tbuckley/cabot-search huggingface dataset:
Epigenetic alternate promoter utilization and association with PD-L1 expression in Epstein–Barr virus positive gastric cancer.
Authors: Raghav Sundar, Aditi Qamra, Angie Lay Keng Tan, Shenli Zhang, Cedric Chuan Young Ng, Bin Tean Teh, Jeeyun Lee, Kyoung-Mee Kim, Patrick Tan
Journal: Journal of Clinical Oncology (2019)

e15509 Background: We recently elicited the role of epigenetic promoter alterations as a mechanism of immune-evasion and primary resistance to immune checkpoint inhibition in gastric cancer. High prevalence of epigenetic modifications are known to occur in Epstein-Barr virus associated gastric cancer (EBVaGC). EBVaGC has high response rates to anti-PD-1 immune checkpoint inhibitors and is associated with high levels of PD-L1 expression. However, not all EBVaGC express PD-L1 and mechanisms that mediate these phenomena are unknown. Methods: We performed NanoString profiling and PD-L1 immunohistochemistry (using Dako PD-L1 IHC 22C3) on tissue from gastric cancer patients undergoing primary tumor resections at Samsung Medical Centre, South Korea. NanoString panel was designed for 90 recurrent somatic alternate promoter-related genes, and immune-related genes including PD-L1. EBV status was determined using EBV-encoded RNA in situ hybridization and categorized as EBVaGC and EBV-negative. Samples in the top-quartile of alternate promoter utilization were classified as AP high and the remaining AP low . Results: A total of 272 samples (EBVaGC n = 79; EBV-negative n = 193) were included in this study. EBVaGC had significantly higher PD-L1 expression (p &lt; 0.001) compared to EBV-negative samples. AP high group (n = 67) consisted of 61 EBV-negative and 6 EBVaGC samples. EBVaGC AP high tumors had significantly lower PD-L1 transcript expression compared to EBVaGC AP low tumors (p = 0.011, Wilcoxon-rank sum). Similar correlation was also found with PD-L1 IHC combined positive score (CPS)(median CPS score 1 vs 8, p = 0.047). There was a trend towards poorer survival for EBVaGC AP high tumors (vs EBVaGC AP low ; HR 0.23, 95% CI: 0.046 – 1.23, p = 0.087). EBV-negative AP high tumors also had lower PD-L1 expression (vs EBV-negative AP low ; p = 0.046, Wilcoxon-rank sum). Conclusions: Increased utilization of epigenetic alternate promoter isoforms correlates with lower transcriptomic and protein expression of PD-L1 in EBVaGC. Here we describe a potential mechanism of immune-evasion to explain low immune-infiltration and PD-L1 expression that occurs in a group of EBVaGC that is traditionally considered highly immunogenic.
First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100).
Authors: Masatoshi Kudo, Kenta Motomura, Yoshiyuki Wada, Yoshitaka Inaba, Yasunari Sakamoto, Masayuki Kurosaki, Yoshiko Umeyama, Yoichi Kamei, Junichiro Yoshimitsu, Yosuke Fujii, Mana Aizawa, Paul B. Robbins, Junji Furuse
Journal: Journal of Clinical Oncology (2019)

4072 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of advanced/metastatic (a/m) hepatocellular carcinoma (HCC). Avelumab is a human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a tyrosine kinase inhibitor selective for VEGF receptors 1/2/3. VEGF Liver 100 (NCT03289533) is a phase 1b study evaluating safety and efficacy of avelumab + axitinib in treatment-naive patients (pts) with HCC; interim results are reported here. Methods: Eligible pts had confirmed a/m HCC, ≥1 measurable lesion, a fresh or archival tumor specimen, ECOG PS ≤1, and Child-Pugh class A. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and objective response (RECIST v1.1; modified [m] RECIST for HCC). Results: Interim assessment was performed after a minimum follow up of 6 months based on the released study data set (clinical cut-off date: Aug 1, 2018). As of the cut-off date, 22 pts (median age: 68.5 y) were treated with avelumab (median: 20.0 wk) and axitinib (median: 19.9 wk). The most common grade 3 treatment-related adverse events (TRAEs) (≥10% of patients) were hypertension (50.0%) and hand-foot syndrome (22.7%); no grade 4/5 TRAEs were reported. Immune-related AEs (irAEs) (≥10% of pts) were hypothyroidism (31.8%) and hyperthyroidism (13.6%). No grade ≥3 irAEs were reported; no pts discontinued treatment due to TRAEs or irAEs. Based on Waterfall plot calculations, tumor shrinkage was observed in 15 (68.2%) and 16 (72.7%) pts by RECIST and mRECIST, respectively. ORR was 13.6% (95% CI, 2.9%-34.9%) and 31.8% (95% CI, 13.9%-54.9%) by RECIST and mRECIST, respectively. OS data were immature at data cutoff. Conclusions: The preliminary safety of avelumab + axitinib in HCC is manageable and consistent with the known safety profiles of avelumab and axitinib when administered as monotherapies. This study demonstrates antitumor activity of the combination in HCC. Follow-up is ongoing. Clinical trial information: NCT03289533. [Table: see text]
Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults
Authors: Kathryn Demanelis, Maria Argos, Lin Tong, Justin Shinkle, Mekala Sabarinathan, Muhammad Rakibuz-Zaman, Golam Sarwar, Hasan Shahriar, Tariqul Islam, Mahfuzar Rahman, Mohammad Yunus, Joseph H. Graziano, Karin Broberg, Karin Engström, Farzana Jasmine, Habibul Ahsan, Brandon L. Pierce
Journal: Environmental Health Perspectives (2019)

Background: Arsenic exposure affects >200 million people worldwide, including >50 million in Bangladesh. Arsenic exposure increases the risk of cancer and other chronic diseases, and one potential mechanism of arsenic toxicity is epigenetic dysregulation. Objective: We assessed associations between arsenic exposure and genome-wide DNA methylation measured at baseline among 396 Bangladeshi adults participating in the Health Effects of Arsenic Longitudinal Study (HEALS) who were exposed by drinking naturally contaminated well water. Methods: Methylation in whole blood DNA was measured at ∼850,000 CpGs using the Illumina InfiniumMethylationEPIC (EPIC) array. To assess associations between arsenic exposure and CpG methylation, we used linear regression models adjusted for covariates and surrogate variables (SVs) (capturing unknown technical and biologic factors). We attempted replication and conducted a meta-analysis using an independent dataset of ∼450,000 CpGs from 400 Bangladeshi individuals with arsenical skin lesions. Results: We identified 34 CpGs associated with log2-transformed creatinine-adjusted urinary arsenic [false discovery rate (FDR)<0.05]. Sixteen of these CpGs annotated to the 450K array, and 10 associations were replicated (p<0.05). The top two CpGs annotated upstream of the ABR gene (cg01912040, cg10003262). All urinary arsenic–associated CpGs were also associated with arsenic concentration measured in drinking water (p<0.05). Meta-analysis (n=796 samples) identified 221 urinary arsenic–associated CpGs (FDR<0.05). The arsenic-associated CpGs from the meta-analysis were enriched in non-CpG islands and shores (p=7.9×10−8) and depleted in promoter regions (p=1.1×10−3). Among the arsenic-associated CpGs (FDR<0.05), we observed significant enrichment of genes annotating to the reactive oxygen species pathway, inflammatory response, and tumor necrosis factor α (TNFα) signaling via nuclear factor kappa-B (NFκB) hallmarks (p<0.05). Conclusions: The novel and replicable associations between arsenic exposure and DNA methylation at specific CpGs observed in this work suggest that epigenetic alterations should be further investigated as potential mediators in arsenic toxicity and as biomarkers of exposure and effect in exposed populations. https://doi.org/10.1289/EHP3849
The impact of sorafenib on the treatment and survival of advanced hepatocellular carcinoma (HCC): Analysis of the National Cancer Database (NCDB) from 2004 to 2014.
Authors: Aman Opneja, Gino Cioffi, Asrar Alahmadi, Nirav Patil, David Lawrence Bajor, Joel N. Saltzman, Jill Barnholtz-Sloan, Richard T. Lee
Journal: Journal of Clinical Oncology (2019)

e15682 Background: HCC is a common cause of mortality in the U.S. among men and women (5 th and 7 th , respectively) with overall five-year survival of ~18%. Sorafenib was the only FDA approved therapy for advanced HCC from 2007 until 2018. This study analyzes trends in the treatment and survival of advanced HCC before and after sorafenib approval. Methods: Adult patients ( &gt; 18 years) with diagnosis of HCC treated with only chemotherapy from 2004 – 2014 were identified in NCDB database. Comparisons were made between 3 time frames: 2004 – 2007 (pre-sorafenib), 2008 – 2011 (early sorafenib) and 2012 – 2014 (late sorafenib). Patients treated with single or multi-agent chemotherapy were analyzed. Cox proportional hazards models were used for univariate and multivariable analyses. Kaplan-Meier method was used for survival analysis. Results: The NCDB contained 33,136 patients with HCC diagnosed between 2004 – 2014 and treated with chemotherapy alone. Patients were generally men (77.4%), over the age of 50 years (92.4%), with an elevated AFP at diagnosis (64.4%), and had limited co-morbidities (76.0%, Charlson/Deyo score of 0-1). The T-stages were T1 (26.3%), T2 (20.5%), T3 (25.6%), and T4 (16.2%). The number and proportion of patients treated with single agent chemotherapy increased significantly during the study period: 2,733 (45.3%) pre-sorafenib, 9,723 (72.7%) early sorafenib, and 13,502 (86.1%) late sorafenib. The proportion of all HCC patients in the NCDB receiving only chemotherapy increased from 17.2% to 26.4% to 28.3% across the 3 time frames. The survival of patients with advanced HCC treated only with chemotherapy improved significantly in the early and late sorafenib cohorts compared to the pre-sorafenib cohort (10.3 months (95% CI: 9.8-10.6) vs. 12.3 months (12.0-12.7) vs. 15.5 months (15.1-15.9), p-value &lt; 0.001). Age &gt; 70 years, male sex, higher Charlson/Deyo score ( &gt; 1), elevated AFP at diagnosis, and higher T-stage were associated with worse survival (p value &lt; 0.001). Conclusions: The approval of sorafenib has dramatically increased the use of chemotherapy for the treatment of advanced HCC and has resulted in a significant survival advantage.
Effect of fractures on overall survival in cancer patients: The NHANES database.
Authors: Beatrice Jara-Almonte Edwards, Xiaotao Zhang
Journal: Journal of Clinical Oncology (2019)

e23024 Background: Fractures are a significant cause of morbidity, institutionalization and mortality in older adults who are cancer-free. We evaluated the effect of fractures on overall survival in older patients with cancer. Methods: The National Health and Nutrition Study (NHANES) assessed the health and nutritional status of the U.S. The NHANES database is publicly available, and this study was exempt from approval by an institutional review board. All participants provided informed consents both before the interview and examination stages. A total of 62,160 individuals participated in NHANES during 1999-2010. We restricted our analyses to older adults (65 years of age and older) with self-reported cancer diagnosis, with a follow-up till 2011. Results: In total, 1,718 older adults with cancer and with available follow up were included for final analysis. There were 303 participants with fractures (17.6%) and 581 deaths (33.8%) that occurred over a median follow up 4.3 years (range 0.1-12.8 years). Mean age was 74.8 ± 0.2, with females 49.6%. Cancer types included solid tumors and hematologic malignancies. Among solid tumors, colorectal 9.0%, breast cancer 17.4%, prostate cancer 17.7%, lung 3.0%. Among hematologic malignancies, lymphoma 1.6%, myeloma 7.2%, CLL 1.2%. Hip fractures were associated with advanced age, obesity, diabetes, stroke, functional impairment, and mortality. Spine fractures were associated with advanced age, cardiovascular disease, functional impairment and mortality. Univariate analysis for factors associated with overall survival in older adults in NHANES revealed an increased risk with spine fractures H.R. = 1.89, (95% CI 1.11, 3.2, p = 0.02) and hip fractures H.R. = 2.66, (95% CI 1.41, 5.02, p &lt; 0.01). Conclusions: In older cancer patients vertebral and hip fractures were associated with an increased risk for mortality.
Absolute lymphocyte count (ALC) as predictor of Pneumocystis Jiroveci Pneumonia (PCP) infection in patients on immune checkpoint inhibitors (ICPi).
Authors: Krishna Prasad Joshi, Dinesh Atwal, Eric R Siegel, Anusha Jillella, Manojna Konda, Richa Parikh, Aneesha Ananthula, Kulsum Bano, Konstantinos Arnaoutakis, Liudmila Schafer, Natasa Milojkovic, Fade Mahmoud, Rangaswamy Govindarajan
Journal: Journal of Clinical Oncology (2019)

e14255 Background: Checkpoint inhibitor pneumonitis (CIP) is an uncommon but serious immune related adverse event needing treatment with prolonged steroids. PCP prophylaxis is recommended for patients on daily prednisone equivalents of 20 mg or greater for at least 1 month. Known risk factors for PCP infection in general population are glucocorticoid use and defects in cell-mediated immunity. We conducted a retrospective study to evaluate the association between ALC and development PCP infection in the patients with CIP treated with steroids. Methods: A retrospective analysis of subjects who received ICPi for any type of cancer from 2011 to 2018 at a single institution was conducted. PCP was diagnosed by PCR of bronchioalveolar lavage. In patients with CIP, ALC at the beginning of steroid treatment, dose and duration of steroids and development of PCP infection was recorded. The median ALC was compared between the patients with PCP infection and without PCP infection via Welch’s t- test at 5% alpha. Results: Out of 515 patients who received ICPi, there were 429 (83.3%) Caucasians, 79(15.3%) African Americans, 7(1.3%) others. CIP developed in 23 (4.38 %) patients. There were 15(65%) males, 8 females (35%), 20(86.9%) Caucasians and 2(8.6%) African Americans. Median age was 67 Yrs. (range 29-80). Six out of 23 (26%) patients with CIP developed PCP infection. Median ALC in the patients with PCP infection was 0.75 K/uL (range 0.2-0.83) compared to 1.14 K/uL (range 0.18 - 1.76) in those without PCP infection (p = 0.0182). Conclusions: In patients with CIP, low ALC and prolonged steroid therapy are more likely to result in PCP infection as opposed to steroid therapy alone. Low ALC and prolonged steroid therapy may select patients who require PCP prophylaxis. [Table: see text]
Tumor and microenvironment evolution during chemotherapy combine with bevacizumab in colorectal cancer liver metastasis.
Authors: Wangjun Liao, Min Shi, Dongqiang Zeng, Na Huang, Yuqi Wang, Jing Li, Chunlin Wang, Xiaoxiang Rong, Yisheng Fang, Siting Zheng, Yichen Xue, Jiao Wang, Jian Guo
Journal: Journal of Clinical Oncology (2019)

3568 Background: Identifying patterns of pathological tumor resistant to treatment regimens and improving tumor’s chemotherapy sensitivity from longitudinal and multi-omics data integration are of paramount importance in order to provide the best chances of cure, especially, for colorectal cancer liver metastases. Methods: We elucidated genomic (ctDNA and whole exome sequencing), immunomic (DNA-based T cell receptor sequencing) and transcriptomic changes from liver metastases, peripheral blood and match primary tumors that accompany the evolution of colorectal cancer liver metastases. In total, 197 histopathologically distinct areas of liver metastases and 72 peripheral blood samples at multiple time points from 15 patients with colorectal cancer were analysis in this study. Results: In responding patients, mutation load from plasma were reduced from baseline ( P &lt; 0.001), but changed slightly in tumor tissues ( P = 0.351). Transcriptomic analysis and immunohistochemistry revealed that increased infiltration of neutrophils and monocytes were associated with worse outcomes and insensitive response to chemotherapy (Neutrophils: P = 0.003; Monocytes: P = 0.032). Activation of fatty acid metabolism, JAK-STAT, PPAR, insulin and TGF-β signaling pathway were observed in progressive tumor. TCR diversity in response metastatic regions was significantly increased compared with non-responder ( P = 0.008). Combination of bevacizumab with chemotherapy facilitated T cell infiltrating to the tumor microenvironment which might consequently benefit from checkpoint immunotherapy ( P = 0.006). Conclusions: Our integrative and comparative genomic analysis provides a new paradigm for understanding the evolution and treatment resistance of colorectal cancer liver metastases, with implications for identifying ways to advance treatment regimen and monitoring treatment response of colorectal cancer liver metastases.
Randomized phase III study comparing FOLFOX + bevacizumab versus folfoxiri + bevacizumab (BEV) as 1st line treatment in patients with metastatic colorectal cancer (mCRC) with ≥3 baseline circulating tumor cells (bCTCs).
Authors: Javier Sastre, Jose María Vieitez, Maria Auxilidora Gomez-España, Silvia Gil Calle, Antonieta Salud Salvia, Begoña Graña Suárez, Pilar Garcia-Alfonso, Eva Martinez de Castro, Guillermo Alfonso Quintero Aldana, Juan José Reina-Zoilo, Encarnación González Flores, Mercedes Salgado Fernández, Carmen Guillen, Rocio Garcia-Carbonero, Maria Jose Safont, Adelaida La Casta Munoa, Beatriz García de Paredes, Rafael Lopez, Enrique Aranda, Eduardo Díaz-Rubio
Journal: Journal of Clinical Oncology (2019)

3507 Background: FOLFOXIRI+BEV has demonstrated a survival benefit compared with FOLFIRI plus BEV (TRIBE Lancet Oncol 2015) in first-line mCRC. Nevertheless, due to its safety profile, this schedule is not recommended for all pts. In addition, we have showed that the detection of ≥3 bCTCs is a poor prognostic factor for survival (MACRO The Oncologist 2012). The VISNU-1 trial compares FOLFOX + BEV vs FOLFOXIRI + BEV in pts with mCRC and ≥3 bCTCs. Progression-free survival (PFS) is the primary endpoint. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Methods: This is an open, multicentric, randomized phase III trial. Patients with mCRC younger than 70 years, ECOG 0-1 were randomized to FOLFOX+BEV (arm A) or FOLFOXIRI+BEV (arm B), stratified per KRAS mutation (mutated vs WT) and number of involved organs (1 vs &gt;1). Results: 349 pts were included in the ITT population; 177 in group A and 172 in group B. Characteristics of the pts, molecular profiling and safety analysis have been previously presented at ASCO 2018 and showed that this schedule had an acceptable toxicity profile. Efficacy analysis in the ITT population is shown in the table. Conclusions: In this population with very bad prognosis, our study met its primary endpoint. Pts who received FOLFOXIRI + Bev benefit for a statistically significative PFS and ORR. OS showed a trend of benefit in the experimental arm. According to these results, FOLFOXIRI-Bev could be considered an adequate treatment option for pts with mCRC and ≥3 bCTCs. Clinical trial information: 2012-000846-37. [Table: see text]
ALK resistance mutations and co-occurring genetic alterations to the ALK tyrosine kinase inhibitors in lung cancer.
Authors: Jin-Ji Yang, Chi Zhang, Jun Zhao, Pingping Dai, Gen Lin, Liankui Han, Chen Chen, Yan-Fang Guan, Ling Yang, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

e20675 Background: Acquired ALK mutations pose a challenge in multiple ALK tyrosine kinase inhibitors (TKIs) for lung cancer. In our study, we examined the profiles of ALK resistance mutations and co-occurring genetic alterations after targeted therapy. Methods: Using targeted gene capture and next-generation sequencing technologies, we analyzed the somatic mutations from174 patients (pts) with post-TKI samples. Among them, 123 pts received first-generation TKI crizotinib only, 51 pts (34 with second-generation TKI, 17 with third-generation TKI) treated with multiple ALK-TKIs. Results: After the treatment of ALK-TKIs, 29% (50/174) patients developed ALK resistance point mutations, including G1202R (22 pts), G1269A (13 pts), L1196M (8 pts), D1203N (5 pts), F1174L (4 pts), I1171T (4 pts), E1210K (4 pts), G1128A (3 pts), F1174C (3 pts), C1156Y (1 pts), G1123S (1 pts), I1171S (1 pts), L1152R (1 pts), and 10 of them had multi-clone. Specifically, G1269A was found a higher proportion in crizotinib group contrast to multi-TKIs cohort (10/24 vs 3/26, p = 0.024). The recalcitrant G1202R was another common resistance mutation, but there was no significant difference between the two groups (p = 0.052). Other concurrent genetic alterations related to clinical response were usually observed in TP53 mutations (46%), furthermore it seemed to be more frequently detected in post-crizotinb compared with multi-TKIs (P = 0.023). Activated bypass signaling may promote tumor progression. In non-ALK resistance point mutations samples (n = 124), co-occurring genomic alterations in EGFR (32/124, p = 0.004) were significantly more enriched in crizotinib group (n = 99). The driver gene mutation may limit crizotinib response. However, EP300 (24%), CDKN2A (12%), TRIM58 (12%), STK11 (12%) or KRAS (8%) mutations were common in the multiple ALK-TKIs group (n = 25). Conclusions: In lung cancer patients, ALK resistance point mutations G1269A was significantly enriched in post-crizotinib, while patients with multiple ALK-TKIs may frequently found G1202R or L1196M. The co-occurring genetic alterations in TP53 or EGFR after the TKIs therapeutic may offer directions for further research and therapy in lung cancer.
Experience and challenges of setting up a new lung cancer chemotherapy clinic in resource limited setting in Nepal.
Authors: Deebya Raj Mishra, Narendra Bhatta, Niharika Shah
Journal: Journal of Clinical Oncology (2019)

e18104 Background: Nepal is a developing country with a Gross Domestic Product per capita of 2400 US dollars. There are only two specialized cancer centers in whole of Nepal. They are at best, understaffed, overburdened and limited by logistics. Cancer diagnosis is easily accepted as a death sentence in the society and treatment rarely done due to the lack of universal coverage or health insurance. The nearest Cancer hospital is 400km away. In this background, in an academic institute serving as the referral center for Eastern Nepal, lung cancer chemotherapy clinic has started in last one year duration. Methods: A prospective Observational Study was done from May 2017 to May 2018 by the newly set up Lung Cancer treatment unit in an academic medical institute in Eastern Nepal. Readiness to undergo biopsy after suspicion of lung cancer as well as readiness for chemotherapy was looked at along with Clinico-radiologic characteristics, demographics, presumptive stage of disease and treatment outcome were recorded. Results: 53 patients were suspected of lung cancer based on imaging. Of these 14 did not agree for biopsy. Of the 39 who underwent biopsy, lung cancer was the diagnosis in 31 cases. In 4 cases the lung biopsy was not definitive for a diagnosis. Histology samples were obtained by USG guided Trans-thoracic needle biopsy in 25 cases and by bronchoscopic biopsy in 14 cases. The predominant histology was Adenocarcinoma (42%, 13/31) followed by Squamous Cell Carcinoma (29%, 9/31). There were 3 cases of Small Cell Carcinoma. Of the cases diagnosed as lung cancer, 45% (14/31) refused treatment. Immunohistochemistry and/or molecular testing for EGFR and ALK are not available routinely in our country. Only 3 patients opted for molecular testing abroad and of these 3, 2 were EGFR positive. Conclusions: Due to perception of poor prognosis, cancer diagnosis is taken as a death sentence and only 50% patients opt for treatment. Treatment is limited by lack of adequately trained surgeons, availability of radiotherapy facilities, lack of Molecular testing and especially by the high cost of treatment. There is an urgent need to train manpower, increase awareness and subsidize the treatment of lung cancer in some form in our country.