bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival outcomes of screening with breast MRI in high-risk women.
Authors: Bae Min Sun , Sung Janice S. , Han Wonshik , Bernard-Davila Blanca , Bara Filipe R. , Sutton Elizabeth J. , Comstock Christopher , Jochelson Maxine S. , Morris Elizabeth Ann
Published: September 2018

1508

Background: Mammography is the only imaging modality proven to reduce mortality from breast cancer. Over the past decade, magnetic resonance imaging (MRI) screening of women with increased risk of breast cancer ( > 20% cumulative life time risk) has been recommended. However, there is little evidence that supplemental screening with MRI improves survival. The purpose of this study was to compare survival outcomes of combined screening with MRI and mammography to screening mammography alone in women at increased risk for breast cancer. Methods: A total of 3,002 women at increased risk underwent at least two screening rounds between 2001 and 2005, with at least 5 years of follow-up. 1,534 women had combined screening (MRI and mammography), and 1,468 had screening mammography alone. Cancer detection yield and survival were determined in the two groups. Results: 60 women were diagnosed with breast cancer, 38 patients in the combined screening group and 22 in the mammography-only group. Cancer yield was 24.8 per 1000 (95% CI, 17.6-33.8) combined screening and 15.0 per 1000 (95% CI, 9.4-22.6) mammography-only. No interval cancers occurred in women undergoing combined screening, while 9 interval cancers were found in women undergoing only mammography screening. During a median follow-up of 10.8 years (range, 0.7-15.2), a total of 11 recurrences and 5 deaths (4 breast cancer cause and 1 unknown cause) were found. Of the 11 recurrences, 6 were in the combined screening group and 5 were in the mammography-only group. All deaths were in the mammography-only group. The Kaplan-Meier estimate for disease-free survival showed no statistically significant difference between the two groups ( P = .325). However, patients in the combined screening group had a significantly better overall survival compared with patients in the mammography-only group ( P = .002). Conclusions: Combined screening with MRI and mammography in women with increased risk of breast cancer resulted in not only a higher cancer detection yield but also better overall survival.
Knowledge and understanding of genetic test results in men undergoing multigene testing for inherited prostate cancer.
Authors: Giri Veda N. , Hegarty Sarah , Obeid Elias , Hyatt Colette , Fang Carolyn Y , Leader Amy
Published: September 2018

1516

Background: Genetic counseling (GC) for prostate cancer (PCA) risk is an emerging field, with limited insights regarding needs of males considering genetic testing (GT). Genetic Evaluation of Men is a prospective multigene testing study to identify inherited mutations linked to PCA, with testing following GC. We surveyed men pre-GT and post-GT on knowledge of cancer risk and genetics (KCRG) and understanding of personal GT results to identify GC needs. Methods: Eligibility for males affected or high-risk for PCA encompass age, race, family history (FH), and PCA stage/grade. Demographic, clinical, and FH data were obtained from participants and medical records. Pre-GT survey included questions on KCRG (15 items) and health literacy/numeracy (6 items). Post-GT survey additionally included understanding of GT results (9 items). Personal and FH were categorized into three hereditary cancer syndromes (HCS) linked to PCA. Factors associated with baseline KCRG were assessed by univariable models followed by multivariable linear regression. McNemar’s test was used to assess concordance of understanding GT results vs. actual results. Results: Among 109 men (mean age 63 years, 81% White, 59% PCA diagnosis) who completed pre- and post-surveys, factors associated with higher pre-test KCRG included meeting HCS criteria (p = 0.006) and higher numeracy (p = 0.025). On multivariable analysis, HCS remained significantly predictive of higher KCRG (p = 0.040). However, of 101 men who responded definitively regarding understanding of personal GT results, 13 responded incorrectly on mutation status indicating significant disagreement with actual results (McNemar’s p < 0.001). Of these 13 men, 12 had > = 1 variant of uncertain significance (VUS). Additionally, 6 men were unsure whether they carried a mutation when their GT results found VUS but no mutations. Conclusions: This is the first report of knowledge and understanding of genetics and cancer risk in the context of multigene testing for PCA. While personal/FH of HCS was associated with higher KCRG, understanding of personal GT results was lacking, and warrants tailored GC strategies for multigene testing for inherited PCA.
The Angiosarcoma Project: Generating the genomic landscape of a rare cancer through a direct-to-patient initiative.
Authors: Painter Corrie , Dunphy Michael , Anastasio Elana , McGillicuddy Mary , Anderka Kristin , Larkin Katie , Lennon Niall , Chen Yen-Lin , Lander Eric , Golub Todd , Wagle Nikhil
Published: September 2018

1519

Background: Angiosarcoma (AS) is a rare soft tissue sarcoma, with an incidence of 300/yr and a 5-year DSS of 30%. The low incidence has impeded large-scale research efforts that may lead to improved clinical outcomes. To address this, we launched a nationwide study, which seeks to empower patients (pts) to accelerate research by sharing their samples and clinical information remotely. Methods: With pts and advocacy groups we developed a website to allow AS pts to participate across the US. Pts are mailed a saliva and blood draw kit for germline and cell free (cf) DNA analysis. We then obtain medical records and stored tumor samples. Whole exome sequencing will be performed on tumor, cfDNA and saliva samples. Transcriptome analysis will be performed on tumor samples. A clinically annotated genomic database will be generated and shared widely to identify genomic drivers and mechanisms of response and resistance to therapies. Study updates will be shared with pts regularly. Results: We conducted a 3-week pilot study to test the feasibility of enrolling geographically dispersed AS pts through a direct-to-patient (DTP) approach. Through social media, we identified 100+ pts willing to participate, 90 within the first day of outreach. We enrolled 15 pts from 10 states to test our ability to remotely obtain pt reported data, online consent, and samples. The average age of pts is 48, ranging 23-71 yrs. Primary locations of AS are breast 6 pts (40%), cardiac 4 pts (27%), scalp 2 pts (13%), liver 1 pt (6%), bladder 1 pt (6%), forehead 1 pt (6%). 9 pts (60%) reported being disease free, 4 pts (27%) reported having AS spread to lung, lymph, bone, and hip. Requests for medical records and tissue samples are underway, and initial saliva samples have been received. We are now opening this study to all AS pts in the USA. Conclusions: A DTP approach enabled rapid identification of an initial cohort of AS pts willing to share tumors, saliva, blood and medical records. We were able to obtain detailed clinical experiences and samples to perform genomic analysis. This study serves as proof of principle that DTP genomics efforts can democratize cancer research for exceedingly rare cancers, which to date have been disproportionately understudied.
Baseline screening and psychosocial results from the UK SIGNIFY study: A whole-body MRI screening study in TP53 mutation carriers and matched controls.
Authors: Eeles Ros A. , Bancroft Elizabeth , Saya Sibel , Killick Emma , Whitehouse Richard W , Koh Dow-Mu , Sohaib Syed A , Walker Leslie ,   The SIGNIFY Study Steering Committee
Published: September 2018

1520

Background: In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. Some centres employ family specific screening with most centres having an “open-door” policy. Recent evidence suggests there may be a survival benefit with more intensive screening, including whole-body MRI. There are no published data on the psychological impact of such screening programmes. Methods: This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers aged over 18 years. Clinical and psychological endpoints were assessed. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. A series of questionnaires is used to assess the psychological impact of screening. Results: 44 TP53 mutation carriers and 44 population controls were recruited. In TP53 mutation carriers, six of 44 (13.6%, 95% CI: 5.2%-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1%, 95% CI: 20.5%-49.9%) and 7 controls (15.9%, 95% CI: 6.6%-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). To date, there is no evidence of clinically significant adverse psychosocial effects. Conclusions: The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. Clinical trial information: NCT01737255.
Prevalence of incidental germline pathogenic (PV) and likely pathogenic (LPV) variants in hereditary cancer-related genes identified in matched tumor/normal sequencing of advanced solid tumors.
Authors: Ileana Dumbrava Ecaterina Elena , Brusco Lauren , Daniels Molly S , Wathoo Chetna , Shaw Kenna Rael , Lu Karen H. , Zheng Xiaofeng , Strong Louise C. , Litton Jennifer Keating , Arun Banu , Eterovic Agda Karina , Routbort Mark , Piha-Paul Sarina Anne , Subbiah Vivek , Hong David S. , Kopetz Scott , Mendelsohn John , Mills Gordon B. , Chen Ken , Meric-Bernstam Funda
Published: September 2018

1524

Background: Next-generation sequencing (NGS) for tumor molecular profiling can reveal germline incidental mutations in hereditary cancer-related genes. The American College of Medical Genetics and Genomics (ACMG) has recommended that laboratories performing clinical sequencing seek and report PV and LPV in 56 genes. We assessed the prevalence of incidental germline LPV and PV in other cancer-related genes among patients undergoing hybrid capture sequencing of 201 cancer-related genes. Methods: Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in 1000 patients (pts) with advanced or metastatic solid tumors enrolled in a molecular testing protocol (NCT01772771) in a research laboratory. We previously reported germline alterations in the putative most actionable genes as designated by ACMG (PMID: 26787237). We assessed the germline LPV and PV in 54 additional cancer-related genes. Results: Among the 1000 patients who underwent tumor and normal DNA sequencing, 37 patients (3.7%) were found to have a germline PV or LPV in the following genes: ATM (4); BAP1 (1); CDH1 (1); CDKN2A (1); CHEK1 (2); CHEK2 (10); EGFR (1); ERCC3 (4); ERCC5 (1); HNF1B (1); HRAS (1); MLL3 (1); NF1 (3); PKHD1 (4); PTCH1 (1) and SMARCA4 (1). Eight pts (22%) had previous genetic counseling and testing for various reasons, but only 3 pts (8%) had previously identified alterations (all with NF1 mutations). After discussion in our return of germline results board, it was decided to return the findings in established hereditary cancer predisposition genes with high penetrance: BAP1 (p.Y401X), CDH1 (p.C688X), CDKN2A (p.G101W), EGFR (p.T790M) and SMARCA4 (p.S332FfsX55) after validation in a CLIA laboratory. Conclusions: Return of the previously unrecognized germline LPV or PV in patients with advanced or metastatic cancers who undergo somatic profiling is of great interest. The exact genes for which the germline results should be returned is controversial. Broader genomic testing is likely to identify additional incidental germline alterations with potential clinical utility to patients and their relatives.
NGS-based multi-gene panel analysis in BRCA1/2-negative breast and ovarian cancer families.
Authors: Pohl Esther , Hauke Jan , Horvath Judit , Dworniczak Bernd , Gehrig Andrea , Niederacher Dieter , Arnold Norbert , Sutter Christian , Smogavec Mateja , Just Walter , Weber Bernhard H.F. , Hentschel Julia , Faust Ulrike , Hackmann Karl , Schmidt Gunnar , Gross Eva , Ramser Juliane , Rhiem Kerstin , Hahnen Eric , Schmutzler Rita K.
Published: September 2018

1526

Background: 24% of familial breast cancer (BC) and/or ovarian cancer (OC) cases analyzed within the framework of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) are due to pathogenic mutations in the BRCA1 or BRCA2 genes. The population-specific mutation prevalence of non- BRCA1/2 genes associated with familial BC and/or OC is largely unknown and was determined in a large German cohort. Methods: Here, we present next-generation sequencing (NGS) data established from TruRisk (GC-HBOC-designed) or TruSight cancer gene panels. A cohort of 6,507 BRCA1/2-negative index cases fulfilling the inclusion criteria of the GC-HBOC for germline testing was analyzed. Illumina sequencing platforms were used and data analysis was carried out at each individual center using different analysis pipelines. Analysis of copy number variations (CNV) was not included in the present data evaluation. Results: By focusing on 8 confirmed BC/OC risk genes ( ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, TP53), the 6,507 cancer patients revealed 165 different deleterious variants in 378 unrelated mutation carriers (5.8%). We found a high prevalence of CHEK2 (n = 150, 2.3%), ATM (n = 89, 1.4% ), and PALB2 (n = 72, 1.1%) mutations while RAD51C (n = 21, 0.3%), TP53 (n = 16, 0.2%), NBN (n = 15, 0.2%), CDH1 (n = 10, 0.2%), and RAD51D (n = 5, 0.1%) were less frequently mutated. Conclusions: The high frequency of pathologic mutations in the genes ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53, together accounting for almost 6% of familial BC/OC risk, highlights the importance of these genes to be included in BC/OC routine diagnostics. The relevance of these mutations in a clinical setting for early detection of breast and ovarian cancer needs to be established.
Clinical implementation of whole genome multi-omics analyses for patients with refractory cancers.
Authors: Radovich Milan , Kiel Patrick , Ratcliff Katie , Geiser Andrew , Jones Shannon , Hunter Cynthia , Finder Rebecca , Moller Teresa , Spradlin Allison , Koselke Elizabeth , Jones Thomas , Ibrahim Sulfikar , Schneider Bryan Paul
Published: September 2018

1531

Background: Relative lack of prior success of genomic technology has been a function of suboptimal target detection and poor timely implementation. We set out to improve patient access to targeted therapy through use of whole genome sequencing (WGS) to optimize targets and operational implementation to identify clinical trials and secure off-label drugs. Methods: We performed a retrospective analysis of our first 100 patients (Feb-Nov 2016) with metastatic disease whose tumors and matched blood were analyzed using whole genome (WGS) and transcriptome sequencing, as well as targeted proteomic analysis in a CLIA setting (NantOmics). Most common tumor types were Colorectal (20%), Breast (15%), and Ovarian (10%). Patients were seen in dedicated precision genomics clinics with results reviewed by a multi-disciplinary molecular tumor board. A dedicated service line with staff to match patients to clinical trials, medication acquisition, and genetic counseling for germline findings was provided. Results: 85% of patients had a finding either on WGS or proteomic analysis that pointed to an FDA approved drug or clinical trial. Common findings included: mutations in the PI3K pathway (15%), BRCA1&2/ATM (15%), and cell cycle genes (11%). Other markers of note include: HER2, TMB/MSI for immune checkpoint therapy, IDH1/2, and MET. WGS also enabled identification of rare actionable findings, particularly translocations, and viral integration for trials requiring HPV-positivity. Cancer predisposition germline findings were observed in 3 patients. Of the 85 patients with actionable findings, 22 went on to be treated with a genomically-directed agent, 13 did not follow recommendations or were sent to hospice, 4 were lost to follow-up, and 46 still remain on their therapy prescribed prior to sequencing. Conclusions: A higher proportion of patients in our program went on to be treated with a genomically-directed agent than previously reported in the literature secondary to comprehensive whole genome multi-omics profiling and a clinical service line dedicated to medication acquisition and matching to clinical trials.
Underutilization of multigene panels among Ashkenazi Jewish patients.
Authors: Fields Jessica , Nasioudis Dimitrios , Zhou Zhen Ni , Carlson Ann , Frey Melissa Kristen , Holcomb Kevin , Chapman-Davis Eloise
Published: September 2018

1533

Background: Approximately one in forty Ashkenazi Jewish (AJ) individuals carry a BRCA1/2 mutation and genetic screening in this population has largely focused on these two genes. With the recent rapid uptake of multigene panel testing for cancer genetic assessment, we sought to explore multigene panels in our cohort which is comprised of AJ and non-AJ patients. Methods: The results of all patients with known ancestry who underwent genetic testing and counseling at the hereditary breast and ovarian cancer center at a single institution between 7/1/2013-12/31/2016 were reviewed. Results: One thousand six hundred and fifty patients with known ancestry underwent genetic testing over the study period, including 681 AJ patients. The median age was 49 (range 20-86). AJ patients were more likely to undergo targeted testing than non-AJ patients (74% vs. 61 %, P<0.001). The use of multigene panels in AJ patients increased over time (2013 – 3.2%, 2014 – 18.7%, 2015 – 27.4%, 2016 – 48.4%, P<0.001). Mutations were more common in AJ patients (75, 11% vs. 66, 7%, P=0.003). Variants of uncertain significance (VUS) were less common in AJ patients (40, 6% vs. 124, 13%, P<0.001), even when excluding patients with single gene testing (32, 19% vs. 98, 27%, P=0.05). Among all patients, mutations in BRCA1/2 were most common (75%). The majority (69%) of non- BRCA1/2 mutations were identified on multigene panels. Rates of mutations in non- BRCA1/2 genes were the same among AJ and non-AJ patients (16, 21% vs. 20, 30%, P=0.3, Table 1). Conclusions: AJ patients have equivalent rates of non- BRCA1/2 mutations and on multigene panels have lower rates of VUS compared to non-AJ patients. However, the majority of AJ patients underwent targeted gene testing. These findings suggest consideration of a change in paradigm for genetic assessment of AJ patients with a focus on BRCA and non- BRCAassociated cancer genes through multigene panel testing. [Table: see text]
Genetic, clinical and pathological characteristics of BRCA-associated breast cancer (BC) in Hispanic patients in the United States (US) and Latin America (LatAm).
Authors: Chavarri Guerra Yanin , Sand Sharon , Cruz Correa Marcia , Ganschow Pamela , Cohen Nancy , Kass Frederic C. , Komenaka Ian K. , Hendricks Carolyn B. , Hake Christopher , Kanowitz Jane , Campbell Fontaine Annette , Unzeitig Gary Walter , Feldman Nancy Renee , Kerlin Deborah , Daneri-Navarro Adrian , Castillo Danielle , Herzog Josef , Guerrero-Llamas Nancy , Weitzel Jeffrey N.
Published: September 2018

1539

Background: Hispanic women with BC present at a younger age, have a higher frequency of BRCA mutations and show a worse incidence-to-mortality ratio than non-Hispanic women. Information regarding the characteristics of BRCA-associated BC in Hispanics is limited. Here, we assess differences in BRCA-associated BC between Hispanic patients in the US and in LatAm. Methods: Hispanic patients from the US and LatAm (Mexico, Colombia, Peru, and Puerto Rico) with a history of BRCA-associated BC enrolled in the Clinical Cancer Genomics Community Research Network registry were included. We compared the genetic, demographic, clinical and pathologic characteristics between Hispanics from the US and LatAm using Fisher’s exact test and x2statistics. Results: Between 1997 and 2016, 3670 Hispanic patients with a history of BC from LatAm (n = 1341) and the US (n = 2329) were identified, of which 490 (13.3%) had a deleterious BRCA mutation. The frequency of BRCA mutations was similar in Hispanics from LatAm (13.8%, n = 185) and the US (13.1%, n = 305). No significant differences were found in the frequency of BRCA1 vs BRCA2 mutations between patients from LatAm (BRCA1 68%, BRCA2 31.8%) and the US (BRCA1 61.3%, BRCA2 39%) (p = .12). The most frequent mutations found in BRCA1 were: ex 9-12del (LatAm n = 24, US n = 15), 185delAG (LatAm n = 13, US n = 18) and 943ins10 (LatAm n = 3, US n = 8), and in BRCA2 3492insT (LatAm n = 3, US n = 28). Mean age at BC diagnosis was 39.1 (SD 9.5) in LatAm and 41.7 (SD 10.6) in the US (p = 0.01). US patients were significantly more likely to present with Stage 0-II BC than those from LatAm (77.1% vs. 47.6%, p < .001). We found no differences in the proportion of hormone receptor positive tumors between patients from LatAm (45%) and the US (47%) (p = .78). Conclusions: The frequency of BRCA-associated BC was similar between Hispanics in LatAm and the US. Women from LatAm with BRCA mutations present at a younger age, as seen for sporadic BC; the causes for this finding warrant further research. Women with BRCA-associated BC in LatAm are more likely to have advanced BC at presentation, which may be a reflection of disparities and barriers in access to care.
The association between proton pump inhibitors (PPI) use for gastro-esophageal reflux disease (GERD) and lung cancer (LC): A nested case-control study.
Authors: Dresler Hadas , Keizman Daniel , Mamtani Ronac , Gottfried Maya , Maimon Natalie , Mishaeli Moshe , Haynes Kevin , Yang Yu-Xiao , Boursi Ben
Published: September 2018

1562

Background: Data suggests that GERD with recurrent reflux and microaspiration of stomach contents, may be associated with lung injury, inflammation, activation of proliferative signals, and eventually DNA damage and malignant transformation. Recently, a large population based cohort study found that GERD may increase the risk of lung cancer in Asians. In the present nested case control study, we aimed to evaluate the association between PPI use as a surrogate for GERD and lung cancer in a large western population. Methods: We conducted a matched case-control study within a population-representative database from the United Kingdom. Study cases were defined as individuals with any diagnostic code of lung cancer. For every case, four eligible controls were matched on age, gender, practice site, time and duration of follow-up. Exposure of interest was PPI use prior to cancer diagnosis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer were estimated using conditional logistic regression. Adjustment was performed for smoking. Results: The study population included 19143 lung cancer cases and 74473 matched controls. PPI use was associated with a significantly increased lung cancer risk (adjusted OR 1.70, 95%CI 1.64-1.77, p < 0.001). In a sensitivity analyses we observed similar associations when PPI use was initiated more than one year prior to cancer diagnosis (adjusted OR 1.18, 95%CI 1.13-1.23, p < 0.001) and more than two years prior to cancer diagnosis (adjusted OR 1.15, 95%CI 1.10-1.20, p < 0.001) Conclusions: ChronicPPI use, as a surrogate for symptomatic GERD, may be associated with a higher lung cancer risk.
PD-L1 expression in patients with metastatic gastric cancer in South Korea.
Authors: Kim Hyo Song , Wu Ting , Kim Hyunki , Chung Hyun Cheol , Ajani Jaffer A. , Ku Geoffrey Yuyat , Kelsen David Paul , Zhu Xingshu , Savage Mary J. , Koshiji Minori , Rha Sun Young
Published: September 2018

1571

Background: Data are limited and conflicting regarding programmed death ligand 1 (PD-L1) expression as prognostic of clinical outcomes in patients (pts) with metastatic gastric cancer (mGC) treated with standard of care (SOC). Factors affecting the association between PD-L1 expression and outcomes include type of assay and antibody, scoring system for PD-L1 expression, and method of tissue collection. We analyzed the association between tumor PD-L1 expression and clinical parameters in Korean pts with inoperable mGC. Methods: A retrospective study was performed in 201 pts with inoperable mGC from Yonsei Cancer Center in Seoul, South Korea. Biopsy samples were collected at diagnosis. Tumor PD-L1 expression was measured by IHC using the 22C3 PD-L1 antibody pharmDx kit (Dako North America, Carpinteria, CA, USA). PD-L1 positivity was defined as a combined positive score (CPS) of ≥1%, where CPS is PD-L1+ cells (tumor cells, macrophages, lymphocytes) over the total number of tumor cells, expressed as a percentage. Survival was analyzed using Kaplan-Meier methods, log-rank test, and Cox proportional hazards models, adjusting for age, sex, and ECOG performance status. Results: A total of 189/201 (94%) pts received chemotherapy as SOC and were included in this analysis. Median age was 56 years (range, 21-82), 37% of pts were women, and 28% had a BMI ≥24. All pts had stage IV metastatic disease and 27%, 49%, and 24% had well to moderately differentiated, poorly differentiated, and signet ring cell tumors, respectively. Prevalence of PD-L1 positivity was 72.5%. PD-L1 positivity was not associated with age, BMI, or histologic grade. Median overall survival (OS) for the PD-L1+ and PD-L1– groups was 10.9 and 10.2 months, respectively ( P= 0.92). The hazard ratio for the PD-L1+ vs the PD-L1–group was 1.02 (95% CI, 0.74-1.39) before adjusting for age, sex, and ECOG performance status and 1.08 (95% CI, 0.77-1.51) after adjusting. Conclusions: Based on this preliminary assay and cutoff, results suggest that PD-L1 expression is not a prognostic factor for mGC. Additional biomarker analyses (eg, immune gene expression profile and microsatellite instability) are planned.
Major stressful life events and risk of developing lung cancer.
Authors: Jafri Syed Hasan Raza , Ali Faisal , Mollaeian Arash , Hasan Syed Mojiz , Hussain Rahat , Akkanti Bindu H , Williams Jessica T , Advani Shailesh M , El-Osta Hazem Edmond
Published: September 2018

1575

Background: Lung cancer is the leading cause of cancer-related mortality linked with smoking, though only 6-18% of heavy smokers die of lung cancer. We hypothesized that major stressful life events are a risk factor for developing lung cancer. Methods: In our matched case-control study, cases (CA) were lung cancer patients diagnosed within past 12 months. Controls (CO) were patients without a prior history of malignancy. CA and CO were matched for age, gender and smoking status. Smokers had at least 10 packs/years history of smoking. Data was collected using standardized research questionnaire on 11 major stressful life events using Holmes and Rahe stress scale. The primary endpoint was odds of having a major stressful life event. A sample of 360 patients (120 CA and 240 CO), was needed to achieve 80% power to detect an odds ratio (OR) of 2.00 using Chi-Square test with a P = 0.05 significance. The study was IRB approved at each institution. Results: Between May 2015 and December 2016, 324 patients were enrolled (23 were excluded due to prior cancer history or incomplete information). 301 (CA = 102; CO = 199) were included in the final analysis. The two groups were well matched in median age (CA = 64.4 years; CO = 63.9years), gender (CA-Male = 48%; CO-Male = 49.2%) and smoking status (ever smoker, CA = 86%; CO = 85%). There was no difference in lifetime stressful life event between CA and CO (95% vs 93.9% P = 0.68%). However, CA were significantly more likely to have had a major stressful life event within the past 5 years than controls (CA = 77.4% vs CO = 65.8%, P = 0.03, (OR = 1.78). Serious life-threatening illness of an immediate family member (P = 0.04) and retirement (P = 0.07) within the past 5 years were noticeably more common among CA. Holmes-Rahe stress score in the last 5 years was higher in men (86.3 vs 63.3, P = 0.07) and those > 65 years old (82.4 vs 57.2,P = 0.04) as compared with CO and in those with squamous histology than with adenocarcinoma (115.6 vs 63.4, P = 0.005). Conclusions: Patients with lung cancer (CA) were significantly more likely to have had a major stressful life event within the past 5 years than the matched controls (CO), especially in older men with squamous histology. Major stressful life events should be considered a risk factor for developing lung cancer.
Determining the clinical value of germline genetic testing coupled with tumor mutation profiling.
Authors: Esplin Edward , Yang Shan , Michalski Scott T. , Ouyang Karen , Fulbright Jennifer , Hamlington Barbara , Erhard Karl , Kang Hio Chung , Tejada Carli , Jacobs Michelle , Lincoln Stephen E , Nussbaum Robert L. , Blanco Amie
Published: September 2018

1577

Background: Somatic mutation analysis by next-generation sequencing (NGS) is an expanding clinical assessment offered to cancer patients. Studies report that 4–12% of patients have a positive tumor mutation profiling (TMP) result in a known cancer predisposition gene also identified in their germline, which has potential implications for the patient’s acute treatment, ongoing surveillance, and the screening of family members. We report a series of patients with TMP coupled with germline genetic testing and include yield of pathogenic germline mutations, discordance between germline and TMP findings, and potential clinical impact. Methods: Our study used de-identified data from 182 consecutive patients who underwent TMP followed by germline testing with an NGS-based hereditary cancer gene panel. Results: 50/182 cases (27%) had one or more likely pathogenic or pathogenic (LP/P) germline variants, which is higher than previous reports. Among these 50, 28 (56%) met guidelines for germline testing by personal or family history criteria, 10 (20%) met recently established NCCN criteria for germline testing of patients with BRCA1/2 tumor variants, and 12 (24%) had TMP results that suggested a germline mutation but did not meet any guidelines for germline testing. We identified 52 LP/P germline variants in BRCA2 (17), BRCA1 (7), PALB2 (6), MUTYH (5), CHEK2 (2), and 15 other genes, all with established guidelines that would impact the clinical management of patients and their family members. In 9/50 cases, germline testing revealed variants that were absent in TMP results and provided new information with clinical implications for patients and their families, including variants in BRCA1 and CHEK2. Conclusions: In TMP patients, 50 of 182 had a medically actionable germline mutation with established management guidelines. Among these 50, 12 (24%) met neither current personal or family criteria nor the latest NCCN guidelines for germline testing in patients with TMP. Also striking were nine patients whose germline LP/P mutations were absent in TMP results. These data suggest that indications for germline testing of cancer patients must be expanded to avoid missing important germline findings in patients undergoing TMP.
BRCA1 and BRCA2 mutations in ovarian cancer patients from China: Association of ethnic-specific mutations in BRCA1 with an increased risk of ovarian cancer.
Authors: Shi Tingyan , Wang Pan , Xie Caixia , Yin Sheng , Shi Di , Wei Congchong , Tang Wenbin , Jiang Rong , Cheng Xi , Wei Qingyi , Wang Qing , Zang Rongyu ,   SGOG
Published: September 2018

1583

Background: BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly (ADP-ribose) polymerase (PARP). Despite a number of small-size hospital-based studies being previously reported, there is not yet, precise data of BRCA1/2mutations among Chinese epithelial ovarian cancer (EOC) pts. Methods: We performed a multicenter cohort study including 916 unselected consecutive EOC pts from eastern China, to screen for BRCA1/2mutations using the next-generation sequencing approach. Results: 153 EOC pts were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C>T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation, c.5470_5477del8 was most likely to be Chinese population-related without an apparent founder origin. This hot-spot mutation was presumably associated with an increased risk of EOC. Taken together, germline BRCA1/2mutations were common in Chinese EOC pts with distinct mutational spectrum compared to Western populations. Conclusions: Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2genetic testing to all Chinese women diagnosed with EOC in order to identify HBOC families, to provide genetic counselling and clinical management for at-risk relatives. Mutation carriers may also benefit from PARP-targeted therapies. [Table: see text]
Vemurafenib in patients with BRAFV600 mutant glioma: A cohort of the histology-independent VE-basket study.
Authors: Hyman David Michael , Kaley Thomas Joseph , Hollebecque Antoine , Subbiah Vivek , Rodon Ahnert Jordi , Lockhart A. Craig , Keedy Vicki Leigh , Hofheinz Ralf , Joly Lobbedez Florence , Blay Jean-Yves , Chau Ian , Puzanov Igor , Raje Noopur , Wolf Juergen , Makrutzki Martina , Riehl Todd , Pitcher Bethany , Baselga Jose
Published: September 2018

2004

Background: Recurrent malignant gliomas (MG) are a universally fatal disease in desperate need of better therapies. Pleiomorphic xanthoastrocytomas (PXA) and juvenile pilocytic astrocytomas (JPA) typically have better outcomes, although when recurrent, also represent an aggressive disease with no proven effective chemotherapy. BRAFV600 alterations have been identified in a substantial proportion of gliomas, including glioblastoma (GBM), astrocytoma, PXA, and JPA. The phase 2, open-label, histology-independent VE-BASKET study of vemurafenib, a selective BRAFV600 kinase inhibitor, in patients with BRAF mutation-positive non-melanoma tumors, included those with gliomas in the ‘all-others’ cohort. We now report final data for patients with recurrent gliomas. Methods: Patients received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints included clinical benefit rate (confirmed complete or partial response or stable disease lasting ≥6 months), progression-free survival (PFS), overall survival (OS), and toxicity. ClinicalTrials.gov NCT01524978. Results: 24 patients (median age 32 years; 18 female, 6 male) with glioma were treated, including mg (n = 11; 6 GBM and 5 anaplastic astrocytoma [AA]), PXA (n = 7), anaplastic ganglioglioma (AG, n = 3), JPA (n = 2), and unknown (n = 1). In patients with mg (n = 11), best response included PR (n = 1; AA), SD (n = 5), PD (n = 3), and unknown (n = 2). Two patients with mg had durable SD lasting 12.9 months (GBM) and 14.9 months (AA). In patients with PXA (n = 7), best response included CR (n = 1), PR (n = 2), SD (n = 3), and PD (n = 1). Additionally, 1 patient with JPA and 1 with AG achieved a PR. The most frequent AEs included arthralgia (67%), melanocytic nevus (38%), palmar-plantar erythrodysesthesia (38%), photosensitivity reaction (38%) and alopecia (33%). Conclusions: Vemurafenib demonstrated activity in patients with BRAFV600 mutant glioma. The safety profile was similar to that seen in previous melanoma studies. Survival data will be presented. Clinical trial information: NCT01524978.
Phase I study of AZD1775 with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) and evaluation of intratumoral drug distribution (IDD) in patients with recurrent GBM.
Authors: Alexander Brian Michael , Ahluwalia Manmeet Singh , Desai Arati Suvas , Dietrich Jorg , Kaley Thomas Joseph , Peereboom David M. , Takebe Naoko , Supko Jeffrey G. , Desideri Serena , Fisher Joy D. , Sims Megan , Ye Xiaobu , Nabors Louis B. , Grossman Stuart A. , Wen Patrick Y.
Published: September 2018

2005

Background: The standard of care treatment for newly diagnosed GBM is maximal safe surgical resection followed by two DNA damaging agents, RT and TMZ. Cellular response to DNA damage involves checkpoints that halt the cell cycle to allow DNA repair. AZD1775 is an oral small molecular inhibitor of a nuclear tyrosine kinase Wee1, a key regulator of the G2/M checkpoint. Abrogation of the G2/M checkpoint prevents repair and pushes cells into mitosis with unrepaired DNA damage. AZD1775 was shown to enhance TMZ and RT effects in preclinical models. Methods: The Adult Brain Tumor Consortium 1202 trial (NCT01849146) is a phase I, open label, multicenter dose-finding study of AZD1775 in combination with standard RT and TMZ followed by an IDD study for patients undergoing surgery for recurrent GBM. The dose finding portion is comprised of two arms, one with AZD1775 given Monday through Friday during concurrent RT/TMZ and a second arm given with adjuvant TMZ qd x 5d/28d cycle. Each arm had standard 3+3 design. A combination cohort with both concurrent and adjuvant AZD1775 at MTD and analysis of PK/PD and IDD at MTD in patients undergoing surgery for recurrent GBM followed. Results: 51 patients enrolled in the dose finding arms. For the concurrent arm, the MTD was 200 mg. At 275 mg one patient had grade 3 fatigue and another had grade 4 thrombocytopenia and neutropenia. Two of 6 total patients enrolled at 200 mg experienced DLTs (grade 4 neutropenia and grade 3 ALT elevation). The MTD for the adjuvant arm was 425 mg as 1 of 6 patients had DLT (grade 4 decrease in ANC). At 500 mg, 2 of 3 patients experienced intolerable diarrhea despite prophylaxis. Enrollment in the combination cohort is completed and evaluation of safety is underway. The drug concentration in contrast enhancing and non-enhancing brain tumor was 4-8 x and 0.5-2.6 x greater than plasma, respectively for patients on IDD portion. Conclusions: The MTD for AZD1775 in combination with RT/TMZ is 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ. IDD and PK/PD analysis is ongoing to inform the decision to proceed to phase II testing. Clinical trial information: NCT01849146.
Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in patients with TKI-naïve, EGFRm NSCLC with CNS metastases.
Authors: Ahn Myung-Ju , Kim Dong-Wan , Cho Byoung Chul , Kim Sang-We , Lee Jong-Seok , Ahn Jin Seok , Kim Tae Min , Lin Chia-Chi , Kim HyeRyun , John Tom , Kao Stephen Chuan-Hao , Goldman Jonathan Wade , Su Wu-Chou , Natale Ronald B. , Overend Philip , Yang Zhenfan , Yang James Chih-Hsin
Published: September 2018

2006

Background: The dose escalation phase is complete forAZD3759, the first EGFR inhibitor primarily designed to cross the blood brain barrier (BBB) to treat patients with EGFRm NSCLC with CNS metastases. AZD3759 is being further evaluated in patients with brain (BM) and leptomeningeal metastases (LM) in TKI-naïve and TKI pre-treated cohorts (data presented separately) (NCT02228369). Methods: The primary objective is safety and tolerability, and secondary objectives include anti-tumor efficacy. Dose levels of 200 and 300 mg BID AZD3759 were assessed based on safety and efficacy data in dose escalation cohorts. Results: As of24 September, 2016,38 patients with EGFRm NSCLC were recruited into the expansion cohorts of this study: 16 patients with TKI naïve BM and 4 patients with TKI naïve LM. 15 and 5 patients were treated with 200 and 300 mg BID of AZD3759, respectively. No DLTs were observed at either dose, while 200 mg BID AZD3759 was better tolerated than 300 mg BID during > 2 month treatment. The longest duration on treatment was > 9 months. Drug-related adverse events (AEs) seen are typically observed for EGFR TKIs. In BM cohort, 56% and 13% of patients had dose interruptions and reductions respectively due to drug-related AEs. The Ctrough free plasma and CSF exposure at both doses were above pEGFR IC90. By investigators’ assessment, the intracranial objective response rate (ORR) was 63% (12 out of 19 evaluable patients) and achieved confirmed/unconfirmed partial/complete response [PR/CR]), extracranial ORR was 50% (10 out of 20 evaluable patients), and the overall ORR was 60% (12 out of 20 evaluable patients). 4 patients have not reached the 6-week RECIST assessment at the data cut-off. 18 of 20 patients are still ongoing (median 4-month follow up). 2 patients have withdrawn, one due to disease progression (de novo T790M mutation in both plasma and CSF), and another due to a non-drug related SAE. Conclusions: AZD3759 was well tolerated at the selected doses, achieved sufficient CNS exposure for target inhibition and demonstrated promising anti-tumor efficacy in both intracranial and extracranial tumors in TKI-naïve patients with CNS metastases. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.
Phase II trial of bevacizumab and temozolomide for upfront treatment of elderly patients with newly diagnosed glioblastoma.
Authors: Nghiemphu Phioanh Leia , Bahng Hye Hyun , Lai Albert , Faiq Nadia , Yong William H. , Green Richard M. , Polikoff Jonathan , Spier Cynthia Elizabeth , Iwamoto Fabio Massaiti , Lassman Andrew B. , Cloughesy Timothy Francis
Published: September 2018

2012

Background: Randomized clinical trials in newly diagnosed, elderly GBM patients have shown that treatment with temozolomide chemotherapy is at least equivalent to treatment with radiotherapy. Glioblastoma in elderly patients may also have high angiogenic activities. Bevacizumab is an antiangiogenic agent, a humanized monoclonal antibody directed against the vascular endothelial growth factor. We conduct a clinical trial of temozolomide and bevacizumab to evaluate the safety and efficacy of this combination in the treatment of elderly patients with newly diagnosed GBM, good performance status, and willing to forgo upfront treatment with radiation therapy. Methods: This is a phase II trial of newly diagnosed GBM patients age ≥70 with no prior treatments other than surgery and Karnofsky Performance Status (KPS) ≥60. Patients receive treatments 4-6 weeks after surgery with bevacizumab (10mg/kg every 2 weeks) and temozolomide (150-200 mg/m2 for 5 days out of 28 days, up to 12 cycles) until tumor progression. Primary outcome measures are overall survival and safety evaluations. Results: From June 2010 to January 2016, 50 GBM patients enrolled in this study. To date, all patients have tumor progression and 3 are still alive. The median age is 75 (range 70 - 87), and median KPS is 80 (range 60-100). 15 patients have a gross total resection. 26 out of 49 patients with tissues available for evaluation have methylation of the MGMT promoter, and no patient has IDH-1 mutation. Median overall survival is 12.3 months (14.8 months for those with methylation of MGMT, 10.0 months for unmethylated MGMT). Serious adverse events related to treatments include wound healing problems (2), CNS hemorrhage (3), pulmonary embolism (4), and bowel perforation (1). Serious hematological adverse events include thrombocytopenia (3) and neutropenia (5). Conclusions: For patients with newly diagnosed GBM age ≥70, KPS ≥60, treatment with temozolomide and bevacizumab may show promising survival benefits and have tolerable side effects. More detailed safety and efficacy analysis will be presented. Clinical trial information: NCT01149850.
Clinical and molecular features associated with long-term survival of elderly patients with glioblastoma.
Authors: Weller Michael , Sill Martin , Hentschel Bettina , Felsberg Joerg , Jones David T. W. , Gramatzki Dorothee , Kaulich Kerstin , Happold Caroline , Tonn Joerg , Herrlinger Ulrich , Schackert Gabriele , Westphal Manfred , Capper David , Kumar Rajiv , Hemminki Kari , Pietsch Torsten , Loeffler Markus , Pfister Stefan M. , von Deimling Andreas , Reifenberger Guido ,   German Glioma Network
Published: September 2018

2013

Background: Glioblastomas in elderly patients are associated with particularly poor outcome, with only few patients demonstrating long-term survival (LTS). Methods: To better characterize clinical and molecular correlates of LTS in elderly glioblastoma patients, we searched the German Glioma Network (GGN) database for patients aged 71 years or more with histological confirmation of glioblastoma and survival of at least two years after diagnosis. Results: Of 2071 glioblastoma patients enrolled in the GGN from 2004-2012, 425 patients were aged 71 years or more; of these, 27 patients (6.4%) survived for 2 years or more (median survival: 37.1 months, 95% confidence interval: 30.0-44.2 months). A comparison of these 27 patients with the 398 patients who survived shorter than 2 years (median survival: 6.2, 95% confidence interval: 5.2-7.2 months) revealed more intensive up-front treatment and a trend towards higher initial Karnofsky performance score as distinguishing clinical factors. Molecular analyses additionally showed more frequent O6-methylguanine-DNA methyltransferase ( MGMT) promoter methylation in the LTS patients. Isocitrate dehydrogenase (IDH) mutation was restricted to single patients and the frequency of telomerase reverse transcriptase ( TERT) promoter mutation did not differ between groups. Genome-wide DNA copy number and methylation profiling using 450k microarray analysis performed for 16 LTS patients and 40 control patients revealed limited differential DNA methylation and no specific copy number profiles linked to LTS. Conclusions: Collectively, our findings confirm that LTS is rare in elderly patients with glioblastoma and that clinical and tumor-associated molecular factors linked to LTS resemble those in standard age patients, except for less common IDH mutation.