tbuckley/cabot-search huggingface dataset:
Effect of JAG2 on migration and invasion in colorectal cancer cell by PRAF2, independent of epithelial-mesenchymal transition.
Authors: Wan He, Han Wu, Dongcheng Liu, Wenwen Li, Ruilian Xu, Chang Zou
Journal: Journal of Clinical Oncology (2019)

e15107 Background: Our previous studies revealed the increased expression of Jagged 2 (JAG2) in most intestinal cancer tissues. In colon cancer cell lines, JAG2 involved in the regulation of migration and invasion without affecting cell proliferation. This study further explored the mechanisms of how JAG2 promotes migration and invasion of colorectal cancer cells. Methods: We analyzed the expression of JAG2 mRNA and protein in normal human colon tissue cells and colorectal cancer cells. The promotive role of JAG2 in migration and invasion was tested by JAG2 siRNA and JAG2 overexpression in various colon cancer cell lines. To understand the mechanisms, we first treated HT29 cells with LY2157299, a TGF-β signaling pathway inhibitor, and Slug siRNA, to identify the cross-talk between JAG2 and EMT pathway. In addition, co-expression status of JAG2 and TGF-β-induced epithelial-mesenchymal transition (EMT) markers was analyzed. Finally, by using siRNA and proteomics technology, co-expressed proteins of JAG2 in colorectal cancer cells were identified. Results: JAG2 was abnormally expressed in colorectal cancer tissues and directly related with clinical stages. Similar to the findings in human tissues, the expression of both JAG2 mRNA and protein was significantly increased in the colorectal cancer cell lines compared with that of normal colorectal cell line CCD18-Co. Interestingly, the promotion of JAG2 in migration and invasion was independent of EMT pathway. Furthermore, we found that the expression of JAG2 was correlated with PRAF2 (PRA1 Domain Family Member 2), a protein involved in the formation of exosome-like vesicles. In the presence of PRAF2, JAG2-rich exosome promoted migration and invasion. JAG2 might regulate the migration and invasion of colon cell through PRAF2. Conclusions: This is the evidence supporting the biological function of JAG2 in migration and invasion through non-EMT-dependent pathways and also the first exploration of the role of PRAF2 in colorectal cancer cells. These findings provide the theoretical basis for potential targeted therapy against JAG2/PRAF2.
SAVANNAH: A Phase II trial of osimertinib plus savolitinib for patients (pts) with <i>EGFR</i>-mutant, <i>MET</i>-driven (<i>MET</i>+), locally advanced or metastatic non-small cell lung cancer (NSCLC), following disease progression on osimertinib.
Authors: Geoffrey R. Oxnard, Mireille Cantarini, Paul Frewer, George Hawkins, Jane Peters, Paul Howarth, Ghada F. Ahmed, Tarjinder Sahota, Ryan Hartmaier, Xiaocheng Li-Sucholeiki, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2019)

TPS9119 Background: The toxicity profile of the third-generation EGFR-tyrosine kinase inhibitor (TKI) osimertinib makes it an attractive backbone for combination with other targeted agents, possibly overcoming acquired resistance mechanisms. Combination with a MET-inhibitor is an intuitive approach as MET-amplification was identified as the most common mechanism of resistance to osimertinib in preliminary ctDNA data from the Phase III FLAURA (15% of pts) and AURA3 (19% of pts) studies. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI that had an acceptable safety profile when combined with osimertinib in the Phase Ib TATTON study, providing the basis for this Phase II SAVANNAH study (NCT03778229). Other mechanisms of acquired resistance to osimertinib, including secondary EGFR mutations (e.g. C797S), RAS/RAF activation, and oncogenic gene fusions, provide additional opportunities for developing osimertinib-based combinations. Methods: Eligible pts will have histologically/cytologically confirmed EGFR-mutant NSCLC, and MET+ disease by central FISH, central IHC, or local NGS (retrospectively confirmed by central FISH/IHC). Pts must have documented radiological progression following 1–3 lines of prior therapy (must include osimertinib). Pts will receive osimertinib 80 mg plus weight-based dosing with savolitinib 300 or 600 mg PO QD, in 28-day cycles. The primary objective is efficacy (RECIST 1.1) by overall response rate (ORR) in pts who are MET+ by central FISH. Secondary endpoints include: ORR ( MET+ by central IHC and all pts); progression-free survival, overall survival, duration of response, percent change in tumor size, HRQoL, and EGFR mutation ctDNA clearance ( MET+ by central FISH, central IHC, and all pts); safety, and pharmacokinetics (all pts). Based on the TATTON study, we anticipate enrolling ~172 MET+ pts to include ≥117 pts with MET+ disease by central FISH. Enrolment began in Q1 2019. Ongoing development of complementary trials targeting other osimertinib resistance mechanisms will also be discussed. Clinical trial information: NCT03778229.
Safety and disease control achieved with the addition of nivolumab (Nivo) to chemoradiotherapy (CRT) for intermediate (IR) and high-risk (HR) local-regionally advanced head and neck squamous cell carcinoma (HNSCC): RTOG Foundation 3504.
Authors: Maura L. Gillison, Robert L. Ferris, Jonathan Harris, A. Dimitrios Colevas, Loren K. Mell, Christina Kong, Richard C. Jordan, Kevin Moore, Minh Tam Truong, Claudia Kirsch, David Anthony Clump, James Ohr, Kai He, Dukagjin Blakaj, John F. Deeken, Mitchell Machtay, Walter John Curran, Quynh-Thu Le
Journal: Journal of Clinical Oncology (2019)

6073 Background: Nivo, which inhibits the programmed death-1 (PD-1) receptor, improved survival for pts with platinum-refractory recurrent/metastatic HNSCC. A clinical trial evaluated the safety of adding nivo to 4 standard intensity modulated (chemo) radiotherapy (RT) regimens (see table) for pts with newly diagnosed IR/HR HNSCC. Primary endpoint was safety and feasibility. Methods: Eligibility included IR (p16+ oropharynx [op], T1-2N2b-N3/T3-4N0-3, &gt;10 pack-years [pys], or T4N0-N3/T1-3N3, ≤10 pys) &amp; HR HNSCC (oral cavity, larynx, hypopharynx, p16- op, T1-2N2a-N3/T3-4N0-3). 10 pts/arm (8 evaluable; 0-2/8 DLTs acceptable). Nivo (dose &amp; schedule varied per arm) started 2 wks pre-RT &amp; continued 3 months post-RT. Feasibility of adjuvant nivo months 3-12 post-RT defined as ≥4 of 8 pts/arm received 7 doses. Arm 4 limited to age ≥70, Zubrod performance status (PS) 2, CrCl &lt;50 ml/min, grade ≥2 hearing loss or ≥ grade 3 neuropathy. Results: Characteristics of 39/40 treated pts: median age 62, 79% male, 49% PS0, 38% HR, 67% &gt;10 pys, 62% p16+ op, 72% T3-4, 85% N2-3. Grade ≥3 nivo-related AEs: adrenal insufficiency, diarrhea-3, anemia, fatigue-2, mucositis-3, nausea, vomiting, lipase increase-6, amylase increase-2, lymphocyte/neutrophil/WBC decrease-4, hyponatremia-3, anorexia, maculo-papular rash. SAE in 4/10, 4/9, 5/10 &amp; 4/10. DLTs, adjuvant chemo feasibility, median follow-up (mo), progression or death events per arm shown in table. Conclusions: Nivo concomitant with all (chemo)RT regimens was safe for patients with newly diagnosed IR/HR HNSCC but adjuvant nivo was infeasible after high-dose cisplatin or in cisplatin-ineligible patients ( NCT02764593 ). Preliminary data on progression/death is provided. Acknowledgements: Support for this study was provided by Bristol-Myers Squibb Company. Clinical trial information: NCT02764593. [Table: see text]
Microsatellite instability assessment of FFPE tumor samples through targeted next-generation sequencing.
Authors: Elaine Wong-Ho
Journal: Journal of Clinical Oncology (2019)

e14213 Background: Immunotherapies to treat malignancies have shown great promise, however, only a fraction of cancer patients respond to immunotherapy, making it imperative to identify biomarkers that predict response. Cancer-associated instabilities at microsatellite locations throughout the genome have been shown to be predictive of response to immunotherapy treatment. Here we determine the accuracy of determining the MSI status through targeted sequencing using Ion Torrent sequencing technology. Methods: We have identified optimal chemistry and developed a novel algorithm to assess MSI status of samples using a large number of markers on the Ion GeneStudio S5 Series sequencer. The diverse marker set includes monomers that vary in length between 10 BP and 40 BP in addition to di-and tri-nucleotide STR markers. Each sample is assigned an MSI score based on features that measure MSI response of markers in the assay. Results: We evaluated performance of the MSI markers in the context of a comprehensive targeted next generation sequencing assay with the MSI algorithm. A large set of FFPE tumor samples and MSI controls were evaluated. The resulting scores were in concordance with results from capillary electrophoresis studies. Conclusions: In summary, a next-generation sequencing based assay using multiple markers was developed to assign MSI status to FFPE tumor samples. The accuracy of the assay was validated using an orthogonal test. This allows us to use Ion Torrent sequencing technology to identify changes in complex repeat regions of the genome as part of a comprehensive genomic profiling approach.
A pilot study of neoadjuvant FOLFIRINOX followed by chemoradiation for gastric and gastroesophageal cancer: Preliminary results.
Authors: Jennifer Yon-Li Wo, Jeffrey William Clark, Jill N. Allen, Lawrence Scott Blaszkowsky, Florence Keane, Lorraine C. Drapek, David P. Ryan, Ryan Bruce Corcoran, Eric Roeland, Aparna Raj Parikh, Melin Janardan Khandekar, Rebecca Suk Heist, Christopher Morse, Beow Y. Yeap, Christine A Ulysse, Benjamin Christopher, Michael Lanuti, David L. Berger, John Thomas Mullen, Theodore S. Hong
Journal: Journal of Clinical Oncology (2019)

4057 Background: We performed a single-arm pilot study of total neoadjuvant approach including FOLFIRINOX and chemoradiation (CRT) with concurrent carboplatin/taxol (C/T) followed by surgery in patients with locally advanced gastric or gastroesophageal junction (GEJ) cancer. Methods: Patients were enrolled on a NCI sponsored, prospective, single arm study (NCT03279237). Key eligibility criteria included: histologically confirmed T3/4 or lymph node (LN) positive gastric or GEJ cancer, ECOG PS ≤1, age 18+, life expectancy &gt; 3 months. Exclusion criteria included: visceral metastases, prior chemotherapy or RT, or prior targeted therapy. Extensive LN disease beyond the surgical field (supraclavicular or para-aortic) was permitted if deemed feasible to be encompassed within a RT field. Laparoscopy was not required. Pts were treated with neoadjuvant FOLFIRINOX x 8, restaging, CRT (45 Gy for gastric, 50.4 Gy for GEJ) with concurrent C/T, restaging, followed by surgical resection. Dose reductions were at discretion of the treating physician. The primary objective was to determine the rate of completion of FOLFIRINOX x 8 followed by CRT delivered in the preoperative setting. Secondary endpoints included: 1) acute toxicity and 2) pathologic complete response (pCR). Results: From Oct 2017 to June 2018, 25 pts were enrolled. Median age was 60 (range:30-76), 17 pts were male (68%). All pts started FOLFIRINOX; 23 (92%) pts completed all 8 planned cycles. Two pts did not complete the planned 8 cycles due to metastatic progression. Rates of grade 3+ overall, gastrointestinal, and hematologic toxicities were 28%, 12%, and 28% respectively. Of the entire cohort, 23 (92%) pts started chemoRT and 22 (88%) pts completed chemoRT (1 pt died during CRT due to pulseless electrical activity arrest). All 22 pts (88%) who completed CRT went for surgical exploration, of whom 2 pts were found with intraoperative metastases. Therefore, 20 (80%) pts underwent surgical resection. At time of abstract, 1 pt’s pathology is in process; 7 pts had a pCR (37% in resected cohort, 28% in ITT cohort), all with R0 resection. Conclusions: Total neoadjuvant FOLFIRINOX followed by CRT is feasible with acceptable rates of treatment completion and grade 3+ toxicity. In our small series, the rate of pCR is promising and a follow-up study is currently planned. Clinical trial information: NCT03279237.
GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.
Authors: Bart Neyns, Laila Ben Salama, Gil Awada, Jennifer De Cremer, Julia Katharina Schwarze, Laura Seynaeve, Stephanie Du Four, Lydia Fischbuch, Anne-Marie Vanbinst, Hendrik Everaert, Alex Michotte, Anne Rogiers, Peter Theuns, Johnny Duerinck
Journal: Journal of Clinical Oncology (2019)

2034 Background: Patients (pts) with recurrent glioblastoma (rGB) have a poor prognosis, and no treatment option demonstrated to improve survival in a randomized trial. Axitinib (AXI), an oral VEGFR 1-3 inhibitor has demonstrated single agent activity in rGB and reduces the need for corticosteroids (CS). Avelumab (AVE) is a fully human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types. Combination of AXI and AVE may improve the outcome of pts with rGB. Methods: This open-label, dual-strata, single-center phase 2 clinical trial investigated the activity of AXI plus AVE in adult pts with rGB following prior surgery, RT and temozolomide. Pts were stratified according to their baseline use of CS. Pts without baseline need for CS initiated treatment with AXI (5 mg oral BID) plus AVE (10 mg/kg IV Q2W) (cohort-1). Pts in need of CS initiated AXI as a monotherapy; AVE could be added to AXI after 6 wks if the CS dose could be tapered to a physiologic dose level or less (cohort-2). Six-month-PFS served as the primary endpoint (with a prespecified threshold of ≥ 50% for cohort-1) according to Fleming one-stage design. Results: Between Jun 2017 and Aug 2018, 54 pts (27 per cohort) were enrolled (med age 55 y [range 19-75]; 63% male; 91% WHO PS 0-1). All pts in cohort-1 and 16 pts (59%) in cohort-2 received at least 1 dose of AVE. The 6-month-PFS was 18% (95% CI 4-33) in both cohorts. At the time of analysis, 2 pts were progression-free and continuing study treatment. Median OS in cohort-1 and -2 was respectively 26 wks (95% CI 21-32) and 18 wks (95% CI 14-22). No clear relation was found between baseline cognitive functioning (Cogstate subtests) and PFS/OS. The best overall response rate (iRANO) was 41% and 26% respectively for pts in cohort-1 and -2. The most frequent all-grade treatment-related adverse events (TRAE) were dysphonia (67%), lymphopenia (50%), diarrhea (48%), hypertension (48%), and fatigue (46%). The incidence of grade 3-4 TRAE was 30%; there were no grade 5 AE. Conclusions: The combination of AVE plus AXI is sufficiently well tolerated but did not meet the threshold for activity justifying further investigation in an unselected population of patients with rGB. Clinical trial information: NCT03291314.
Clinical downstaging and quality of life after neoadjuvant chemotherapy in patients with locally advanced rectal cancer: Interim analysis from a phase II clinical trial.
Authors: Ahmed Abdalla, Amr M. Aref, Amer Alame, Danny Ma, Mohammed Barawi, Susan Szpunar, Karrah Lambert, Zyad Kafri
Journal: Journal of Clinical Oncology (2019)

e15178 Background: The role of neoadjuvant FOLFOX in achieving clinical downstaging and improvement in quality of life (QOL) in patients with locally advanced rectal cancer (LARC) remains to be established. We are conducting a phase II prospective clinical trial to evaluate the use of six cycles of FOLFOX as neoadjuvant chemotherapy in patients with T2-T3/N0-N+ rectal cancer. We now report tumor clinical downstaging and patient-reported QOL in our first patient cohort. Methods: Eleven Patients enrolled in our phase II prospective trial. Patients received three months of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) administered every two weeks. After three weeks of recovery, each patient was treated with conventional chemo-radiotherapy (5FU or capecitabine) All patients had an MRI and endorectal ultrasound at baseline and after completion of FOLFOX. A compilation of validated QOL questionnaires were also administered before and after FOLFOX. Results: A total of 11 patients completed the chemotherapy regimen. Based on pelvic MRI, complete clinical response (T0N0) was achieved by seven patients (64%), one patient (9%) was clinically downstaged but three (27%) didn’t have any changes following FOLFOX. Importantly, we found no disease progression during the FOLFOX course. QOL assessment after FOLFOX regimen showed trend towards improvement in general health, mobility, bladder control and psychological health. These changes in QOL were not statistically significant due to the small sample size. Patients self-grading of their general health before starting FOLFOX was 50% compared to 75% after. Of the five patients with pain at time of diagnosis, four reported complete pain relief while the fifth reported improvement from extreme to moderate pain. Three patients reported improvement in their anxiety/depression. In terms of bowel function, although there was trend towards improvement in the urgency subscale, other bowel functions subscales were unchanged. In general, scores for mobility, selfcare, and bladder function were slightly better after FOLFOX. Conclusions: This study suggests that adding only six cycles of neoadjuvant FOLFOX before CRT not only resulted in clinical downstaging of (LARC) but showed a trend toward improved QOL. This result provides some reassurance for oncologists that this approach does not diminish QOL with no risk of disease progression during the time of neoadjuvant chemotherapy. These findings need to be validated in a larger phase III trial.
Association of PFS with levels of pretreatment lactate dehydrogenase in patients with EML4-ALK rearrangement non-small cell lung cancer treated with ALK tyrosine kinase inhibitor.
Authors: Hongge Liang, Di Ma, Yan Xu, Jing Zhao, Minjiang Chen, Xiaoyan Liu, Wei Zhong, Mengzhao Wang, Li Junling
Journal: Journal of Clinical Oncology (2019)

e20513 Background: We performed a retrospective analysis to investigate the association between the lactate dehydrogenase (LDH) levels and progression-free survival (PFS) in patients with echinoderm microtubule-associated protein-like 4-anaplasticlymphoma kinase (EML4-ALK) rearrangement non-small cell lung cancer (NSCLC) receiving treatment with crizotinib. Methods: Advanced NSCLC patients with EML4-ALK rearrangement receiving treatment with crizotinib were enrolled at Peking Union Medical College and Cancer Hospital Chinese Academy of Medical Sciences between January 2007 and January 2016. Pre-treatment or post-treatment serum LDH levels were analyzed with progression-free survival (PFS) and patients’ clinical parameters. Results: Overall, 212 patients were studied. Kaplan-Meier univariate analysis showed that elevated pre-treatment LDH level (7.9 vs. 14.1 months, P = 0.004) were associated with PFS, while the mean value of post-treatment LDH level (14.3 vs. 13.3 months, P = 0.970) were not associated with PFS. Coxproportional hazards model also identified that pre-treatment LDH level (hazard ratio [HR] = 1.841, 95% confidence interval [CI] 1.062-3.190, P = 0.030) was associated with the PFS. Logistic regression analysis showed that post-treatment LDH level was associated with creatine kinase(OR = 6.712, 95% CI 3.395-13.273, P &lt; 0.01), CKMB (OR = 6.297, 95% CI 2.953-13.427, P &lt; 0.01), and hemoglobin(OR = 4.163, 1.741-9.956, P = 0.001). Conclusions: An elevated pre-treatment serum LDH level ( &gt; 250U/L) is significantly associated with shorter PFS in patients with EML4-ALK rearrangement NSCLC. Post-treatment elevated serum LDH level is associated with multiple factors including muscle damage and anemia, rather than PFS.
PRIMUS-002: A multicentre, open-label, phase II study examining FOLFOX and <i>nab</i>-paclitaxel (FA) and <i>nab</i>-paclitaxel and gemcitabine (AG) as neoadjuvant therapy for (borderline) resectable pancreatic cancer (PC), focusing on biomarker and liquid biopsy development.
Authors: Derek B. Grose, Colin J McKay, Susie Cooke, Janet Shirley Graham, Fraser Duthie, Nigel Jamieson, Reena Ravikumar, Aileen Duffton, David McIntosh, Rebecca Goody, Ganesh Radhakrishna, Maria A Hawkins, Dave Colville, Christine Willshire, Jon Stobo, James Paul, Sarah Bradley, Judith Dixon-Hughes, Andrew Victor Biankin, David Kuang-Fu Chang
Journal: Journal of Clinical Oncology (2019)

TPS4166 Background: There is increasing evidence suggesting benefit from a neoadjuvant approach to PC. However, the optimal regimen is unclear and will likely require a precision medicine approach, where patient and tumor attributes define therapy. Platinum-containing regimens have shown survival benefit for PC, with occasional exceptional responders, but biomarkers (BM) of response are not well defined and treatment decisions are often based on patient performance status (PS) and co-morbidity. Tumors with defects in BRCA1/2and other Fanconi Anemia genes show defective DNA damage response (DDR), conferring potential selective sensitivity to DNA-damaging agents (e.g. platinum) and newer targeted agents. We have shown that DDR deficiency (DDRd) is present in up to 20% of PC. This study aims to exploit DDRd as a therapeutic vulnerability, with integrated analysis to define candidate BM for FA and AG response. Methods: PRIMUS-002 will enroll patients registered on the Precision-Panc Master Protocol who are molecularly profiled using the Precision-Panc Clinical Cancer Genome including a novel DDRd assay, and the transcriptome with longitudinal sampling (pre-, during, and post-treatment). Patients receive either FA ( nab-paclitaxel 150mg/m 2 IV,oxaliplatin 85mg/m 2 , folinic acid 350mg flat dose, fluorouracil infusion 2400mg/m 2 continuous IV infusion), orAG ( nab-paclitaxel 125mg/m 2 , gemcitabine 1000 mg/m 2 ) for 3 months,based on patient age and PS.Following initial safety analysis, chemoradiation may be introduced. The primary endpoint is disease progression (DP) during neoadjuvant therapy. The study is designed to detect a 20% difference in DP between the BM+ve (10%) and BM –ve (30%) in patients treated with FA (90% power, 5% 1-sided level of statistical significance)., Exploratory translational endpoints include surrogate therapeutic response assessment using CA19.9, PET-CT SUV, DWI-MRI and ctDNA. Current Enrolment: 2 patients enrolled to date: 1 to receive FA and 1 to AG treatment. Clinical trial information: ISRCTN34129115.