bluuebunny/crossref_metadata_2025_split huggingface dataset:
The mutational landscape of gastrointestinal malignancies as reflected by circulating tumor DNA.
Authors: Riviere Paul , Fanta Paul T. , Ikeda Sadakatsu , Baumgartner Joel Micah , Heestand Gregory M. , Kurzrock Razelle 
Published: September 2018

11574 Background: Liquid biopsy of circulating tumor DNA (ctDNA) is a novel method of detecting genetic alterations in cancer patients without tissue acquisition. Methods: Our analysis surveyed the genomic landscape of 213 patients with various gastrointestinal malignancies using next generation sequencing of plasma ctDNA across a 68 gene panel (www.guardanthealth.com/guardant360/). Data analysis was performed following UCSD IRB guidelines for de-identified database (NCT02478931). Results: The most common cancer types were colorectal adenocarcinoma (N = 55 (26%)), appendiceal adenocarcinoma (N = 46 (22%)), hepatocellular carcinoma (N = 31 (15%)), and pancreatic ductal adenocarcinoma (N = 25 (12%)). 70% of patients had discernible alteration(s), and 58% of patients had ≥1 characterized alterations. The median number of characterized alterations per patient was 1 (range 0-13). The number of detected alterations per patient varied between cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had > 1 characterized alteration(s), whereas 76% of patients (35/46) with appendiceal adenocarcinoma had no characterized alterations. Overall, of 123 patients with characterized alterations, > 99% (122/123) had ≥1 hypothetical (experimental or approved) treatment options available. Potentially targetable alterations varied between cancer types, proportionally to the detection rate of characterized alterations. The median percent ctDNA of characterized alterations was 2.50% (IQR 0.76-8.96%). Of interest, 95% of patients (117/123) had distinct molecular portfolios. Altogether, there were 143 unique characterized alterations within 56 genes. Overall concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy (105 patients) (https://www.foundationmedicine.com/) in the four most common alterations ( KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Conclusions: Our observations suggest that many patients with gastrointestinal tumors have discernible and pharmacologically tractable ctDNA alterations. Hence, ctDNA assessment through non-invasive liquid biopsy may have an important role in clinical practice.
Rare tumor clinic: The UCSD Moores Cancer Center experience with a precision therapy approach.
Authors: Kato Shumei , Kurasaki Kellie , Ikeda Sadakatsu , Kurzrock Razelle 
Published: September 2018

11578 Background: Rare tumors have an incidence of < 15/100,000 per year; utra-rare, prevalence < 2000 in the USA. Patients (pts) may lack approved treatments and clinical trial access. Although each rare tumor is uncommon, cumulatively they account for > 20% of cancers. We recently initiated a Rare Tumor Clinic that emphasized a precision medicine strategy (genomic and proteomic analysis and individualized therapy). We report our preliminary experience. Methods: We investigated outcome among the first 40 pts presenting to the Rare Tumor Clinic at UC San Diego Moores Center for Personalized Cancer Therapy. Whenever possible, next-generation sequencing (NGS) of tissue and plasma-derived circulating tumor DNA (ctDNA) as well as proteomic markers were assessed. Results: Median age was 58 (range, 31 – 78 yo); 70% (28/40) were women; median number of previous systemic therapies, 2 (range, 0-7). The most common diagnoses were sarcoma (N = 7) for solid tumors; Erdheim-Chester disease (N = 5), for hematologic malignancies. Twenty distinct diagnoses were seen. Examples of ultra-rare tumors included ameloblastoma, yolk sac liver tumor, ampullary cancer, Castleman's disease, and desmoid tumor. 82.5% of pts (33/40) had tissue NGS (182 to 405 genes); 7.5% (3/40), inadequate tissue. The median number of characterized tissue alterations was 3 (range, 0 to 24); 32 pts (80%) had ≥1 characterized genomic alteration. 33 pts (82.5%) had ctDNA analysis; 15 pts had ≥1 characterized alteration. Among those 15 pts, median number of characterized alterations was 3 (range, 1 to 14). 92.5% (37/40) of pts had ≥ 1 actionable target based on either genomic (32 pts) or proteomic markers (27 pts) (FDA-approved [mostly off-label] or investigational agent). 52.5% (21/40) received matched therapy; 52.4% (11/21) achieved SD≥6 months (N = 3)/CR (N = 2)/PR (N = 6). Matched therapy resulted in significantly longer PFS compared to last prior unmatched therapy (HR: 0.26, 95% CI: 0.10 – 0.71 [p = 0.008]). Conclusions: Identifying genomic and proteomic markers in pts with rare and ultra-rare tumors was feasible. When therapies were matched, > 50% of pts attained SD≥6 months/CR/PR. Further clinical investigations focusing on rare and ultra-rare tumors are urgently needed.
Role of ERBB signaling in RET-rearranged lung cancer and contribution of EGFR amplification to cabozantinib resistance.
Authors: Smith Roger , Drilon Alexander E. , Kunte Siddharth , Suzawa Ken , Hayashi Takuo , Delasos Lukas , Tai Huichun , Hitchman Tyler , Khodos Inna , Mattar Marissa , Kohsaka Shinji , de Stanchina Elisa , Lockwood William , Ladanyi Marc , Somwar Romel 
Published: September 2018

11583 Background: Lung cancers driven by oncogenic RET fusions have lower response rates to targeted monotherapy such as cabozantinib (28%) relative to response rates typically observed in ALK- or ROS1- rearranged lung adenocarcinomas (60-80%). Methods: To identify targetable co-dependencies or cooperating pathways for RET fusion-positive lung cancers, we performed high-throughput chemical and genetic screens to find FDA-approved drugs or genes that when inhibited, would synergize with cabozantinib in RET fusion-positive lung cancer cell lines. In addition we performed NGS of a pair of pre-treatment and post-cabozantinib progression samples. Results: We identified EGFR siRNAs and anti-EGFR drugs as synergistic with cabozantinib. Combinations of drugs that target EGFR (cetuximab, afatinib, erlotinib, gefitinib, neratinib) and RET (cabozantinib, CEP-32496, lenvatinib, vandetanib) were more effective at reducing growth of RET cell lines than any single agent in vitro and in xenograft models. Cabozantinib treatment of RET fusion-positive cell lines inhibited EGFR and RET phosphorylation, an observation not seen in RET wild-type cell lines. Co-immunoprecipitation studies reveal that RET and EGFR interact. Ectopic expression of CCDC6-RET in NIH-3T3 or human bronchial epithelial cells resulted in upregulation of multiple ERBB receptors and ligands (not seen in a ROS1 fusion-positive cell line) and a concomitant increase in EGFR stability. Treatment with ERBB pathway ligands or overexpression of EGFR decreased sensitivity to cabozantinib in two RET fusion-positive cell lines. Finally, sequencing of a pair of pre-treatment and post-progression samples from a lung cancer patient treated with cabozantinib revealed acquired amplification of EGFR in the latter sample. Conclusions: Taken together, these results suggest that the tumorigenic potential of RET fusion oncogenes is dependent on deregulation of ERBB-activated pathways and that a combination of RET and EGFR drugs could be more effective in treating RET fusion-positive tumors. Moreover, amplification of EGFR is a potential driver of resistance to cabozantinib in RET-rearranged lung cancers.
Impact and correlation of mutational load (ML) and specific mutations (mts) assessed by limited targeted profiling (LTP) with PD-L1 tumour expression (exp) in resected non-small cell lung carcinoma (NSCLC).
Authors: Sui Jane Sze Yin , Teo MinYuen , Toomey Sinead , Rafee Shereen , McFadden Julia , Gately Kathy , Barr Martin P , Gray Steven G. , Hennessy Bryan , O'Byrne Ken , Cuffe Sinead , Finn Stephen P. 
Published: September 2018

11587 Background: The advent of immunotherapy represents a paradigm shift in the treatment of NSCLC compared to conventional chemotherapy. Recent studies have shown higher mts burden assessed by exome sequencing are associated with improved objective response and clinical benefit. We performed this study to evaluate the impact of ML assessment by LTP, correlating with PD-L1 exp and clinicopathological variables in resected NSCLC. Methods: NSCLC patients(pts) who underwent curative resection between 1998 and 2006 at our institution were included. PD-L1 status was assessed using Ventana SP124 antibody on archival FFPE surgical tumour specimens cores. PD-L1 was scored positive if membranous staining was present in >1% of tumour cells aggregated across the replicate cores to address heterogeneity. In collaboration with the Lung Cancer Genomics Ireland Study a targeted panel of 49 genes were assessed by Sequenom MassArray including genes in MAPK and PI3K pathways. Clinical data was obtained from hospital electronic database. Results: Ninety-one pts were included, of which 51 (56.0%) were males, with a median age of 65 years (range: 42 – 82). 51.6%, n=47 with squamous histological subtypes, 46.2%, n=42 were ex-smoker and 49.5%, n=45 had Stage I disease. 23.1%, n=21 had PD-L1 positivity. 149 mts were identified of which, 32(21.5%) with PHLPP2, 31(20.9%) with PIK3R1 and 21(14.1%) with TP53. The presence of PI3K and TP53 mts are associated with positive PD-L1 status (see table). An inverse correlation of PD-L1 positivity with ML of (1 vs 2 vs 3: 53.8% vs 30.8% vs 15.4%) was noted. Conclusions: We did not identify higher PD-L1 exp with higher ML assessed by a LTP widely used in clincial practice. However, positive PD-L1 exp was correlated with PIK3R1 and TP53 mts , warranting further investigation as potential modulators or surrogates of positve PD-L1 expression. [Table: see text]
Genomic alterations in 670 patients with diverse cancers analyzed by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA).
Authors: Schwaederle Maria Clemence , Chattopadhyay Ranajoy , Kato Shumei , Fanta Paul T. , Banks Kimberly , Piccioni David Eric , Ikeda Sadakatsu , Talasaz AmirAli , Lanman Richard B. , Bazhenova Lyudmila , Kurzrock Razelle 
Published: September 2018

11593 Background: NGS of blood-derived ctDNA allows non-invasive tumor profiling. Liquid biopsy studies with clinical correlation have so far been mainly limited to small size cohorts. Methods: We performed comprehensive plasma genomic testing of ctDNA (NGS) in 670 patients (pts) (54-70 genes); Guardant Health, Inc.; (Clinical Laboratory Improvement Amendment certified and College of American Pathologists accredited). Results: The most represented cancers were gastrointestinal (31.8%), brain (22.7%), and lung (20.7%) (Table). Sixty-three percent of pts (N = 423) had ≥1 alteration. The most frequent alterations (characterized and variants of unknown significance (VUSs)) were in TP53 (32.5% of pts), followed by EGFR (13%), KRAS (12.5%), and PIK3CA (9.1%); for characterized alterations, the breakdown was 30.7% ( TP53), 7.6% ( EGFR), 12.2% ( KRAS), and 7.7% ( PIK3CA). Interestingly, 32% of brain tumors had ≥1 ctDNA alteration. Head and neck tumors were independently associated with a higher number of alterations (P=0.019). Forty-eight percent of pts (320/670) had potentially actionable alterations; in 241, (75% of 320), by an FDA-approved drug (mostly off label). Illustrative examples of clinical utility will be presented such as a patient with gastric cancer and EGFRamplification in ctDNA who received anti-EGFR treatment (60% regression), as well a patient with aggressive gynecologic malignancy who received immunotherapy based on a hypermutated ctDNA profile. Conclusions: Most pts, including a subset of those with brain tumors, demonstrated ctDNA alterations. Pts with head and neck tumors harbored higher numbers of alterations. Overall, three quarters of pts with alteration(s) had ≥1 aberration that could potentially be pharmacologically tractable, suggesting the need to further assess the utility of ctDNA in a therapeutic setting. [Table: see text]
Association of immune-related genes to neutrophil-lymphocyte ratio (NLR) with survival of cetuximab treatment for metastatic colorectal cancer (mCRC): JACCRO CC-05/06AR.
Authors: Sunakawa Yu , Yang Dongyun , LaFleur Bonnie , Luecke John , Thompson Debrah , Moran Miriana , Astrow Stephanie H. , Hsiang Jack , Zhang Wu , Tsuji Akihito , Takahashi Takehiro , Tanioka Hiroaki , Negoro Yuji , Takagane Akinori , Tani Satoshi , Yamaguchi Tatsuro , Eto Tetsuya , Fujii Masashi , Ichikawa Wataru , Lenz Heinz-Josef 
Published: September 2018

11613 Background: The antitumor activity of cetuximab (cet) may be affected by extracellular immune mechanisms. We have reported that immune-related genes are associated with survival in mCRC patients (pts) treated with cet (ASCO 2016 abstract#11591). NLR reflects cancer-related inflammation and is a validated prognostic maker in many types of cancers; however, it is not currently used for treatment decision-making. The association between NLR and clinical outcome of cet treatment for mCRC is unknown, and which genes are affecting the NLR remain to be identified. Methods: We enrolled 77 pts (57% males and 15% right-colon cancer) with KRAS exon 2 wild-type from 2 phase II trials (JACCRO CC-05 or CC-06) of 1st-line therapy with FOLFOX or SOX plus cet. All patients’ tissues were measured for expression levels of 354 immune-related genes by HTG EdgeSeq Oncology Biomarker Panel using next generation sequencing for quantitative analysis of targeted RNAs. The association between the NLR and clinical outcome was evaluated using Spearman’s rank correlation coefficient. In addition, the two-sample t-test was performed to investigate which genes had significantly different expression level between NLR-low and high groups in top 100 genes associated with survival among all measured genes. Results: Seventy-one of 77 pts were available for NLR data. The NLR was associated with progression-free survival (PFS) and overall survival (OS) (r = 0.24; p= 0.04, r = 0.29; p= 0.01, respectively). When stratified by median value of NLR, the Kaplan-Meier curve of NLR-low (n = 36) vs. high (n = 35) had a significant difference in both PFS (median 11.8 vs. 9.1 m, p= 0.036) and OS (median 42.8 vs. 26.7 m, p= 0.029). The two-sample t-test revealed that LYZ, TYMP, and CD68 genes expressed significantly differently between NLR-low and high groups (t-test p-value < 0.005, FDR p-value < 0.150). Conclusions: NLR is significantly associated with survival of 1st-line cet treatment for mCRC. Genes encoding for activities on tissue macrophages and endothelial cells may affect the level of NLR associated with outcome of cet combination chemotherapy. Clinical trial information: UMIN000010635.
A randomized trial of selenium and vitamin E for primary prevention of non-melanoma skin cancer: Trial results and experience from a low-resource setting.
Authors: Argos Maria , Dignam James J. , Parvez Faruque , Rahman Mahfuzar , Hore Samar K , Shahriar Mohammad H , Sarwar Golam , Islam Tariqul , Slavkovich Vesna , Graziano Joseph , Gamble Mary , Harjes Judith , Anton Kristen , Kibriya Muhammad Ghulam , Jasmine Farzana , Kamal Mohammed , Shea Christopher R , Yunus Md , Baron John A. , Ahsan Habibul 
Published: September 2018

1511 Background: Selenium and vitamin E supplementation previously have shown some evidence of a beneficial effect in the secondary prevention of non-melanoma skin cancer (NMSC). More than 100 million people worldwide are at increased risk of NMSC and other cancers due to arsenic exposure from drinking water and diet – a risk that persists for several decades even after the exposure has terminated. Here, we report on the design, methods and main results of the Bangladesh Vitamin E and Selenium Trial (BEST) – a population-based chemoprevention study conducted among 7,000 adults with visible arsenic toxicity. Methods: BEST is a 2 × 2 full factorial, double-blind, randomized placebo controlled trial of 7,000 adults having manifest arsenical skin lesions evaluating the efficacy of 6-year supplementation with alpha-tocopherol (100 mg daily) and L-selenomethionine (200 μg daily) for the prevention of NMSC incidence. Results: Excellent compliance was maintained through the course of the trial, based on data from pill counts, self-reported compliance, and bioadherence. Among participants on treatment through the end of the 6-year intervention period, > 85% were adherent to at least 80% of study supplements. More than 500 new NMSC cases were ascertained using a three-tiered biopsy protocol. No significant beneficial effects were observed on NMSC incidence during the study period for selenium or vitamin E. Among more than 500 observed deaths (including 182 cancer-related deaths), there were also no significant treatment effects on total mortality, cancer-related mortality or arsenical cancer-related mortality. Conclusions: This large population-based trial does not support any beneficial effect of vitamin E or selenium supplementation for the primary prevention of NMSC or mortality in an arsenic-exposed population. With the rapidly increasing burden of preventable cancers in low- and middle-income countries, efficient and feasible chemoprevention study designs and approaches, such as employed in Bangladesh, may prove impactful in conceiving large scale cancer chemoprevention trials in low-resource settings. Clinical trial information: NCT00392561.
Comparison of epigenetic aging in normal breast tissue from women with and without breast cancer.
Authors: Hofstatter Erin Wysong , Horvath Steven , Chagpar Anees B. , Wali Vikram , Bossuyt Veerle , Storniolo Anna Maria , Patwardhan Gauri , Von Wahlde Marie-Kristin , Pusztai Lajos 
Published: September 2018

1522 Background: Age is one of the most important risk factors for developing breast cancer. However, why increasing age is associated with increasing incidence of breast cancer remains poorly understood. We hypothesize that accumulated epigenetic alterations in the breast contribute to the development of breast cancer, and that such changes accumulate more rapidly in the breast during the lifetime of women who develop breast cancer as compared to their healthy peers. We therefore sought to identify an epigenetic pattern of accelerated breast tissue “aging” in women with breast cancer. Methods: Samples of normal breast tissue were collected from four cohorts of women: age < 50 years with and without breast cancer, and age ≥50 years with and without breast cancer (BC). Samples were obtained from the Susan G. Komen Tissue Bank at IU Simon Cancer Center, reduction mammoplasties and adjuvant mastectomy specimens at Yale. The Illumina Human 450K BeadChip microarray was used to generate DNA methylation profiles. Data was analyzed using the “Epigenetic Clock”, a published biomarker of aging based on 353 specific CpGs in the human genome. Clinical data collected for each subject included: age, height, weight, ethnicity, medical and reproductive history, tobacco and alcohol use, family history of breast cancer, current medications, and tumor characteristics. Results: Normal breast tissue samples from 90 subjects were analyzed (age < 50 with BC = 22, age < 50 without BC = 30, age ≥50 with BC = 15, age ≥50 without BC = 23). Age range was 24-82 years and 18-82 years for cohorts with and without BC respectively. In the cohort with BC, 95% of tumors were estrogen receptor-positive. Overall, DNA methylation tissue age (DNAmAge) was strongly correlated with chronologic age (r = 0.88, p < 0.001). However, normal breast tissue from women with breast cancer demonstrated significantly accelerated DNAmAge as compared to healthy peers (p < 0.001). Conclusions: Normal breast tissue from women with breast cancer demonstrates evidence of an accelerated epigenetic "aging" process. DNAmAge of normal breast tissue may prove to be a useful tool in identifying those women at highest risk, and lend insight into novel mechanisms of breast cancer prevention.
The frequency of a novel KANK1 and NTRK3 translocation and BRAFV600E mutation in patients diagnosed with metanephric adenoma utilizing molecular mechanisms.
Authors: Catic Aida , Sophian Ardis , Mazur Lech , Rakheja Dinesh , Kozaric Amina Kurtovic , Beslija Semir , Kogan Jillene , Pins Michael 
Published: September 2018

1537 Background: Renal metanephric adenoma (MA) is a very rare benign renal tumor, which is frequently misclassified when microscopic features alone are applied. Despite the classification of adenoma as a benign tumor, it is difficult to differentiate from other renal carcinomas such as malignant papillary renal cell carcinomas and in children it can be mistaken with Wilms tumor. The correct classification of a renal tumor is critical for diagnostic, prognostic, and therapeutic purposes. Despite the advancements in cancer genomics, there is limited data available regarding the genetic alterations critical to the metanephric adenoma development. Recent data suggest that 90% of MA have BRAFV600Emutations; the genetics of the remaining 10 % are unclear. Methods: This study was conducted on 13 FFPE specimens from patients who were diagnosed with renal metanephric adenoma. H&E stained slides from all cases were reviewed by study pathologist, and representative tissue blocks were further selected for BRAFV600E sequencing and fluorescent in situ hybridization was adapted to detect chromosomal rearrangement between KANK1 on chromosome 9 (9p24.3) and NTRK3 on chromosome 15 (15q25.3). Results: In this study, we identified a novel chromosomal translocation t(9;15)(p24;q24) between KANK1 and NTRK3, and provided new insights into molecular mechanisms which might identify a subset of metanephric adenomas. Such findings imply that recurrent cytogenetic aberrations may be of prognostic significance as well. Interestingly, our data suggested mutual exclusivity of BRAFV600Eand t(9;15) aberrations. Conclusions: Molecular and cytogenetic analyses have allowed us to elucidate a genetic aberration, which may be specific to metanephric adenoma. Aberrant expression of the KANK1-NTRK3 gene fusion may be one mechanism by which functionally relevant genes are altered in the development of metanephric adenoma, and thus mark a subgroup of metanephric adenomas with particular clinicopathological features. Also, our study adds KANK1 and NTRK3 to the list of candidate genes that may play a role in the 10% of renal metanephric adenomas that lack a BRAFV600E mutation.