leading to non-uniform clinical practices. The purpose of this study was to estimate breast and ovarian cancer risks for true-negatives from the EMBRACE prospective cohort study. Methods: Risks were calculated separately for incident invasive breast cancer and epithelial ovarian cancer (EOC). We used cohort analysis to estimate incidences, cumulative risks and standardised incidence ratios (SIRs). Results: A total of 1895 unaffected women were eligible for inclusion in the breast cancer analysis and 1736 for the ovarian cancer analysis. There were 23 incident invasive breast cancers and 2 EOCs diagnosed during follow-up. The cumulative risk of invasive breast cancer was 9.4% (95% CI 5.9%-15%) by the age of 85-years, whilst the corresponding risk of EOC was 0.6% (95% CI 0.2%-2.6%). The SIR for breast cancer was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in non-carriers from BRCA1 families and 1.03 (95% CI 0.57-1.87) in non-carriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort and 1.74 (95% CI 0.44-6.98) in non-carriers from BRCA2 families. Conclusions: This is the largest cohort to date of prospectively ascertained true-negatives from BRCA1/ BRCA2 families. Our results did not provide evidence for elevated risks of invasive breast cancer or EOC in proven non-carriers. Risk-reducing bilateral mastectomy and risk-reducing salpingo-oophorectomy may not be appropriate for these individuals. Female relatives of a known BRCA1/BRCA2 mutation carrier should be advised towards genetic testing to avoid unnecessary surgical procedures. However, we were not able to investigate variation in risks by cancer family history. Therefore, we cannot rule out that risks may be slightly higher for close relatives of affected mutation carriers. In such cases, model-based estimates incorporating family history, such as those given by BOADICEA, can be used in the counselling process.
Hormone replacement therapy (HRT) among BRCA mutation carriers.
Authors: Centers Nicole , Ivanov Olga , Buffington Cynthia , Caceres Aileen
Published: September 2018

1561

Background: BRCA mutation carriers are often offered risk-reducing surgery (oophorectomy, hysterectomy) and medication regimens (hormone modulators, chemotherapy) in a preventative format. These therapies cause premature menopause and associated symptoms including reduced libido and sexuality. Hormone replacement therapy (HRT) is beneficial in alleviating climacteric symptoms of menopause. However, due to high risk for breast cancer in BRCA mutation carriers, many within the healthcare community oppose the use of HRT, despite recent studies that fail to demonstrate an adverse effect on oncologic outcomes. The purpose of this study was to identify current HRT practices among BRCA1,2 mutation carriers. Methods: The study population included 763 BRCA1,2 mutation carriers (52% previvors, 48% survivors) who are members of Facing Our Risk of Cancer Empowered, a support, education, and advocacy group for individuals with gene mutations. Data was collected via an online survey that included questions pertaining to patient characteristics, preventative procedures, menopausal status and symptoms, HRT use, and provider recommendations. Results: According to the survey findings, 73% of BRCA mutation carriers were postmenopausal (59% previvors, 88% survivors) and, among these, 81% had become menopausal prematurely due to risk-reducing surgery or medications. Major postmenopausal concerns of BRCA mutation carriers involved low libido/sexuality (78%) and an increased risk for weight gain (83%), cardiovascular disease (77%), and osteoporosis (65%). Despite the high incidence of premature menopause and associated symptomatology of the population, HRT usage was low (13% previvors, 28% survivors). According to the survey respondents, only 26% of healthcare providers for the previvors and 8% for the survivors favored HRT use. Conclusions: High rates of premature menopause with related symptoms occur among BRCA1,2 mutation carriers in association with cancer preventative therapies. Despite the young age of this postmenopausal population, only a small percentage are on HRT. These findings suggest the need for improved education to patients and providers regarding HRT and cancer risk, as well as the exploration of HRT options.
BROCA gene panel testing in African descendants from northeastern Brazil: Genetic susceptibility profile of an admixed population.
Authors: Felix Gabriela Espirito Santo , Zheng Yonglan , Guindalini Rodrigo Santa Cruz , Machado-Lopes Taisa Manuela Bonfim , Zhang Jing , Côrtes Juliana , Oliveira Pollyanna Carozo , Santos Irlânia S , Bomfim Thais , Garicochea Bernardo , Toralles Maria Betania , Abe-Sandes Kiyoko , Nascimento Ivana Lucia Oliveira , King Mary-Claire , Walsh Tom , Olopade Olufunmilayo I.
Published: September 2018

1572

Background: The rising global burden of breast cancer (BC) in developing countries demands innovative interventions to accelerate progress in cancer control and prevention. Given the high rates of aggressive young onset breast cancer in Brazil, we sought to examine genetic susceptibility to the disease in the State of Bahia in the Northeast of Brazil, which has the largest population of African descendants. Methods: We screened cases, high-risk breast cancer patients with and without family history of breast cancer, and controls (cancer-free women) for twenty-eight breast cancer susceptibility genes using a validated targeted capture and multiplex sequencing approach – the BROCA panel. Each participant gave informed consent under IRB approved protocols and provided clinical-pathological and epidemiological data. Results: A total of 292 consecutive and unrelated individuals (173 cases and 119 controls) were included. Nearly 2/3rds of the cases (116/173) and about 90% of the controls (108/119) self-reported as African-descendant. Mutations considered pathogenic were identified in 37 (21.4%) cases and in one control (0.84%, RAD51C c.266insA), OR = 27.75 and p = 0.008. The mutated genes in cases were BRCA1 (in 12 patients), BRCA2 (10), ATM (3), PALB2 (3), BRIP1 (3), BRCA2/ BARD1 (1), FAM175A (1), FANCM (1), NBN (1), SLX4 (1) and TP53 (1). Three recurrent mutations accounted for 12.4% (9/37) of the total: 3 BRCA1 c.3331_3334delCAAG (known European mutation), 3 BRCA1 c.211A > G (known Galician mutation), and 3 PALB2c.1671_1674delTATT (novel mutation). Conclusions: Mutations in BRCA1 and BRCA2 (64.85%) or another breast cancer gene (35.15%) occur in one in five high-risk breast cancer patients in the largest study of Northeastern Brazil to date, and a significant proportion were recurrent mutations of European origin, which can be explained by the admixture pattern of the Brazilian population. This result underscores the importance of using multigene panel in cancer genetic epidemiologic research of understudied populations where unexpected findings, such as the recurrent and novel variant in PALB2 c.1671_1674delTATT, can be detected.
Smoldering Waldenström’s macroglobulinemia (SWM): Analysis from the National Cancer Database (NCDB).
Authors: Pophali Priyanka Avinash , Bartley Adam C. , Kapoor Prashant , Gonsalves Wilson I. , Ashrani Aneel A. , Marshall Ariela L. , Siddiqui Mustaqeem Ahmad , Go Ronald S.
Published: September 2018

1573

Background: There are no epidemiologic studies of SWM due to lack ofICD codes specific for smoldering status. Methods: The NCDB represents ~70% of cancer cases in the US. It records the time to initial treatment or reasons for not receiving treatment. Using the 2004-2012 database, we estimated the overall proportion of new adult WM cases that are smoldering and analyzed outcomes according to socio-geo-demographic subgroups. Patients who were recommended treatment (irrespective of administration status) or died within 120 days of diagnosis were considered to have active WM while those who did not require treatment and had follow-up ≥120 days after diagnosis were considered to have SWM. Results: 2322 (28%) of 8302 patients diagnosed with WM were SWM. Median age at diagnosis was 71 (range 28-90) years. Median age did not change significantly during 2004-2012 (P = 0.83) but the proportion of smoldering disease decreased with time (P = 0.02). The proportions of SWM according to socio-geo-demographic subgroups are shown in the Table. Conditional survival (given survival to 4 months) at 5-years was 66% vs. 70% and at 10-years was 38% vs. 46% for active WM vs. SWM, respectively. The OS for SWM was significantly better among females and those who were younger, privately insured, with less co-morbidities and residing closer to a health facility. However, the OS did not differ by racial groups or era of diagnosis 2004-2008 vs 2009-2012. On multivariate analysis, sex, age group and co-morbidity index were significant factors affecting OS while race, insurance, distance from health facility and era of diagnosis were not. Conclusions: Approximately 28% of WM cases in the US are smoldering at diagnosis. The prevalence of SWM varied among socio-geo-demographic subgroups. Sex, age and co-morbidities significantly affect survival of SWM. [Table: see text]
Melanoma genetic testing to promote reductions in tanning: Results from the Utah BRIGHT project.
Authors: Aspinwall Lisa , Stump Tammy K. , Taber Jennifer M. , Kohlmann Wendy , Champine Marjan , Drummond Danielle , Cassidy Pamela , Leachman Sancy Ann
Published: September 2018

1582

Background: Predictive genetic testing for familial cancer may alert people to highly elevated risk prior to disease onset. Genetic test reporting has been shown to improve uptake of prophylactic screening and procedures, but whether test reporting also promotes increased performance of primary preventive behavior is unknown. Methods: Unaffected adult participants ( N= 124) from high-risk melanoma families, ages 16-69 (mean = 35.24, 52% men) were enrolled. Participants from families that carried a CDKN2A/p16 mutation received a personal genetic test result and counseling about management recommendations whereas control participants from families without a CDKN2A/16 mutation received equivalent counseling and management recommendations based on family history alone. Photoprotection outcomes were compared between CDKN2A/p16 participants (31 carriers, 44 noncarriers) and the no-test control group ( n= 49), allowing the effects of receiving a genetic test result to be distinguished from the effects of counseling alone. Assessments were seasonally timed to capture tanning during the summer months. Melanin Index (MI) scores, measures of skin tanning obtained through reflectance spectroscopy, were assessed at the dorsal wrist and face. Tanning of the dorsal wrist and face were calculated by subtracting baseline MI scores at an unexposed site on the same individual. Results: Multilevel model analyses examined changes in tanning over time while controlling for clinician-rated skin type, age, gender, date of assessment, and group differences in phenotypic factors and family medical history. Participants who received positive test results were significantly less tan at the wrist one year after their previous summer baseline ( b= -.11, p< .001). No-test controls and noncarriers had no change in tanning. The magnitude of decrease in tanning measurements observed among CDKN2A/ p16 carriers approximated one skin type. Facial tanning did not differ from baseline for any group. Conclusions: A positive melanoma genetic test result promotes reduced UVR exposure. Future research should examine why positive genetic test reports were more motivating to patients than equivalent counseling based on family history.
Unexpected germline mutations in a pan-cancer analysis including sarcoma, renal, and other cancers.
Authors: Yang Shan , Michalski Scott T. , Holle Jennifer , Ekstein Tali , O'Leary Erin , Pardo Carolina , Heidari Nastaran , Anderson Michael , Ouyang Karen , Nussbaum Robert L. , Lincoln Stephen E , Esplin Edward D.
Published: September 2018

1584

Background: Multi-gene testing for cancer predisposition is increasingly utilized in clinical care. Although the diagnostic yield and management implications of such testing in breast, ovarian and colorectal cancer are relatively well understood, data for other cancer types are still emerging. In this study we retrospectively examined 39,147 patients referred for hereditary cancer syndrome testing for pathogenic germline variants in 80 cancer risk genes, focusing on those patients with renal, sarcoma, paraganglioma, melanoma, and pancreatic cancers. Methods: Test results and personal/family history were extracted from a sequential series of de-identified clinical test reports. Data for genes not clinically ordered were analyzed under an IRB approved research protocol. Common low penetrance risk alleles were excluded. Results: Overall, 14.3% (5,589) of patients carried germline pathogenic mutations in 80 cancer risk genes. Of the 949 patients with renal cancer 20% (190) were positive, and 44% of these findings were “unexpected”, meaning they appeared in genes that are not commonly requisitioned in renal cancer patients. Of the 423 sarcoma patients, 16% (68) had positive findings, 45% of which were “unexpected”. For both cancer types, greater than 90% of these “unexpected” findings were in genes with published management recommendations. Similar results were observed in melanoma, paraganglioma and pancreatic cancer patients. A second or third pathogenic variant, many of which were also “unexpected”, were found in 3.6% of positive cases. Conclusions: In this series of patients we estimate almost 12% of pathogenic variants across cancer indications are “unexpected”. These data suggest many actionable pathogenic variants are being missed due to adherence to overly restrictive, narrowly constructed tumor-specific panels. Clinicians should expand the scope of their test panels in order to capture variants with the potential to impact patients and their family members by informing implementation of established management guidelines.
A phase II trial of temozolomide (TMZ) 1 week on/1 week off as initial treatment for high risk low grade oligodendroglial tumors: An AINO (Italian Association for Neuro-Oncology) study.
Authors: Ruda Roberta , Pellerino Alessia , Franchino Federica , Pace Andrea , Carapella Carmine Maria , Dealis Cristina , Caroli Manuela , Faedi Marina , Bomprezzi Chiara , Soffietti Riccardo
Published: September 2018

2026

Background: The efficacy of dose-dense temozolomide (TMZ, 1 week on/1 week off ) in grade II gliomas is not well known and could depend on the molecular subtype. Methods: Between 2006 and 2010 a single arm phase II study on 60 patients with grade II oligodendroglial tumors was performed. Inclusion criteria were as follows: 1) age ≥ 18 years; 2) KPS ≥ 70; 3) biopsy-proven grade II oligodendroglioma or oligoastrocytoma ; 4) a measurable residual tumor after surgery. The primary endpoint was tumor response on MRI according to RANO criteria, while the secondary endpoints were progression-free survival (PFS), overall survival (OS), and seizure control. Most patients (65%) had seizures. Molecular factors (IDH 1-2 mutations, 1p19q codeletion, MGMT methylation) were available in 49/60 patients (81.7%). The median number of cycles was 11 (2-18). Median follow up was 64 months (7-112). Results: Response rate was PR in 21/60 (35%) patients, minor PR (mPR) in 14/60 (23%), SD in 21/60 (35%) and PD in 4/60 (7%). Most patients achieved the best tumor response within 6 months after the start of TMZ. Among patients with mPR and PR, 15/49 (30.6%) were IDH1-2 mutated with a PFS of 71.4% at 36 months and 28.6% at 60 months with a median value of 46 months while 11/49 (22.4%) were IDH 1-2 wild-type with a PFS of 45.8% at 36 months and 25% at 60 months with a median value of 34 months. OS was 90.5% at 36 months and 66.7% at 60 months with a median value of 76 months in the IDH1-2 mutated/1p19q codeleted subgroup, while OS was 66.7% at 36 months and 50% at 60 months with a median value of 60 months in the IDH1-2 wild-type subgroup. Responses were higher in MGMT methylated patients. Seizure improvement was achieved in 29/34 patients (85%): 17/33 (52%) patients at 12 months and 18/29 (62.1%) at 24 months were seizure-free. Time to maximal seizure response was earlier than that observed on MRI (3 vs 6 months). Conclusions: Dose-dense TMZ has shown a significant activity in terms of tumor and seizure control, especially in IDH1-2 mutated/1p19q codeleted patients. Seizure reduction could represent an early indicator of response to chemotherapy and maybe predict the duration of response. Clinical trial information: 2007-000386-38.
Comparison of high dose methotrexate treatments in CNS lymphoma patients: The Henry Ford experience.
Authors: Selim Ranya , Philip Joyce , Donthireddy Vijaya
Published: September 2018

2028

Background: The main backbone of therapy for CNS lymphoma involves systemic treatment with high dose methotrexate (HDMTX)-based regimens,with radiotherapy reserved only for cases that fail systemic therapy due to the significant cognitive toxicity of radiation. Over the last decade, rituximab and subsequently temozolomide were added to HDMTX chemotherapy regimens. Methods: Patients diagnosed with CNS lymphoma between 2009 and 2015 were identified. A retrospective cohort study was conducted of patients who received HDMTX alone (Cohort A), HDMTX and rituximab (Cohort B) and HDMTX, rituximab and temozolomide (Cohort C). Data collected included treatment related adverse events along with OS and PFS. Results: 31 patients were diagnosed with CNS lymphoma. 11, 10 and 6 patients were in cohorts A, B and C respectively. Median PFS and OS for the entire cohort were 14 and 25 months respectively. Cohort results were compared to the respective reference trials published in the literature. Cohort A had a PFS of 11 months and OS of 12 months compared to 12.8 months and 22.8+ months in the reference Phase II trial. Cohort B had a median PFS of 25+ months and OS of 41 months compared to 21 months and 33.5 months in the reference trial. Cohort C had a 2-year PFS of 0.50 compared to 0.57 in the reference trial. 3 (9.6%), 5 (16.1%), and 2 (6.4%) patients developed renal dysfunction in cohorts A, B and C respectively. 4 (12.9), 2 (6.4%), and 0 patients developed leukopenia in cohorts A, B and C respectively. 3 (9.6), 2 (6.4%), and 1 (3.2%) patients developed anemia in cohorts A, B and C respectively. 1 (3.2%), 1 (3.2%) and 1 (3.2%) patient developed thrombocytopenia in cohorts A, B and C respectively. Conclusions: The addition of Rituximab to HDMTX treatment for the treatment of CNS lymphoma increased the PFS and OS compared to HDMTX alone and is in concordance with the reference phase II trials reported in the literature if not better. In addition, our data at HFH shows no increased risk of adverse events with combination therapies compared to HDMTX alone. The addition of Temozolomide to Rituximab and High Dose methotrexate treatment showed a median 2 year PFS of 0.50 which is comparable to published reports of a 2-year PFS of 0.59.
Retrospective review of safety and efficacy of checkpoint inhibition in refractory high-grade gliomas.
Authors: Reiss Samantha , Yerram Prakirthi , Modelevsky Lisa , Grommes Christian
Published: September 2018

2033

Background: Treatment options for refractory high grade gliomas (HGG) are limited. Programmed cell death ligand-1 (PD-L1) expression has been reported in 0-61% of HGGs and therefore might be a suitable target in HGG. The purpose of this study was to describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs. Methods: This IRB approved single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with an age ≥18 years who received a PD-1 inhibitor between 9/2014 and 10/2016 outside of a clinical trial. Results: Twenty five HGGs were identified. All patients received the PD-1 inhibitor pembrolizumab (pembro) as part of compassionate use. Median age was 49 years (range 30-72); 44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2 anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Patients received a median of 4 prior lines of therapy (range 1-9). Nineteen (76%) previously failed bevacizumab. Median baseline KPS was 80 (range 50-100). Concurrent treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2 (8%) patients. Median number of doses administered was 3 (range 1-14). Treatment toxicity and response was assessed in 24 patients. PD-1 inhibitor related adverse events (AEs) included LFT elevations (33%), hypothyroidism (17%), diarrhea (17%), myalgias/arthralgias (13%), and rash (8%). Other common AEs were hyperglycemia, fatigue, thrombocytopenia, lymphopenia, headache, and nausea in the setting of concomitant therapy and additional supportive care (dexamethasone). Grade 3 AEs included seizure (4%), headache (4%), nausea (4%), and vomiting (4%). Best radiographic response was partial response (n = 2), stable disease (n = 5), and progressive disease (n = 17). Median progression free survival (PFS) was 42 days (range 7-282) and median overall survival was 121 days (range 15-415). Three patients (12%) had a PFS > 90 days; of these, 2 received single agent pembro. Conclusions: Patients with HGG had low response rates. However, a small number of patients had prolonged PFS. Pembro was tolerated with few serious AEs, even in patients receiving concomitant therapy.
Clinical and molecular subgroups of ependymoma in adulthood: An analysis of the German Glioma Network.
Authors: Gramatzki Dorothee , Witt Hendrik , Hentschel Bettina , Pajtler Kristian W. , Schackert Gabriele , Westphal Manfred , Herrlinger Ulrich , Pietsch Torsten , Loeffler Markus , Reifenberger Guido , Pfister Stefan M. , Tonn Joerg , Weller Michael ,   German Glioma Network
Published: September 2018

2038

Background: Ependymoma is a subtype of glioma that is rare in adults. Its classification has remained entirely morphological until recently, and surgery and radiotherapy remain the mainstays of treatment. Here we characterized DNA methylation profiles and their clinical correlates in the prospectively assembled cohort of the German Glioma Network. Methods: The GGN cohort was screened for patients diagnosed with myxopapillary ependymoma, subependymoma, classic ependymoma and anaplastic ependymoma for whom clinical data and remaining tumor tissue were available. Tumors were subjected to DNA methylation profiling using the Illumina Infinium HumanMethylation450 BeadChip platform. Molecular data were correlated with morphological tumor and clinical patient characteristics. Results: One hundred and twenty-two ependymoma patients with available tumor tissue were identified. Each adult tumor could be assigned to one of the previously defined methylation classes of ependymoma. Molecular entities of ependymal brain tumors display distinct copy-number variations. PF-EPN-B and ST-EPN-RELA tumors tend to have a worse prognosis than other ependymal subtypes in adults. Conclusions: Molecular classification of adult ependymal methylation subclasses should be implemented in routine diagnostics. Patients with PF-EPN-B and ST-EPN-RELA subtypes might benefit from early treatment beyond surgery.
Changes in survival of primary central nervous system lymphoma based on a review of national databases over 40 years.
Authors: Mendez Joe Sammy , Quinn Ostrom T , Kruchko Carol , Barnholtz-Sloan Jill , Grommes Christian
Published: September 2018

2040

Background: There has been significant improvement in treatment outcomes of Primary Central Nervous System Lymphoma (PCNSL) at specialized centers over past decades, and it is unclear if these changes have translated to benefits in the general population. In this study, we utilized national databases to examine survival trends over time. Methods: Incidence rates were obtained from the Central Brain Tumor Registry of the United States (CBTRUS, 2000 – 2013) and 18 Surveillance, Epidemiology and End Results (SEER, 1973 – 2013) registries. Data for survival analysis was obtained from SEER and analyzed using SEER*STAT. To focus on non-HIV-associated PCNSL, patients with “other infectious and parasitic diseases including HIV” as cause of death and follow up were excluded. CBTRUS identified 19,027 patients over 13 years and SEER 6,765 over 40 years. Results: The annual incidence of PCNSL in 2013 was 0.4 per 100,000 population (CBTRUS/SEER). Incidence increased from 0.1 per 100,000 in the 1970s to 0.4 per 100,000 in the 1980s, correlating with an increase in the diagnosis of elderly patients, ≥70 (1973:0.2 vs 2013:2.1 – SEER). Incidence rates differed greatly between young and elderly patients (20-29: 0.08 vs 70-79: 4.32 – CBTRUS). The median overall survival (mOS) of all patients is 17 months (m) with no survival benefit based on sex. Survival doubled from 12.5 m in the 1970s to 26 m in the 2010s. There was a significant difference in survival based on age: < 50: 83 m vs 50-69: 25 m vs ≥70: 6 m (p-value < 0.0001). In patients < 50, mOS increased from 35.5 m in the 1970s to 134 m in the 2000s (mOS not achieved in 2010s). In patients 50-69, mOS increased from 8 m in the 1970s to 35 m in the 2010s. However, mOS in the elderly population, ≥70, has not changed in the last 40 years (6 m in the 1970s vs 7 m in the 2010s, p-value = 0.1). Conclusions: PCNSL is a disease that more frequently affects the elderly. Although overall survival has increased over the past 4 decades, reflecting current literature in PCNSL, survival in the elderly has not changed since the 1970s. Identification of this vulnerable patient population highlights the need for clinical trials targeting the elderly in hopes of improving treatment strategies and ultimately outcomes.
Assessment of tumor hypoxia in BEV resistant GBM using FMISO 18F-PET and MRI.
Authors: Liu Yichu , Lee Eudocia Quant , Huang Shiliang , Muzi Mark , Reardon David A. , Wen Patrick Y. , Brenner Andrew Jacob
Published: September 2018

2045

Background: Glioblastoma (GBM) is the most common malignant brain tumor in adults, and is characterized by poor survival and marked resistance to treatment. Hypoxic volume is directly correlated with poor outcome in GBM, with structural and functional tumor vasculature changes regarded as a primary driver of tumor hypoxia. As part of an ongoing clinical trial with a hypoxia activated prodrug, we sought to explore the correlation between abnormal tumor vasculature and hypoxia in bevacizumab (BEV) resistant GBM. Methods: MRI and 18F-FMISO PET scans were acquired at study entry. The MRI protocols include standard anatomical sequences as well as Dynamic Susceptibility Contrast (DSC/perfusion) imaging. Enhancing tumor ROIs were determined from Delta T1 maps, non-enhancing tumor ROIs were obtained from FLAIR images, ratio between enhancing and non-enhancing volumes were calculated, values from standardized rCBV maps were extracted from corresponding enhancing ROIs. Decay correction was applied to18F-FMISO images and converted to SUV units. After registration to MR images, cerebellar regions were used as surrogates for blood activity. The FMISO images were then normalized to generate tissue to blood ratio (TB). A threshold of TB > 1.2 was used in discriminating the hypoxia volume (HV). Correlation between parameters was assessed using Pearson correlation. Results: 7 patients from University of Texas Health Science center and 7 patients from Dana-Farber Cancer Institute had evaluable MR and PET imaging. We compared MRI parameters (enhancing and non-enhancing tumor volumes, srCBV) with hypoxia (HV and maxSUV). There was a positive correlation between HV and enhancing volume (R = 0.732, p = 0.0029) as well as between HV and ratio (R = 0.644, p = 0.013. The correlation between other pairs were not statistically significant (HV vs srCBV: p = 0.862, T1 vs maxSUV p = 0.492, srCBV vs maxSUV: p = 0.393, ratio vs maxSUV = 0.178). Conclusions: The hypoxic volume following bevacizumab failure correlates with both the volume of enhancement and the fraction of enhancement within the mass. The clinical implications of this is being assessed in an ongoing phase 2 study. Clinical trial information: NCT02342379.
A two-part safety and exploratory efficacy randomized double-blind, placebo-controlled study of a 1:1 ratio of the cannabinoids cannabidiol and delta-9-tetrahydrocannabinol (CBD:THC) plus dose-intense temozolomide in patients with recurrent glioblastoma multiforme (GBM).
Authors: Twelves Chris , Short Susan , Wright Stephen ,   Cannabinoid in Recurrent Glioma Study Group
Published: September 2018

2046

Background: Several plant-derived cannabinoids have shown efficacy in animal models of GBM, particularly when co-administered with temozolomide, a commonly-used treatment in both primary and recurrent disease. Methods: We conducted a two-part study in patients with recurrent GBM following standard chemo-radiotherapy treatment as described by Stupp et al. In Part 1 of the study, 6 patients were treated to an MTD of 1:1 CBD:THC oro-mucosal spray, as an adjunct to dose-intense temozolomide (DIT), to assess the safety of the combination. Part 2 was a double blind, randomized, placebo-controlled study in a planned 20 patients receiving either their individualized dose of 1:1 CBD:THC or placebo plus DIT. The primary endpoint was tolerability of 1:1 CBD:THC plus temozolomide. Results: There were no Grade 3 or 4 toxicities in Part 1 of the study. In Part 2, 12 patients were randomized to CBD:THC and 9 to placebo. Mean age was 58 years in both treatment groups, but there were more males in the placebo group (5 of 12 and 8 of 9, respectively). Baseline median Karnofsky score was 90 in both groups and median time from diagnosis of recurrence to start of treatment (day 1) was similar (3.6 and 3.0 weeks in the CBD:THC and placebo group, respectively). The median number of days of dosing with CBD:THC or placebo was similar (155 days [range: 50-356] and 134 days [range: 13-359]). Median survival in the placebo group was 369 days, and > 550 days in the CBD:THC treatment group (NS) and 1 year survival was 83% and 56% in the CBD:THC and placebo groups, respectively (p = 0.042). PFS6 was 42% in the CBD:THC group and 33% in the placebo group (NS). Overall, the commonest treatment related toxicities were dizziness (in 11/18 patients) and nausea (in 7/18 patients). Results of biomarker analyses are awaited. Conclusions: This randomized study provides preliminary evidence that 1:1 CBD:THC offers some efficacy in patients with recurrent GBM when used as an adjunct to dose-intense temozolomide and confirms the safety and feasibility of individualized dosing. Clinical trial information: NCT01812603.