tbuckley/cabot-search huggingface dataset:
A randomized phase II study of nab<i>-</i>paclitaxel + durvalumab + neoantigen vaccine versus nab-paclitaxel + durvalumab in metastatic triple-negative breast cancer (mTNBC).
Authors: Leonel Fernando Hernandez-Aya, Feng Gao, Peter S. Goedegebuure, Cynthia X. Ma, Foluso Olabisi Ademuyiwa, Haeseong Park, Lindsay Leuthen Peterson, Nusayba Ali Bagegni, Ron Bose, William E. Gillanders
Journal: Journal of Clinical Oncology (2019)

TPS1114 Background: mTNBC is associated with poor outcomes and lacks targeted therapies. Immune modulation with PD-1/L1 inhibitors are emerging as effective anticancer therapies. In mTNBC, atezolizumab (anti-PD-L1) plus nab-paclitaxel demonstrated an improvement in PFS compared to nab-paclitaxel alone. Cancer vaccines targeting neoantigens may enhance the activity of immune checkpoint inhibition (ICI). Neoantigens are targets for CD8 T-cells following ICI. T-cell responses to neoantigens are high in affinity and are not limited by central mechanisms of self-tolerance. Next-generation sequencing and epitope prediction algorithms are used to identify/prioritize neoantigens for vaccine design and development. Preclinical studies have shown that neoantigen vaccines are well tolerated and may be synergistic with anti-PD-1/L1 therapy. Methods: Eligible mTNBC patients are randomized to either Arm-1 ( nab-paclitaxel + durvalumab + neoantigen vaccine) or Arm-2 ( nab-paclitaxel + durvalumab). Initially, all participants are treated with a run-in of gemcitabine + carboplatin (18-weeks; Part A). During this time sequencing and neoantigen vaccine production is performed. Subsequently, patients are treated with nab-paclitaxel + durvalumab + neoantigen vaccine vs. nab-paclitaxel + durvalumab (Part B). The neoantigen vaccine is given subcutaneously. Participants in Arm-1 receive vaccinations on Days 1, 4, 8, 15, 22, 50 and 78. Durvalumab is administered at 1500 mg IV every 4 weeks. Nab-paclitaxel is administered at 100 mg/m 2 IV on Days 1, 8, and 15 of each 28-day cycle. Key eligibility criteria include patients with newly diagnosed mTNBC; measurable disease; and tumor accessible for biopsy. The primary endpoint is PFS defined as time from the initiation of Part B to progression or death. Secondary endpoints include safety, objective response rate, clinical benefit rate and OS. The exploratory endpoints include evaluating the immune response induced by the neoantigen vaccine, investigating biomarkers of response including TILs, PD-L1, and immune signature by gene expression, and mutational landscape. This trial is currently recruiting patients (NCT03606967).
Pilot study of [<sup>18</sup>F] fluorodexoyglucose positron emission tomography-magnetic resonance imaging (FDG-PET-MRI) for staging of muscle-invasive bladder cancer.
Authors: Patrick Eulitt, Ersan Altun, Arif Sheikh, Terence Z. Wong, Michael Woods, Tracy L Rose, Eric Wallen, Raj Pruthi, Angela Smith, Matthew Edward Nielsen, Young E. Whang, William Y. Kim, Paul Alphonso Godley, Ethan M. Basch, Grace David, Juanita Ramirez, Allison Mary Deal, Joseph Lee, Matthew I. Milowsky
Journal: Journal of Clinical Oncology (2019)

e16002 Background: Standard of care imaging for staging MIBC is computed tomography (CT) abdomen and pelvis despite poor diagnostic accuracy. The addition of FDG-PET to evaluate biologic activity has been shown to improve detection of metastatic bladder cancer. Better soft tissue characterization with MRI may improve detection of local disease. We hypothesized that simultaneous acquisition of FDG-PET and MRI images (PET-MRI) would allow for more accurate preoperative staging in patients with MIBC. Methods: 21 patients with MIBC and planned radical cystectomy with lymph node dissection were enrolled. Four radiologists (2 senior, 2 junior) with expertise in MRI and PET independently reviewed MRI and FDG-PET scans, respectively, to determine: 1) extent of the primary bladder tumor; and 2) involvement of local lymph nodes and distant sites of disease. Combined radiologist reads were performed (senior MRI and junior PET and vice versa). Imaging results were compared to surgical pathology. Results: 18 patients were included in the final analysis (3 PET-MRI scans excluded due to technical pitfalls with image acquisition). Final pathology revealed 10 patients (56%) with muscle invasion and only 2 patients (11%) with lymph node involvement. Combined analyses of PET-MRI accurately detected the extent of the primary tumor (sensitivity 0.84, specificity 0.50, PPV 0.70, NPV 0.70), but was less accurate for the detection of lymph node involvement (sensitivity 0.00, specificity 1.00, no calculable PPV, NPV 0.91). Senior MRI radiologist had improved PPV and NPV for extent of primary tumor compared to junior MRI radiologist (PPV 0.71 vs 0.56, NPV 0.83 vs. 0.50), and senior PET radiologist had improved PPV with similar NPV for extent of primary tumor (PPV 1.00 vs 0.78, NPV 0.50 vs 0.55). No patient was determined to have distant metastatic disease. Conclusions: To our knowledge, this is the first study exploring the use of PET-MRI for staging MIBC. This novel imaging modality demonstrated promise in detecting the extent of the primary tumor. Further investigation of FDG-PET-MRI is needed to better determine its potential utility in staging MIBC.
Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node
Authors: Kim M. van Pul, Ronald J.C.L.M. Vuylsteke, Rieneke van de Ven, Elisabeth A. te Velde, Emiel J. Th. Rutgers, Petrousjka M. van den Tol, Hein B.A.C. Stockmann, Tanja D. de Gruijl
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune regulated pathways influence both breast cancer (BrC) development and response to (neo)adjuvant chemotherapy. The sentinel lymph node (SLN), as the first metastatic site, is also the first site where BrC-induced suppression of immune effector subsets occurs. Since intricate knowledge of the phenotypic and functional status of these immune effector subsets is lacking, we set out to map the immune landscape of BrC SLN. <h3>Methods</h3> Viable LN cells from BrC SLN (<i>n</i> = 58) were used for detailed flowcytometry-assisted mapping of the immune landscape of BrC SLN in a comparative analysis with healthy (i.e. prophylactic mastectomy-derived) axillary lymph nodes (HLN, <i>n</i> = 17). Findings were related to clinicopathological characteristics. <h3>Results</h3> Our data show that BrC-induced immune suppression in tumor-involved SLN, as evidenced by increased Treg and MDSC rates as well as by a generalized state of T cell anergy, coincides with hampered activation of LN-resident (LNR) dendritic cell (DC) subsets rather than of migratory DC subsets. Importantly, suppression of these LN-resident DC subsets preceded profoundly disabled T cell effector functions in tumor-involved SLN. Furthermore, we provide evidence that the suppressed state of LNR-cDC is not only related to nodal involvement but is also related to high-risk breast cancer subtypes that lack expression of hormone receptors and may be a negative predictor of disease-free survival. <h3>Conclusion</h3> These data thus provide new insights in the mechanisms underlying loco-regional immune suppression induced by BrC and how these relate to clinical outcome. They identify the LNR-cDC subset as a pivotal regulatory node in cellular immune suppressive pathways and therefore as a promising therapeutic target to combat immune suppression and secure the induction of effective antitumor immunity, e.g. in combination with neo-adjuvant chemotherapy.
A phase Ib study of oraxol in combination with ramucirumab in patients with gastric or esophageal cancers who failed previous chemotherapy.
Authors: Yi-Ping Hung, Yee Chao, Ming Huang Chen, David Cutler, Douglas Kramer, Wing Kai Chan, Rudolf Kwan, Noelyn Anne Hung, Tak Hung, Laura LaNiel Tenner
Journal: Journal of Clinical Oncology (2019)

e15518 Background: Oraxol consists of oral paclitaxel (PTX) administered with the novel P-glycoprotein inhibitor HM30181A which enables the oral absorption of PTX. Ramucirumab (RAM) + intravenous weekly PTX is FDA approved 2 nd line treatment of gastric cancer. Oraxol (oral PTX) 200mg/m 2 days 1-3, weekly results in similar exposure to weekly 80/m 2 intravenous PTX. This phase 1 clinical trial is to determine the maximum tolerated dose (MTD) of Oraxol + RAM. Methods: Eligible patients (pts) have gastric or esophageal cancers and failed prior fluoropyrimidine or platinum containing chemotherapies. Dose escalation followed the standard 3+3 design: Cohort 1: Oraxol 200mg/m 2 days 1-3, weekly. Cohort 2: Oraxol 250mg/m 2 days 1-3, weekly. Cohort 3: Oraxol 300mg/m 2 days 1-3, weekly. Dose of RAM is standard 8 mg/kg IV every 2 weeks. Pts were monitored for dose limiting toxicity (DLT) by week 4. Adverse events (AEs) were assessed per CTCAE v4.03 and response by RECIST v1.1. Results: Cohort 1: One febrile neutropenia (DLT) observed in 6 pts. Partial response (PR) = 2/6, stable disease (SD) = 1/6 and progressive disease (PD) = 3/6 pts. Cohort 2: One grade-3 neutropenia with treatment delay (DLT) in 7 pts. PR = 3/6 and PD = 3/6 in 6 evaluable pts. Cohort 3: One febrile neutropenia (DLT) in 3 pts and study is ongoing. All pts had complete recovery of their DLT. PK showed increase of plasma PTX exposure with dose. Conclusions: The MTD for Oraxol has not been reached yet in combination with RAM. Preliminary results showed that Oraxol + RAM is tolerable and have encouraging anti-tumor activity in gastric or esophageal cancers pts who failed prior chemotherapies. Final results of this study will be presented. Clinical trial information: NCT02970539.
Genome-wide association study using whole-genome sequencing to identify a novel locus associated with cardiomyopathy risk in adult survivors of childhood cancer: Utility of a two-stage analytic approach.
Authors: Yadav Sapkota, Qi Liu, Kyla C. Shelton, Xuexia Wang, Carmen Louise Wilson, Zhaoming Wang, Daniel A. Mulrooney, John L Jefferies, Kevin C. Oeffinger, Lindsay M. Morton, Jinghui Zhang, Gregory T. Armstrong, Smita Bhatia, Melissa M. Hudson, Leslie L. Robison, Yutaka Yasui
Journal: Journal of Clinical Oncology (2019)

1516 Background: Survivors of childhood cancer are at increased risk of treatment-related cardiomyopathy, found to be modified by genetic factors. To further investigate genetic risks of cardiomyopathy, we utilized whole-genome sequencing (WGS) in a clinically phenotyped cohort of long-term survivors of pediatric cancer. Methods: Utilizing a novel 2-stage analytic approach, we first performed association analysis for ejection fraction (EF) using WGS data in European-descent childhood cancer survivors from the St. Jude Lifetime Cohort (SJLIFE). EF was analyzed as a continuous variable to increase statistical power for genetic discovery. Common variants (minor allele frequency (MAF) &gt; 0.05) were analyzed using linear regression, adjusting for age at diagnosis, sex, age at follow-up, doses of anthracycline and average radiation dose to the heart, and eigenvectors. Rare/low-frequency variants were aggregated by different functional annotations and agnostic 4-kb sliding windows, testing jointly using Burden/SKAT test. In the second stage, only the variant showing genome-wide significance with EF was tested for its association with cardiomyopathy risk. Results: Among the 2,015 SJLIFE survivors with WGS data, a locus on 6p21.2 near KCNK17achieved genome-wide significance with EF (rs2815063; MAF = 0.13; per allele beta = -0.016; P = 2.10´10 -8 ), which replicated in 320 SJLIFE African survivors (MAF = 0.48; beta = -0.015; P = 0.004). In SJLIFE Europeans, 282 had a CTCAE Grade 2-5 cardiomyopathy. rs2815063 was significantly associated with increased risk of cardiomyopathy [per allele odds ratio (OR) = 1.38; P = 0.02], which replicated in 3,957 European survivors from the Childhood Cancer Survivor Study (163 CTCAE Grade 3-5 self-reported cases; per allele OR = 1.39; P = 0.038). rs2815063 alters DNA binding motif of EWSR1-FLI1, whose expression was found to lead to cardiomyopathy and death due to chronic cardiac failure in mice. Conclusions: Using a 2-stage approach, we report a novel locus for cardiomyopathy in childhood cancer survivors, which warrants additional work to gain mechanistic insights.
A novel patient-centric approach between sites, CRO, and sponsor to accelerate FPI and drive more patients into oncology protocols.
Authors: Krystyna Kowalczyk, Rhonda U. Henry, Bellinda Conte
Journal: Journal of Clinical Oncology (2019)

6573 Background: According to the Journal of Clinical Oncology, 50% of sites performing clinical trials never enroll a patient. And on top of that, it can take several months to activate a site for an oncology clinical trial; precious time that patients cannot afford when they’ve had a cancer diagnosis and precious time sponsors need when developing new compounds for market. While many patients are interested in participating in trials, they are limited in their opportunities because they do not live near a research site or work with a physician performing clinical trials. So with this crisis in the oncology field, research needs to be more efficient and inclusive. Methods: A combined partnership of sites, physicians, CRO and sponsor leveraging Just-in-Time enrollment methodology helped expedite clinical trial enrollment and diversify trial access driving faster first patient enrolled and expanding the potential patient denominator. Results: This on-demand methodology augmented existing sites that had access to oncology patients by providing broader access, faster, and with no quality loss. Strong partnerships between CRO and sponsor then facilitated two-week site activation allowing every identified patient to be converted to a study subject. This methodology was repeated across seven protocols driving patents on trials within six weeks of trial available. Conclusions: The benefits of this Just-in-Time methodology touch all areas of clinical trials: Patients have greater clinical trial access: A larger denominator of patients across broader geographies have local access to portfolios of clinical trials; Trials start to enroll faster: Patients can be randomized into oncology clinical trials within two weeks of study start up driving trial time to completion; Sites have more trial options to consider: Sites have a broader portfolio of trials to access on demand without added administrative burden; Trials complete faster: Sponsors accrue patients faster driving expedited timelines and accelerating drug development.
Long-term toxicity following radiation therapy for head and neck squamous cell carcinoma: A retrospective study analyzing the effect of concurrent chemotherapy and advanced t-stage on late treatment-induced toxicities.
Authors: William Barrett, Christine Cassidy
Journal: Journal of Clinical Oncology (2019)

e17560 Background: There are approximately 436,000 survivors of head and neck squamous cell carcinoma (HNSCC) in the U.S. Toxicities related to definitive chemoradiation or radiation therapy can persist for many years, with some toxicities not presenting clinically until five or more years after definitive treatment. Long-term management of late radiotherapy effects is thus warranted. Methods: This retrospective chart review has three aims: (1) comprehensively assess overall late effects of definitive radiation and chemoradiation; (2) compare treatment-related toxicities between definitive radiation and chemoradiation; and (3) compare treatment-related toxicities between patients with TNM stage T1/T2 tumors to T3/T4 tumors. Late term effects were assessed using 17 toxicity categories including xerostomia, dysphagia, and neck fibrosis. HNSCC patients included in the study were those seen by a single practitioner for follow-up of definitive radiation or chemoradiation, without a history of surgical intervention to the primary site, between June 2017 and June 2018 (N = 49). Results: The median time from the end of treatment to the most recent follow-up was 8.53 years (1.17-24.08 years). In the total cohort, the most common late effect was xerostomia (78%, N = 38), followed by dysphagia (43%, N = 21), and neck fibrosis (27%, N = 13). For the majority of toxicity categories (11 of 17), the cohort that received definitive chemoradiation had higher rates of toxicity than the cohort that received definitive radiation alone. Additionally, for the majority of toxicity categories (10 of 17), the cohort of T3/T4 tumors had higher rates of long-term toxicity than the cohort of T1/T2 tumors. Conclusions: Although the patient population in this study has excellent locoregional control after definitive radiation or chemoradiation, the majority of patients suffer from long-term treatment-related toxicities. Long-term follow up care is needed to manage the late effects of radiotherapy that can develop and persist for years after treatment completion.
The HGF-MET signaling pathway is enriched in LUAC brain metastases.
Authors: Maria A Velez, Zachary A. Yochum, Uma R. Chandran, Anish Chakka, Saveri Bhattacharya, Aswin Somasundaram, William LaFramboise, Gerald Wallweber, Roy Ravanera, Brenda F Kurland, Sanja Dacic, Laura P. Stabile, Timothy F. Burns
Journal: Journal of Clinical Oncology (2019)

e20597 Background: Brain metastases occur in over 40% of non-small cell lung cancer (NSCLC) patients leading to a poor prognosis. c-Met (MET) is a receptor tyrosine kinase that upon binding hepatocyte growth factor (HGF), mediates proliferation, epithelial-mesenchymal transition (EMT), invasion, angiogenesis and metastasis. We have previously shown that the EMT transcription factor, TWIST1 is required for proliferation in MET driven NSCLC. Therefore, the HGF/MET/TWIST1 pathway may be a significant determinant of metastatic potential to the brain. Methods: We evaluated 125 lung adenocarcinoma (LUAC) brain metastases for MET amplification by FISH as well as other molecular alterations using targeted next generation sequencing in a subset of brain metastases (N = 74) and primary LUAC (N = 171) samples including 13 paired primary and brain sets. MET activation was examined in paired tumors using a HGF-MET proximity binding, dual-antibody assay (VeraTag; Monogram Biosciences). TWIST1 and EMT markers in the paired sets were measured by immunohistochemistry. Results: Compared to primary LUAC, we found that 17 pathogenic variants including TP53, SMAD4, RB1, RET, APC, ALK, FGFR3, EGFR, STK11 and MET alterations were significantly more common in LUAC brain metastases (adj. p values ≤ 0.02). Specifically, MET amplification was significantly enriched in LUAC brain metastases (23/125, 19%) compared to 2-4% in non-brain metastatic and primary sites. Among paired samples, 2/13 brain metastases had MET amplification that was not found in the primary tumor. MET mutations were also present in 16/74 brain cases (22%) compared to 9% (16/171) observed in the lung. VHL mutations were associated with MET altered cases compared to non- MET altered cases. MET expression was increased in the majority of brain metastases compared to the paired LUAC and there were 3 cases with brain specific MET activation. We found that TWIST1 was induced by HGF and determined response to MET TKIs in vitro. Among paired samples, TWIST1 was increased in brain metastases compared to primary LUAC in a subset of cases. Further analyses of TWIST1 and EMT markers is ongoing. Conclusions: Over a third of brain metastases have MET alterations compared to primary LUAC and may be responsive to MET inhibitors.
Employing an oncology decision-support system to quantify treatment variation.
Authors: Jun Liang, Irene Dankwa-Mullan, Yan-ping Ren, Alan Chen, Van Willis, Gretchen Jackson, Nathan Levitan, Kyu Rhee, Tian-le Li
Journal: Journal of Clinical Oncology (2019)

e18067 Background: Factors affecting cancer treatment may include evidence for effectiveness, cost, and preference. These influences can lead to treatment variation across institutions and populations. Decision-support systems have been proposed as tools to reduce variation. This study quantified concordance between treatment provided by oncologists in China and therapeutic options presented by a decision-support tool. Methods: We identified and analyzed concordance studies in nine unique institutions located in seven provinces in China, published in 2017-2018 using Watson for Oncology (WFO), a clinical decision-support tool. Published rates of concordance were compared by cancer type and institution. Results: Concordance of all combined cases was 59% (2012/3388). Concordance rates varied by cancer type and institution (Table). Concordance rates were highest for ovarian (96%), rectal (94%) and breast (89%) cancers but lowest in gastric (12%), ovarian (43%) and breast (55%) cancers. Conclusions: Concordance between treatments and therapeutic options from an oncology decision-support tool varied significantly across cancer types and institutions in China, suggesting significant practice variation. Without established guidelines for treatment, clinical decisions may be influenced by preferences and local factors. Future studies are needed to identify reasons for variation and improve adherence to regional evidence-based guidelines. [Table: see text]
Effect of Cryopreservation on Autologous Chimeric Antigen Receptor T Cell Characteristics
Authors: Sandhya R. Panch, Sandeep K. Srivastava, Nasha Elavia, Andrew McManus, Shutong Liu, Ping Jin, Steven L. Highfill, Xiaobai Li, Pradeep Dagur, James N. Kochenderfer, Terry J. Fry, Crystal L. Mackall, Daniel Lee, Nirali N. Shah, David F. Stroncek
Journal: Molecular Therapy (2019)

As clinical applications for chimeric antigen receptor T cell (CART) therapy extend beyond early phase trials, commercial manufacture incorporating cryopreservation steps becomes a logistical necessity. The effect of cryopreservation on CART characteristics is unclear. We retrospectively evaluated the effect of cryopreservation on product release criteria and in vivo characteristics in 158 autologous CART products from 6 single-center clinical trials. Further, from 3 healthy donor manufacturing runs, we prospectively identified differentially expressed cell surface markers and gene signatures among fresh versus cryopreserved CARTs. Within 2 days of culture initiation, cell viability of the starting fraction (peripheral blood mononuclear cells [PBMNCs]) decreased significantly in the cryo-thawed arm compared to the fresh arm. Despite this, PBMNC cryopreservation did not affect final CART fold expansion, transduction efficiency, CD3%, or CD4:CD8 ratios. In vivo CART persistence and clinical responses did not differ among fresh and cryopreserved final products. In healthy donors, compared to fresh CARTs, early apoptotic cell-surface markers were significantly elevated in cryo-thawed CARTs. Cryo-thawed CARTs also demonstrated significantly elevated expression of mitochondrial dysfunction, apoptosis signaling, and cell cycle damage pathways. Cryopreservation during CART manufacture is a viable strategy, based on standard product release parameters. The clinical impact of cryopreservation-related subtle micro-cellular damage needs further study.