bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liquid biopsy: A community-based oncology practice experience.
Authors: Choucair Khalil , Mattar Bassam Ibrahim , Truong Quoc Van , Koeneke Travis Lee , Truong Phu Van , Dakhil Christopher , Cannon Michael W. , Page Seth Joel , Deutsch Jeremy Michael , Carlson Eric A. , Moore Dennis Frederic , Nabbout Nassim H. , Kallail K. James , Dakhil Shaker R. , Reddy Pavan S. 
Published: May 2020

3527 Background: Liquid biopsy is a promising and minimally invasive genetic test examining plasma circulating tumor DNA. Coupled with the rapidly developing next-generation sequencing (NGS) technologies, it holds the potential for implementation in selecting signal-matched therapeutic options. Methods: A retrospective chart review was conducted on adult patients with advanced solid tumors whose tumors were tested with Guardant360 assay, between December 2018 and December 2019. A total of 178 patients were referred for testing by 12 oncologists within a single community cancer center. Results: Referral rates varied widely (2.25% - 22%). The majority of patients (98%) were tested upfront for molecular marker evaluation, in either newly diagnosed advanced cancer patients, or in recurrent patients without enough tissue for testing. Other patients (2%) were evaluated after failure of 1 st line therapy to assess for acquired mutations. A total of 18 histological types were tested, with lung (LCa; n = 90; 50.56%), breast (BCa; n = 31; 17.42%), and colorectal (CRCa; n = 14; 7.87%) cancers being the most common types. In 86.11% of all tests (n = 180), ≥ 1 alteration was detected, while 13.89 % of tests did not reveal any tumor-related mutation, and were considered negative. The average number of alterations per test was 3.1 (±2.14; n = 481), and varied across types: CRCa (4.36), prostate cancer (2.73), BCa (2.97), and LCa (2.59), had the highest average number of alterations per test. Similarly, LCa (48.44%), BCa (19.13%), and CRCa (12.68%), harbored most of the detected somatic alterations (n = 481). Of all the alterations of practical significance (n = 457), TP53 (32.17%), PIK3CA (8.53%), EGFR (7.66%) and KRAS (7.22%), were the most commonly altered genes. Only 1 patient had a positive MSI-H status, amenable to immune-therapy. Of those with positive test results (n = 155), 31 (20%) had ≥ 1 FDA approved, target-matched therapeutic opportunity. Similarly, 71 patients (45.81%) had ≥ 1 target-matched therapeutic opportunity, outside current indications. Lastly, when no FDA-approved target-matched therapy was available (n = 39), results from liquid biopsy testing offered signal-based clinical trial opportunity in 39/39 patients. Conclusions: Implementation of NGS-based liquid biopsy testing is feasible within a community practice. In the era of precision oncology, such assays have the potential to expedite the efforts towards target-matched therapies and signal-based clinical trial opportunities. Further studies are warranted to identify the most-cost effective testing strategies.
Genomically informed longitudinal monitoring of circulating tumor DNA (ctDNA) to predict outcomes of cancer therapy.
Authors: Gouda Mohamed Alaa , Huang Helen J , Piha-Paul Sarina Anne , Call S. Greg , Karp Daniel D. , Fu Siqing , Naing Aung , Subbiah Vivek , Pant Shubham , Tsimberidou Apostolia Maria , Hong David S. , Rodon Ahnert Jordi , Meric-Bernstam Funda , Janku Filip 
Published: May 2020

3533 Background: Short fragments of ctDNA can be detected and quantified from blood samples of patients with cancer. We hypothesize that dynamic changes in quantity of ctDNA in patients with advanced solid cancers during the first few weeks of therapy can predict treatment outcomes reported by standard imaging. Methods: We enrolled patients with advanced cancers treated with experimental therapies, who had blood collection for ctDNA isolation and testing at baseline, mid-cycle and at the time of restaging imaging. Patients who were treated with multiple treatment lines were included with separate record for each therapy. Genomically informed molecular testing of ctDNA was performed using unamplified droplet digital PCR (QX200, Bio-Rad) designed based on known molecular profile of tumor tissue and ctDNA was quantified as aggregate variant allele frequency (VAF%) for detected molecular aberrations. Patients were classified based on results of their first restaging imaging as responders (complete [CR] or partial response [PR]) vs. non-responders (stable disease [SD], progressive disease [PD]) and progressors (PD) vs. non-progressors (CR, PR, SD). Results: Total of 85 patients who received 132 courses of therapies between May 2012 and June 2019 were analyzed. Breast (N = 21), melanoma (N = 14) and cholangiocarcinoma (N = 14) were most frequent tumor types. Aggregate VAF at mid-cycle was higher in non-responders (3.98%) compared to responders (0.40%, P = 0.016) and in progressors (4.40%) compared to non-progressors (2.10%, P = 0.019) as measured by 5% trimmed mean. Similarly, aggregate VAFs at first imaging restaging was higher in non-responders (5.10%) compared to responders (0.10%, P = 0.001) and in progressors (10.80%) compared to non-progressors (0.90%, P < 0.001). Progressors demonstrated increase in ctDNA VAF at the time of the first imaging restaging compared to decrease in non-progressors (0.7% vs. -4%, P = 0.015). In addition, increase in ctDNA VAF at the first imaging restaging was associated with more PD (44% vs. 8%, P = 0.019) and less PR/CR (0% vs. 31%, P < 0.001). Median time-to-treatment failure was shorter in patients with increase in ctDNA VAF at the time of the first imaging restaging (52 days vs. 89 days, P = 0.002). Conclusions: Dynamic changes in quantity of blood-derived ctDNA within the first few weeks of therapy correspond with treatment outcomes reported by the first restaging imaging and time-to-treatment failure.
Circulating tumor DNA dynamics to predict cancer recurrence/metastasis in Chinese pathologic stage I lung adenocarcinoma.
Authors: Cheng Chao , Yang Weixiong , You Na , Jia Minghan , Yeung Sai-Ching , Yu Man , Wang Yinguang , Fu Xiayu , Liu Zhenguo , Zeng Bo , Ou Qiuxiang , Wu Xue , Shao Yang , Wang Siyu 
Published: May 2020

3537 Background: Pathologic(p)stage I lung adenocarcinoma (LUAD) patients exhibit high levels of genetic heterogeneity and the association between the genomic characteristics of (p)stage I LUADs and tumor recurrence remains poorly understood. Circulating tumor DNA (ctDNA) monitoring after resection represents a useful tool to predict response to therapy and tumor recurrence but its application in (p)stage I LUAD patients remains controversial. In addition, it is of great clinical interest to decipher the difference of genetic features between ground-glass opacity (GGO) and solid nodules (non-GGO) subgroups. Methods: Tumor tissues and matched post-operative plasma samples were collected from a total of 86 Chinese (p)stage I LUAD patients who were enrolled in a clinical study (NCT03172156). Comprehensive genomic profiling was performed using capture-based hybrid next generation sequencing by targeting 422 cancer relevant genes. Results: EGFR and TP53 represent commonly mutated genes in this cohort of (p)stage I lung adenocarcinoma, followed by alterations in ALK, PIK3CA, STK11and MYC. For a median follow up period of 21.54 months after surgical resection, we observed that ctDNA positivity significantly correlated with an increased probability of early tumor recurrence or metastasis ( P= 0.03, HR = 7.9), and in particular, the EGFR mutation status of ctDNA samples rather than that of primary tumor samples significantly correlated with shorter disease-free survival (DFS). Further comparison between GGO and non-GGO subgroups indicated that the frequency of TP53 mutations in non-GGO was markedly higher than that in GGO (48% vs 20%, P< 0.05). In addition, pathway analysis showed that the epigenetic regulation pathway was more frequently affected in the GGO subgroup, while impaired apoptosis/cell cycle pathway was more enriched in the non-GGO LUADs. Conclusions: Our data show that ctDNA positivity, including the EGFR mutation status, significantly correlated with early relapse or metastasis after surgery, representing a useful tool to predict treatment response and tumor relapse in (p)stage I LUAD patients. Mutated TP53 was more abundant in non-GGO comparing to GGO (p)stage I LUADs that may act as potential oncogenic driver in LUAD development and/or disease progression. Clinical trial information: NCT03172156 .
Noninvasive identification of lineage-specific circular RNA for ER-positive breast cancer.
Authors: Brown Jason , Shah Palak , Vo Josh , Xiao Lanbo , Niknafs Yashar , Cao Xuhong , Chinnaiyan Arul 
Published: May 2020

3543 Background: Non-invasive testing in plasma using RNA biomarkers has been limited by exoribonuclease-mediated degradation of RNA. Circular RNA (circRNA) are covalently closed RNA structures that resist this degradation due to their circular structure. Therefore circRNA are more stable than their linear counterparts. CircRNA are formed by alternative backsplicing of the 3’ end of a downstream exon to the 5’ end of an upstream exon. Here, we propose a novel method for non-invasive identification of circRNA and demonstrate circularized forms of several lineage and cancer specific targets for estrogen receptor-positive breast cancer. Methods: Capture RNA sequencing on cancer tissue was previously performed to determine the relative expression of potential circRNA isoforms in breast cancer patients. These isoforms as well as those predicted by intron length were screened using a quantitative PCR-based assay on ER-positive breast cancer cells. RNA extracted from breast cancer cells are exposed to ribonuclease R to demonstrate stability of circRNA. CircRNA derived from targets with known universal expression are used as positive controls as well as for analysis on plasma. Results: We identify the circRNA isoforms with highest expression for five genes, including ESR1, that are differentially expressed in ER-positive breast cancer compared to other cancers and normal breast tissue. We determine that the circRNA corresponding to all five targets is specifically expressed in breast cancer cell lines with at least 1000-fold higher expression than in non-ER positive breast cancer cell lines. We demonstrate that the highest expressing circRNA isoforms are resistant to degradation by ribonuclease R, whereas corresponding linear mRNA is susceptible. We also demonstrate the presence and stability of positive control circRNA in plasma from patients without cancer. Conclusions: CircRNA are promising biomarkers for early non-invasive detection of cancer due to their stability in plasma. This assay reliably detects ER-positive breast cancer specific circRNA, and exoribonuclease resistance has been validated. Application of this diagnostic assay to plasma from breast cancer patients is underway.
Circulating microtumors: A functional hallmark for cancer detection and management.
Authors: Datta Vineet , Akolkar Dadasaheb B , Patil Darshana , Crook Timothy , Page Raymond , Limaye Sewanti , Patil Revati , Fulmali Pradip , Fulmali Pooja , Devhare Pradip , Apurwa Sachin , Patel Shoeb , Patil Sanket , Schuster Stefan , Sims Cynthe , Chougule Rohit , Srinivasan Ajay , Datar Rajan 
Published: May 2020

3544 Background: There are presently no accepted non-invasive means for detection of cancers in asymptomatic individuals or suspected cases. Radiological and serological investigations, though non-invasive, are not confirmatory and necessitate an invasive biopsy to establish malignant status of suspected findings. Invasive biopsies, in turn, face challenges due to non-representative tumor tissue or in cases where biopsy is impossible or unviable. We hypothesized that Circulating Microtumors (also called as C-ETACs: Circulating Ensembles of Tumor Associated Cells) in peripheral blood are universally present in solid organ cancers and their detection can be linked to malignant status. Methods: We obtained peripheral blood from 14,138 patients with various solid organ cancers as well as 10,625 asymptomatic individuals with age associated elevated risk of cancer. Out of the 14,138 patients with cancer, 25.1 % had local (non-metastatic) disease and 56.4% had metastatic disease as confirmed by radiological evaluation. C-ETACs were enriched and harvested from PBMCs using an epigenetically activating medium that is cytotoxic towards non-malignant epithelial and hematolymphoid cells in blood but confers survival benefit on apoptosis resistant circulating cells of tumorigenic origin and their heterotypic clusters (C-ETACs) in peripheral blood. Viable C-ETACs were identified and further characterized by immunocytochemistry (ICC) profiling. Results: C-ETACs were detected in 89.7% of samples from solid organ cancers irrespective of stage, treatment or present radiological status. C-ETACs were rarely detected (3.0%) in asymptomatic individuals. The asymptomatic individuals where C-ETACs were detected are being followed up periodically so as to enable detection of cancer based on clinical or radiological manifestation of symptoms. Conclusions: C-ETACs are ubiquitous in cancers and unexpected in asymptomatic individuals. Detection of C-ETACs in asymptomatic individuals may be indicative of risk of latent undiagnosed malignancy. The non-invasiveness of this approach makes it convenient for screening large populations for cancer.
Exploring the Cancer Genome Atlas (TCGA) for the molecular profile of young onset colorectal cancers.
Authors: Khalessi Hosseini Seyed Ali , Morrissey Christy , Nakamura Takahiro , Becker Daniel Jacob 
Published: May 2020

3548 Background: Colorectal cancer (CRC) incidence and mortality has been declining, in part due to increased implementation of screening, but the incidence among patients under 50 (young onset, YO) is increasing at a rate of 2% per year. The cause of this increasing incidence remains poorly understood, but differences in mutation profiles can help understand pathogenesis, prognosis, and identify targets for therapy. Methods: Genomic and clinical data for 488 TCGA CRC patients was used to evaluate differences in genetic alterations between YO and patients over 50. Chi-squared tests were used to determine differences in somatic mutation frequency in critical pathways implicated in CRC: DNA MMR, P53, WNT, RAS-MAPK, PI3K/AKT/mTOR, and TGF-B pathways. For 85 of the patients, proteomic data via RPPA was also available and analyzed. Results: The average age of included patients was 66 (SD 12.8). 76 (12.2%) were under 50 at time of diagnosis. When comparing YO with those over 50, there were no differences in microsatellite instability, histologic type (adeno or mucinous), location (colon or rectal), tumor size, or metastasis. YO patients were more likely to have nodal involvement (p = 0.007) and higher histological grade (p = 0.022). YO patients were more likely to have mutations in the MMR pathway (43% vs 23%, p = 0.002) and the PI3K/AKT/mTOR pathway (70% vs 54%, p = 0.024). Specifically, YO were more likely to have mutations in MSH2 (7% vs 1%, p = 0.001), MSH6 (24% vs 7%, p = 0.000); ATM (46% vs 30%, p = 0.015); FZD10 (7% vs 2%, p = 0.007); ERBB2 (15% vs 7%, p = 0.027); PIK3R1 (20% vs 9%, p = 0.014), PTEN (61% vs 35%, p = 0.000), and TGFBR2 (13% vs 4%, p = 0.004). When looking at proteomic data, YO were more likely to have decreased expression of MSH2 (p = 0.003) and MSH6 (p = 0.005). Conclusions: Patients with YO CRC are more likely to have somatic mutations in genes involved in the MMR pathway and the PI3K/AKT/mTOR pathway. Specifically, in MSH2, MSH6, ATM, FZD10, ERBB2, PIK3R1, PTEN and TGFBR2. When including proteomic data, significant differences were only seen in expression of MSH2/6. Some of these genes (e.g. ERBB2/HER2) are targets for existing therapies, and others are being actively investigated as potential therapeutic targets. Establishing differences in tumor genetic profiles is a first step towards understanding the increase in YO CRC, and simultaneously identifies targets for therapy. However, because of post-transcriptional changes (e.g. RNAi, methylation), genetic profiling alone cannot always reliably establish differences in protein expression, and thus therapy targets.
Phase I expansion study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC): Preliminary efficacy, safety, and biomarker results in patients with previously treated metastatic ovarian cancer (OC) or non-small cell lung cancer (NSCLC).
Authors: Richardson Debra L. , Barve Minal A. , Strauss James Fredric , Ulahannan Susanna Varkey , Moore Kathleen N. , Hamilton Erika Paige , Johnson Melissa Lynne , Papadopoulos Kyriakos P. , Zarwan Corrine , Anderson Charles K , Buscema Joseph , Doroshow Deborah Blythe , Edenfield William Jeffery , Matulonis Ursula A. , Burns Timothy F. , Huebner Dirk , Jansen Valerie Malyvanh , Mosher Rebecca , Jarlenski Donna , Tolcher Anthony W. 
Published: May 2020

3549 Background: XMT-1536 is a first-in-class ADC targeting the sodium-dependent phosphate transport protein NaPi2b, broadly expressed in NSCLC and ovarian cancer. XMT-1536 utilizes the Dolaflexin platform to deliver 10-12 DolaLock auristatin payload molecules per antibody. In the dose-escalation portion of the Phase I study (NCT03319628), XMT-1536 showed clinical activity at doses >20mg/m2 with confirmed responses and prolonged stable disease in heavily pretreated OC and NSCLC patients, without preselection for NaPi2b expression. XMT-1536 was generally well-tolerated without the severe toxicities observed with other ADC platforms such as neutropenia, peripheral neuropathy, or ocular toxicity (Tolcher et al., ASCO 2019; Richardson et al., SGO 2020). Here, we report on the expansion (EXP) cohort, which included patients with fewer prior lines of therapy, in the ongoing Phase I study. Methods: Doses administered intravenously every 4 weeks (q4w) of 36 and 43 mg/m2 were evaluated in two cohorts (1) high grade serous ovarian, fallopian tube, or primary peritoneal cancer (OC) with up to 4 prior lines of therapy and (2) NSCLC adenocarcinoma; prior treatment with a platinum-based therapy, immune checkpoint inhibitor, and TKI, if indicated. Archival tumor tissue and tissue from a new tumor biopsy were required for retrospective evaluation of NaPi2b expression. Results: As of 10 February 2020, 23 patients (19 OC and 4 NSCLC) were enrolled in the EXP cohort: 16 dosed at 36 mg/m2 and 7 dosed at 43 mg/m2. Adverse events were generally similar to those previously reported, including transient AST elevation, fatigue, nausea, and pyrexia. Clinical responses and stable diseases have been observed. Efficacy data (objective response rate) and initial correlation of NaPi2b score with clinical response will be reported. Available data from all patients with data cutoff in May 2020 will be included. Conclusions: Overall, XMT-1536 treatment demonstrated clinical activity in high grade serous ovarian cancer and NSCLC adenocarcinoma and was generally well-tolerated with no new safety signal trends identified in the EXP. Clinical efficacy and the relevance of NaPi2b expression for treatment with XMT-1536 will be presented. Clinical trial information: NCT03319628 .
A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing, advanced solid tumors.
Authors: Mansfield Aaron Scott , Hong David S. , Hann Christine L. , Farago Anna F. , Beltran Himisha , Waqar Saiama Naheed , Hendifar Andrew Eugene , Anthony Lowell Brian , Taylor Matthew H. , Bryce Alan Haruo , Tagawa Scott T. , Lewis Karl D. , Niu Jiaxin , Chung Christine H. , Cleary James M. , Rossi Michael , Ludwig Carrianne , Valenzuela Ricardo , Luo Yan , Aggarwal Rahul Raj 
Published: May 2020

3552 Background: Delta-like 3 (DLL3) is highly and specifically expressed in solid tumors, such as neuroendocrine carcinomas (NECs), malignant melanoma (MM), and medullary thyroid carcinoma (MTC). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Methods: This Phase 1/2 study (NCT02709889) enrolled patients with relapsed/refractory DLL3+ (>1% by IHC) advanced solid tumors and ECOG performance status of 0-1. Rova-T was given IV at 0.2, 0.3, or 0.4 mg/kg on d 1 of each 6-wk cycle (q6wk) for dose escalation (3+3 design) in disease-specific cohorts in Phase I. The recommended Phase 2 dose (RP2D) was tested in Phase II. Safety and dose-limiting toxicities (DLTs) were primary endpoints; efficacy outcomes were secondary endpoints. Results: The study enrolled 200 patients; 101 had NECs (large cell NEC [n=13], neuroendocrine prostate cancer [n=21], high-grade gastroenteropancreatic NEC [n=36], other [n=31]) and 99 had other solid tumors (MM [n=20], MTC [n=13], glioblastoma [GBM; n=23], other [n=43]). The median age was 61 y (range, 28-84); 63% were male. The RP2D was 0.3 mg/kg q6wk for 2 cycles in all cohorts. There were 7 DLTs in 5 patients: 2 with 0.2 mg/kg (Grade [Gr] 3 photosensitivity reaction, Gr 3 dyspnea), 2 with 0.3 mg/kg (1 with Gr 2 effusion, Gr 3 tumor lysis syndrome, and Gr 3 rhabdomyolysis; 1 with Gr 4 kidney injury), and 1 with 0.4 mg/kg (Gr 4 thrombocytopenia). Despite only 1 DLT identified with 0.4 mg/kg, the totality of the safety data suggested that this dose is not well tolerated. Common adverse events (AEs) in patients given 0.3 mg/kg (n=145) are shown (Table). Serious AEs occurred in 77/145 patients (53%), most commonly (≥3%) malignant neoplasm progression (n=18; 12%), pleural effusion (n=7; 5%), pericardial effusion (n=6; 4%), and dyspnea (n=5; 3%). The objective response rate (ORR) was 11% (21/200): 14 had NEC, 2 had MM, 2 had MTC, 2 had small cell carcinoma (SCC) not of lung origin (all partial responses), and 1 had GBM (complete response). In patients with NECs given 0.3 mg/kg, ORR, clinical benefit rate, and progression-free survival trended in favor of those with high DLL3-expressing tumors (≥50% by IHC) which represented 51% of NECs. Conclusions: Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Clinical trial information: NCT02709889 . [Table: see text]