bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementing decision support for breast cancer chemoprevention in primary care.
Authors: Telfort Jersen , Trivedi Meghna S. , Yi Hae Seung , Colbeth Hilary , Vanegas Alejandro , Vargas Jennifer , Sandoval Rossy , Wood Jeffrey , Dimond Jill , Finkelstein Joseph , Kukafka Rita , Crew Katherine D
Published: September 2018

e13038

Background: Breast cancer risk assessment and chemoprevention with anti-estrogens among high-risk women are underutilized. We developed web-based decision support tools for high-risk women, RealRisks, and their primary care providers (PCPs), BNAV, which are integrated into clinic workflow. Methods: We conducted a pilot study in 50 women who were found to have a 5-year risk of invasive breast cancer ≥1.67% according to the Gail model during screening mammography. RealRisks includes modules on breast cancer risk and chemoprevention, as well as interactive games to communicate risk and preference elicitation for chemoprevention. A tailored patient and provider action plan is generated summarizing their breast cancer risk profile. Before and after interacting with RealRisks, participants completed validated questionnaires on breast cancer and chemoprevention knowledge and chemoprevention intention. Prior to their next clinic visit, their PCPs were given access to the BNAV reference toolbox. High-risk referrals and chemoprevention uptake were assessed by medical chart review. Paired t-tests and chi-square tests were used to analyze continuous and categorical variables pre/post-intervention, respectively. Results: From Mar to Aug 2016, 50 high-risk women were enrolled and 40 were evaluable. Median age 64.5 years (range, 49-72); white/black/Hispanic (%): 37.5/25/37.5; 35% had adequate health literacy; median 5-year breast cancer risk was 2.2% (range, 1.7-3.9). Before and after interacting with RealRisks, we observed an increase in adequate breast cancer knowledge (60% vs. 84%, p = .01) and chemoprevention knowledge (5% vs. 25%, p < .01). After viewing RealRisks, 30% of women were interested in taking an anti-estrogen for chemoprevention, 33% not interested, and 37% unsure. Thus far, only 2 were referred for high-risk consultations and no high-risk women initiated chemoprevention. Conclusions: Despite increased interest in chemoprevention after exposure to RealRisks, additional barriers to chemoprevention uptake exist, including competing comorbidities and time constraints during the clinical encounter. Targeting younger women with higher breast cancer risk may increase chemoprevention uptake. Clinical trial information: NCT02954900.
Greenville health system (GHS) experience with risk reduction endocrine therapy for women diagnosed with breast lobular carcinoma in situ (LCIS).
Authors: O'Neal Richard , Cornett Wendy R. , Jones Yonge R , Stewart Morgan , Franco Regina A. , Perkins Leann , O'Rourke Mark Allen
Published: September 2018

e13041

Background: LCIS is associated with a 1% annual risk of developing invasive breast cancer, twice that of the general population. Endocrine therapy for chemoprevention has been shown to decrease this risk by 56% in women with LCIS. Barriers include failure to offer endocrine therapy and failure to tolerate it. This study examined a population of women with LCIS and their experience with endocrine therapy for breast cancer risk reduction. Methods: 337 patients with LCIS from 2010-2015 at the GHS were retrospectively identified through electronic health record review. Median age was 55.5 years; 303 underwent breast-conserving surgery and 34 mastectomy. Chart review assessed the documented recommendations for endocrine therapy, duration of adherence, and presence of side effects. Results: Endocrine therapy was prescribed in 155 (46%), refused in 33 (10%), and not recommended in 120 (36%). Of the 146 women who were started on endocrine therapy for risk reduction and followed for six months, 75% adhered to the endocrine therapy. Of the 94 followed for 2 years, 71% adhered. The rate of documented side effects was 14% and was the most commonly cited reason for discontinuation (78%). Conclusions: The number of women with LCIS that were not prescribed endocrine therapy in the absence of absolute contraindications was substantial (36%). Under documentation in the medical record may account for a portion of this. The rate of side effects of those started on endocrine therapy (14%) is lower than expected, although this may represent underreporting. With a low refusal rate (10%) and a high adherence rates (75% at 6 months and 71% at 2 years) in the treated population, improving the number of women with LCIS that are offered endocrine therapy has considerable potential for reducing breast cancer risk. Controlling side effects can increase the benefit further.
Examining screening behaviors at a high-risk ovarian cancer clinic.
Authors: Lynam-Scherr Courtney , Hope Kisha T , Helenowski Irene B. , Kocherginsky Masha , Keene Melissa , Strohl Anna Everett , Marshall-Fricker Charlotte , Guo Xiaoyue Mona , Shahabi Shohreh , Shulman Lee P
Published: September 2018

e13047

Background: Women with deleterious BRCA1/2mutations have a significantly increased lifetime risk to develop ovarian cancer. Prophylactic surgery can significantly reduce ovarian cancer risk. The Northwestern Ovarian Cancer Early Detection and Prevention Program (NOCEDPP) was established to monitor this high-risk population prior to risk-reducing surgery. For such patients, providers in the NOCEDPP recommend screening with CA-125 and transvaginal ultrasound (TVUS) biannually. The aim of this study was to examine screening rates of women who have not had surgery but attend the NOCEDPP. Methods: We reviewed electronic health records of 1,662 women who attended the NOCEDPP clinic between October 2005 – October 2015. Demographic and clinical characteristics and utilization of screening were analyzed retrospectively using descriptive statistics and Kruskal-Wallis H-tests to examine differences in screening rates by age, race, ethnicity and insurance type. Results: Of the 1,662 women initially identified, 385 had a known BRCA mutation, 303 had an appointment with at least 6 months between first and last procedure – the sample included in the final analysis. Compared with women ages 35-45 (median = 1.91) and 45+ (median = 1.18), women ages 20-35 attended the most screenings per year (median = 2.12) p = 0.001, a rate consistent with biannual recommendations. There were no significant differences in screening rate by race, ethnicity, or insurance coverage. Conclusions: Despite changes in national guidelines, providers in our high-risk clinic continue to recommend CA-125 and TVUS biannually. Our preliminary data indicates patients’ attendance is uninfluenced by race, ethnicity, or insurance coverage. Further exploration of the impact of age is warranted. Implication of findings indicate a high-risk clinic may positively impact screening behaviors above and beyond factors typically associated with non-adherence.
Evaluating pulmonary nodules to detect lung cancer: Does Fleishner criteria really work?
Authors: Azharuddin Muhammad , Malik Aamir , Adamo Noor , Livornese Douglas S
Published: September 2018

e13053

Background: The Fleishner Society recommends interval computed tomography (CT) follow-up for managing incidental small pulmonary nodules detected in CT scans. This study evaluates the clinical application of 2013 Fleishner criteria using a large cohort of patients at high risk for lung cancer with low-dose CT screening. Methods: During 2012-2016, a retrospective study of 176 patients was reviewed for incidental lung nodules. Patient eligibility included: men and women aged 55-74; 30 pack-year smoking history who quit in the last 15 years; no cancer history in the last 5 years; and no previous CT chest scan done. Follow-up and management was calculated using the Fleishner criteria. Nodules were classified based on several features including size and shape. Nodule characteristics were tabulated and analyzed. Results: Out of 176 patients, 117 had nodules and a total of 210 nodules were detected. Table 1 categorizes all nodule features including Fleishner Criteria. Of the entire cohort, two patients (1.1%) showed malignancy: one part-solid nodule of 10.2mm, and one multiple subsolid groundglass nodule (GGN) of 20.1mm. Twenty-one patients (17.9%) had undergone unnecessary follow-up CT scans, including those with solid nodules, and solitary pure GGNs. Conclusions: This study emphasizes the need to revise the Fleishner guidelines to more accurately estimate the risk of malignancy, including minimizing over-diagnosis, unnecessary follow-up CTs, and invasive procedures for benign pulmonary nodules. Further analysis of lung cancer contributory factors is also required. [Table: see text]
Genomic features of normal tissues from prophylactic surgery in BRCA1/2 mutation carriers.
Authors: Kotoula Vassiliki , Demiri Efterpi , Fostira Florentia , Vrettou Eleni , Charalambous Elpida , Tikas Ioannis , Papazisis Konstantinos , Zaramboukas Thomas , Asimaki-Vlachopoulou Anthoula , Miliaras Spyros , Fountzilas Elena , Ananiadis Ananias , Chrisafi Sofia , Poulios Christos , Natsiopoulos Ioannis , Tsiftsoglou Aris , Fountzilas George
Published: September 2018

e13055

Background: Genomic alterations in normal tissues from pathogenic germline BRCA1/2 mutation (mut) carriers are as yet poorly described. We investigated the genomic status of normal breast (NB) and hystero-salpingo-oophorectomy (GYN) tissues removed upon prophylactic surgery in a real-life cohort of BRCA1/2 carriers. Methods: By using targeted NGS we examined the mut status of 220 samples (39 peripheral blood and 181 paraffin tissue) from 53 BRCA1/2 carriers who underwent prophylactic surgery, 42 with and 11 without prior cancer manifestation (PCM). We compared germline BRCA1/2 mut status with tumor, NB and GYN mut status. Results: Eight patients carried germline BRCA2 and 45 BRCA1 mut. Somatic mut were most frequent in BRCA2 (28%), BRCA1 (17%), TP53 (7%) among 136 NB and GYN samples; and, in TP53 (49%; p < 0.001) and BRCA1 (38%; p = 0.039) among 45 tumor samples. Among all tissue types, the 85 NB had the lowest mut load (p = 0.001). In NB and GYN, mut load was higher in BRCA1 vs. BRCA2 carriers (p = 0.027) and in those with BRCA1 substitutions/indels vs. exon deleting and skipping mut (p < 0.001). In tumors, only germline BRCA1 substitutions/indels were associated with higher mut load (p = 0.014). Preservation of germline mut in tissues was assessable in 84 samples from 26 patients. The germline mut was lost in 8 tumor and NB samples from 6 patients (23%) with PCM. Somatic deleterious mut in the BRCA1 BRCT-domain emerged in two such cases; the rest had combinations of TP53, MRE11A and NF1 mut. GYN samples from these patients retained the germline mut and presented the highest mut load among all examined samples (p < 0.001). Conclusions: Somatic mut in normal tissues from BRCA1/2 carriers are affected by the inherited mutated gene and by the type of the germline mut concerning BRCA1. Germline BRCA1 mut may be substituted by somatic mut in tumor and normal tissues, in an organ specific manner. Mutagenesis in tumors and normal tissues appear to be driven by different pathways. Our findings shed new light on the biological impact of BRCA1/2 mut in tissues.
Genetic ancestry in normal breast tissue donors from the Susan G. Komen tissue bank at the IU Simon Cancer Center (KTB).
Authors: Marino Natascia , McCarty Julia , Jiang Guanglong , Johnson Mariah L , Mahin Teresa , Scherer Nicholas , Storniolo Anna Maria
Published: September 2018

e13065

Background: When studying complex diseases with a heritable component, such as breast cancer, chances of finding disease susceptibility genes can be increased by accounting for genetic ancestry within the population investigated. The limitation in using self-reported race to reveal population genetic substructure has been extensively reported. Therefore, we employed a panel of genetic polymorphisms, or Ancestry Informative Markers (AIMs), to genetically determine the racial and ethnic background of the tissue donors in the KTB, the only existing biobank of breast tissue cores taken from healthy women. Methods: 4112 women donated breast tissue between 2006 and 2016, and also provided race and ethnicity information. We used a panel of 41 AIMs to estimate genetic ancestry and to maximize the difference between European/ Middle East (Caucasian, C), East Asia and Central/South Asia (Asian), African, and Hispanic populations. We employed the Bayesian Markov chain Monte Carlo (MCMC) method implemented in the program STRUCTURE 2.2. A reference set was obtained from the Human Genome Diversity Project. Results: In women self-identified as Black/African American (AA),White and Asian, the assigned genetic ancestry proportions were 93.8% African, 95% C and 96.6% Asian respectively, while the racial composition among the 318 self-identified Hispanics (of which only 178 were confirmed by the genetic ancestry) was 45.3% C, 5.3% African, and 14.7% Asian. Interestingly, 46.9% of the Asian population failed to report the racial background. This percentage was lower for C (1.3% ) and AA (0.5%). Women with African ancestry were younger (≤35 yrs) at the time of donation (24%), as compared to the C (32%) and Asian (33.7%) donors. The obesity rate (BMI > 30) is higher in the AA (60.6%) and C (36.6%), as compared to the Asian population (26.6%). Conclusions: A well-characterized genetic background of the normal breast tissue donors in the KTB will allow a more accurate examination of the association of the genetic ancestry with breast cancer events or risk factors with the ultimate goal of more fully understanding breast cancer racial disparities and their possible role in the risks for and outcomes of breast cancer.
Cancer events in Belgian nursing home residents (NHR): An EORTC prospective cohort study.
Authors: Wildiers Hans , Elseviers Monique , Mauer Murielle E. , de Wolf Jonas , Bastiaens Edith , Hatse Sigrid , Hamaker Marije , Buntinx Frank , de Lepeleire Jan , Uytterschaut Geert , Tryfonidis Konstantinos , Janssen-Heijnen Maryska
Published: September 2018

e13066

Background: A large prospective cohort study was designed to describe cancer events, referral patterns, anticancer treatments and outcome in NHR. Methods: The study was set up in 39 nursing homes from the Armonea network in Belgium, covering 4262 nursing home beds. Cancer events were defined as a new cancer event (new cancer or progressive disease of a previously known cancer) where a diagnostic/treatment decision had to be taken; and patients with strong clinical suspicion (physician’s judgement) of a new cancer event, but where the decision was made not to take further diagnostic/therapeutic steps. Cancer events in NHR were collected during a 1y-period in these 39 nursing homes. After training, each site’s local staff identified patients with cancer events in collaboration with the treating general practitioner (GP). NHR were included after informed consent, and relevant data, including a questionnaire for the GP at baseline, were recorded at least every 3 months up to 2 years. Results: The study was open from 3-2015 till 3-2016 in 37 nursing homes (and 2 pilot nursing homes started and stopped 6 months earlier). In only 9 NHR (median age 87y, range 72-92), cancer events were recorded during this period (incidence rate = 222/100,000 NHR per year). The 9 tumor cases were: one strong clinical suspicion of new prostate cancer, and one undefined cancer; a strong clinical suspicion of breast cancer progression; 3 newly diagnosed cancers (angiosarcoma of the breast, head and neck plus gingiva cancer, and one undefined) ; 3 cases with diagnosed progression of a previously known tumor (skin cancer, head and neck cancer plus skin cancer, bladder cancer). During follow-up, 6/9 NHR died, with a median overall survival of 5 Mo (range 2-16 Mo). Further details on diagnostic/therapeutic approach and outcome are pending. Conclusions: This study evaluated for the first time cancer events prospectively in a large nursing home population. Clinically relevant cancer events occur at a much lower frequency in NHR than expected from cancer incidence data in the general older population, supporting several previous retrospective observations that cancer events are much less frequent and problematic in very frail older persons than previously expected. Clinical trial information: NCT01910376.
Sex differences in cancer risk and survival.
Authors: Radkiewicz Cecilia , Johansson Anna , Dickman Paul , Lambe Mats , Edgren Gustaf
Published: September 2018

e13074

Background: The ongoing global cancer increase poses immense challenges for cancer care. Few comprehensive analyses of sex differences in cancer risk and survival based on robust data have been conducted. Methods: We performed a large cohort study using nationwide Swedish Cancer Register data for years 1970-2014, including all adult incident, non-breast, non-genital cancer cases (504,379 male, 368,018 female). To assess the strength of association between sex and cancer we estimated male-to-female incidence rate ratios†. Relative survival models were used to quantify differences in survival and were expressed as excess mortality ratios*. We applied Poisson regression and adjusted for age and calendar year in both. Results: Men were at significantly increased risk for 34 of 39 sites, and had significantly poorer prognosis for 27 of 39, compared to increased risk for 5 of 39 sites and poorer survival for 2 of 39, in women. Incidence rate ratios in male predominant sites ranged from 1.05; 95% CI, 1.03-1.08 (lung adenocarcinoma) to 8.00; 95% CI, 7.50-8.53 (larynx), corresponding to 0.38; 95% CI, 0.36-0.39 (thyroid well-differentiated) to 0.69; 95% CI, 0.63-0.75 (thyroid anaplastic) in female predominant sites. In sites with poorer survival in men, excess mortality ratios ranged from 1.07; 95% CI, 1.03-1.10 (colon) to 2.08; 95% CI, 1.53-2.84 (well-differentiated thyroid). Conclusions: Male sex is an independent risk factor and associated with poorer survival for a large majority of cancer sites. The excess risk in men remains elevated over time for most sites. Identifying and eliminating factors driving sex differences may reduce global cancer burden considerably. [Table: see text]
Choriocarcinoma in males: A Surveillance, Epidemiology, and End Results (SEER) analysis.
Authors: Howard Alexander , Drury Lane , Han Yimei , Ersek Jennifer Lynne , Symanowski James Thomas , Riggs Stephen Boyd , Feldman Rebecca , Kim Edward S.
Published: September 2018

e13079

Background: Choriocarcinoma (CCA) is a rare tumor. In men, the main site is testis. Pure CCA composes < 0.3% of testicular germ cell tumors. Other sites may represent metastatic disease (dz) or a non-testicular primary CCA. Surgery (S) is the preferred treatment as diagnosis prior to resection is difficult. We analyzed SEER data to determine demographic/clinical characteristics of male CCA patients (pts) and assess survival outcomes. Methods: Male pts with a confirmed diagnosis of CCA as their only primary tumor were included. Pts were grouped into cohorts by dz site (testis, other primary sites, all). S was defined as any type of surgery or no surgery. Stage was defined as local/regional or distant. Dz type was defined as pure or mixed. Overall survival (OS) and disease-specific survival (DSS) were analyzed with Cox proportional hazards (PH) models and Kaplan-Meier methods (5-yr landmark rates reported). Results: 1221 men were identified from 1988-2013. Median age = 28 (range 0-84). Other characteristics included: White (86.9%), mixed CCA (64.9%), local/regional (45.4%), S (78.7%) and testis (83.0%). For other primary site pts (17.0%), lung/mediastinum was most common (36.7%). Stage and S significantly impacted OS and DSS, regardless of dz site. For testis pts, OS (95% vs 56%; p < .001) and DSS (96% vs 61%; p < .001) were significantly better for pts with local/regional dz, as were OS (68% vs 27%; p = 0.032) and DSS (68% vs 29%; p = 0.042) for other primary site pts. Testis pts with S had significantly improved OS (83% vs 34%; p < .001) and DSS (85% vs 40%; p < .001), as did other primary site pts with S (OS: 54% vs. 23%; p = 0.004 and DSS: 62% vs. 34%; p = 0.002). OS for all pts was analyzed with a multivariable Cox PH model, including age, marital status, dz site and type, stage, and S. Testis pts had a reduced risk of death compared to other primary site pts (HR 0.66; 95% CI 0.47-0.92). Pure CCA pts had a 61% increased risk of death compared to mixed CCA pts (HR 1.61; 95% CI 1.24-2.08). S pts had a 48% reduced risk of death compared to pts without S (HR 0.52; 95% CI 0.40-0.67). Conclusions: Pure CCA and non-testicular primary pts have poorer outcomes. S is an important component to survival in men with CCA. This is the first descriptive analysis of male CCA utilizing SEER.
Incidence of second primary malignancies (SPM) in men with castration-resistant prostate cancer (CRPC) in SEER-Medicare database.
Authors: Kaye James A. , Saltus Catherine W , Calingaert Brian , Harris David H , Hunter Shannon , Zong Jihong , Brobert Gunnar Persson , Soriano-Gabarro Montse , Andrews Elizabeth B
Published: September 2018

e13080

Background: A number of population-based epidemiological studies have been conducted to estimate incidence rates of SPM (newly detected malignancies) among cancer survivors, including those with prostate cancer. However, such data in patients with CRPC are limited. This study was conducted to estimate the incidence of SPM and overall survival (OS) in men with CRPC in the US. Methods: In the SEER-Medicare database, men aged > 65 years with prostate cancer diagnosed in 2000 through 2011 were eligible for the study if they had no other prior malignancy, had surgical or medical castration, and met the protocol-defined criteria for ascertaining castration resistance based on subsequent treatment with any of these therapies: abiraterone, cabazitaxel, docetaxel, enzalutamide, mitoxantrone, or sipuleucel-T. First SPM were identified in Medicare data as 1 inpatient claim, 2 outpatient claims, or 2 physician claims; or in SEER data as 1 diagnosis. Follow-up data ended in 2013. We estimated incidence of SPM as events per 100 person-years (py) with 95% confidence intervals (CI) and survival by the Kaplan-Meier method. Results: Among 2,234 men with CRPC (83.6% white; mean age, 76.6 years; 80.4% with bone metastases), we identified 172 with SPM, of which 20 (11.6%) were in SEER data. The incidence of all first SPM was 5.9 per 100 py (95% CI, 5.0-6.8). The most common of these were lung (n = 29), bladder (n = 22), colorectal (n = 21), other genitourinary cancers (n = 18), and non-colorectal gastrointestinal cancers (n = 17). Mean (SD) time from CRPC ascertainment to SPM was 1.0 (1.1) year. Median OS for the entire study population was 1.2 years (95% CI, 1.1-1.3) after CRPC ascertainment; estimated survival probabilities (95% CI) at 1, 3, and 5 years were 56% (54%-58%), 17% (15%-18%), and 9% (7%-11%), respectively. Conclusions: Most CRPC patients had claims for a diagnosis of bone metastasis when CRPC was ascertained. SPM were common among the study population and occurred relatively soon after CRPC. Most SPM were identified in Medicare rather than SEER data. These results provided context for the incidence of SPM in men with CRPC up to 2013.
Characterization of germline and tumor genomic profile in unselected young black breast cancer patients.
Authors: Pal Tuya , Cragun Deborah , Wang Xuefeng , Yoder Sean J. , MESA Tania , Rosa Marilin , Tezak Ann , Weidner Anne , Vadaparampil Susan Thomas , Phelan Catherine
Published: September 2018

e13090

Background: Young black women bear a disproportionate burden of breast cancer (BC), yet there is limited characterization of these cancers based on BRCA1 and BRCA2 ( BRCA) status and tumor genomics. In this pilot study, we characterized: tumor and clinical characteristics based on BRCA carrier status and overlap of basal-like (BL) and triple negative (TN) BC. Methods: A population-based sample of 481 black women diagnosed with invasive BC < age 50 were recruited through the Florida Cancer Registry (FCR). BRCA status was determined based on germline testing. TN status was determined based on pathology reports and FCR data. Among a subset of 90 participants, gene expression profiling (GEP) was conducted on tumor samples through PAM50 analyses to classify intrinsic subtypes and risk of recurrence (ROR) scores. Results: Mean age at BC diagnosis was 41.9 (range: 25-50) and mean ROR score was 49.6 (range: 8.7-80.7). Participants included 7 BRCA1 carriers, 5 BRCA2 carriers, 67 non-carriers (NC), and 11 with no confirmed testing. Of 46 BL tumors, 33 were TN (71.7%) constituting 94.3% of TN tumors (the remaining 5.7% were Luminal A). All BRCA1 carriers had BL tumors, of which 5 were TN. Sensitivity, positive predictive value, and negative predictive value in identifying BRCA1 carrier was higher based on BL compared to TN status (Table 1). BRCA2-associated tumors included 3 Luminal A, 1 Luminal B, and 1 BL. Mean ROR score was highest among BRCA1 carriers (57.7), followed by NC (50.5) and BRCA2 carriers (41.5). Conclusions: Study findings suggest BL status predicted BRCA1 positivity better than TN status. BRCA2- (compared to BRCA1-) associated tumors were more heterogeneous with over half being Luminal A, which may explain the lower ROR among BRCA2 carriers. Additional follow-up and expansion of this cohort with collection of clinical outcomes will be useful in assessing the predictive utility of ROR scores among young black women with BC. [Table: see text]
Ancestry-based differences in hereditary cancer genetic testing.
Authors: Olopade Olufunmilayo I. , Nielsen Sarah , Wang Shengfeng , Bernhisel Ryan , Brown Krystal , Cox Hannah C , Cummings Shelly , Rosenthal Eric Thomas , Saam Jennifer , Lancaster Johnathan M. , Huo Dezheng
Published: September 2018

e13107

Background: Ancestry-based disparities in genetic testing for the hereditary breast and ovarian cancer (HBOC) genes BRCA1/2 have been well documented, but it is unclear whether this extends to other cancer-risk genes. Given reduced costs and broader access to multi-gene panels, we evaluated ancestry-based differences in the utilization and outcomes of HBOC and pan-cancer panel testing. Methods: Individuals who had genetic testing for BRCA1/2only (2006-2016) or with a multi-gene pan-cancer panel (2013-2016) were assessed. Clinical information was obtained from provider-completed test request forms. The most commonly reported ancestries [European (EU), Latin American/Caribbean (LA/C), African (AF), Asian (AS)] were evaluated. Individuals of Ashkenazi Jewish ancestry were not included in the EU group. Results: The relative utilization of HBOC testing in 2013-2016 increased in AF and LA/C individuals (vs 2006-2013) and was similar to panel testing in all ancestries (Table). The positive mutation rate for panel testing was 6.7%; AF (6.4%), LA/C (6.6%), AS (7.1%), EU (7.1%). The positive rate for HBOC testing from 2006-2013 was 5.7%. Of significance, the HBOC positive rate from 2013-2016 dropped to 4.1% and ancestry-specific positive rates were much lower relative to panel testing (Table). Gene-specific mutation prevalence differed by ancestry, but mutations were identified in a wide range of genes for all ancestries. Possible founder mutations were identified in BRCA1/2 and other genes. Conclusions: In this cohort, broader access to genetic testing has reduced disparities in recent years and panel testing shows improved clinical utility relative to HBOC testing in all ancestries. [Table: see text]
Understanding barriers to receiving genetic testing after referral.
Authors: Murray Drew , Mandadi Mounika
Published: September 2018

e13108

Background: About 5-10% of breast cancers are hereditary. Identifying women with hereditary breast and ovarian cancer syndromes helps implement screening strategies, chemoprevention regimens, preventative surgeries and identify family members at risk. Little is known about reasons for non-compliance with genetic testing after referral by an oncologist. To gain insight we investigated these barriers in a population of patients in Louisville, Kentucky. Methods: The study design was a IRB approved single institution retrospective analysis of all newly diagnosed breast cancer patients in the year 2014. Data on age, gender, race, education, insurance status, family history, referral orders and genetic testing results were analyzed for 204 patients. Characteristics of patients who received genetic testing after referral was made were compared to patients who did not receive genetic testing, despite referral. The categorical variables were compared using the Pearson Chi-square test for contingency tables while the t-test was used for continuous variables. Significance level was set at p≤0.05. All calculations are performed with SAS statistical software (SAS Institute Inc., Cary, NC). Results: Of 204 newly diagnosed breast cancer patients seen in 2014, 109 met NCCN guidelines for genetic testing. 89 total patients were referred for genetic testing. 67 patients received genetic testing after referral, while 22 patients did not receive the testing despite being referred. 29 patients met criteria for testing but were never referred. Statistical significance existed (P = 0.019) for the insurance status variable, those with private insurance being more likely to receive testing after being referred, and those without insurance being less likely to show up for genetic testing after being referred. There was no statistical significance for age(P = 0.787), race(P = 0.555), or education (P = 0.322). Conclusions: Being covered by private insurance was associated with increased completion of genetic testing after being referred by an oncologist. Age, race, and education did not impact the likelihood of receiving testing if referred. Further investigations will be made into reasons for non-referral in patients who met NCCN guidelines for testing.
Frequency of germline patghogenic mutation in breast cancer patients at high risk hereditary cancer.
Authors: Shin Hee-Chul , Han Wonshik , Lee Han-Byoel , Moon Hyeong-Gon , Lee Eunshin , Noh Dong Young
Published: September 2018

e13110

Background: Next-generation sequencing technology allows the simultaneous sequencing of multiple target genes. We developed a gene panel containing 64 genes which were associated with various hereditary cancers. This study was performed to evaluate the frequency of pathogenic mutations associated with hereditary cancer among Korean patients at high risk hereditary breast cancer using multi-gene sequencing panel. Methods: A total of 252 breast cancer patients with high-risk hereditary cancer were included. Among them, 179 patients (71.0%) had multiple primary cancers including breast cancer, 27 patients (10.7%) were diagnosed with bilateral breast cancer at age 40 or younger. Thirty-five patients (13.9%) had breast cancer family history of more than 2 relatives. With the 64 gene panel, sequence variants were detected by next-generation sequencing technology. Results: Sixty seven patients (26.8%) were found to have 77 germline pathogenic mutations, 12 in BRCA1, 13 in BRCA2, 9 in CDH1, 3 in FH, 5 in MSH2, 2 in MSH6, 4 in NAT1, 6 in PTCH1, 3 in RAD51, 7 in RET, 4 in SPINK1, 3 in TP53 and one each in ALK, BRIP1, CHEK2, MLH2, MUTYH, and PTEN. In 20 patients (4.0%), 2 (n = 9) or 3 (n = 1) pathogenic mutations were detected. In 227 patients with BRCA1/2 negative, CDH1 (n = 7), RET (n = 7), PTCH1 (n = 5), and MSH2 (n = 5) were the most prevalent pathogenic mutations. Conclusions: The 64 gene panel detected germline pathogenic mutations in 26.8% of Korean breast cancer patients with feature of hereditary cancer. Mutations of BRCA1, BRCA2, CDH1, RET, and PTCH1 were the most prevalent variants.Mutation carriers were considered as high risk to develop malignancy and recommended to receive genetic counseling and intensive cancer screening.
Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology.
Authors: Lim Howard John , Schrader Kasmintan A , Young Sean , Nelson Jessica , Fok Alexandra , Pleasance Erin , Jones Martin , Shen Yaoqing , Armstrong Linlea , Virani Alice , Rassekh Shahrad Rod , Deyell Rebecca , Yip Stephen , Roscoe Robyn , Karsan Aly , Marra Marco , Laskin Janessa J.
Published: September 2018

e13113

Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.
Prognostic implication of GATA3 gene mutation on survival in invasive ductal carcinoma of the breast.
Authors: Kailasam Karthik , Omaira Mohammad , Chhatrala Hardik Satish , Ravichandar Marie
Published: September 2018

e13114

Background: GATA3 encodes a transcription factor, which is involved in activation and suppression of genes involved in cell maturation. GATA3 is necessary in the adult mammary gland to maintain the integrity and function of the luminal epithelium. Methods: METABRIC project funded by cancer research UK, the British Columbia cancer foundation and the Canadian breast cancer foundation mapped 173 gene mutations and amplifications in 2,433 primary breast tumors. Retrospective analysis was done for patients with invasive ductal carcinoma of the breast in the age group 30-60; to study the effect of GATA3 mutation on survival. Median survival was obtained from Kaplan-Meier plot, and mortality between groups was compared by Odds ratio (OR). Results: A total of 1500 patients across all age groups had invasive ductal carcinoma. 650 were within the age group 30-60; of which 234 died due to the disease, 360 were alive and 55 died due to other causes. 398 patients (61.2%) tested positive for estrogen receptor (ER) and 521 patients (80.2%) were negative for HER2 (human epidermal growth factor receptor 2). TP53 (50%) and PIK3CA (36%) mutations were more prevalent. GATA3 mutation was found in 79 patients (12.34%); among which, all 79 patients tested positive for ER (100%) and 74 patients (94.9%) negative for HER2. 10 patients (12.7%) died due to the disease, 62 patients (78.5%) were alive and 7 patients (8.9%) died due to other causes. Hence, patients with GATA3 mutations were more likely to survive (OR 4.66; CI 2.33-9.29 p < 0.0001) than patients without the mutation. The median survival for patients with GATA3 mutation (300 months) was also greater than patients without the mutation (219 months). In addition, patients with GATA3 mutation were more likely to be ER positive and HER2 negative. Conclusions: In the mammary gland, GATA3 is required for luminal epithelial cell differentiation. Loss of GATA3 results in de-differentiation to stem cell phenotype. It is found that GATA3 mutation correlates with a better prognosis compared to more common TP53 and PIK3CA gene mutations.
Determining the prevalence of germline BAP1 mutations in malignant mesothelioma (MM).
Authors: Zauderer Marjorie Glass , DuBoff Mariel A. , Siegel Beth , Robson Mark E. , Arnold Angela G. , Berliner Janice , Harlan Fleischut Megan , Mandelker Diana , Ladanyi Marc
Published: September 2018

e13118

Background: Somatic BAP1 mutations are very common in MM tumors (Bueno et al. Nat Genet 2016, Bott et al. Nature Genet 2011) and germline BAP1 mutations have also been shown to segregate in numerous families with clusters of malignancies including MM (Testa et al. Nat Genet 2011). However, the prevalence of germline BAP1 alterations in an unselected population of MM patients remains unknown. Methods: Unselected patients with MM were enrolled on a prospective trial (NCT01773655) to collect germline DNA, detailed family history, exposure questionnaires, and tumor tissue if available. De-identified germline DNA sequencing was performed to evaluate for the presence of BAP1 mutations. Patients with prespecified high-risk criteria (age < 50 yrs, no asbestos exposure, personal/family history of choroidal nevus, uveal melanoma, melanoma, or mesothelioma, or cancer in ≥ two 1st degree relatives) were contacted by Clinical Genetics and offered counseling and identified BAP1 testing. Results: 120 patietns with MM were enrolled. The majority are male (63%) with pleural mesothelioma (78%) and mostly epithelioid histology (75%). Sixty-seven percent met high-risk criteria for identified testing and 27 patients have consented for identified testing. Both deidentified and identified testing is ongoing. To date, among 17 patients tested, 3 have been identified with germline pathogenic BAP1 alterations. Two of those three patients had a personal history of an associated malignancy. Additional testing results will be reported at the meeting. Conclusions: Germline BAP1 mutations may be more common than previously thought among MM patients. Further work is needed to clarify those at high risk for germline mutation so they and their at-risk family members may receive testing and genetic counseling regarding their risk of malignancy. Additionally, ongoing work to define associations between genotype and phenotype should continue so that the full scope of diseases and risks are outlined for this new BAP1 associated cancer predisposition syndrome.
A feasibility study of the Nativis Voyager system in patients with recurrent glioblastoma multiforme (GBM): Interim results of first-in-human study.
Authors: Barkhoudarian Garni
Published: September 2018

e13506

Background: The Nativis Voyager® ulRFE™ system, a non-invasive investigational device, was studied in a first-in-human feasibility study to assess if it is a safe and feasible treatment for recurrent glioblastoma multiforme (GBM). The anti-mitotic therapy delivers ultra-low radio frequency energy ( ulRFE) profiles produced by changes in molecular electrostatic surface potential to the brain. The interim results of the first stage of a 2-stage study are presented here. Methods: In this prospective, multi-center trial, patients with GBM, following recurrence after receiving standard-of-care chemotherapy and/or radiotherapy were considered for the study. Patients were treated with Voyager alone or with Voyager plus concurrent chemotherapy or Avastin at the discretion of the investigator. Safety was assessed by incidence of any adverse events associated with the investigational therapy. Tumor progression at 8 weeks (2 cycles) was assessed by radiological response by local site. Patients were followed at least every 8 weeks during treatment and every 4 months thereafter. Results: Fourteen patients were enrolled and treated at four clinical sites across the United States. Eleven subjects were followed per protocol. Three subjects withdrew consent prior to the first radiological assessment (day 28) for reasons not associated with the study or investigational therapy, and were not included in the analysis. The local sites reported a partial response in the first 2 months of treatment in 2 of the 11 subjects. These subjects were Avastin-naïve. Two were reported to be progression free after 6 cycles (24 weeks) of treatment. No serious adverse events associated with the investigational therapy were reported. Conclusions: The Nativis Voyager appears to be feasible and safe for the treatment of recurrent GBM. Given that therapy is delivered non-invasively, and no serious adverse events attributed to the investigational therapy were reported, further prospective study in an expanded study of the investigational device is warranted. Clinical trial information: NCT02296580.
Primary brain tumor and risk of venous thromboembolism.
Authors: Dwary Ashish Dutta , Gupta Ankita , Burton Gary Von , Peddi Prakash
Published: September 2018

e13518

Background: Venous thromboembolism (VTE) is frequently associated with primary brain tumors (PBT). Brain tumors have been associated with higher rates of VTE in multiple studies. Studies comparing VTE incidence in meningioma (MEN), astrocytoma (AA), oligodendroglioma (OG) and glioblastoma multiforme (GBM) are lacking. The aim of this retrospective study is to report the VTE outcomes in all of the above brain tumors. Methods: Retrospective data from 476 patients with PBTs diagnosed between 1995-2015 at Louisiana State University Health Sciences Center-Shreveport was analyzed. The incidence of VTE (deep vein thrombosis or pulmonary embolism) was studied in these patients. Results: Out of 476 patients, 298 were females and 179 were male. One hundred and twenty seven (127) patients had GBM, 52 had AA, 33 had OG and 264 had MEN. Only two patients out of 264 with MEN had VTE (one patient had central line catheter associated DVT). VTE incidence did not correlate with the type of primary treatment i.e surgery verses radiation verses observation in this patient group. The incidence of VTE was 7.8 % in GBM patients. The risk of VTE in AA and OG patients were 7.7% and 9.0 % respectively. The VTE event in the OG, AA and GBM occurred during all phases of treatment including inpatient hospitalization for surgical resection, during concurrent chemo-radiation and in maintenance phase. Biopsy versus partial resection versus complete resection of GBM didn’t correlate with VTE occurrence. Conclusions: VTE is prevalent among adult patients with both low and high grade glial tumors. The thrombotic events occur during all phases of therapy indicating hypercoagulable state for many patients. Life-long anticoagulation may be necessary in these patients with thrombotic events. Thrombotic events in patients with MEN, however, are rare ( < 1%). MEN do not appear to be a hypercoagulable and life-long anticoagulation is probably unnecessary in those with VTE.
Malignant hemangiopericytoma: Treatment patterns and survival.
Authors: Barjas Rolando , Piccioni David Eric
Published: September 2018

e13520

Background: Hemangiopericytoma (HPC), or solitary fibrous tumor of the central nervous system (CNS), is a rare mesenchymal tumor that arises from the pericytes of the meningeal capillaries. These tumors account for less than 1% of all CNS tumors and are categorized into low-grade (WHO grade I and II) or high-grade (WHO grade III, anaplastic) neoplasms. The optimal treatment for grade III HPC is unclear. The aim of this study was to evaluate treatment patterns and survival for grade III HPC using the California Cancer Registry (CCR). Methods: Treatment and demographic data were extracted from the CCR for patients with grade III HPC of the CNS, from 1988-2010. Overall Survival (OS) was evaluated as a function of treatment (surgery, radiation or both), as well as extent of resection. Kaplan Meier survival analyses were performed for OS. Bivariate and multivariable analyses were done via cox proportional hazard regression models for all demographic and treatment variables. Results: A total of 94 patients with grade III HPC were identified from the registry. The most prevalent demographics were age > 50 years (59%), female (61%), non-Hispanic White (60%), and married (54%). 54% received radiation, and subtotal resection (STR) (63%) was the most common surgical outcome. However, survival was greatest in patients that received gross total resection (GTR) with radiation (median OS not reached). GTR/radiation (median OS not reached) demonstrated improved OS compared to STR/radiation (median OS 10.3 years; HR = 0.389, 95%CI 0.157-0.960) or GTR alone (median OS 6.6 years; HR = 0.254, 95%CI 0.073-0.880). Age < 50 (median OS 15.7 years), Asian/PI (median OS not reached) and married (median OS 9.9 years) were significant predictors of OS. In the multivariable cox model worse overall survival remained for older age (HR = 3.079, 95%CI 1.428-6.636) and divorced/widowed/separated (HR = 2.027, 95%CI 1.054-3.897) when compared to their younger and married counterparts. Conclusions: Patients that received GTR and radiation demonstrated the best long-term prognosis. Demographic analyses identified additional independent predictors of survival.
Use of immunotherapy in recurrent glioblastoma.
Authors: Sumrall Ashley Love , Jennings David Lowell , Haggstrom Daniel Ernest , Symanowski James Thomas
Published: September 2018

e13523

Background: With the recent explosion of interest in immunotherapy to treat cancer, it has moved into management of glioblastoma (GBM). Several trials are ongoing, investigating use of checkpoint inhibition for newly diagnosed and recurrent GBM. Methods: We reviewed the records of patients with recurrent glioblastoma (including gliosarcoma). Six of the eight patients demonstrated PD-1 positivity via immunohistochemical (IHC) staining. Two patients demonstrated PD-L1 positivity as 2+ staining intensity via IHC. Patients were managed with checkpoint inhibitors for at least four weeks. When feasible, patients had tumor profiling of initial tumor and recurrent tumor. Patients were followed for response, progression, and survival. Results: Eight patients were identified with recurrent GBM who received immunotherapy with checkpoint inhibitors. They ranged from first through fifth recurrence following radiation and temozolomide. Three patients received pembrolizumab. Of those, two were PD-L1 positive. Five patients received nivolumab, and all were PD-1 positive. There were no partial or complete responses. Five of the eight subjects died, and the median survival time among the 8 subjects was 3.6 months. Six of eight subjects progressed on treatment, and the median PFS was 2.2 months. Bevacizumab was given to two patients for suspected “tumor flare” while on nivolumab. Four of the eight patients had tumor profiling completed at initial diagnosis and recurrence. Treatment was well-tolerated with only minimal toxicity observed. Conclusions: Despite increasing interest in utilizing these medications for recurrent glioblastoma, overall survival in our cohort was consistent with historical control (3 to 5 months). Additionally, we did not witness any responses.