tbuckley/cabot-search huggingface dataset:
Phase I study of PD-L1 inhibition with avelumab and laser interstitial thermal therapy in patients with recurrent glioblastoma.
Authors: Adilia Hormigo, John Mandeli, Constantinos Hadjipanayis, Sacha Gnjatic, Seunghee Kim-Schulze, Saadi Ghatan
Journal: Journal of Clinical Oncology (2019)

TPS2074 Background: Glioblastoma (GBM) the most frequent malignant brain tumor in the adult has a dismal prognosis and limited treatment options. Current advances have highlighted how tumors and specifically GBM evade the immune system by exploiting the mechanisms of tolerance and inducing local and systemic immunosuppression. Another hurdle in the treatment of GBM is the blood-brain barrier (BBB). Recent work suggests that MRI-guided laser interstitial thermal therapy (LITT) can increase the permeability of the BBB and may have an abscopal effect. Therefore, utilizing MRI-guided LITT, a potential immunogenic cell death-inducing procedure that disrupts the BBB and makes Avelumab a PD-L1 monoclonal antibody being more accessible to GBM tumors, seem a valid approach for immunomodulation and successful implementation of a combined regimen to treat brain cancer. Methods: This is a prospective non-randomized open label to characterize the tolerability and safety profile of Avelumab in combination with LITT in patients with recurrent glioblastoma who were treated with radiation therapy with concurrent Temozolomide chemotherapy at diagnosis, and whose tumor at recurrence measures less then 3 cm 3 . Avelumab is administered within a week after real-time MRI-guided LITT therapy and every 2 weeks thereafter. On part A patients are treated with intravenous Avelumab alone and on part B patients receive Avelumab in combination with MRI-guided LITT. Part A completed enrollment without DLT. Enrollment on part B began in October 2018. A Simon minimax two-stage design is being used for efficacy. Toxicity will be scored using the NCI-CTCAE 4.03 criteria. Blood samples and tumor tissue will be collected for correlative studies. Quantification of the changes in inflammatory and immunosuppressive profiles across time points for patients receiving treatment with Avelumab will be obtained. This information will instruct future immunotherapy approaches to treat GBM and the rational for those combinations. Clinical trial information: NCT03341806.
Hormone replacement therapy (HRT) and risk of distant recurrence in newly diagnosed ER+, node-negative (N-) breast-cancer (BC) patients: A retrospective population-based matched-cohort study.
Authors: Ariel Hammerman, Ilan Feldhamer, Sari Greenberg-Dotan, Nicky Liebermann, Rinat Yerushalmi
Journal: Journal of Clinical Oncology (2019)

6591 Background: Observational studies have shown an increased risk of BC with use of HRT. However, data on the prognosis of BC that develop in HRT users are inconsistent. The association between HRT use and results of the 21-gene Recurrence Score (RS) assay (Oncotype DX, Genomic Health Inc.) has not been investigated. We aimed to analyze this association, and examine the actual rate of distant recurrence or death in this population. Methods: Clalit Health Services (CHS) is the largest health maintenance organization (HMO) in Israel. We identified all CHS newly diagnosed ER+, N- breast-cancer patients, aged 45-60 that performed a RS assay between 01/2006-12/2012 and that were treated for at least three months with HRT during the eight years before BC diagnosis. A 1:4 matched-cohort analysis was performed, with matching made according to age and year of BC diagnosis. Clinical and demographic data were extracted from the CHS centralized registry for all patients. RS assay scores was grouped according to the TAILORX categorization and distribution was compared using Chi-square test. Kaplan-Meier analysis with log-rank test was performed in order to compare time to a combined outcome of distant-recurrence and mortality. Results: A cohort of 259 HRT-treated patients was identified and matched with 1001 controls, not treated with HRT. The proportions of low-risk patients (RS 0-25) and high-risk patients (RS 26-100) were 76.8% and 23.2%, respectively, within HRT-treated patients, and 80.4% and 19.6% within controls. Chi square test was not found significant (χ 2 = 1.634, p = 0.201). The mean follow-up time was 148.4 months for the cases and 146.9 months for controls, with log-rank test not showing a significant difference between groups. Conclusions: These data did not show significant association between HRT use and higher RS assay scores, and also did not find an association between HRT use and actual distant recurrence or death. Although the proportion of patients with high risk RS appeared to be slightly higher within HRT treated patients, this difference had not reached significance and further studies are required.
Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors.
Authors: Kyriakos P. Papadopoulos, Karen A. Autio, Talia Golan, Konstantin Dobrenkov, Elliot Chartash, Xiaoyun Nicole Li, Richard Wnek, Georgina V. Long
Journal: Journal of Clinical Oncology (2019)

9509 Background: Ligation of GITR on immune cells decreases T reg -mediated suppression and enhances T cell proliferation. MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. Data from the first-in-human phase 1 study (NCT02132754) of MK-4166 as monotherapy (mono) or in combination with pembro (combo) are presented. Methods: MK-4166 was tested alone (0.0015 mg IV-900 mg Q3W ×4 doses) or with pembro (fixed dose 200 mg IV Q3W up to 35 doses) in the absence of toxicity or progression. Study included a dose escalation/confirmation cohort (metastatic solid tumors) and an expansion cohort (treatment-naive and pretreated melanoma). A T cellinflamed gene expression profile (GEP) was assessed using RNA from baseline tumor samples. End points  primary: safety/tolerability, maximum tolerated dose (MTD) of MK-4166; secondary: pharmacokinetics (PK), pharmacodynamics (PD); exploratory: objective response rate (ORR) per irRECIST1.1. Results: Of 113 pts, 48 received mono and 65 combo; 20 were in the melanoma expansion. Common AEs ( &gt; 20%) were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus; 43 pts had grade ≥3 AEs (38.1%); 6 (5.3%) were treatment-related. One dose-limiting toxicity (bladder perforation in a urothelial pt with a neobladder) possibly related to study drug was observed with mono. MTD was not reached. No treatment-related deaths were observed. MK-4166 PK/PD showed target-mediated drug disposition concomitant with decreased GITR availability on T cells in blood with increasing doses. Four objective responses (4/45; ORR, 9%) were seen with combo in dose escalation. For ICI-naive melanoma pts (n = 13) in expansion, ORR was 69% (95% CI, 38-91), including 4 CRs and 5 PRs. No response was observed in 7 pts previously treated with ICI. High ORRs were observed in noninflamed and inflamed ICI-naive melanoma pts. Conclusions: MK-4166 at a dose up to 900 mg as monotherapy and in combination with pembro was well tolerated, with dose-related evidence of target engagement. Responses were observed with MK-4166 900 mg plus pembro, particularly in pts with melanoma naive to ICIs. Clinical trial information: NCT02132754.
Assessing the impact of clonal hematopoiesis in disease monitoring using targeted cell-free DNA (cfDNA) sequencing technology.
Authors: Stephanie J. Yaung, Liu Xi, Corinna Woestmann, Christine Ju, Daniel M. Klass, Fergal Casey, Bernd Hinzmann, Claus Peter Heussel, Michael Thomas, Felix Herth, Thomas Muley, Birgit Wehnl, John F. Palma, Xiaoju Max Ma
Journal: Journal of Clinical Oncology (2019)

e14530 Background: Somatic variants found in plasma cell-free DNA (cfDNA) may derive from either solid tumors or clonal hematopoiesis (CH). Little is known about how this may impact plasma-based longitudinal disease monitoring using targeted sequencing of circulating tumor DNA (ctDNA). Methods: To assess the potential impact of CH in disease monitoring, we evaluated monitoring algorithms by targeted sequencing with and without matched peripheral blood mononuclear cells (PBMC). Samples were collected from a prospective observational study, where 62 late stage lung adenocarcinoma subjects were treated with first-line chemo or chemoradiation therapy. Pre-treatment plasma cfDNA and matched PBMC were analyzed with the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), a sequencing panel of 198 kilobases targeting cancer genes. Median input amounts of 25 ng cfDNA and 50 ng PBMC DNA were sequenced to median deduplicated depths of 4582 and 6134, respectively. Results: A median of 120 single nucleotide variants were detected per cfDNA sample, with 93.1% of these identified in matched PBMC. Most PBMC-matched cfDNA variants were germline SNPs, with allele frequency (AF) ~ 50% or 100%. A median of 1 (range 0-5) PBMC-matched cfDNA variants per sample were detected with an AF &lt; 10%, consistent with CH. The number of these variants was positively associated with age (p-value = 0.0039) and the most frequently mutated gene was TP53. The remaining somatic variants (i.e., in cfDNA and not PBMC) had an AF range 0.03-40.9%. These PBMC-informed variants (median of 7 per sample) were used in longitudinal monitoring in the first post-treatment plasma sample to assess early response to therapy. Association between ctDNA level and progression-free survival using the same monitoring algorithm yielded nearly identical results on somatic variants derived from filtering approaches independent of matched PBMC (HR 0.32; 95% CI 0.16 - 0.65; log-rank P = 0.0009) and the PBMC-informed method (HR 0.31; 95% CI 0.14 - 0.66; log-rank P = 0.0013). Conclusions: A targeted panel focused on solid tumors by design has limited impact from CH. For disease monitoring applications in a non-MRD setting, measuring multiple variants instead of a single variant further enables robust classifiers that can moderate the impact of variants, if any, from CH.
NSCLC mutation frequency in the central American and Caribbean region.
Authors: Luis Corrales-Rodriguez, Erik Alexander Arauz, Ludwing Alexander Bacon Fonseca, Mario Lanza, Luis Homero Matos, Carmen Vargas
Journal: Journal of Clinical Oncology (2019)

e14278 Background: Lung Cancer (LC) constitutes a leading cause of death in the World. Non-small cell lung cancer subtype adenocarcinoma (NSCLC-A) has been associated with epidermal growth factor receptor (EGFR) mutations, which is essential for treatment decisions. The EGFR mutation frequency has been proven to have regional variability in this NSCLC-A population. The current study presents the EGFR mutation incidence and T790M frequency in NSCLC-A cases diagnosed in Central American and Caribbean(CA&amp;C) region. Methods: A cross-sectional evaluation was performed in patients diagnosed with NSCLC-A between 2016 and 2018 in five CA&amp;C countries. Patients were obtained from Reference Centers in Dominican Republic, Nicaragua, Panama, Honduras and Costa Rica through the AstraZeneca testing program. EGFR mutations were evaluated through Real-Time PCR. Results: The research included 972 cases. Mean of age at the diagnosis was 62.79(28.12-90.46) years. Overall distribution of cases by gender was female in 52.37% (509/972) and male in 47.64% (463/972). For the group of antiEGFR TKI naïve patients, tissue samples were processed in 67.83% (601/886). For the group of post antiEGFR TKI patients plasma samples were processed in 90.70% (78/86). For the group of antiEGFR TKI naïve patients, EGFR mutations were present in 26.64% (236 / 886), the mean of age was 63.17 years (28.12-113.47). The frequency of Exon 19 was 53.38(126/236)% and Exon 21 was 27.54%(65/236)% and 11.01% (26/236) were complex mutations. T790M mutations in this treatment naïve population was 2.14%(19/886). For the group of post antiEGFR TKI patients the frequency of T790M mutation was 50.00% (43/86) where 78.57% were obtain from plasma samples. Conclusions: The frequency of NSCLC EGFR mutation positive patients in the CA&amp;C region was similar to that previously described in other Latin American (LA) countries. In the treatment naïve population, tissue samples remain the most important sample to analyze for EGFR mutations. T790M mutations can be seen in treatment naïve population. For patients that progressed to an antiEGFR TKI, T790M mutations were seen in a similar frequency as describe in previous LA countries. For post antiEGFR TKI patients, plasma samples were the preferred method to evaluate T790M mutations with an adequate sensibility.
Living in a war zone increases heart disease and stroke risk years after conflict ends, study finds
Authors: Elisabeth Mahase
Journal: BMJ (2019)

People who live in war zones may have a higher risk of heart disease and stroke even years after the conflict has ended, research has shown.1

In a systematic review by Imperial College London and the London School of Hygiene and Tropical Medicine, researchers found that conflicts were linked to an increased risk of coronary heart disease, stroke, diabetes, raised blood pressure and cholesterol, and increased alcohol and tobacco use.

The findings should be considered by governments leading public health efforts during and after conflicts, said the researchers. But they also highlighted that getting high quality data in this area is difficult …
Abstract P341: Community Environment Associated with Cardiovascular Disease Hospitalization Rates in Denver, Colorado
Authors: Ronica N Rooks, Kathryn DeYoung, Emery Shekiro, Edward Havranek, Arthur Davidson
Journal: Circulation (2017)

Introduction: Hospitalization rates for acute myocardial infarction (AMI), coronary heart disease (CHD), and stroke have decreased over time, although trends are debatable for heart failure (HF). These trends are unequally distributed. There is a growing literature documenting the relationship between social and economic characteristics of people’s communities and cardiovascular disease (CVD). Based on a social ecological model of health through the life course, we descriptively examined associations between CVD hospitalization rates and patient characteristics and census tract (CT)-level community environment. Hypothesis: CVD hospitalization rates will be higher in community environments with higher percentages of individuals living below the federal poverty level, racial/ethnic minority groups, and non-residential (i.e., commercial/office, industrial, open space, public/civic, vacant, and miscellaneous space) vs. residential land use. Methods: Colorado Hospital Association (2009-2013) data were used to measure ICD-9 coded hospitalization rates (per 1,000) for Denver, Colorado residents ≥20 years. Data were merged with American Community Survey (2009-2013) and Denver County land use (2010) data. Using chi-square analysis, we examined associations between age-adjusted CVD hospitalization rates (N=15,521) and CT-level community environment (in quartiles) (N=144). Results: Denver’s annual CVD hospitalization rate was 6.6. Patient-level AMI (1.7), CHD (2.8), and HF (2.2) rates were higher among men. Women had higher stroke-related rates (2.4). Across CVD types, rates for those ≥65 years (6.5-13.5) were higher than middle-aged groups (2.1-3.4). Average annual age-adjusted AMI hospitalization rates were higher in CTs with the highest quartile of Hispanic Americans (2.0), Native Americans (1.9), and individuals below poverty (1.9). CHD rates were higher in CTs with higher percentages of Hispanic Americans (3.1), individuals below poverty (3.1), and Native Americans (3.1). HF rates were higher in CTs with higher percentages of industrial/office land use (3.5), individuals below poverty (3.3), and Hispanic Americans (3.2). Stroke rates were higher in CTs with higher percentages of Native Americans (3.0), industrial/office land use (3.0), and African Americans (3.0). The largest disparities for rate ratios comparing the highest to the lowest quartiles for each exposure by CVD outcome were the percentage of individuals below poverty (AMI 2.2; CHD 2.1; HF 2.4; Stroke 1.7), non-Hispanic Whites (AMI 0.7; CHD 0.7; HF 0.7; Stroke 0.7), Hispanic Americans (AMI 1.5; CHD 1.5; HF 1.5), and Native Americans (Stroke 1.30). Conclusions: In conclusion, associations exist between community environment and CVD hospitalization rates, suggesting opportunities for health policy development in Denver’s city government, council districts, and neighborhoods .
Association between past medical history (PMH) of autoimmune events and adverse events of special interest (AESI).
Authors: Jamie Renee Brewer, Virginia Ellen Maher, Chana Weinstock, Sundeep Agrawal, Michael Holman Brave, Yang-Min Ning, Harpreet Singh, Daniel L. Suzman, James Xu, Amna Ibrahim, Julia A. Beaver, Richard Pazdur
Journal: Journal of Clinical Oncology (2019)

2565 Background: PD-1/L1 inhibitor therapy has become the standard of care for many advanced solid tumors. A notable limitation of PD-1/L1 inhibitor therapy is the concern for AESI that are likely to be immune related. It is unclear whether a history of autoimmune events is a predisposing risk making these adverse events more likely. We aimed to evaluate the association between autoimmune-associated PMH and AESI on PD-1/L1 inhibitors. Methods: We pooled data across seven pivotal trials for PD-1/L1 inhibitors in urothelial cancer (UC) identifying patients with AESI submitted from 2016 - 2017. AESI were determined using a pooled preferred term list for each trial. Information collected from trials included PMH, AESI events and toxicity grade. Results: In total, 1747 immunotherapy treated patients were identified, with 1068 (61%) having an AESI and 277 (26%) having an autoimmune-related PMH. The most common autoimmune-associated events in the PMH were thyroid disorders (64%), asthma (23%), atopic dermatitis/eczema (6%), irritable bowel syndrome (5%), and psoriasis (4%). AESI occurred in 68% of patients with an autoimmune-related PMH and 60% of patients without an autoimmune-related PMH. The most common AESI in patients with an autoimmune-related PMH were diarrhea (35%), rash (27%), renal disorder (27%), and pruritis (23%). The most common AESI in the general trial population were diarrhea (28%), pruritis (26%), rash (25%), increased creatinine (14%), and elevated AST and ALT (10% and 9%). The majority of events were Grade 1-2 (87% in patients with an autoimmune-related PMH and 84% in the general trial population). Conclusions: Pooled clinical trial data shows a slight numeric increase in AESIs in patients with autoimmune-associated PMH. Limitations include potential lack of consistency of PMH documentation and adverse event reporting. There did not appear to be a pattern of association between PMH and type of AESI event. Grades of AESI events in the population with autoimmune-associated PMH were similar to the general trial population. This suggests that PD-1/L1 inhibitors may be safely administered to patients with UC and a PMH of some autoimmune-associated events. Further exploration is needed.
BRCA1/2 germline mutations and response to PARP inhibitor treatment in lung cancer.
Authors: Wenfeng Fang, Xiuyu Cai, Huaqiang Zhou, Yinguang Wang, Yaxiong Zhang, Shaodong Hong, Yang Shao, Li Zhang
Journal: Journal of Clinical Oncology (2019)

e13007 Background: Germline mutations in BRCA1/2 (BReast CAncer genes 1 and 2), which are targets for PARP inhibitors in breast and ovarian cancer, have been previously identified in patients with non-small cell lung cancer (NSCLC). However, its prevalence and clinical outcomes to targeted therapy in NSCLC still remains unknown. Methods: We conducted a retrospective review of 9,324 Chinese NSCLC patients who underwent targeted next-generation sequencing (NGS) during 2015/11/01 and 2018/10/31. Patients with BRCA1/2 somatic and germline mutations were identified. We summarized their prevalence and explored their co-existing driver mutations. Then we initially reviewed the response to PARP-inhibitor targeted therapy in patient with BRCA2 germline mutation. Results: 459 (4.9%) patients are BRCA1/2 positive (germline/somatic mutation). Most patients are diagnosed with LUAD (372, 81.1%), with a median age of 63 years (range: 2-101). Slightly more male patients were carrying BRCA1/2 mutations (59.9%, 275 out of 459). The prevalence of BRCA1 and BRCA2 somatic mutations was similar (145, 1.56% vs. 169, 1.81%, p = 0.19). BRCA2 germline mutation was more common in lung cancer than BRCA1 germline mutation (148, 1.59% vs. 20, 0.21%, p &lt; 0.0001). When specified to the common driver gene mutation subgroups, the prevalence of BRCA2 germline mutation is similar to the entire population (EGFR 1.79%; ALK 1.74%; KRAS 2.05%; BRAF 2.86%; ERBB2 0.93%; p &gt; 0.05). K2729N is the most common BRCA2 germline mutation (41, 27.7%), followed by C315S (26, 17.6%), V2109I (12, 8.1%), R2108C (11, 7.4%), I2490T (10, 6.8%), T582P (5, 3.4%). About 20% patients with BRCA2 germline mutation carried at least one concomitant mutations of DNA repair genes, including MLH1, MLH3, MSH6, CHEK2, BARD1, BLM, BRCA1, MUTYH, RAD50, RECQL4 and XRCC1. One 56-year-old male LUAS patient, with germline BRCA2 rs80359490 frameshift deletion mutation (p.S1722Yfs*4), received the targeted therapy with PARP inhibitor Olaparib after multi lines therapies. This patient showed a great PR response to Olaparib, with a PFS of at least 6 months. Conclusions: BRCA1/2 germline mutations were rare in Chinese NSCLC patients. Patients with BRCA2 germline mutations might benefit from PARP-inhibitor treatment.