tbuckley/cabot-search huggingface dataset:
Implementation of a low-dose computerized tomography (LDCT) lung cancer screening program (LCSP) across a large integrated health system.
Authors: Marija Bjegovich-Weidman, Steven Leh, Daniel Malone, Raul Mendoza-Ayala, Anne Marie Barry-Weers, Laurie Dlouhy, Jody Wesolowski, Dorry Mitchell, Kevin Clement, Bock Amy, James L. Weese
Journal: Journal of Clinical Oncology (2019)

1537 Background: The LDCT LCSP was launched as a critical component of our Cancer Program to support tobacco cessation efforts and increase early detection. Initially it was offered as a self-referral low cost screening. The program was expanded when the Affordable Care Act and Center for Medicare/Medicaid Services covered it as a preventative services benefit in January 2015. Methods: 9 LDCT LCSP locations were implemented between 2014-September 2016. Program data are submitted to the American College of Radiology Lung Cancer Data Registry since 2016. In 2017, a Best Practice Alert was created within our electronic health record (EHR) to alert the primary care clinician if his/her patient met criteria for a LDCT. Each of the sites managed their own programs up until September 2018 when a dedicated team (Team) of two nurses and one data support specialist was justified. The Team focus is to increase awareness of the LDCT LCSP and criteria for eligibility, improve tobacco history taking and pack year documentation in the EHR, increase smoking cessation counseling and referral, and facilitate presentation of all Lung RADS category 4 cases for review at one of our two Multidisciplinary Lung Cancer Case Conferences. Standardized management of key incidental findings was developed for coronary artery calcification, non-lung masses, thoracic aortic aneurysm, and critical pulmonary conditions. To date, we have not examined the impact of the LDCT LCSP on smoking cessation rates. All 9 program sites have been named a Screening Center of Excellence by the Lung Cancer Alliance. Results: In 2016, 1849 LDCT Screenings were performed, 4701 (154% increase) in 2017 and 7154 (52.5% increase) in 2018. Cancer Detection rates were 1.3% in 2016, 1.8% in 2017 and 1.3% for January-June 2018. Cancer registry data reports a 9% increase in Stage 0, 1, 2A and a 7.2% decrease in Stage IV at time of diagnosis from 2014-2017. Conclusions: The implementation of a LDCT LCSP has increased the percentage of patients diagnosed at an earlier stage of lung cancer. With standardized management of key incidental findings, we anticipate improvement in early detection and management of cardiac and pulmonary diseases.
CALLA: Efficacy and safety of durvalumab with and following concurrent chemoradiotherapy (CCRT) versus CCRT alone in women with locally advanced cervical cancer: A phase III, randomized, double-blind, multicenter study.
Authors: Bradley J. Monk, Jyoti Mayadev, Ana T Nunes, Alicja Dabrowska Brown, Michelle Marcovitz, Mark C. Lanasa
Journal: Journal of Clinical Oncology (2019)

TPS5597 Background: CCRT is the standard of care for locally advanced cervical cancer. CCRT with PD-1/PD-L1 pathway blockade may promote a more immunogenic environment through increased phagocytosis, cell death, and antigen presentation, leading to enhanced immune-mediated tumor surveillance. This Phase 3, randomized, multicenter, international, double-blind, placebo-controlled study is designed to determine the efficacy and safety of durvalumab with and following CCRT vs. CCRT alone in women with locally advanced cervical cancer (NCT03830866). Methods: The study will enroll immunotherapy-naïve adult patients (pts) with histologically confirmed cervical adenocarcinoma or cervical squamous or adenosquamous carcinoma (FIGO Stages IB2-IIB with node [N] positive and IIIA-IVA with any N) and no prior definitive surgical, radiation, or systemic therapy for cervical cancer. Approximately 714 pts will be randomized 1:1 to receive either durvalumab (1500 mg intravenously [IV]) or placebo every 4 weeks for 96 weeks. All pts will receive CCRT to the pelvis or pelvis + para-aortic radiotherapy field (45 Gy), followed by image-guided brachytherapy with cisplatin (40 mg/m 2 ) IV or carboplatin (AUC2) IV once weekly for 5 weeks (6 th dose optional). Randomization will be stratified by disease stage (FIGO Stage &lt; III and N positive, FIGO Stage ≥III and N negative, or FIGO Stage ≥III and N positive) and region (US, Canada, EU, South Korea, and Japan vs. rest of the world). The primary endpoint is progression-free survival (assessed by investigator per RECIST v1.1 or histopathologic confirmation of local tumor progression). Secondary endpoints are overall survival, objective response and complete response (CR) rates, duration of response in pts with CR, incidence of local or distant disease progression or secondary malignancy, disease-related symptoms, and health-related quality of life (EORTC QLQ-C30 and EORTC QLQ-CX24). Pharmacokinetics, immunogenicity, and safety of durvalumab will also be assessed. Pt enrollment is ongoing. Clinical trial information: NCT03830866.
Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343
Authors: Marlon J. Hinner, Rachida Siham Bel Aiba, Thomas J. Jaquin, Sven Berger, Manuela Carola Dürr, Corinna Schlosser, Andrea Allersdorfer, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Louis Matis, Shane Anthony Olwill
Journal: Clinical Cancer Research (2019)

4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in cancer. To overcome limitations of current 4-1BB-targeting antibodies, we have developed PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 is designed to facilitate T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation.PRS-343 was generated by the genetic fusion of 4-1BB-specific Anticalin proteins to a variant of trastuzumab with an engineered IgG4 isotype. Its activity was characterized using a panel of in vitro assays and humanized mouse models. The safety was assessed using ex vivo human cell assays and a toxicity study in cynomolgus monkeys.PRS-343 targets 4-1BB and HER2 with high affinity and binds both targets simultaneously. 4-1BB-expressing T cells are efficiently costimulated when incubated with PRS-343 in the presence of cancer cells expressing HER2, as evidenced by increased production of proinflammatory cytokines (IL2, GM-CSF, TNFα, and IFNγ). In a humanized mouse model engrafted with HER2-positive SK-OV-3 tumor cells and human peripheral blood mononuclear cells, PRS-343 leads to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. In IND-enabling studies, PRS-343 was found to be well tolerated, with no overt toxicity and no relevant drug-related toxicologic findings.PRS-343 facilitates tumor-localized targeting of T cells by bispecific engagement of HER2 and 4-1BB. This approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity compared with current monospecific approaches. The reported data led to initiation of a phase I clinical trial with this first-in-class molecule.See related commentary by Su et al., p. 5732.
Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations.
Authors: Joon Oh Park, Yin-Hsun Feng, Yen-Yang Chen, Wu-Chou Su, Do-Youn Oh, Lin Shen, Kyu-Pyo Kim, Xiufeng Liu, Yuxian Bai, Huimin Liao, Jing Nie, Min Qing, Qinmei Ji, Jiongyan Li, Mianzhi Zhao, Peter De Porre, Manish Monga
Journal: Journal of Clinical Oncology (2019)

4117 Background: Patients (pts) with advanced CCA who progressed on or after first line chemotherapy have no approved treatment options. Fibroblast growth factor receptor (FGFR) gene alterations are observed in many tumor types including 14-17% in CCA. Erdafitinib, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown clinical activity against solid tumors with FGFR alterations. Methods: LUC2001 is an open-label, multicenter, Ph2a study in advanced CCA pts with FGFR alterations (FoundationOne), who progressed after ≥ 1 prior treatment. The primary endpoint is objective response rate (ORR; RECIST 1.1). The secondary endpoints are disease control rate (DCR), progression free survival (PFS), duration of response (DOR), safety and pharmacokinetics (PK). Disease is evaluated every 8 weeks until disease progression (PD). Results: As of 3 Dec 2018, 222 CCA pts were molecularly screened; 34 had FGFR alterations, of whom 14 (8 FGFR2 fusion, 3 FGFR2 mutation, 1 FGFR3 fusion, 2 FGFR3 mutation) were dosed 8 mg once daily with up titration option. Median age was 51.5 years. 13/14 and 12/14 pts had prior platinum or gemcitabine based therapy respectively, 7/14 pts got re-treated with platinum or gemcitabine based therapy, and 9/14 pts had ≥2 prior lines of therapy. Median number of treatment cycles was 5.0 (range: 1; 22) and treatment duration was 4.83 (range: 0.5; 20.3) months. In 12 evaluable pts, there were 6 confirmed partial response (PR), 4 stable disease (SD) and 2 PD; ORR (CR+PR) was 6/12 (50.0%), DCR (CR+PR+uCR+uPR+SD) was 10/12 (83.3%); median DOR was 6.83 months (95% CI: 3.65; 12.16); median PFS was 5.59 months (95% CI: 1.87, 13.67). In 10 evaluable FGFR2+ pts, ORR was 6/10 (60.0%); DCR was 10/10(100%); median PFS was 12.35 months (95% CI: 3.15, 19.38). The most common TEAEs ( &gt; 30%) were hyperphosphatemia, dry mouth, stomatitis, and dry skin. 9 pts had ≥ Grade 3 AEs (8 Grade 3,1 Grade 5), of which 7 drug related. TEAE led to treatment 1 discontinuation, 6 dose reductions and 1 death (not drug related). The results of PK and PK/PD relationship were consistent with other erdafitinib studies in different ethnic background pts. Conclusions: Asian advanced CCA pts with FGFR alterations treated with erdafitinib had encouraging efficacy and acceptable safety profile similar to experience in other tumor types and populations. Clinical trial information: NCT02699606.
Serial circulating tumor DNA analysis indicating the efficacy and prognosis of neoadjuvant chemotherapy for locally advanced breast cancer.
Authors: Yidong Zhou, Yaping Xu, Yuhua Gong, Jiaolin Zhou, Yaping Lu, Changjun Wang, Ru Yao, Li Peng, Yan-Fang Guan, Jiayin Wang, Xuefeng Xia, Ling Yang, Xin Yi, Qiang Sun
Journal: Journal of Clinical Oncology (2019)

e12089 Background: The efficacy evaluation of neoadjuvant chemotherapy (NCT) for locally advanced breast cancer (LABC) is still a questionable issue. The clinical imaging is always discrepant from pathological assessment postoperatively, and conventional tumor markers, such as CEA and CA15-3, did not show significantly correlation with the response to NCT in breast cancer patients. Analysis of circulating tumor DNA (ctDNA) from blood may provide a promising alternative. Methods: Collectively, 63 tissue and 204 blood samples from 32 patients with LABC were collected. There were four sampling nodes for blood collection: at baseline, during chemotherapy, after chemotherapy and after operation. Hybrid capture-based genomic profiling with a 1021-gene panel was carried out for both tissue and blood samples. Results: Totally, 151 somatic mutations were detected in tissue samples from 32 patients. TP53 (n = 14, 43.75%) and PIK3CA (n = 13, 40.63%) were the most recurrent mutant genes. Among 11 patients with HER2 overexpression, 10 (90.91%) carried ERBB2 amplification. All of 21 patients with normal HER2 present diploid ERBB2. The overall concordance between HER2 overexpression and ERBB2 amplification was 96.88%. At least one tissue mutation could be detected in blood collected at baseline for 21 patients, during chemotherapy for three patients, after chemotherapy for nine patients, and after operation for four patients. There was no tissue mutation in blood collected during and after chemotherapy for four patients reached pathologic complete response (pCR). The median of pathological tumor decrease in situ was 54.63% (17.07% to 98.04%) for patients with tissue mutations in blood collected either during or after chemotherapy, and 86.53% (7.69% to 98.04%) for patients without tissue mutation in both blood samples. Furthermore, the median number of pathologically involved lymph nodes was 3.5 (0 to 16) and 1 (0 to 9) for two patients cohort, respectively. All of four patients with tissue mutations in postoperative blood experienced distant metastasis during follow-up, while only 7.14% (2/28) of those without tissue mutation relapsed. The median DFS was 9.8 and 22.7 months, respectively (HR 26.14, 95% CI 1.161 to 588.5, p &lt; 0.0001). Conclusions: Sequential genomic profiling of blood ctDNA can be used to evaluate the therapeutic efficacy of NCT, as well as the postoperative survival. This study highlights the feasibility of integrating ctDNA profiling into the clinical management for LABC undergoing NCT. Clinical trial information: NCT02797652.
Elucidation of qualitative patient-reported outcome (PRO) data using latent dirichlet allocation (LDA) in patients (pts) undergoing radical cystectomy.
Authors: Thomas Michael Atkinson, Bruce D. Rapkin, Elizabeth Schofield, Bernard H. Bochner, Yuelin Li
Journal: Journal of Clinical Oncology (2019)

e18245 Background: As PROs become commonplace in clinical trials and routine care, we must identify efficient analytic methods to better understand and ultimately integrate this information into clinical decision-making. While PROs are often captured via qualitative methods to provide context and pt voice to traditional objective and/or quantitative assessments, the current analytic standard is resource intensive and impractical for timely delivery of this information to clinicians and trialists. To address this problem, we propose the use of LDA, a natural language processing technique that automates the distillation of vast amounts of free-text data into underlying topics. Methods: As part of a prospective longitudinal trial of pts ( N = 200; M age = 63.8; 20% female; 46%) undergoing radical cystectomy (52% stage T2-T4) and urinary diversion (49% continent) for bladder cancer (ClinicalTrials.gov identifier NCT00745355), pts completed 30 minute interviews at baseline and 6-months post-surgery where they were asked to characterize their quality of life with respect to goals or milestones they would like to reach, problems they would like to solve, situations they would like to prevent, things they would like to remain the same, and commitments they would be willing to let go. LDA was used to extract latent topics and themes, stratified by time. Results: LDA extracted 7 latent topics and showed shifting patient priorities. At baseline, pt primary concerns were related to surgery and recovery. Six months post-surgery, pt goals transitioned toward themes related to concerns about cancer recurrence, regaining a sense of normalcy, return to work, enjoyment of life and increased appreciation of friends and family. Conclusions: LDA was used as an automated tool to illustrate a shift in pt goals and concerns as they transition into survivorship. This novel data analytic technique offers the possibility of significantly reducing the resources required to summarize qualitative PRO data. As such, this information may now be more readily available for immediate inclusion in the decision-making process as part of routine care and clinical trials. Clinical trial information: NCT00745355.
Evaluation of predictive biomarkers for AR therapy and to identify the LAR subtype of TNBC.
Authors: Sahil Seth, James Crespo, Lei Huo, Alastair Mark Thompson, Elizabeth A. Mittendorf, Kenneth R. Hess, Jennifer Keating Litton, Gaiane M Rauch, Beatriz E Adrada, Senthil Damodaran, Rosalind P Candelaria, Banu Arun, Wei Tse Yang, Lumarie Santiago, Rashmi Krishna Murthy, Aysegul A. Sahin, William Fraser Symmans, Stacy L. Moulder, Naoto T. Ueno, Bora Lim
Journal: Journal of Clinical Oncology (2019)

595 Background: Androgen-receptor-like (LAR) triple-negative breast cancer (TNBC) is a subtype identified using Vanderbilt’s molecular signature. LAR subtype has the lowest pCR rate for NACT among all TNBC subtypes (10% vs. 28% for TNBC in general). We launched a clinical trial to determine the effectiveness of enzalutamide and paclitaxel (ZT) in improving this poor chemo. response in the neoadjuvant setting for pts with anthracycline-refractory, androgen receptor (AR)+ TNBC (NCT02689427). However, we do not yet have a robust predictive biomarker to detect an activated AR pathway and have not seen a robust correlation between molecular LAR subtype and AR IHC staining intensity. Methods: Molecular profiling and immunohistochemical analysis of key biomarkers (LAR, Ki67, and vimentin) was performed for all pts enrolled in A Randomized triple negative breast cancer enrolling Trial to Confirm Molecular Profiling Improves Survival (ARTEMIS; NCT02276443). Patients receive 4 cycles of AC, followed by an experimental arm or standard taxane, tailored using nuclear IHC staining. IHC staining of ≥30% AR+ was used as a threshold for selection for enzalutamide combination arm. We evaluated the concordance between LAR-subtype using molecular profiling vs % AR+ cells via IHC. Results: As part of the clinical trial, tumors with ≥30% AR+ cells were classified as LAR. In addition, we used RNA profiling to assign Vanderbilt subtype scores, resulting in classification of 15 tumors as LAR+. We observed a significant correlation (r=0.75) between LAR score and %AR+ cells, with 13 of 15 LAR tumors having ≥30% AR+ cells. Among patients with high % of AR+ tumor cells, 11 received enzalutamide, with 43% (3/7) having responses (pCR or RCB-I). Conclusions: Comparison on numerical scores for Vanderbilt subtype and IHC scores suggests ≥30% AR+ IHC staining as the threshold (ppv=0.65, npv=0.98, Table) to identify the molecular LAR subtype. We observed a trend where response rate was higher in patients with ≥ AR+ IHC scores treated with enzalutamide; however, these results need confirmation in a larger cohort of patients. Clinical trial information: NCT02689427, NCT02276443. [Table: see text]
EPHA genetics for prediction of paclitaxel-induced peripheral neuropathy sensitivity.
Authors: Lauren A Marcath, Kelley M. Kidwell, Ellen M. Lavoie Smith, Kiran Vangipuram, Christina L Gersch, Monika Leigh Burness, Jennifer J. Griggs, Catherine H. Van Poznak, Daniel F. Hayes, Norah Lynn Henry, Andreas S. Beutler, Daniel Louis Hertz
Journal: Journal of Clinical Oncology (2019)

532 Background: Chemotherapy induced peripheral neuropathy (CIPN) is a common, debilitating paclitaxel side effect that has been primarily attributed to cumulative systemic paclitaxel exposure. Paclitaxel dose-adjustment to achieve target systemic exposure decreases but does not eliminate severe CIPN, suggesting some patients are inherently CIPN-sensitive. Ephrin ( EPHA) polymorphisms have been reported to increase CIPN occurrence (Baldwin 2012, Leandro-Garcia 2013, Boora 2016) but replication has been challenging, perhaps due to the inability to isolate CIPN-sensitivity by accounting for systemic exposure differences. The study purpose was to determine if EPHA genetic variants previously associated with CIPN occurrence are associated with CIPN-sensitivity. Methods: PN was assessed at baseline and weekly using the 8-item sensory subscale (CIPN8) of the patient-reported EORTC CIPN20 in patients receiving paclitaxel 80 mg/m 2 weekly x 12. EPHA4, EPHA5, EPHA6, and EPHA8 were sequenced in germline DNA. Associations with higher PN-sensitivity were tested for three genetic models (total variants, coding variants, and rs7349683) by incorporating genetics into previously published CIPN8 predictive models that included measured paclitaxel exposure. Significant associations were tested for association with higher risk of PN-related treatment disruption (i.e. dose decrease, delay, or discontinuation). Results: In the 59 included patients, carrying EPHA5 rs7349683 was associated with greater CIPN sensitivity (beta coefficient: 0.40, standard error: 0.14, p = 0.005), indicating these patients had a greater increase in CIPN8 during treatment than would be predicted based on cumulative paclitaxel exposure. Rs7349683 was not associated with increased PN-induced treatment disruption, perhaps due to the low number of events (n = 19). Conclusions: Using a novel approach that isolates CIPN-sensitivity by accounting for measured paclitaxel exposure, our results provide further evidence that EPHA5 rs7349683 may be a promising marker for CIPN. If additional validation studies confirm this association, genetic testing could enable personalized treatment strategies to prevent CIPN in patients with breast cancer.
IDH1 polymorphism G105G (rs11554137) as a prognostic factor in gliomas.
Authors: Enrico Franceschi, Dario De Biase, Alicia Tosoni, Alexandro Paccapelo, Giorgia Acquaviva, Annalisa Pession, Giovanni Tallini, Chiara Maria Argento, Stefania Bartolini, Alba Ariela Brandes
Journal: Journal of Clinical Oncology (2019)

e14734 Background: IDH mutational status is required for diagnosis according to the 2016 WHO criteria. The single nucleotide polymorphism (SNP) rs11554137 ( IDH1 105GGT ) at codon 105 of IDH1 has been reported in patients with several tumor types, including glioma. The aim of this study is to investigate the prognostic role of IDH1 105GGT Methods: We analyzed our institutional data warehouse for consecutive patients (pts) with newly diagnosed, histologically proven grade II or Grade III gliomas. IDH sequencing was performed using the 454 GS-Junior next generation sequencer (NGS) (Roche Diagnostic, Mannheim, Germany). All analyses were performed on DNA from formalin fixed and paraffin embedded (FFPE) specimens. Results: The analysis included 77 pts with grade II (n = 51, 66.2%) or grade III glioma (n = 26, 33.8%). Median follow up of this study was 91 months. Patients received biopsy/partial resection/complete resection in 7.8%, 70.1% and 22.1%, respectively. Postsurgical RT and/or chemotherapy was delivered in 64.9% of pts. IDH mutations affecting codons 132 (for IDH1) and 172 (for IDH2) were found in 71 pts (92.2%). IDH1 105GGT was found in 11 pts (14.3%), mainly harboring also IDH mutations (81.8%), and was more frequent in grade 3 (30.8%) than in grade 2 gliomas (5.9%, P = 0.006). Pts harboring both IDH mutations and IDH1 105GGT showed a significantly longer progression-free survival compared with pts with IDH mutation alone (78.7 months vs 49.9 months, p = 0.041). Conclusions: IDH1 105GGT represents a promising novel biomarker in IDH mutated grade 2 and 3 gliomas and warrants further investigations.