tbuckley/cabot-search huggingface dataset:
A multicenter, randomized, double-blind study of gefitinib in combination with anlotinib or placebo in previously untreated patients with EGFR mutation-positive advanced non-small cell lung cancer (FL-ALTER).
Authors: Li Zhang, Wenfeng Fang, Yunpeng Yang, Qitao Yu, Di Wu, Yingcheng Lin, Hua Zhang, Junfei Zhu, Guowu Wu, Bin Lan, Zeqiang Zhou, Zibing WANG, Xiaolin Lei, Haifeng Lin, Xiaohua HU, Suming Pan
Journal: Journal of Clinical Oncology (2021)

TPS9131 Background: Preclinical and clinical evidence has demonstrated that the dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutated advanced NSCLC population. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that effectively inhibits VEGFRs, FGFRs, PDGFRs, c-kit and MET. It has been proved to be safe and effective in advanced lung cancer after second-line standard chemotherapy failure. A cohort study of Anlotinib plus Erlotinib has shown a favorable safety profile and promising antitumor activity with an objective response rate (ORR)92.6%. This phase III study aims to evaluate the efficacy and safety of Anlotinib or placebo plus Gefitinib in patients(pts) with untreated EGFR-mutated metastatic NSCLC. Methods: Eligible pts were aged 18̃75 years old, had stage IIIB or IV NSCLC, with an EGFR 19del or 21L858R mutation, an ECOG PS of 0 or 1, measurable lesion according to RECIST v1.1 and adequate organ function. We randomly assigned eligible pts in a 1:1 ratio to receive oral Gefitinib (250 mg QD) plus either Anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or matching placebo until progressive disease or unacceptable toxicity. Randomization was done by an interactive web response system with a computer-generated sequence and stratified by EGFR mutation status, gender, ECOG PS and pathological type. The primary endpoint is progression-free survival(PFS). Secondary endpoints include overall survival, ORR, disease control rate, time to progression, duration of response, quality of life and the safety profile. The peripheral blood of the pts will be detected three times by polygenic detection to monitor the resistance mechanism (before treatment, during the first evaluation, during tumor progression, each time 10ml peripheral blood). Independent Data Monitoring Committee and Independent Review Committee will be used in this study. According to previous report (Erlotinib plus Bevacizumab vs. Erlotinib alone: 16.0 vs. 9.7 mos, HR 0.54, Lancet Oncol, 15(11):1236-1244), the sample size was determined based on a median PFS of 15 months for the Anlotinib + Gefitinib group and median PFS of 10 months for the Placebo + Gefitinib group. To achieve 80% power at a two-sided α = 0.05 and an anticipated dropout rate of 20%, 310 patients (with 192 events required for the analyses) were needed. In total, 310 patients will be enrolled in this trial at 16 sites in China. From April 2019, 224 patients have been enrolled. Clinical trial information: NCT04028778.
A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery
Authors: Jeroen H A Creemers, W Joost Lesterhuis, Niven Mehra, Winald R Gerritsen, Carl G Figdor, I Jolanda M de Vries, Johannes Textor
Journal: Journal for ImmunoTherapy of Cancer (2021)

Predicting treatment response or survival of cancer patients remains challenging in immuno-oncology. Efforts to overcome these challenges focus, among others, on the discovery of new biomarkers. Despite advances in cellular and molecular approaches, only a limited number of candidate biomarkers eventually enter clinical practice.A computational modeling approach based on ordinary differential equations was used to simulate the fundamental mechanisms that dictate tumor-immune dynamics and to investigate its implications on responses to immune checkpoint inhibition (ICI) and patient survival. Using in silico biomarker discovery trials, we revealed fundamental principles that explain the diverging success rates of biomarker discovery programs.Our model shows that a tipping point-a sharp state transition between immune control and immune evasion-induces a strongly non-linear relationship between patient survival and both immunological and tumor-related parameters. In patients close to the tipping point, ICI therapy may lead to long-lasting survival benefits, whereas patients far from the tipping point may fail to benefit from these potent treatments.These findings have two important implications for clinical oncology. First, the apparent conundrum that ICI induces substantial benefits in some patients yet completely fails in others could be, to a large extent, explained by the presence of a tipping point. Second, predictive biomarkers for immunotherapy should ideally combine both immunological and tumor-related markers, as a patient's distance from the tipping point can typically not be reliably determined from solely one of these. The notion of a tipping point in cancer-immune dynamics helps to devise more accurate strategies to select appropriate treatments for patients with cancer.
Differences in the tumor genomic landscape between African Americans (AA) and Caucasians (CA) advanced prostate cancer (aPC) patients (pts) by comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA).
Authors: Pedro C. Barata, Raquel Reisinger, Mehmet Asim Bilen, Elisabeth I. Heath, Lakshminarayanan Nandagopal, Umang Swami, Adam Kessel, Ellen Jaeger, Sergiusz Wesolowski, Jonathan Chipman, Alleda Mack, Deepak Ravindranathan, Benjamin L. Maughan, Roberto Nussenzveig, Mark Yandell, Manish Kohli, Michael B. Lilly, A. Oliver Sartor, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2021)

5058 Background: Emerging data suggest differences in the tumor genomic profile of AA compared with CA men with aPC. We hypothesized that there will be significant differences in the tumor genomic landscape between AA and Ca pts as detected by cfDNA CGP. Methods: Pts with aPC and available cfDNA CGP by the Guardant (G360) 73 gene panel were included. In addition, G360 74 gene panel was used to identify CDK12 mutation (not detected in 73 gene panel) in an independent cohort of aPC pts. Barnard’s test was used to evaluate the association between genetic mutation and gene. Genomic landscape was also compared by a Bayesian Network (BN) machine learning approach. Results: A total of 552 pts (125 AA, 427 CA) tested by G360 73 gene panel were included. Multiple genomic aberrations were enriched in AA patients (Table). In the independent cohort of 261 aPC patients (AA=106 pts, CA=155 pts) tested by G360 74 gene panel, CDK12 mutation was significant enriched in AA pts. (9.4% vs. 1.9%, p=0.006). Machine learning analysis supported these results, and will be presented at the meeting. Conclusions: These hypothesis generating data suggest significant differences in the tumor genomic profile between AA and CA pts with aPC. Identification of molecular drivers of tumor progression enriched in AA pts may allow development of tailored systemic therapy for these men, and decrease disparities in disease related outcomes. Data need external validation. PB,RR,MAB contributed equally to this work.[Table: see text]
Comprehensive understanding of genomic profile of bone cancer by the combination of DNA and RNA detection.
Authors: Xianbiao Xie, Junqiang Yin, Yiying Bian, Ziliang Zeng, Yueting Qu, Xiaoliang Shi, Lin Zhang, Liwei Wang, XiaoWei Dong, Jingnan Shen
Journal: Journal of Clinical Oncology (2021)

e23513 Background: The diagnosis of bone tumors is mainly based on clinical manifestations, imaging examination, tissue biopsy and laboratory examination. However, most of the bone tumors have no specific clinical manifestations, which makes the diagnosis and differential diagnosis difficult. The genomic profile of bone tumor is helpful to provide molecular basis for its molecular diagnosis. Methods: A total of 357 Chinese bone cancer patients were enrolled in this study. The NGS-based YuanSu S panel which includes both DNA and RNA detection was performed by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, Shanghai, China, for genomic alteration identification. Results: The 357 Chinese bone cancer patients were enrolled, including 206 adult patients and 151 juvenile patients, with a median age of 20 years old (ranged from 1 to 88 years). Among them, there were 214 males and 143 females. The most commonly mutated genes with a mutation frequency more than 10% were TP53 (31.65%), NCOR1 (15.69%), VEGFA (13.73%), RB1 (12.61%), CCND3 (11.76%), CDKN2A, GID4, and CCNE1 (11.48%, for each), TERT (10.64%), and MAP2K4 (10.08%). Germline mutations were detected in 28 patients, including 13 patients with HRD related mutations, such as ATM, FANCA, BRCA2, RAD50, RAD51D and FANCD2. A total of 179 gene fusions were detected in 130 bone cancer patients. Notably, 19 gene fusions such as SH2D2A-NTRK1, EMILIN1-ALK, and SZRD1-SPEN, were detected in 16 patients with the assistance of RNA detection. Statistical analysis showed that the mutations of NCOR1 (P = 1.1X10 -4 ), VEGFA (P = 3.4X10 -6 ), CCND3 (P = 1.0X10 -5 ), GID4 (P = 1.1X10 -6 ), CCNE1 (P = 3.0X10 -7 ), RB1 (P = 0.03), and MAP2K4 (P = 1.5X10 -4 )were significantly associated with juvenile patient group, as well as the mutation of H3F3A (P = 7.5X10 -5 ) was significantly associated with adult patient group. Conclusions: Here we identified the mutational characteristics of Chinese bone tumor patients. In addition, the inclusion of RNA detection effectively increased the detection of gene fusions. Our results provided the evidence for the precise treatment of bone tumors in the future.
LGG-17. CLINICAL OUTCOME OF PEDIATRIC LOW GRADE GLIOMA WITH POSITIVE BRAF-FUSION TREATED WITH MEK INHIBITOR
Authors: T L Ku Dennis, Anthony P Y Liu, Eric Fu, Chung-Wing Luk, Jeffrey P W Yau, Siu-Cheung Ling, Matthew M K Shing, Godfrey C F Chan
Journal: Neuro-Oncology (2021)

Abstract Background Low grade glioma (LGG) is the most common central nervous system (CNS) tumor in children. Some are treated with surgery alone, while chemotherapy is given for unresectable tumor with clinical symptoms or progression. Conventional chemotherapy is effective but 30–40% patients may have reactivation of disease requiring re-treatment throughout lifetime. MEK inhibitor for BRAF-fusion positive LGG is a new treatment option for refractory cases. Methods Retrospective search in territory-wide pediatric oncology registry for children diagnosed with LGG from 2010–2020 in Hong Kong. To identify patients with molecular confirmed BRAF-fusion positive LGG and any treatment with MEK inhibitor. Results Twelve patients (N=12) were identified with BRAF-fusion positive LGG, male:female was 1:2, age 0.3–15.1yr (median 5.0yr) at presentation. The median follow up duration was 1.8yr. Five patients (42%) had surgical resection only. Seven patients (58%) were given chemotherapy with Carboplatin / Vincristine. Five out of seven (n=7) treated patients (71%) have partial response at their initial treatment. Two patients (29%) had progressive disease during treatment and switched to second-line chemotherapy, vinblastine however without improvement. Three patients required re-treatment as disease reactivation. Total five patients had refractory diseases were treated with MEK inhibitor, Trametinib including one diagnosed NF-1. All of them have adverse skin reaction and raised transaminase with one required dose reduction. They have been taking the MEK inhibitor for 0.1–3.3 yr with sustainable partial response. Conclusion Pediatric LGG has overall favourable prognosis. Some of them treated with surgery alone while conventional chemotherapy could also achieve satisfactory disease control. For refractory disease with BRAF-fusion positive, MEK inhibitor is a well tolerated treatment option showing sustainable partial response. However, prolonged medication and disturbing skin reaction are still a major concern for this group of patients. On-going clinical trials to compare conventional chemotherapy versus MEK inhibitor could give us more insight about the clinical benefit, patient selection and treatment duration.
A comparative analysis of mortality between black and white stage III non–small cell lung cancer patients in the United States.
Authors: Elizabeth Blessing Elimimian, Rafael Arteta-Bulos, Hong Liang, Nadeem Bilani, Leah Elson, Diana Saravia, Evan W. Alley
Journal: Journal of Clinical Oncology (2021)

8552 Background: Lung cancer remains the leading cause of cancer death in the United States (U.S.). For stage III non-small cell lung cancer (NSCLC), concurrent chemotherapy (CT) plus radiotherapy (RT) within 30 days (CCRT) confers a survival benefit. The proportion of Black and White NSCLC patients not receiving CCRT and their outcomes have not been explored. Methods: Stage III NSCLC in Black and White patients diagnosed between 2004 and 2015 from the U.S. NCDB were included. Those with multiple tumors and who received surgery were excluded. Six groups were analyzed: CCRT (0-30 days between CT and RT), SCRT (31-120 days between CT and RT), RT (only RT), CT (only CT), No-RT-nor-CT (didn’t receive RT nor CT), and other (uncategorized). Univariate, multivariate, and Kaplan-Meier analyses were utilized (p&lt;0.05). Results: A total of 22,459 Black (CCRT 42.3%, SCRT 7.6%, RT 13.8%, CT 15.1%, and No-RT-nor-CT 21.2%) and 138,477 White (CCRT 43.9%, SCRT 7.0%, RT 12.7%, CT 14.9%, and No-RT-nor-CT 21.5%) stage III NSCLCs were analyzed. Male gender and White race were positive predictive factors for receiving CCRT (Table). In Black patients SCRT (HR 1.1; 95% CI 1.04-1.17), RT only (HR 1.2; 95% CI 1.81-1.99), CT only (HR 1.4; 95% CI 1.36-1.49), and No RT or CT (HR 2.6; 95% CI 2.49-2.69) was associated with decreased overall survival (OS) compared to CCRT. In White patients, SCRT (HR, 1.0; 95% CI, 0.99-1.03) did not decrease OS compared to CCRT, whereas RT only (HR 1.8; 95% CI, 1.74-1.80), CT only (HR 1.3; 95% CI, 1.29-1.34), and No RT or CT (HR 2.6; 95% CI, 2.59-2.67) were associated with decreased OS. Median OS with CCRT was 18 months for Black patients, versus 16 months for White patients (p&lt;0.0001). Conclusions: OS was highest when CCRT was given. A lower proportion of Black cases were managed with CCRT, but Black patients benefit more from CCRT and had improved OS than White patients. Despite the known benefits of CT and RT in stage III NSCLC, the second largest management cohort received neither RT nor CT.[Table: see text]
Underwater endoscopic mucosal resection for en bloc resection of a neuroendocrine tumor in the duodenal bulb
Authors: Hugo Uchima, Alberto Diez-Caballero, Jaume Capdevila, Mercé Rosinach, Alfredo Mata, Román Turró, Jorge Espinós
Journal: Endoscopy (2021)

Duodenal neuroendocrine neoplasms (d-NENs) may be sporadic or associated with multiple endocrine neoplasia type 1 [1] [2]. Classification, based on morphology and proliferation rate, includes well-differentiated neuroendocrine tumors (NETs; G1–G3) and poorly differentiated neuroendocrine carcinomas (G3).
Real-world outcomes from the systemic use of CDK 4/6 inhibitors (CDKIs) in the management of ER positive (+) HER2 negative (-) metastatic breast cancer (mBC).
Authors: Karen DeSouza, Daniel Yeo, Maria Diossy, Sumbal Umar, Emma Gore, Sachin Trivedi, Anjana Anand, Srinivasan Madhusudan, Sarah Khan
Journal: Journal of Clinical Oncology (2021)

e13031 Background: The use of CDKIs have transformed the management of ER+HER2- mBC. As the real-world data matures, this project describes patterns in response to systemic therapy that may inform treatment planning and prognostication. Methods: We analysed the ER+HER2- mBC dataset at Nottingham University Hospitals NHS Trust (NUH) generated by reviewing clinical notes, radiology and e-prescribing records to collect clinical data on patients treated with CDKIs between 01/10/2016 - 01/10/2020. Results: 272 patients with a median age of 65 years (30-90 years) were treated with CDKIs (palbociclib 54.0% (n=147); ribociclib 19.5% (n=53); abemaciclib 26.5% (n=72)) in combination with endocrine therapies (letrozole, anastrozole, exemestane and, fulvestrant). Median overall survival was 49.5 months. Treatment with first-line CDKIs (69.8%; n=190) resulted in superior PFS when compared to CDKIs in a ≥ second-line setting (30.2%; n=82) i.e., mPFS 21.3 vs 12.2 months (HR 0.67; 95% CI, 0.47-0.96; P=0.02). Univariate analysis shown in the table below indicates the benefit to PFS from presentations with de novo mBC and the absence of visceral metastases. In patients treated curatively for early breast cancer (EBC), better outcomes were demonstrated in patients presenting with mBC, &gt;12 months versus ≤12 months of completion of adjuvant endocrine therapy i.e., mPFS 28.4 vs 12.1 months (HR 0.50; 95% CI, 0.30-0.84; P=0.004) when treated with first-line CDKIs. A multivariate analysis identified benefit to PFS from first-line therapy with CDKIs (HR 0.70; 95% CI, 0.49-1.01; P=0.05) and presentation with de novo mBC (HR 0.56; 95% CI, 0.37-0.85; P=0.006). The presence of visceral metastases was associated with poorer outcomes (HR 1.52; 95% CI, 1.08-2.15; P=0.01). Conclusions: This analysis confirms the PFS benefit from CDKIs demonstrated in clinical trials is mirrored in the real-world setting. The analysis was not powered to delineate survival benefit between the individual CDKIs. Presentations with mBC following a prior history of EBC, within ≤12 months of completion of adjuvant endocrine therapy, and with visceral metastases may help predict poorer clinical outcomes and may need to be considered when prognosticating and in treatment planning. This analysis is hypotheses-generating and we will confirm our findings in a prospective manner as the dataset is expanded.[Table: see text]
Preliminary data on antitumor activity of extracorporeal subtraction of soluble TNFRs to unleash the activity of endogenous TNFα combined with chemotherapy in treatment-refractory, advanced, triple-negative breast cancer patients.
Authors: Piotr Jan Wysocki, Adam Ostrowski, Robert Segal, Pawel Potocki, Kamil Wladyslaw Konopka, Lukasz Kwinta, Lawrence Florin, Stephen Prince
Journal: Journal of Clinical Oncology (2021)

e13052 Background: Tumor necrosis factor-alpha (TNFα) is a pleiotropic cytokine, with known antitumor activity, produced mainly by activated immune cells. Cancer cells neutralize TNFα by shedding soluble TNF receptors 1&amp;2 (sTNFRs), which act as TNFα-binding decoys. In addition, sTNFRs can directly promote proliferation, survival, and chemoresistance of cancer cells by binding to membrane-bound TNFα and initiating retrograde signaling. Therefore, the reduction of systemic and intratumoral concentrations of sTNFRs represents a novel and unique strategy to reinvent the anticancer use of TNFα. Methods: In this clinical trial (CP7-005; NCT04004910) we evaluated extracorporeal Immunopheresis (subtractive apheresis) with the novel LW-02 immunoadsorption column in advanced chemo-refractory metastatic triple-negative breast cancer (mTNBC). The LW-02 column, which utilizes a proprietary, recombinant single-chain TNFα as the sTNFR-scavenger ligand has received FDA breakthrough designation for cancer treatment. Here we present data on the second cohort of mTNBC patients treated with LW-02 combined with weekly chemotherapy; Cohort 1 (n=10) evaluated Immunopheresis as monotherapy only. In Cohort 2, patients are treated with LW-02 immunopheresis only in week 1 (3 treatments involving processing of 2 plasma volumes (2PV)). From week 2, paclitaxel [60 mg/m 2 ]+carboplatin[AUC2] combination is administered once weekly along with LW-02 immunopheresis (2PV 3x/week). Results: To date, 7 mTNBC patients who failed ≥2 lines of chemotherapy (median=3; 2-5) in the advanced setting have been enrolled. The combination of LW-02 column immunopheresis and chemotherapy resulted in a 29% ORR (1CR, 1PR). In 5 patients who completed at least 4 weeks of treatment, the ORR was 40%. Median OS in the whole population as of this report is 13.3 weeks, and 18.4 weeks in the patients treated for &gt;4 weeks. Treatment-related AEs occurred in most patients; however, most being attributed to chemotherapy - CTCAE G3-4 in 71% (anemia – 71%, neutropenia 29%, thrombocytopenia 29%). Immunopheresis-related G3-4 AEs were CVC complications (29%), hypophosphatemia (14%) and hypercalcemia (14%). Conclusions: The combination of LW-02-column immunopheresis and weekly chemotherapy procedure was shown to be generally safe and provided early, promising signs of antitumor activity in heavily pretreated mTNBC patients with short life expectancy. Further clinical evaluation of the antitumor activity of LW02-based immunopheresis combined chemotherapy is ongoing; however, due to myelotoxicity, the chemotherapy regimen will be adapted accordingly. Clinical trial information: NCT04004910.
Survival outcomes in primary angiosarcoma of the head and neck: A systematic review and meta-analysis.
Authors: Sondos Zayed, Cindy Lin, Gabriel Boldt, Pencilla Lang, Nancy Read, Varagur Venkatesan, Jinka Sathya, Fung Kevin, Danielle MacNeil, Adrian Mendez, John Yoo, Andrew Warner, Anthony C. Nichols, David A. Palma
Journal: Journal of Clinical Oncology (2021)

e18039 Background: Angiosarcoma of the head and neck (ASHN) is a rare entity and confers substantial morbidity and mortality. Yet, the optimal management of ASHN remains unclear. This study aimed to describe the epidemiology of ASHN and to identify the most favorable treatment approach. Methods: We performed a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, using the PubMed (Medline), EMBASE, and Cochrane Library databases, queried from 1990 until present. Articles in the English language reporting on survival outcomes of adult primary ASHN treated with curative-intent, were included. All estimates were weighted based on sample size. Analysis of variance (ANOVA) and two-sample t-tests were used as appropriate. This study was registered with PROSPERO, CRD42021220970. Results: A total of 3652 studies were identified, with 14 articles reporting on 2265 ASHN patients, meeting inclusion criteria. Mean ± SD age was 70.6 ± 7.7 years with 1621 (66.6%) men and 812 (33.4%) women. ASHN involved the scalp (n = 176, 57.9%) and the face (n = 128, 42.1%). 249 patients had early stage I-II disease (39.6%) whereas 379 had late stage III-IV disease (60.4%). Most (n = 529, 45.6%) received surgery and radiotherapy (RT), 305 (26.3%) received surgery alone, 210 (18.1%) received definitive RT/chemoradiotherapy (CRT), 75 (6.5%) received surgery and CRT, and 33 (2.8%) received surgery and chemotherapy. Negative margins were achieved in 471 (55.9%) whereas 371 (44.1%) had positive margins. Mean ± SD follow-up was 41.7 ± 15.4 months. Weighted mean, 1-, 5-, and 10-year overall survival (OS) were 26.9 months, 67.3%, 30.6%, and 20.8% respectively. Mean and 5-year disease-specific survival (DSS) were 72.9 months and 50.3% respectively. Mean ± SD local recurrence rate (LRR) was 32.1 ± 11.7%. Median RT dose delivered was 60 Gy (interquartile range: 60-70). Patients who received surgery had a significantly higher mean OS (34.9 vs. 18.7 months, P = 0.04) and 5-year OS (30.1 vs. 14.2%, P = 0.01) compared with those who did not receive surgery. There was no significant difference in mean OS for receiving adjuvant chemotherapy (P = 0.99) or RT (P = 0.51). Conclusions: In the largest ASHN study to date, definitive surgical resection was associated with an improvement in OS. Multimodality treatment did not confer an OS benefit. Randomized trials are needed to establish the optimal treatment approach for ASHN.
Self-assembled hyaluronic acid nanoparticles for osteoarthritis treatment
Authors: Li-Jung Kang, Juhwan Yoon, Jun Gi Rho, Hwa Seung Han, Seulbi Lee, Young Soo Oh, Hwan Kim, Eunha Kim, Seok Jung Kim, Yong Taik Lim, Jae Hyung Park, Woo Keun Song, Siyoung Yang, Wook Kim
Journal: Biomaterials (2021)