tbuckley/cabot-search huggingface dataset:
Survival according to mutations in BRAF, KRAS, or microsatellite instability (MSI-H) after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastases from colorectal cancer.
Authors: Stein G Larsen, Svein Dueland, M Goscinski, Sonja Steigen, Eva Hofsli, Kjersti Flatmark, Halfdan Sorbye
Journal: Journal of Clinical Oncology (2019)

3565 Background: Patients with metastatic colorectal cancer (mCRC) and mutations in BRAF V600E (mutBRAF) or KRAS (mutKRAS) have a worse prognosis after liver or lung surgery/ablation, whereas the impact of microsatellite instability (MSI-H) has not been well studied. Few patients with mutBRAF receive liver or lung surgery (1-4%), whereas mutBRAF is present in 5-12% of mCRC trial patients and in up to 20% of the general mCRC population. The frequency and prognostic role of mutBRAF, mutKRAS and MSI has not been well studied after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases from colorectal cancer. Methods: The Norwegian Radium Hospital is the only center offering CRS and HIPEC in Norway. From 2004 to 2015 257 patients with histology proven peritoneal metastasis from colorectal cancer, appendiceal cancer excluded, was consecutively enrolled. Molecular analyses of KRAS, BRAF and MSS/MSI in mutBRAF were done. Fourteen patients were excluded due to missing tumour blocks (7), unsuccessful analysis (4) and other malignant disease (1). Results: 180 of 243 patients obtained complete cytoreductive surgery and received HIPEC for 90 minutes with Mitomycin C (45-70mg). Median survival for the 180 patients was 47 months and 5-year survival rate 40.1%. Median disease-free survival was 10 months. mutBRAF was found in 23.4% of cases, mutKRAS 35.1% and double-wild type 41.5%. mutBRAF with MSS was found in 16.4%, mutBRAF with MSI-H in 7.0%. 3-year disease free survival (DFS) and median overall survival (OS) was 38.9% and 59 months with mutBRAF with MSI-H, significantly higher compared to 24.2% and 30 months in patients with double wild type, 13.2 % and 41 months in mutKRAS and 17.9% and 22 months in mutBRAF with MSS. Conclusions: A surprisingly high frequency of mutBRAF was seen in mCRC patients after CRS and HIPEC for peritoneal metastatic disease. Patients with mutBRAF and MSI-H had a significantly better DFS and OS after CRS and HIPEC. DFS for patients with mutBRAF and MSS was numerically lower but not statistically different from patients with mutKRAS or double wild type.
Validation of an artificial intelligence algorithm applied to a metabolic substrate analysis of urine for detection of urothelial cancer.
Authors: Nikola Kaludov, Mohummad Minhaj Siddiqui, Max Kates, Hemantkumar Tripathi, Amatul Nasir Salma, Yair Lotan, Gary D. Steinberg
Journal: Journal of Clinical Oncology (2019)

e16008 Background: Urine tests such as urine cytology are commonly used for the diagnosis and monitoring of urothelial cancer. These tests are often limited by issues related to sensitivity or specificity. It is well known that derangement of cellular metabolism is one of the hallmarks of carcinogenesis. As urothelial cancer is in constant contact with urine, we hypothesize that metabolite composition in the urine may provide insight into possible urothelial cancer presence in the urinary tract. In this study, we evaluated a metabolomics based urine test for the detection of urothelial cancer. Methods: In this prospective, multi-institutional IRB approved study, urine samples were collected from a total of 57 urothelial cancer patients and non-urothelial cancer controls. Gas chromatography profiles of urine small molecule metabolites were generated to yield over 2400 data points of metabolite peaks and troughs for every urine sample. A machine-learning based algorithm (Abilis Life Sciences) was constructed to predict urothelial cancer versus non-cancer controls through analysis of peaks and trough patterns of urine metabolomics profiles. Predictions were made in a blinded fashion and descriptive statistics of test sensitivity and specificity were generated. Results: The urine metabolite composition of 57 patients were analyzed and urothelial cancer predictions were generated. The test demonstrated an overall accuracy of 89.5% (51 out of 57 cases correctly predicted). The sensitivity of the test was 97.1% (34 out of 35) and specificity was 77.3% (17 out of 22). The Positive Predictive Value is 87.2%, while the Negative Predictive Value is 94.4%. The area under the curve for the receiver operating characteristic curve was 0.87. Conclusions: Urine based metabolic profile analysis using artificial intelligence algorithms is a promising potential diagnostic test for detection of urothelial cancer. Further testing is ongoing to increase robustness of the validation.
Safety and pharmacokinetics of BXQ-350 in a phase 1a and 1b trial of solid tumors and high-grade glioma.
Authors: Olivier Rixe, John Charles Morris, Vinay K. Puduvalli, John L. Villano, Trisha Michel Wise-Draper, Robert Wesolowski, Emrullah Yilmaz, Sheena M Lanverman, Vidhya Karivedu, Maria T Patterson, Xiaoyang Qi
Journal: Journal of Clinical Oncology (2019)

e13531 Background: BXQ-350 is composed of the multifunctional, lysosomal-activator protein Saposin C and phosphatidylserine lipid with demonstrated antitumor effects in vitro and in vivo. In this abstract we update the safety and pharmacokinetic (PK) profile based on an ongoing Phase 1 trial. Methods: BXQ-350 was administered in a Phase 1a dose-escalation trial (NCT02859857), and an ongoing Phase 1b trial (data cut off at max of 6 cycles, 01DEC2018) to refractory solid tumor/high-grade glioma patients (pts). In Phase 1a, pts received escalating IV BXQ-350 doses of 0.7, 1.1, 1.4, 1.8, or 2.4 mg/kg on days 1, 2, 3, 4, 5, 8, 10, 12, 15, 22 (cycle 1), 29 (cycle 2), and thereafter 28-day cycles. PK was assessed over a 24-hr period following the first dose. The Saposin C level was analyzed by ELISA and PK parameters were calculated using noncompartmental methods. Results: The 1a cohort of 18 pts (age 24-69) had a median of 3 cycles and 1b cohort of 20 pts (age 31-80) had median of 2 cycles with no treatment-related serious adverse events to date. Moderately severe related adverse events (AEs, n case, n events) are reported with serious non-related events. The most common treatment-related AE was fatigue (2 at dose 1.1, 2 at 1.8, 1 at 2.4mg/kg and 3 in 1b), at 2.4 mg/kg, 1 pt had moderate blood pressure elevation. Exposures in the 1.4 and 1.8 mg/kg cohorts were less than dose-proportional, likely due to higher clearance in those groups. The overall mean clearance and half-live values were 66.8 (mL/kg/h) and 4.03 h, respectively. Conclusions: BXQ-350 has had no serious related AEs during dose-escalation or in the on-going trial supporting a tolerable safety profile at 2.4 mg/kg. Clinical trial information: NCT02859857. [Table: see text]
Circulating tumor cells in patients with locally advanced breast cancer in evaluation of antitumor treatment efficacy.
Authors: Aleksandr B. Sagakyants, Oleg I. Kit, Natalia Yu. Samaneva, Liubov Yu Vladimirova, Oksana G. Shulgina, Elena P. Ulianova, Inna A. Novikova, Irina S Mitashok, Tatiana A. Snezhko
Journal: Journal of Clinical Oncology (2019)

e12064 Background: Circulating tumor cells (CTC) are of great importance in modern cancer research. Biological characteristics of CTC allow using them as tumor markers of high prognostic value. Their quantitative evaluation during treatment can be used to monitor the response to treatment in patients receiving systemic chemotherapy (CT). The purpose of the study was to assess the role of CTC in the prognosis of treatment efficacy in patients with locally advanced Her-2 negative breast cancer. Methods: The study included 42 patients aged 30-65 years with stage IIIA, IIIB, IIIC locally advanced Her-2 negative breast cancer, ECOG-WHO Performance Status from 0 to 2, Karnofsky Performance Status from 100% to 80%. CTC were determined using the CellSearch Veridex System (Johnson &amp; Johnson, USA), taking into account morphological characteristics and expression of epithelial cell adhesion markers EpCAM, CD45 and cytokeratins 8, 18 and 19. Results: CTC were found in 86% (36 of 42 patients) before treatment. CTC were not registered in 6 (14%) patients. 1 CTC was detected in 14% (6 patients); 2-3 CTC – 33% (14 patients); more than 3 CTC – 38% (16 patients). 12% (5) patients showed more than 10 CTC, with the maximum of 64 CTC in 1 patient. After 2 cycles of polychemotherapy, CTC were detected in 50% (21 patients). Other 21 patients did not show presence of CTC. Among CTC-positive patients, 1 CTC was detected in 4 patients (19%); from 2 to 3 CTC – in 9 patients (43%); more than 3 CTC – 8 patients (38%). 2 patients (10%) still showed more than 10 CTC – 28 and 33 CTC in the peripheral blood. After 2 cycles of polychemotherapy, the number of patients with more than 1 CTC decreased from 86% to 50%. Polychemotherapy regimen was changed for patients with increasing amounts of CTC. Conclusions: Determination of the CTC number allows evaluation of the treatment efficacy and is a specific marker for the change of applied polychemotherapy for such cancer type.
JAVELIN BRCA/ATM: A phase 2 trial of avelumab (anti–PD-L1) plus talazoparib (PARP inhibitor) in patients with advanced solid tumors with a BRCA1/2 or ATM defect.
Authors: David Michael Hyman, Amelia B. Zelnak, Todd Michael Bauer, Susanna Varkey Ulahannan, James M. Ford, Rossano Cesari, Margaret Hoyle, Colombe Chappey, Ross Stewart, Umberto Conte, Timothy A Yap
Journal: Journal of Clinical Oncology (2019)

TPS2660 Background: Defects in DNA damage response genes, including BRCA1/2 and ATM, confer sensitivity to PARP inhibitors. Talazoparib is a potent, oral PARP inhibitor with a dual mechanism of action (PARP enzyme inhibition and PARP trapping). Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody with a wild-type Fc region that has shown clinical activity in multiple tumor types. Preclinical and early clinical data suggest that combining a PARP inhibitor with an immune checkpoint inhibitor may provide improved activity. Methods: JAVELIN BRCA/ATM (NCT03565991) is an ongoing, open-label, multicenter, phase 2 trial assessing the combination of avelumab and talazoparib. Enrollment of ≈200 patients with a histologically confirmed locally advanced or metastatic solid tumor that has progressed on &gt; 1 line of standard-of-care treatment for locally advanced or metastatic disease and has a germline or somatic defect in BRCA1 or 2 (cohort 1) or ATM (cohort 2) genes is planned. Patients with concomitant defects in &gt; 1 gene ( BRCA1, BRCA2, or ATM) will be enrolled in cohort 1. Exclusion criteria include prior treatment with an immune checkpoint or PARP inhibitor, prior treatment with any other anticancer or radiation therapy within 2 weeks prior to enrollment, a known history of an immune-mediated or autoimmune condition, and known symptomatic brain metastases requiring steroids. The primary endpoint is confirmed objective response by blinded independent central review according to RECIST v1.1 and according to the Prostate Cancer Working Group 3 (PCWG3) for patients with metastatic castration-resistant prostate cancer (mCRPC). Secondary endpoints include safety; investigator-assessed confirmed objective response, time to tumor response, duration of response, and progression-free survival (per RECIST v1.1 and per PCWG3 for patients with mCRPC); overall survival; pharmacokinetic parameters; and potential predictive biomarkers. The study is currently enrolling patients at centers in the United States and Europe. Clinical trial information: NCT03565991.
Peptide-modulated self-assembly as a versatile strategy for tumor supramolecular nanotheranostics
Authors: Shukun Li, Qianli Zou, Ruirui Xing, Thimmaiah Govindaraju, Rawil Fakhrullin, Xuehai Yan
Journal: Theranostics (2019)

Advances in supramolecular self-assembly have promoted the development of theranostics, the combination of both therapeutic and diagnostic functions in a single nanoplatform, which is closely associated with antitumor applications and has shown promising potential in personalized medicine. Peptide-modulated self-assembly serves as a versatile strategy for tumor supramolecular nanotheranostics possessing controllability, programmability, functionality and biosafety, thus promoting the translation of nanotheranostics from bench to bedside. In this review, we will focus on the self-assembly of peptide-photosensitizers and peptide-drugs as well as multicomponent cooperative self-assembly for the fabrication of nanotheranostics that integrate diagnosis and therapeutics for antitumor applications. Emphasis will be placed on building block design, interaction strategies and the potential relationships between their structures and properties, aiming to increase understanding of the critical role of peptide-modulated self-assembly in advancing antitumor supramolecular nanotheranostics.
Utility of the Breast Cancer Index (BCI) in the clinical practice.
Authors: Saranya Kodali, Eswar Tipirneni, Kim Dittus
Journal: Journal of Clinical Oncology (2019)

e14723 Background: Extended endocrine therapy (EET) greater than 5 years in early stage hormone receptor positive (HR+) breast cancer (BC) patients has shown benefit. However, EET is associated with side effects and there is no validated assay to determine which group of patients would derive benefit. Breast Cancer Index (BCI) is a validated bio-marker test that incorporates 2 distinct genomic assays and is prognostic/predictive. The objective of this study is to assess patient characteristics, pathologic features and patient preferences with regards to extending endocrine therapy after reviewing the BCI results. Methods: We performed a retrospective chart review on early stage HR+ BC patients from Jan, 2016 to Jan, 2017 at the University of Vermont Medical Center. We identified 25 cases on whom BCI was submitted. Results: Median age was 68 years. Majority of the patients were stage IA (64%). 56% of the tumors were moderately differentiated. All patients were ER +ve and 12% were HER2+. Median tumor size was 1.4 cm (0.3-4). 76% had poor tolerance to the ET and preferred the test to be sent. In LN-patients, BCI identified 42% as high risk and 52% as low risk for late recurrence and 32% who derive high benefit from EET. In LN+ patients, BCI identified 75% as high risk for late recurrence and 25% as low risk for late recurrence. 40% of the entire group were identified to highly benefit from EET (70% agreed to continue ET and 30% denied due to side effects). Conclusions: BCI is a reasonable test to consider in early stage HR+ BC, especially in patients with poor tolerance to ET. This test might aid in decision making with tolerability/compliance challenges to EET. [Table: see text]
IMRT pelvic radiotherapy with simultaneous integrated boost in high-risk prostate cancer: Results after 10 years.
Authors: Christian Ekanger, Olav Dahl
Journal: Journal of Clinical Oncology (2019)

5084 Background: To report 10 year results after image guided intensity-modulated radiotherapy (IMRT) with hypofractionated simultaneous integrated boost (SIB) in high-risk prostate cancer. Methods: Between 2007 and 2009, 97 patients with an estimated risk of lymph node metastases above 15% (Roach equation) were prospectively included in a phase II study. Patients were treated with 2-2.7 Gy to the prostate, vesicula seminalis and elective pelvic field in 25 fractions over 5 weeks with androgen deprivation therapy for 2 years. Toxicity was scored according to RTOG criteria and biochemical free survival (BFS) using the Phoenix definition. Patients were divided into three groups; very high-risk patients (VHR) according to NCCN 2015 criteria (n=50), high-risk patients (HR) (n=32), and patients with N+ disease and/or pretreatment s-PSA ≥100 (n=15). Differences were examined using Kaplan Meier estimates with log rank test. Results: Ten year BFS in the entire cohort was 63%. Metastasis-free survival (MFS) was 77% and prostate-cancer-specific-survival (PCSS) 88%. Overall survival (OS) was 69% and local failure rate was 11%. VHR vs. HR subgroups had significant different BFS; 58% vs 84% (p=0.01) respectively. MFS and PCSS in the VHR group compared to the HR group was 78% vs 91% (p=0.108) and 86% vs 97% (p=0.157) respectively. Patients with N+ and/or PSA&gt;100 had worse outcome compared to the HR/VHR groups, but not all had treatment failure. BFS was 33% vs 68% (p=0.001), MFS 47% vs 83% (p=0.000) and PCSS 73 % vs 90% (p=0.04), respectively. Patients who reached a PSA nadir value below 0.1 (n=80) had significant better outcomes, with PCSS 93% vs 65% (p= 0.001) and BFS 74% vs 12% (p=0.000), respectively. Acute gr 2 GI and GU toxicity was observed in 27% and 40%, gr 3 GI and GU toxicity in 1% and 3%. Late gr 2 GI and GU toxicity at 3 years appeared in 3% and 4% with no gr 3 toxicity. Conclusions: High-risk prostate cancer patients treated with IMRT with SIB obtained favorable outcomes with few serious side effects. There were significant better results in the HR versus the VHR group, both better than the N+/PSA≥100 group.
Resensitization of uveal melanoma (UM) to immune checkpoint inhibition (ICI) by IMCgp100 (IMC).
Authors: Jessica Yang, Marlana M. Orloff, Joseph J. Sacco, Leonel Fernando Hernandez-Aya, Karla Lee, Sophie Merrick, Paul D. Nathan, Samuel Pan, Jose Lutzky, Mark R. Middleton, Alexandra Nesson, Shahnaz V. Singh-Kandah, Susana Hernandez, Takami Sato, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2019)

9592 Background: ICI responses in UM are rare (~5% with anti-CTLA4/PD1 monotherapy; 10-12% with combination ICI). IMC is a bispecific agent composed of a high affinity T cell receptor targeting the gp100 melanoma antigen fused to an anti-CD3 scFv that increases intratumoral CD8+ T cell infiltration and PD1/PDL1 expression, and may enhance response to post-IMCgp100 ICI. Methods: We previously reported on 19 UM pts treated in the phase I dose escalation cohort of IMC (IMCgp100-102). We performed a retrospective analysis of clinical features and response to pre- and post-IMC ICI for the 12 pts in this cohort as well as 17 other pts (n = 29) treated with post-IMC ICI at 7 centers from 8/2016 to 1/2019. 21/29 pts (including 10/12 pts from IMCgp100-102) are evaluable for response and/or survival and are included in the analysis. Results: Baseline characteristics (n = 21): median age 56 (range 45-69); 57% female; median number of prior therapies 2 (range 1-4). Pre- and post-IMC ICI included: IPI+NIVO (3 pre; 8 post), anti-PD1 monotherapy (7 pre; 8 post), and anti-CTLA4 monotherapy (4 pre; 5 post). 20 pts were evaluable for post-IMC ICI response (1 died before restaging): 3/20 (15%) had partial responses (53-78% regression); 5/20 (25%) had stable disease (SD) &gt; 16 weeks; 1/20 had SD of unknown duration. Median PFS and OS from the initiation of post-IMC ICI were 4.9 (95% CI 2.7-10.7) and 10.1 (95% CI 5.7-NR) months, respectively. 13 pts received pre-IMC ICI, all with eventual disease progression. 3 pts had treatment duration or SD lasting &gt; 6 months. Of these 3 pts, 2 had clinical benefit (defined as objective response or SD &gt; 16 weeks) with post-IMC ICI. There was no clear association between rates of Gr ≥ 2 irAE with pre- or post-IMC ICI and response. For the 10 evaluable pts treated on IMCgp100-102, no marked difference in prior response to IMC (3 SD among 5 ICI responders vs 2 SD among 4 ICI non-responders) or mean tumor shrinkage with IMC (-14.0% vs -18.0%) was observed, but rates of Gr ≥ 2 fever, rash, and/or hypotension with IMC were higher among ICI responders (80% vs 50%). Conclusions: Survival outcomes with post-IMC ICI compare favorably to historical figures in pretreated UM pts. IMC may re-sensitize pts who had prior clinical benefit with ICI to subsequent ICI.
Phase II study of tepotinib in NSCLC patients with <i>MET</i>ex14 mutations.
Authors: Paul K. Paik, Remi Veillon, Alexis B. Cortot, Enriqueta Felip, Hiroshi Sakai, Julien Mazieres, Frank Griesinger, Leora Horn, Helene Senellart, Jan P. Van Meerbeeck, Javier de Castro Carpeño, Jyoti D. Patel, Marina Chiara Garassino, Masahiro Morise, Niels Reinmuth, Santiago Viteri, Takaaki Tokito, Tomohiro Sakamoto, Jürgen Scheele, Xiuning Le
Journal: Journal of Clinical Oncology (2019)

9005 Background: MET exon 14 skipping ( METex14) mutations - reported in 3~4% of NSCLC patients (pts) - are activating, sensitive to MET inhibition and can be conveniently detected using liquid biopsy (LBx). We report data from an ongoing single-arm phase II study of tepotinib, a highly selective MET inhibitor, in NSCLC pts with METex14 mutations identified by LBx or tumor biopsy (TBx) (NCT02864992). Methods: Pts with advanced WT EGFR/ALK NSCLC, prospectively enrolled via either LBx (≥60 pts) or TBx (≥60 pts, overlap anticipated) central RNA-based METex14 mutation testing, receive tepotinib 500 mg QD until progression, intolerable toxicity or withdrawal. Primary endpoint: objective response rate (ORR) by independent review (IRC). Secondary endpoints: ORR by investigator assessment (INV) and safety. Results: To date, 85 pts have been enrolled (55 LBx pts and 52 TBx pts). At data cut-off (16 Oct 2018), in 35 evaluable LBx pts (≥2 post-baseline assessments or discontinuation for any reason), ORR was 51.4% by IRC and 63.9% by INV. In 41 evaluable TBx pts, ORR was 41.5% by IRC and 58.5% by INV. Median duration of response (mDoR) and ORR by line of treatment are shown in the table. Any grade treatment-related adverse events (TRAEs) reported by ≥10% of 69 pts evaluable for safety were peripheral edema (47.8%), diarrhea (18.8%), nausea (15.9%), asthenia (10.1%). No TRAEs were grade 4 or led to death. TRAEs led to permanent discontinuation in 2 (2.9%) pts (1 ILD, 1 diarrhea &amp; nausea). Conclusions: Tepotinib has promising activity with a long DoR across treatment lines in NSCLC pts with METex14 mutations detected by LBx or TBx. The safety profile was favorable. Recruitment is ongoing. Clinical trial information: NCT02864992. [Table: see text]
EMSY expression affects multiple components of the skin barrier with relevance to atopic dermatitis
Authors: Martina S. Elias, Sheila C. Wright, Judit Remenyi, James C. Abbott, Susan E. Bray, Christian Cole, Sharon Edwards, Marek Gierlinski, Mateusz Glok, John A. McGrath, William V. Nicholson, Lavinia Paternoster, Alan R. Prescott, Sara Ten Have, Phillip D. Whitfield, Angus I. Lamond, Sara J. Brown
Journal: Journal of Allergy and Clinical Immunology (2019)