bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.