bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiviral therapy to reduce hepatocellular carcinoma recurrence in patients with low HBV-DNA levels: A randomized controlled trial.
Authors: Huang Gang , Li Peng-Peng , Lau Wan Yee , Pan Ze-Ya , Zhao Ling-Hao , Wang Zhen-Guang , Wang Meng-Chao , Zhou Wei-Ping
Published: May 2019

1510

Background: Despite antiviral treatment has been shown to reduce hepato- cellular carcinoma (HCC) recurrence after curative treatment for hepatitis B virus (HBV)-related HCC in patients with high preoperative HBV-DNA levels, it is still unclear whether antiviral therapy is useful in reducing recurrence in patients with low preoperative HBV-DNA levels. Methods: In this randomized controlled trial, 200 patients who underwent curative resection for HCC with low baseline HBV-DNA levels were ran- domly assigned to receive preemptive antiviral therapy or not. The primary endpoints were recurrence-free survival. This study was censored on March 31, 2015 when all surviving patients had a minimum follow-up of 60 months. The analysis was done on an intention-to-treat basis. Results: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.9%, 55.2%, and 52.0% and 80.6%, 40.9%, and 32.3%, respectively. The corresponding overall survival rates for the 2 groups were 94.0%, 75.7%, and 64.1% and 90.0%, 62.4%, and 43.7%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P 1/4 0.016, P 1/4 0.004, respectively). After adjusting for confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.601 [95% confidence interval (CI), 0.409– 0.884; P 1/4 0.010] and 0.509 (95% CI, 0.333–0.778; P 1/4 0.002), respectively. Antiviral therapy was an independent protective factor of late tumor recur- rence (hazard ratio [HR] 1/4 0.316, 95% CI 0.157 – 0.637; P 1/4 0.001) but not of early tumor recurrence (HR 1/4 0.782, 95% CI, 0.493–1.240; P 1/4 0.296). Conclusions: In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence after R0 hepatic resection. Clinical trial information: ChiCTR-IPR-15006587.
Adequacy of self-reported family history in electronic health record for genetic risk assessment for Lynch syndrome.
Authors: Pande Mala , Okon Connie , You Y. Nancy , Peterson Susan K. , Arun Banu , Lynch Patrick M.
Published: May 2019

1515

Background: Self-reported family cancer history (FCH) is one of the key indicators of hereditary cancer risk. Studies have shown that accurate FCH documentation by healthcare providers is suboptimal, but data regarding patient-provided FCH are limited. We evaluated the quality of FCH as entered by the patient into the electronic health record (EHR) to determine its adequacy for Lynch syndrome (LS) risk assessment. Methods: At our tertiary referral cancer center, FCH is self-reported via an online questionnaire sent prior to appointment, which is reviewed/updated by clinic nurse during initial visit and then imported into EHR review of systems. Records of all new patients from September 2016 to August 2017 were retrospectively reviewed and analyzed. FCH quality was estimated by calculating rates of reporting of 3 FCH variables required for PREMM5, a risk-prediction model for LS. Parameters required for the model were sex, age, personal history of cancer, and for FCH, degree of kinship (first/second degree), cancer site/type, and age at diagnosis. Results: Of 47,647 unique patients, 47.5% reported FCH for 1 or more relative (46.1% were first degree, 64.8% second degree, 3.0% other, and 2.4% missing). A cancer type/site was specified for 88.8% reporting FCH. Age at diagnosis was listed for 21.7% of the relatives’ cancers. Overall, only 20.9% provided all 3 FCH data elements required for running PREMM5 (9.9% of the total sample, n=4738). Fewer men (9.5%) than women (28.1%) provided all 3 FCH elements. Furthermore, 46.7% of breast cancer patients, 21.9% of gastrointestinal cancer patients, 47.2% and 23.1% of patients seen for cancer prevention screening and endoscopy respectively, reported 3 FCH elements. Lower rates were observed for other cancers. Conclusions: Patient self-reported FCH is suboptimal for estimation of LS risk and genetic counseling referral. Future steps to optimize online patient-facing FCH collection to enable routine automated risk-assessment in an essentially provider-free setting may include, patient education regarding importance of FCH, EHR prompts for FCH completion, and implementation of algorithms in EHRs using FCH to identify patients at risk for hereditary cancer predisposition syndromes.
Preventive surgery after multiplex genetic panel testing (MGPT).
Authors: Idos Gregory , Kurian Allison W. , Ricker Charité , Sturgeon Duveen , Culver Julie , Kingham Kerry , Koff Rachel , Chun Nicolette M. , Rowe-Teeter Courtney , Levonian Peter , Hong Christine , Mills Meredith , Ma Cindy , Lancaster Johnathan M. , Brown Krystal , Kidd John , McDonnell Kevin , Ladabaum Uri , Ford James M. , Gruber Stephen B.
Published: May 2019

1525

Background: Guidelines recommend consideration of prophylactic surgery for patients with a germline pathogenic variant in some cancer predisposition genes. We assessed surgery utilization in a prospective, multi-institutional cohort study of MGPT. Methods: 2000 patients had MGPT and completed questionnaires at 3, 6, and 12 months. Patients reported surgical utilization and indication (treatment or prevention). Surgery utilization was assessed according to cancer history and MGPT test results: Positive, pathogenic variant; VUS, variant of uncertain significance; Negative, benign variants. Results: Overall, 12.9% (198/1537) of patients reported surgery after MGPT (median follow-up 13 months). Only 31.3% (62/198) of patients specified that their surgery was preventive. Preventive surgery utilization was significantly higher among patients who tested positive (n=30, 14.9%) compared to those testing negative (n=20, 2.3%, p<0.001) or VUS (n=12, 2.2%, p<0.001). Preventive surgery was very low among patients testing negative or VUS who had no personal history of cancer in the relevant organ (Table). For example, mastectomy was not reported among any patients testing negative or VUS who had no personal history of breast cancer (Table). Conclusions: More than one year after MGPT, prophylactic surgery use was low among patients with VUS or negative results, especially among those with no personal history of cancer at the relevant site. Surgery utilization. [Table: see text]
Germline variants in urothelial carcinoma: Analysis of pathogenic and likely pathogenic variants in 645 subjects.
Authors: Abou Alaiwi Sarah , Nassar Amin , Mouw Kent William , Kwiatkowski David J. , Choueiri Toni K. , Curran Catherine , Van Allen Eliezer Mendel , Esplin Edward D. , Yang Shan , Garber Judy Ellen , Rana Huma Q. , Sonpavde Guru
Published: May 2019

1528

Background: While small studies have supported a genetic cancer predisposition among subjects with urothelial carcinoma (UC), systematic germline evaluation of this population is lacking. Here, we report the prevalence of germline variants among subjects with UC from multiple centers completing panel-based testing at a large, commercial laboratory. Methods: 1149 UC subjects underwent germline testing of 1 to 126 genes using massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number alterations. Pathogenic (P) and likely pathogenic (LP) were confirmed using orthogonal technology in accordance with Invitae standard operating practices. Analysis was limited to 645 subjects who completed testing of a shared set of 42 genes. P/LP variants including single nucleotide variants/indels/ copy number variants are reported. De-identified personal and family cancer histories were evaluated. Fisher’s Exact test and the Mann-Whitney test were used to analyze categorical and continuous variables respectively. Results: Among the 645 UC subjects with 42-gene testing for any indication, median age at testing was 60 years (6-88) and 326 (51%) were female. P/LP variants were identified in 21 (50%) of the 42 genes in 98 (15%) of subjects, including Lynch syndrome genes (n = 26 [4%]), BRCA1/2 (n = 16 [2.5%]), CHEK2 (n = 15 [2.3%]), and heterozygous MUTYH (n = 12 [1.9%]). Among 18 DNA damage repair (DDR) genes assessed, 90 P/LP variants were detected in 88 subjects (12.2%). There was no significant association between presence of a DDR gene variant and age at diagnosis, gender or reported family history of UC in a first degree relative (n = 48). Among subjects with documented history of UC only without other cancers (n = 195), 24 (12.3%) had P/ LP variants, of which 23 (11.8%) were in a DDR gene. Conclusions: Germline P/LP variants were identified in 15% of UC subjects most of which (92%) were in DDR genes, including 27% in Lynch syndrome genes. PARP and T-cell checkpoint inhibitors may warrant evaluation in subjects with germline DDR mutations. Further validation in unselected UC pts is warranted to propose examining germline P/LP variants in all UC patients.
Prognosis value of a genetic score based on germline genetic variants in a prospective cohort of early triple-negative breast cancer patients.
Authors: Curtit Elsa , Henriques Julie , Paget-Bailly Sophie , Ladoire Sylvain , Darut-Jouve Ariane , Debled Marc , Romieu Gilles , Garnier-Tixidre Claire , Jacquin Jean-Philippe , Soulie Patrick , Jouannaud Christelle , Rios Maria , Petit Thierry , Bachelot Thomas Denis , Faure-Mercier Céline , Gambotti Laetitia , Blanché Hélène , Deleuze Jean-Francois , Cox David , Pivot Xavier
Published: May 2019

1529

Background: Triple-negative breast cancers (TNBC) are a heterogeneous group of tumors with poor outcome. In this study, the association between germline genetic variants and invasive disease-free survival (iDFS) was analyzed in TNBC patients. Methods: A genome wide-association study (GWAS) aimed to identify variants (single nucleotide polymorphisms – SNPs) associated with prognosis in 1121 patients with TNBC in the SIGNAL prospective cohort. Associations between gene variants and iDFS were assessed in univariate Cox regression models. Variants were combined in a score to identify risk categories. A prognostic model based on breast cancer stage and genetic variants was estimated using a multivariate Cox regression. Interaction between stage and genetic score was tested. Discrimination of the model was assessed by the Harrell’s C statistic and internal validity by bootstrap method. Results: The characteristics of the 1121 patients were representative of a population with early TNBC. Four SNPs on chromosomes 9 and 2 were found significantly associated to iDFS in univariate Cox models. Homozygous status for the most frequent allele was associated with poorer iDFS for two SNPs and this status was present in 50% and 57% of the population. For the two other SNPs, the most frequent allele was associated with more favorable iDFS. Three prognostic categories were derived from the genetic score. The following table presents the results from the multivariate Cox model including genetic score and disease stage. Clinical trial information: RECF1098. Conclusions: In a prospective cohort of 1121 patients with early TNBC, 4 genetic variants (SNPs) were associated with iDFS. A score involving SNPs provided similar prognostic indications as breast cancer stages. A search assessing the function and the role of the involved genes is ongoing.[Table: see text]
Test of InheRET, an online tool to facilitate NCCN Guideline compliant referrals for cancer genetic counseling.
Authors: McCain Lynn , Milliron Kara J. , Cook Amanda , Schroeder Lee , Arthurs James , Harper Diane M , Ernst Susan , Zazove Philip , Parvaz Jasmine Diana , Keren David , Merajver Sofia
Published: May 2019

1530

Background: Identifying the ~60 million unaffected persons in the US at risk for inherited cancers has the potential to reduce their cancer risk by up to 95%. However, most of these individuals are not identified currently because of multifactorial deficits in the 3-generation pedigree collection in clinical settings. Methods: Here we evaluated the impact InheRET, an online family history gathering and risk assessment reporting tool, has on facilitating National Comprehensive Cancer Network (NCCN) Guideline-compliant referrals for cancer genetic counseling/genetic evaluation by decreasing and/or removing the barriers of 1) in-clinic 3-generation family history collection, and 2) interpretation of the family and personal history in light of current NCCN Guidelines. Patients enrolled from primary care and specialty clinics completed the family health history from a web-enabled devices using InheRET Inherited Risk Evaluation Tool. Results: Of 255 enrolled patients, 78.4% completed the history form and, of these, 86.5% completed the feedback survey. 39.2% of primary care and 79.9% of specialty cancer genetics patients were found to be at increased risk. Patients with ≤ HS education ranked InheRET at 4.7/5.0 for Understandability and 3.33/5.0 for Ease of Use. Following the addition of clarifying directions, they ranked InheRET at 5.0 and 4.0, respectively. Pts. <60 ranked InheRET between 3.5 and 3.8 on Ease of Use, while those 60-69 and 70+ ranked it 3.0 and 2.7, respectively, potentially reflective of lower technical skills. Age did not impact Understandability. In the cancer genetics clinic, 86% of pts. completed the online survey, in ~ 1 week, compared to paper forms, which required reminders, and >4 weeks to obtain. Conclusions: In this pilot, InheRET accelerated appropriate referrals and efficient utilization of genetic counseling services; improvements to navigation are being implemented prior to dissemination.
Effectiveness of low-dose CT scan for lung cancer screening in the community setting.
Authors: Mouabbi Jason Aboudi , Hadid Tarik H. , Uh Eugene
Published: May 2019

1543

Background: Lung cancer is the leading cause of cancer death in the United States (US) and worldwide. Chest X-ray (CXR) is ineffective in reducing lung cancer mortality. National Lung Cancer Screening Trail (NLST) reported 20% reduction in mortality with the use of low-dose computed tomography (LDCT) scan to screen high risk individuals. Therefore, major organizations including US Preventive Services Task Force has adopted LDCT for lung cancer screening in high risk populations. However, The generalizability of this approach in community setting is yet to be confirmed. Our objective is to assess the ability of LDCT in detection of lung nodules and lung cancer in the community setting and compare the results to those reported in the NLST. Methods: Charts of subjects who underwent LDCT screening between 2013 and 2016 at SJHMC were retrospectively reviewed. Demographic data, the results of the LDCT scans, interventions performed, complications of procedures and pathology findings were collected. All cancer cases found by LDCT and the stage of cancers were documented. The results of our study were statistically compared to the results of both arms of the NLST (CT and CXR arms). Since CXR is ineffective for lung cancer screening, CXR arm serves equivalently to no screening. Results: The baseline characteristics of the subjects are significantly different between this study and NLST. LDCT in our study detected significantly higher positive findings. There are more cancers detected in this study compared to NLST CT and CXR arms, which could reflect higher incidence of cancer in this community or higher proportion of current smokers in our study. In this study, LDCT detected cancers at higher stages compared to that of the NLST CT arm but similar stages to NLST CXR arm. This may indicate that LDCT when performed in the community is less effective in detecting cancer at early stages. Conclusions: The community population have different characteristics compared those enrolled in clinical trials. This may limit the generalizability of the results. Population-based studies are needed to confirm the results of the NLST. [Table: see text]
A comparison of risk factors for cigarette and e-cigarette use in the United States adult population.
Authors: Chen Leo , Wang Nai Wen , Cheung Winson Y.
Published: May 2019

1546

Background: The US CDC and public health agencies have reported alarming increases in e-cigarette (ecig) use among youth, even as cigarette (cig) use among youth decline. In this study, other risk factors for cig and ecig use are compared. Methods: This study used data from the Health Information National Trends Survey 5 Cycle 1 survey, conducted in 2017. Univariate survey-weighted logistic regression analyzed responses as a nationally representative US population. Results: Inverted trends included being 35 or older (cig: OR=1.22, p<0.01; ecig: OR=0.79, p<0.01), being a student (cig: OR=0.77, p<0.01; ecig: OR=1.24, p<0.01) or retired (cig: OR=1.09, p<0.01; ecig: OR=0.89, p<0.01) compared to being employed, and being single (cig: OR=0.92, p<0.03; ecig: OR=1.18, p<0.01). Having considered quitting smoking was not significantly associated with ecig use. Conclusions: Segments of the US adult population educated with anti-tobacco campaigns may remain at increased risk for ecig use.[Table: see text]
Does ethnicity affect the relationship between body mass index (BMI) and overall survival (OS) in non-small cell lung cancer (NSCLC)? A pooled analysis of 17,326 International Lung Cancer Consortium (ILCCO) patients (pts).
Authors: Fares Aline Fusco , Shepshelovich Daniel , Lu Lin , Brown M. Catherine , Yang Ping , Zhang Jie , Ryan Brid M , Christiani David C. , Schwartz Ann , Chen Chu , Adonina Garcia , Schabath Matthew B. , Shiraishi Kouya , Down Teare , Le Marchand Loic , Zuo-Feng Zhang , Brenner Hermann , Xu Wei , Hung Rayjean J , Liu Geoffrey
Published: May 2019

1562

Background: In Caucasian-predominant populations, overweight or obese NSCLC pts (BMI≥25-kg/m2) have better prognosis while underweight (BMI≤18.5-kg/m2) pts have a worse prognosis. A large pooled sample allowed us to evaluate the role of ethnicity in this BMI-NSCLC OS relationship. Methods: Using individual data, survival analysis was performed on 15 ILCCO studies, assessing the interactions between ethnicity and BMI on overall survival (OS). Adjusted Hazard Ratios (aHR) from Cox models and adjusted penalized smoothing spline plots were generated. Results: Among 13416 (77%) Caucasian, 2975 (17%) Asian, and 935 (5%) Black NSCLC pts analyzed, we confirmed that for all pts, being underweight at NSCLC diagnosis was associated with worse OS (aHR=1.68, CI 1.5-1.8, p<0.001), while overweight/obese pts had improved survival (aHR 0.89, CI 0.8-0.9, p<0.001), when compared to pts with normal BMI. In general, Black pts had poorer OS than Caucasian pts (aHR 1.26 CI 1.1-1.4, p<0.001). However, the BMI-OS relationship differed according to ethnicity (BMI-ethnicity interaction, p=0.009): Caucasian underweight pts had poorer OS (aHR 1.67, CI 1.5-1.8, P<0.001) while overweight/obese pts had improved OS (aHR 0.89, CI 0.8-0.9, P<0.001). In Asian pts, these two associations were aHR 1.15, CI 0.8-1.5, P=0.33, and aHR 0.91, CI 0.7-1.1, P=0.32, respectively. In Black pts, these two associations were aHR 1.06, CI 0.7-1.5, p=0.73 and 0.75, CI 0.6-0.8 p<0.001, respectively. For overweight/obese patients, as BMI rises from 25-kg/m2 through 45-kg/m2, the prognosis worsens for Caucasian pts, remains stable for Asian pts, but improves for Black pts. Conclusions: InCaucasian pts, being underweight had a greater negative impact on OS than for Asian or Black pts, while being obese had a greater beneficial impact in Blacks than in other ethnic groups. These ethnic differences likely reflect genetically-informed muscle/adipose tissue distributions, where Black pts may have less sarcopenic obesity than other ethnicities. In future prognostic studies, BMI relationships must account for ethnic differences.
Outcomes associated with rapid genetic testing for BRCA1 and BRCA2 at time of breast cancer diagnosis.
Authors: Metcalfe Kelly A. , Poll Aletta , Eisen Andrea , Lerner-Ellis Jordan , Narod Steven
Published: May 2019

1577

Background: Bilateral mastectomy improves survival for women with BRCA-associated breast cancer. Most women do not know their BRCA status at the time of BC diagnosis when making surgical decisions. Rapid genetic testing (RGT) allows a woman to have genetic test results prior to treatment decision making, but it is unclear if RGT has an impact on treatment choices. It is also unclear if there are psychosocial implications associated with genetic testing at the time of breast cancer diagnosis. The objective of the current study was to assess the impact of RGT at the time of BC diagnosis on surgical decision-making and psychosocial functioning. Methods: Eligible women were referred from participating surgeons at BC diagnosis. Women completed baseline questionnaires assessing treatment preferences, cancer related distress, anxiety, and depression. All participants received in-person pre-test genetic counselling and genetic test results were given within 10 days. Participants completed surveys at 1 week and 1 year post-genetic testing to assess treatments and psychosocial functioning. Results: 1010 women consented to participate and 60 (5.9%) were identified with a BRCA mutation. 15% of those identified with a BRCA mutation did not meet provincial eligibility criteria for genetic testing, and 20% were eligible prior to a breast cancer diagnosis but had not received testing. Mean levels of cancer-related distress, anxiety and depression declined significantly from baseline to 1 year for all women (all p < .05), and there were no differences at any time point between those with and without a BRCA mutation. Of those identified with a BRCA mutation, 67.3% reported that their surgery choice changed. 73.7% of BRCA carriers had a bilateral mastectomy, compared to 20.2% of BRCA negative (p < 0.001). Most women used genetic testing results for surgical decision making (96.1% of BRCA positive and 86.4% for negative). Conclusions: Rapid genetic testing for BRCA1 and BRCA2 at the time of BC diagnosis does not have a negative impact on psychosocial functioning. There are no differences in cancer-related distress, anxiety or depression between women who receive a positive result compare to a negative genetic test result. Furthermore, surgical choice changed for many women identified with a BRCA mutation, with the majority electing for bilateral mastectomy.
Early results from the BRCA Founder Outreach (BFOR) Study: Population genetic screening using a medical model.
Authors: Morgan Kelly , Gabriel Camila , Symecko Heather , Lester Jenny , Levin Jeffrey , Kamara Daniella , Spielman Kelsey , Jenkins Colby , Hamilton Jada G. , Fesko Yuri Anthony , Heitler Jacob , Block Jeremy , Pace Lydia , Robson Mark E. , Nathanson Katherine , Tung Nadine M. , Domchek Susan , Karlan Beth , Garber Judy Ellen , Offit Kenneth
Published: May 2019

1578

Background: Barriers to population screening for BRCA mutations include access, availability of counseling, and readiness of care providers to participate in this process. The BRCA Founder OutReach (BFOR) study evaluates a digital approach to genetic testing of a defined population using a medical model and risk-adapted follow-up. Methods: The BFOR study (Bforstudy.com) includes web-based enrollment open to individuals in four US cities who are age 25 or older and have at least one grandparent of Ashkenazi Jewish (AJ) ancestry. Participants receive web-based education, provide consent, complete questionnaires, and note their preference for receiving results either from their primary care provider (PCP) or BFOR staff. BRCA AJ founder mutation results are disclosed by (e)mail or phone, depending on need for additional counseling/genetic testing. Participants will be surveyed by email for up to 5 years; a subset of PCPs is also being surveyed. Results: From March 2018 to January 2019, 2562 participants enrolled: 78% female; < 30 years old, 8%; 30-50 years, 39%; > 50 years, 53%. At enrollment, 33% requested disclosure of results by PCP. Among 847 PCPs invited to disclose results, 45% accepted, 50% declined and 5% have yet to respond. 69 (3.2%) participants tested positive for a BRCA founder mutation, of whom 8 (12%) had no significant family history. 2087 participants tested negative, of whom 6% reported a known family mutation, 38% reported a family history of breast/ovarian cancer, and 56% no such history. The most common reason for study participation was referral by a friend. One individual with a distant history of breast cancer tested positive for a BRCA2 mutation and underwent risk reducing surgery that identified an early stage fallopian tube carcinoma. Her daughter then tested positive and underwent prophylactic surgeries. Conclusions: Population screening of individuals at higher risk for cancer-predisposing mutations is feasible and identifies individuals who would not have been tested using clinical criteria. Preliminary findings reveal challenges for engaging PCPs and at-risk individuals, particularly men. Ongoing follow-up and a second phase of the study will address these barriers to testing. Clinical trial information: NCT03351803.
Disparities in pretest genetic counseling among a population-based sample of young breast cancer patients.
Authors: Reid-Lawrence Sonya , Pal Tuya , Mayer Ingrid A. , Shu Xiao-Ou , Tezak Ann , Weidner Anne , Cragun Deborah , Vadaparampil Susan Thomas , Ye Fei , Fan Run
Published: May 2019

1579

Background: Per national practice guidelines, pre-test genetic counseling (GC) through a board-certified or credentialed genetics health professional (GHP) is recommended when testing for hereditary cancer. We sought to compare differences in rates of pre-test GC among young breast cancer (BC) patients tested with or without GHP involvement across three racial groups (Black, Hispanic and non-Hispanic white (NHW)). Methods: A population-based sample of Black, Hispanic and NHW women diagnosed with invasive BC ≤ age 50 from 2009 to 2012 were recruited through the Florida State Cancer Registry. Participants were asked to complete a baseline questionnaire and release medical records for verification of clinical information and genetic testing. We compared the rates of pre-test GC across racial groups in women tested with or without GHP involvement using Analysis of Variance. Multivariate logistic regression analysis was also conducted to adjust for potential confounders. Results: Of 1618 participants, 828 had genetic testing based on medical records and/or self-reported on their questionnaire. There were 170 (20.5%) with GHP involvement (either through consultation and/or test ordering) and the remaining 658 women (79.5%) had no documentation of GHP involvement. Among patients tested without GHP involvement, rates of pre-test GC were significantly lower among Black women (34.8%) compared to Hispanics (80%) and NHW (78.7%) (p < 0.001). In contrast, among those with GHP involvement, rates of pre-test GC were similar among Black (89.7%), Hispanic (81.1%) and NHW (84.6%) (p = 0.89). Conclusions: Our results suggest that among young breast cancer patients tested for hereditary cancer without GHP involvement, Blacks were significantly less likely to receive pre-test GC, compared to the other two groups. In contrast, rates of pre-test GC among those with GHP involvement were similar across all groups. These results suggest a disparity in receipt of pre-test GC (which is standard of care per national guidelines) among Blacks tested without GHP involvement. These findings are concerning given the need to offer guideline-adherent care to all patients receiving hereditary cancer testing.
Incidence of second primary neoplasms among cancer survivors in the United States, 2000 through 2015.
Authors: Adjei Boakye Eric , Jenkins Wiley D , Osazuwa-Peters Nosayaba , Wang Maggie , Lee Min Jee , Chen Betty , Agamah Edem S. , Sharma Arun
Published: May 2019

1586

Background: The number of cancer survivors in the United States is projected to exceed 20 million by 2024. Survivors are at risk of developing a second primary neoplasm (SPN) – a leading cause of survivor death. We described the risk of developing a SPN among survivors of common cancers (smoking-related vs non-smoking-related) in the United States. Methods: We identified patients aged ≥18 years who were diagnosed with a primary cancer from the 10 sites with highest survival rates and stratified as smoking-related (urinary bladder, kidney & renal pelvis, uterine cervix, oral cavity & pharynx, and colon & rectum) and non-smoking related (prostate, thyroid, breast, corpus & uterus, and non-Hodgkin lymphoma) from Surveillance, Epidemiology, and End Results (2000-2015). SPN was defined as the first subsequent primary cancer occurring ≥2 months after first cancer diagnosis. Excess SPN risk was quantified using standardized incidence ratios (SIRs) stratified by sex. Results: A cohort of 2,908,349 patients (50.1% female) was identified and 260,267 (9.0%) developed SPN (7.6% of females and 10.3% of males). All index cancer sites were associated with a significant increase in SPN risk for females and males (except prostate cancer). Index smoking-related cancers (SIR range 1.20 – 2.17 for females and 1.12 – 1.91 for males) had higher increased risk of SPN than non-smoking-related cancers (SIR range 1.08 – 1.39 for females and 0.55 – 1.38 for males) relative to the general population. Conclusions: Nearly 10% of cancer survivors developed an SPN, and those with smoking-related cancers had higher risk. Given the increasing number of cancer survivors and importance of SPN as a cause of cancer death, these findings can improve secondary prevention and surveillance guidelines. [Table: see text]
Phase I study of a brain penetrant mutant IDH1 inhibitor DS-1001b in patients with recurrent or progressive IDH1 mutant gliomas.
Authors: Natsume Atsushi , Wakabayashi Toshihiko , Miyakita Yasuji , Narita Yoshitaka , Mineharu Yohei , Arakawa Yoshiki , Yamasaki Fumiyuki , Sugiyama Kazuhiko , Hata Nobuhiro , Muragaki Yoshihiro , Nishikawa Ryo , Shinojima Naoki , Kumabe Toshihiro , Saito Ryuta , Ito Kazumi , Tachibana Masaya , Kakurai Yasuyuki , Nishijima Soichiro , Tsubouchi Hiroshi
Published: May 2019

2004

Background: WHO grade II/III gliomas frequently harbor isocitrate dehydrogenase 1 ( IDH1) mutations, resulting in intratumoral accumulation of oncometabolite 2-hydroxyglutarate (2-HG) and subsequent clonal expansion. DS-1001b is an oral selective inhibitor of mutant IDH1 R132X that was designed to penetrate the blood-brain barrier. Methods: In this first-in-human, multicenter, phase I study (NCT03030066), eligible patients (pts) with recurrent/progressive IDH1 mutant glioma received DS-1001b twice daily (bid), continuous. A modified continual reassessment method was used for dose escalation. RANO and RANO-LGG criteria were used to assess tumor response. Pts who planned to undergo salvage surgery after developing progressive disease (PD) and who provided informed consent received DS-1001b treatment until surgery. Tumor samples were also obtained from those pts to measure the free form of DS-1001b and 2-HG levels. Results: Between Jan 2017 and Oct 2018, DS-1001b (125-1400 mg bid) had administered for 45 pts (median age 44 yrs, prior radiation therapy 100%, prior chemotherapy 82%), and 17 pts were continuing treatment. Maximum tolerated dose (MTD) was not reached. Most AEs were Gr 1-2. Gr 3 AEs were observed in 42.2% of pts. No Gr 4 or 5 AEs or serious drug-related AEs were reported. One dose limiting toxicity was Gr 3 white blood cell count decreased (1000 mg bid). Common AEs ( > 20%) were skin hyperpigmentation, diarrhea, pruritus, nausea, rash, and headache. Of 29 evaluable pts with contrast enhancing gliomas, one, three and 10 achieved complete response, partial response and stable disease (SD), respectively. Of evaluable nine pts with contrast non-enhancing gliomas, two achieved minor response and seven achieved SD. Peak plasma concentration (Cmax) and area under the curve (AUC) increased dose-dependently. The brain/plasma ratio of free form of DS-1001b ranged 0.19‒0.77 in 3 pts. Conclusions: DS-1001b was well tolerated up to 1400 mg bid with favorable brain distribution, and MTD was not reached. Recurrent/progressive IDH1 mutant glioma pts responded to treatment. Investigation is ongoing to determine the recommended Phase II dose. Clinical trial information: NCT03030066.
Trabectedin for recurrent WHO grade II or III meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG).
Authors: Preusser Matthias , Silvani Antonio , Le Rhun Emilie , Soffietti Riccardo , Lombardi Giuseppe , Sepúlveda Juan M. , Brandal Petter , Beaney Ronald Philip , Bonneville-Levard Alice , Lorgis Veronique , Vauleon Elodie , Bromberg Jacqueline , Erridge Sara , Cameron Alison , Marosi Christine , Golfinopoulos Vassilis , Gorlia Thierry , Weller Michael , Wick Wolfgang
Published: May 2019

2007

Background: EORTC-1320-BTG investigated the activity, safety and quality of life of therapy with the tetrahydroisoquinoline alkaloid trabectedin (Yondelis) in patients with recurrent higher-grade meningiomas. Trabectedin was originally derived from the Caribbean sea squirt, Ecteinascidia turbinata, and currently is manufactured by total synthesis. Methods: Adult patients with histological diagnosis of WHO grade II or III meningioma and radiologically documented progression after maximal feasible surgery and radiotherapy were randomly assigned in a 2:1 ratio to receive intravenous trabectedin (1.5 mg/m2every three weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Results: Within 22.1 months, we randomized a total of 90 patients (n=29 in LOC arm, n=61 in trabectedin arm) in 35 institutions and nine countries. In the LOC arm, the following treatments were administered: hydroxyurea (n=11), bevacizumab (n=9), none (n=4), chemotherapy (n=3), somatostatin analogue (n=1), combined chemotherapy and somatostatin analogue (n=1). With 71 PFS events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00-2.03; p=0.204) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) in the LOC and 21.1% (95% CI, 11.3%-32.9%) in the trabectedin arm. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR for death, 0.98; 95% CI, 0.54-1.76; p=0.94).Grade 3 to 5 adverse events occurred in 44.4% (18.5% related, 4 serious adverse events, 0 lethal events) of the patients in the LOC and 59% (32.8% related, 57 serious adverse events and 2 toxic deaths) of patient in the trabectedin arm. Conclusions: In this first prospective randomized trial performed in recurrent grade II or III meningioma, trabectedin did not improve PFS and OS and was associated with significantly higher toxicity as compared to LOC treatment. The data collected in this study may serve as benchmark for future clinical trials in this setting. Clinical trial information: NCT02234050.
A randomized phase II trial of veliparib (V), radiotherapy (RT) and temozolomide (TMZ) in patients (pts) with unmethylated MGMT (uMGMT) glioblastoma (GBM).
Authors: Khasraw Mustafa , McDonald Kerrie Leanne , Rosenthal Mark , Lwin Zarnie , Ashley David M. , Wheeler Helen , Barnes Elizabeth , Foote Matthew C. , Koh Eng-Siew , Sulman Erik P. , Back Michael , Buckland Michael , Sim Hao-Wen , Fisher Lauren , Leonard Robyn , Hall Merryn , Yip Sonia , Simes John
Published: May 2019

2011

Background: TMZ offers minimal benefit in uMGMT GBM pts. V is synergistic with both RT and TMZ in preclinical models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. This study examined a novel approach to patients with uMGMT GBM. Methods: VERTU is a randomized Phase 2 trial comparing Arm A (Standard of care) = RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2D 1–5) every 28 days for 6 cycles vs Arm B (experimental arm) = RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2D 1–5) + V (40mg bid, D 1–7) every 28 days for 6 cycles in pts with newly diagnosed centrally determined uMGMT GBM. The study aims to randomize 120 pts (2:1 to the experimental arm). The primary endpoint was 6 months progression free survival (6mPFS) with multiple secondary and tertiary endpoints. Evaluation of feasibility and safety was planned after completion of RT in the first 60 pts (Stage 1). (ANZCTR #ACTRN12615000407594). Tumor tissue and serial bloods were collected for translational research. Results: 125 pts were randomized (41 Arm A, 84 Arm B). Mean (range) age 58 (22–78) years, 70% male, 61% ECOG 0, 86% macroscopic resection, 14% biopsy. At the time of analysis (cut-off date: 04/Feb/2019), median follow up was 16.5 months, 76 pts had died. 6mPFS (95% CI, Kaplan-Meier estimate) was 37% (22–52) in Arm A and 53% (41–63) in Arm B, and median PFS was 4.4m (95% CI 4.0–6.0) for Arm A and 6.2m (95% CI 4.9–7.1) for Arm B (HR = 0.81, 95%CI 0.54–1.21). 50% of pts in Arm A and 53% in Arm B experienced ≥ G3 adverse events (AEs). The most common G 3/4 AEs were decreased platelets, seizures, hyperglycemia and diarrhea (each 5%) in Arm A and decreased platelets (13%) and seizures (11%) in Arm B. Conclusions: In this multicenter, randomized study, the experimental therapy was feasible and well tolerated. The observed 6mPFS appeared longer in Arm B, but at the time of submitting the abstract, this result did not meet the prespecified primary endpoint. More mature results will be presented at the annual meeting. QoL in VERTU is reported separately. Central MR review, biomarker analyses, including DNA repair and methylation signature analyses are ongoing. Clinical trial information: ACTRN12615000407594.
Glioblastoma evolution pattern under surgery and radio(chemo)therapy (RCHT) to identify novel methylome based glioma subtypes.
Authors: Knoll Maximilian , Debus Juergen , Furkel Jennifer , Warta Rolf , Bougatf Nina , Rapp Carmen , Brors Benedikt , Wick Wolfgang , Unterberg Andreas , Herold-Mende Christel , Abdollahi Amir
Published: May 2019

2012

Background: Identification of isocitrate dehydrogenase mutations (IDHm) and glioma CpG island methylator phenotype (G-CIMP) as well as methylation of O6-methylguanine DNA methyltransferase (MGMT) promotor has substantially improved stratification of glioma patients into prognostic subgroups. In extension of static pre-therapy diagnostic, we sought to investigate the impact of glioblastoma evolution under selection pressure of standard therapy on methylome level. Methods: For the training cohort (T), methylome (450k Illumina) data of paired samples from 50 patients with glioblastoma (GBM, 11 G-CIMP+) were analyzed, i.e., primary (P) and at the time point of recurrence (R, re-surgery) after standard therapy at NCT. For 39 pairs matching RNASeq data was analyzed. Validation cohorts consisted of Heidelberg (V1) total n = 650, GBM (n:585, 8 G-CIMP+), grade III (n:65, CIMP+ 65), Austrian GBM (V2, n = 499, 36 IDHm, pyrosequencing data) and the TCGA (V3) Lower-grade-glioma cohort (LGG, n = 477, grade III n: 247, 178 G-CIMP+, grade II n: 228, 206 G-CIMP+). Results: Limited number of consensus differentially methylated probes (DMP) were found across all P vs. R samples (nCpG = 411 CpGs, FDR < 0.05). In contrast, heterogeneity in GBM evolution was found by similarity analysis of delta-methylome data of 50 PR pairs resulting in two distinct clinical subgroups and one “intermediate” group. Intriguingly, n = 114.652 DMP (FDR < 0.05) was found by comparing the evolutionary “poor” (n = 15) vs. “good” (n = 13) GBM phenotypes. A random forest classifier was built to identify the evolutionary subgroups in P samples. The performance of “good” prognosis classifier was in T cohort HR: 0.54 [0.30-0.97], p = 0.04; V1: 0.57 [0.43-0.76], p < 0.001, V2: 0.62 [0.47-0.82], p < 0.001, LGG: 0.16 [0.08-0.32], p < 0.001. In “good” prognosis group (T), neither G-CIMP+ (n = 3) nor MGMT-STP27 (oddsratio, OR: 0.56, p = 0.47) was enriched. MGMT-STP27 OR was 0.47 (V1, p = 0.47) or 1.28 (V2, p = 0.45), respectively. The evolutionary subgroups remain prognostic independent of GCIMP status in LGG (V3). “Poor” glioma are enriched for RTKI/II methylome subtypes, and contain less frequently the mesenchymal subtype. Bevacizumab treatment showed a survival benefits only in “poor” subtype (V1+2). Conclusions: Discovery of a methylome based classifier of glioma evolution informs on “good” and “poor” prognosis subtypes and may have ramification for stratifying patients for therapy such as e.g., antiangiogenesis.
Quantitative radiographic analysis of phase II and III trials in recurrent glioblastoma treated with VB-111 with or without bevacizumab or bevacizumab monotherapy.
Authors: Ellingson Benjamin M. , Raymond Catalina , Yao Jingwen , Chakhoyan Ararat , Turley Dallas , Tsung Joseph , Goldman Jodi , Schlossman Jacob , Tan Caleb , Brenner Andrew Jacob , Butowski Nicholas A. , Wen Patrick Y. , Rachmilewitz Minei Tamar , Cohen Yael Chava , Harats Dror , Cloughesy Timothy Francis
Published: May 2019

2018

Background: VB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab (BV) or BV monotherapy. Methods: MRI data from a phase 2 (NCT01260506) and randomized, double arm, controlled phase 3 (GLOBE; NCT02511405) trial of VB-111 in recurrent GBM were used in current study: Arm A) VB-111 monotherapy until progression followed by combination VB-111 and bevacizumab (BV) (“Primed Combination”; Phase 2; N = 24); Arm B) VB-111 in combination with BV (“Unprimed Combination”; Phase 3; N = 124) and Arm C) BV monotherapy (“Control”; Phase 3; N = 120). Contrast enhanced T1-weighted digital subtraction was used to quantify tumor volume at all time points. Results: Baseline tumor volume was not significantly different between patient cohorts (Kruskal-Wallis; P = 0.1482; median~20mL). Continuous measures of baseline tumor volume were prognostic for OS in all treatment groups when controlling for therapy and age (Cox, P < 0.001, HR = 1.02). In patients with small tumors ( < 25mL), the “primed combination” cohort (Arm A) from the phase 2 trial had a significant OS advantage compared to both upfront combination of VB-111 and BV (Arm B; P = 0.0094, HR = 0.5328; median OS = 7mo vs. 15mo) as well as BV alone (Arm C; P = 0.0248, HR = 0.5776; median OS = 8.5mo vs. 15mo). Patients with a radiographic response ( > 65% reduction) had a significant survival difference from non-responders when controlling for age, baseline tumor volume, and treatment arm ( P = 0.0014, HR = 0.5822). Notably, in responders to VB-111 monotherapy or combination therapy after priming with VB-111 exhibited characteristic, expansive areas of necrosis in areas of initial disease. Conclusions: Small recurrent tumors have a significant OS advantage when “priming” with VB-111 monotherapy prior to combination VB-111 and BV at recurrence. Patients responding to VB-111 exhibit specific imaging characteristics related to the drug mechanism of action. Clinical trial information: NCT02511405; NCT01260506.
First-in-human phase I trial of the combination of two adenoviral vectors expressing HSV1-TK and FLT3L for the treatment of newly diagnosed resectable malignant glioma: Initial results from the therapeutic reprogramming of the brain immune system.
Authors: Lowenstein Pedro R. , Orringer Daniel A , Sagher Oren , Heth Jason , Hervey-Jumper Shawn L. , Mammoser Aaron Gerald , Junck Larry , Leung Denise , Umemura Yoshie , Lawrence Theodore Steven , Kim Michelle Miran , Wahl Daniel Richard , McKeever Paul , Camelo-Piragua Sandra Ines , Lieberman Andrew , Venneti Sriram , Comba Andrea , Altshuler David , Muraszko Karin , Castro Maria
Published: May 2019

2019

Background: This is the initial report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. The absence of functional dendritic cells from the brain precludes anti-brain tumor immune responses. We combined tumor cytotoxicity (Ad-HSV1TK) with recruitment of dendritic cells to the brain (Ad-Flt3L) to induce an effective anti-tumor immune response. This strategy induced an efficacious, cytotoxic CD8 and CD4 T-dependent immune response in many animal models of glioma. This immune response also generated anti-tumor memory, and the capacity for neoantigen recognition. Methods: The trial was approved by FDA and all institutional cttees. Treatment was administered intraoperatively following complete glioma resection in newly diagnosed tumors. The trial consisted of vector dose escalation, starting at 1x10^9 i.u., and increasing to 1x10^11 i.u. of each vector. Dose escalation proceeded by increasing the vector dose through a total of 6 combinations administered to 6 cohorts of 3 patients each. Two cycles of 14 days each of valacyclovir were administered to activate HSV1-TK cytotoxicity. Cycle 1 starts on Day 1-3 post surgery for 14 days, and Cycle 2 on Week 8-12. Standard radiation, i.e., 60 Gy in 2 Gy fractions over 6 weeks, with concurrent temozolomide, was followed by cyclic temozolomide. Results: Examination of tumor samples at primary resection and first recurrence show an increase in the infiltration of inflammatory cells. The experimental treatment was well tolerated. At this time the MTD has not been reached. There were approx. 248 AEs, and 26 SAEs; these have not been linked to treatment. At this time the MTD has not been reached. A secondary outcome is overall survival. Preliminary analysis of partial data may suggest that the combined viral vector therapy may provide a clinically significant survival. Conclusions: Our results show for the first time that reprogramming of the host’s brain immune system to recognize gliomas reveals a new approach for the treatment of highly malignant brain tumors. Clinical trial information: NCT01811992.