tbuckley/cabot-search huggingface dataset:
Consolidation nivolumab/ipilimumab versus nivolumab following concurrent chemoradiation in patients with unresectable stage III NSCLC: A planned interim safety analysis from the BTCRC LUN 16-081 trial.
Authors: Melissa Yan, Greg Andrew Durm, Hirva Mamdani, Vinicius Ernani, Salma K. Jabbour, Jarushka Naidoo, Borys Hrinczenko, Ticiana Leal, Lawrence Eric Feldman, Goetz H. Kloecker, Naomi Fujioka, Mary J. Fidler, Nasser H. Hanna
Journal: Journal of Clinical Oncology (2020)

9010 Background: Consolidation PD-1/PD-L1 inhibition after chemoradiation (CRT) for unresectable stage III NSCLC improves overall survival. In stage IV NSCLC, the combination of nivolumab/ipilimumab improved overall survival compared to chemotherapy in patients with PD-L1 &gt; 1% and performed favorably in patients with PD-L1 &lt; 1%. The safety of consolidation nivolumab/ipilimumab after CRT has not been previously assessed. Methods: In this randomized, multi-center, phase II study, a total of 105 planned pts with unresectable stage IIIA/IIIB NSCLC will receive chemoradiation, then randomize 1:1 to either nivolumab 480mg IV q4 wks (Arm A) or nivolumab 3mg/kg IV q2 wks + ipilimumab 1mg/kg IV q6 wks (Arm B), for up to 24 wks. In this planned interim analysis, the safety of the first 50 patients, with 25 patients treated on each arm, is assessed. Results: From 9/2017 to 6/2019, the first 50 patients were accrued and analyzed for this planned safety analysis. Baseline characteristics for Arm A/B: median age 64/62, stage IIIA 17/16, stage IIIB 8/9, non-squamous 14/13, squamous 11/12. The median number of cycles completed in Arm A was 6 (range 1-6, cycle length q4 wks) and in Arm B was 4 (range 1-4, cycle length q6 wks). The rate of treatment-related adverse events leading to discontinuation of therapy was 16% in Arm A and 40% in Arm B. The percentage of patients with any &gt; grade 3 adverse event (AE) was 32% in Arm A and 44% in Arm B. With respect to immune-related AE (irAEs), the percentage of patients with any ≥grade 2 was 44% in Arm A and 60% in Arm B; any ≥ grade 3 irAEs was 16% in Arm A and 32% in Arm B. The incidence of &gt; grade 2 pneumonitis was 16% in Arm A and 36% in Arm B. The percentage of patients with &gt; grade 3 pneumonitis was 4% in Arm A and 20% in Arm B. No treatment-related deaths were reported on either arm. Conclusions: In the post chemoradiation setting, the incidence of &gt; grade 3 toxicity was greater in the consolidative nivolumab/ipilimumab arm, which resulted in a higher rate of treatment discontinuation than nivolumab alone. The Data and Safety Monitoring Board recommended continued enrollment without modification to the trial and the study currently remains open to accrual (66 of 105 patients have been enrolled as of 1/17/2020). Clinical trial information: NCT03285321.
Insights into Chinese prostate cancer germline gene mutation profile: HOXB13 G84E mutation is unsuitable for genetic testing.
Authors: Baijun Dong, Bin Yang, Yonghong Li, Wei Chen, Jing Li, Zhenzhou Xu, Kaijie Wu, Fengbo Zhang, Shimiao Zhu, Lu Yi, Lixin Hua, Hao PAN, Hong Ma, Zhongquan Sun, Huihua Cheng, Zhenting Zhang, Mingzhao Li, Zhiwen Chen, Fangqin Wang, Wei Xue
Journal: Journal of Clinical Oncology (2020)

e17515 Background: Philadelphia Prostate Cancer Consensus Conference 2017 developed an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA. However, the consensus was mainly based on data from Caucasian populations. Genetic differences in the PC molecular landscape between Asian and Caucasian men have been established. Whether Caucasian-based genetic information can be used to guide clinical practice in Chinese population needs further evidence. Methods: 1123 patients with confirmed prostate cancer admitted from March 2018 to August 2019 from 18 Chinese centers were included in this retrospective study. We sequenced the association of 50 gene with prostate cancer risk, clinical treatment implications and predisposition, focusing on DNA repair gene and genetic susceptibility genes pathogenic mutations in Philadelphia Prostate Cancer Consensus Conference. Only protein-truncating alterations (nonsense/stop-gains, frameshift insertions and deletions, and donor and acceptor splice-site mutations) were coded as pathogenic or likely pathogenic protein-truncating alterations. Results: Among all cases, DNA repair gene pathogenic mutations were found in 133 men (11.84%), including BRCA2 (62 [5.5%]), ATM (15 [1.3%]), PALB2 (11 [0.97%]), GEN1 (7 [0.62%]), BRCA1 (6 [0.53%]), MLH3 (4 [0.35%]), MUTYH (4 [0.35%]), PMS1 (4 [0.35%]), RAD50 (4 [0.35%]), ATR (3 [0.27%]), CHEK2 (3 [0.27%]), FANCD2 (3 [0.27%]) etc. Similar germline DRG mutation frequencies were observed between our cohort and Caucasian men. Noticeably, G84E mutation in HOXB13, a rare but recurrent missense mutation associated with a significantly increased risk of hereditary prostate cancer was not found in our cohort of patients. Furthermore, the frequency of HSD3B1 (1245C) allele in the Chinese patients is much lower than that in the Caucasian populations (11.7% vs 63%). Conclusions: Our study retrospectively analyzed germline mutation profile of prostate cancer in Chinese population. The frequency of HSD3B1 (1245C) allele varies across ethnic populations in spite of the similar DNA repair gene mutations rates. Considering the gene list should be tested based on clinical/familial scenarios from the Philadelphia Prostate Cancer Consensus Conference, a prevalence of certain mutations, G84E mutation in HOXB13 was unnecessary for genetic testing in Chinese population.
Cell-free DNA comparative analysis of hormone receptor-positive, first-line metastatic breast cancer genomic landscape in the United States and China.
Authors: Huiping Li, Andrew A. Davis, Xiao-ran Liu, Feng Xie, Xin-Yu Gui, Yi-Fei Chen, Qiang Zhang, Lorenzo Gerratana, Youbin Zhang, Ami N. Shah, Amir Behdad, Firas Wehbe, Yong Huang, Jian-Jun Yu, Peter Du, Shi-Dong Jia, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2020)

1059 Background: Metastatic breast cancer (MBC) is a heterogeneous disease associated with known somatic mutations of variable biological value in different subtypes. Furthermore, the clinical evolution of the disease demonstrates clonal evolution resulting in disease resistance more accurately detected using blood-based sequencing. Few studies have explored differences in genomic features of tumors across populations. Here, we performed circulating tumor DNA (ctDNA) sequencing to compare the genomic landscape of patients with hormone-receptor positive MBC at time of first recurrence or de-novo metastatic diagnosis in the United States (US) and China. Methods: Twenty-three US patients from Northwestern University and 65 Chinese patients from Peking University had ctDNA sequencing from plasma performed using the harmonized CLIA-certified, 152-gene PredicineCARE assay in laboratories in the US and China, respectively. The data analysis was conducted in China. Institutional Review Boards at each site approved the study. Fisher’s exact test was performed to compare mutational frequencies across populations. Results: Median age of patients at MBC diagnosis was 51 in the US cohort and 55 in the Chinese cohort. 87% of US patients and 82% of Chinese patients had received prior therapy for primary breast cancer, including endocrine therapy. Mutations were detected in 17 of 23 (74%) US patients and 59 of 65 (91%) Chinese patients. CNAs were observed in 57% of US patients and 58% of Chinese patients. The most common mutations detected in US patients were TP53 (26%), PIK3CA (22%), AKT1 (22%), CDH1 (17%), PTEN (13%), and ESR1 (9%) vs. PIK3CA (46%), TP53 (35%), ESR1 (12%), and BRCA2 (11%) in Chinese patients. Frequency of AKT1 and CDH1 mutations were significantly higher in the US population (P &lt; 0.05), while PIK3CA mutations were higher in the Chinese population (P &lt; 0.05). CNA gains in CCND3 and CDK4 were significantly higher in the US cohort, and FGFR1 was significantly more common in the Chinese cohort (all P &lt; 0.05). Conclusions: To our knowledge, this is a first cross-regional comparison study in HR+ MBC patients in the US and China using a harmonized cfDNA NGS platform. At a population level, there were notable differences observed in somatic variants in two cohorts. Future sequencing efforts and clinical trials should include patients of diverse ethnic backgrounds to explore the impact of differences in genomic landscape on probability of benefit from treatments. A larger validation cohort is required to confirm these findings.
Apparent diffusion coefficient as a valuable quantitative parameter for predicting clinical outcomes in patients with newly diagnosed primary CNS lymphoma.
Authors: Dong Won Baek, Soo Jung Lee, Byung Woog Kang, Joon Ho Moon, Jong Gwang Kim, Sang Kyun Sohn, Yee Soo Chae
Journal: Journal of Clinical Oncology (2020)

e14532 Background: Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma (NHL). Although, there are various treatment options for PCNSL which include methotrexate based chemotherapy and whole brain radiotherapy (WBRT), half of the patients who initially achieved complete response experience disease relapse. Accordingly, we attempted to identify novel prognostic factors using MRI in patients with newly diagnosed PCNSL. Methods: We retrospectively evaluated 672 patients who were diagnosed with central nervous system (CNS) cancers between January 2011 and May 2018. Enrollment criteria were i) pathologic diagnosis of CNS lymphoma, ii) no evidence of systemic involvement, iii) no evidence of human immunodeficiency virus-1 infection or other immunodeficiencies, and iv) available magnetic resonance imaging (MRI) examinations at diagnosis. Fifty-two patients met these criteria and were enrolled. Results: Patients with low apparent diffusion coefficient (ADC) showed inferior overall survival (OS) compared to those with high ADC. Patients with a hyperintense signal on T2-weighted image and homogenous enhancement showed better failure-free survival (FFS), while patients with low ADC and necrosis showed poor FFS. In the multivariate survival analysis, old age ( &gt; 60) (hazard ratio (HR) 20.372, p= 0.001), Eastern Cooperative Oncology Group performance status ((ECOG PS) ≥ 2 (HR 10.429, p &lt; 0.001), higher levels of lactate dehydrogenase (LDH) (HR 7.408, p= 0.001), and low ADC (HR 0.273, p= 0.009) were associated with inferior OS, while ECOG PS ≥ 2 (HR 10.319, p= 0.021), presence of necrosis (HR 6.372, p= 0.008), and low ADC (HR 0.226, p= 0.020) were unfavorable factors for FFS. Conclusions: We conclude that ADC, a characteristic MRI finding, had significant prognostic value for long-term survival in our study of patients with newly diagnosed PCNSL Specifically, low ADC was an independent unfavorable prognostic factor, suggesting that ADC measurements through non-invasive MRI can improve the current prognostic scoring system.
Outcome of elderly patients with classical Hodgkin lymphoma (HL) in British Columbia.
Authors: Phoebe Tsz Man Cheng, Diego Villa, Alina S. Gerrie, Ciara L Freeman, Graham W Slack, David W. Scott, Joseph M. Connors, Laurie Helen Sehn, Kerry J. Savage
Journal: Journal of Clinical Oncology (2020)

8031 Background: Outcomes in elderly patients (pts) with Hodgkin lymphoma (HL) have traditionally been poor. We evaluated the survival of elderly pts (&gt;60 years [y]) with classical HL in British Columbia (BC). Methods: All pts aged &gt;60 y newly diagnosed with classical HL from 1961 to 2019 were identified in the BC Cancer Lymphoid Cancer Database. Limited stage was defined as non-bulky (&lt;10 cm) stage 1A/IB or 2A (before 2000 1B = advanced stage), with the remainder considered advanced stage. Results: Following exclusions (HIV positive n=4, incomplete data n=21, prior or concurrent other lymphoproliferative disease n=67), 713 pts were identified. With a median follow up of 6.0 y (0.1 - 24.0 y) in living pts, there has been an improvement in 5 y DSS/OS (both p&lt;.001) by decade comparison: 1960s (n=52) 25%/17%; 1970s (n=75) 38%/31%; 1980s (n=90) 51%/43%; 1990s (n=115) 53%/42%; 2000s (n=180) 66%/57%; 2010s (n=201) 63%/53%. To account for advances in diagnosis, staging, supportive care, and therapy in the modern era, we evaluated the outcome of pts diagnosed since 01/1995. A total of 368 pts were treated with curative intent (Table). Most pts received multi-agent chemotherapy (n=359, 98%: ABVD[like] n=351, alkylator-based n=7, CHOP n=1), 8 pts had radiotherapy (RT) alone, and 1 pt had surgery (primary CNS HL). The 5 y DSS, PFS, and OS were 74%, 57%, and 62%, respectively. Increasing age was associated with inferior outcomes (5 y DSS/PFS/OS): 61-70 y (81%/70%/74%), 71-80 y (69%/47%/52%), and &gt;80 y (59%/27%/31%) (DSS p=.011; PFS p&lt;.0001; OS p&lt;.0001). Of 318 pts that received bleomycin, 60 (19%) developed pulmonary toxicity, including 22 cases that occurred after cycles 1 and 2. Overall, 24/368 pts (7%) died of acute treatment toxicity (pulmonary [bleomycin n=10, radiation n=1], infection n=10, cardiac n=3). There was no association between age and developing bleomycin (p=.80) or lethal treatment toxicities (p=.74). Conclusions: The outcome of elderly pts with HL has improved in recent decades. However, treatment related toxicity remains a concern and use of multi-agent chemotherapy, particularly bleomycin-containing regimens, should be undertaken with caution. [Table: see text]
Clinical trials in pancreatic cancer: A comprehensive analysis.
Authors: Erryk Stephan Katayama, Jonathan J. Hue, David Lawrence Bajor, Lee Mayer Ocuin, John Brian Ammori, Jeffrey Hardacre, Jordan Michael Winter
Journal: Journal of Clinical Oncology (2020)

e16730 Background: Pancreatic cancer is the most aggressive of common cancers and desperately in need of novel therapies. Unlike many other common cancers, there have been no new paradigm-changing therapies in the past 40 years beyond chemotherapy. The most urgent question in the field then is what is coming down the pike? In this study, we perform the first comprehensive analysis of the current clinical trial landscape in pancreatic cancer to better understand the pipeline of new therapies. Methods: We queried clinicaltrials.gov for registered pancreatic cancer clinical trials. Studies were curated and categorized according to the phase of study, the clinical stage of the study population, the type of the intervention under investigation, and the biologic mechanism targeted by the therapy. This compendium revealed the full landscape of investigational therapeutic trials. Results: As of May 18, 2019, there were 440 total trials testing 600 distinct interventions. 104 of these trials spanned multiple phases, yielding 544 trials across phases. These included 38 trials (8.6%) in phase III testing, 269 (61%) in phase II, and 237 (54%) in phase I. With respect to therapeutic category, 186 (31%) were investigating immunotherapies, 66 (11%) targeted cell signaling pathways, 140 (23%) targeted cell cycle or DNA biology, and 32 (5%) targeted metabolic pathways. Of the 38 phase III trials, only 10 are currently testing novel drugs that are not already FDA approved or routinely used in patients for another indication. Conclusions: A large number of novel therapeutic strategies are currently under investigation. They include a broad range of therapies targeting diverse biologic processes. However, only a small number of novel therapies are in late-stage testing, suggesting that future progress is likely several years away, and dependent on the success of early-stage trials. [Table: see text]
The AVI-PDX: An innovative in vivo platform of miniaturized patient-derived xenografts for preclinical developments and personalized medicine.
Authors: Frédéric Berget, Clélia Costechareyre, Loraine Jarrosson, Céline Delloye-Bourgeois, Valerie Castellani
Journal: Journal of Clinical Oncology (2020)

e15607 Background: The conception of preclinical paradigms to predict the patient response is a major goal for the development of novel therapies and the design of personalized treatments in oncology. Patient-Derived Xenograft (PDX) mouse models require tumoral material in significant amount, not always compatible with practiced biopsies, are limited by a very low tumor intake rate, and a long delay to obtain exploitable tumors. Moreover, xenografts in mice are usually performed subcutaneously, thus in a tissue irrelevant regarding microenvironmental specificities. Finally, these models are not scaled for global molecular analysis to uncover biomarkers of patient heterogeneity and response to treatments. Apart from shortening tumor formation, alternatives of grafting tumoral cells on the chicken chorio-allantoid membrane (CAM model) bare all inconvenient of mice models Methods: We have developed an innovative in vivo technological platform, consisting in (i) grafting tiny human tumoral samples within tissues of chicken embryos, selected for their homology to primary or metastatic sites, (ii) administrating therapeutic treatments, (iii) analyzing tumor responses using 3D imaging and identifying treatment-specific molecular signatures. Results: Originally conceived for a pediatric cancer (Delloye-Bourgeois et al, 2017), the platform was next adapted to a range of adult cancers. Grafted cells from patient samples exhibited exceptionally fast and efficient rate of tumor ingrowth, and replicas retained molecular features of the initial sample. The platform is already exploited for the identification of novel therapeutic targets, the evaluation of candidate therapies efficacy, the design of combination of therapies and the characterization of molecular signatures in several cancer indications, including germ line tumors, neuroblastoma, pancreatic cancers, triple negative breast cancer and melanoma. Conclusions: Overall, this breakthrough technology should considerably improve and shorten the process of molecule discovery and accelerate access of novel therapies to patients.
Tolerability of single agent nivolumab in cancer patients—A meta-analysis.
Authors: Judy Huang, Alejandro Ramon Carvajal, Shenhong Wu
Journal: Journal of Clinical Oncology (2020)

e15146 Background: Nivolumab, a PD-1 immune checkpoint inhibitor, is being widely utilized in a number of cancers as a single agent. Adverse events, including those that are immune mediated, have been reported that resulted in discontinuation of the drug. We conducted a meta-analysis of published clinical trials to further investigate the tolerability of nivolumab in cancer patients. Methods: Databases, including PubMed and abstracts presented at American Society of Clinical Oncology annual meetings from 2015 to December 2019 were searched to identify relevant studies. This included randomized controlled trials and single arm trials that reported a discontinuation rate due to adverse events. Incidences and relative risks were calculated based on the heterogeneity of included studies. Results: Seventeen studies published between 2015 and 2019 were selected, which included a total of 4216 patients. Overall, the discontinuation rate of nivolumab due to adverse events was 6.7% (95% CI 4.7-9.5%). The rate varied significantly with the type of cancer (p &lt; 0.001). The lowest discontinuation rate was in NSCLC of 2.1% (95% CI 1.3-2.3%), and the highest discontinuation rate was in melanoma of 15.2% (95% CI 6.8-30.6%). In addition, significantly higher intolerability is associated with the fixed dose of nivolumab at 240 mg than 3 mg/kg (P = 0.004). In comparison with chemotherapy controls, the intolerability in the nivolumab group was not significantly different, with a relative risk of 0.97 (95% CI: 0.36-2.6). Conclusions: The intolerability of nivolumab as monotherapy may be similar to chemotherapy, and can be improved with dose adjustment.
Monty Seymour Losowsky
Authors: Peter Howdle
Journal: BMJ (2020)

Monty Seymour Losowsky was born in the East End of London, the son of immigrant parents, who today would probably be classed as illegal immigrants, fleeing from antisemitic persecution in eastern Europe. His father went on to fight for the British in the first world war and was decorated. Monty was brought up in the straitened circumstances of the 1930s. His mother had had no formal education and had to work hard to support the family financially after the sudden death of her husband. His early education was fragmented by his experience as an evacuee—he attended 14 different secondary schools during the six years of the second world war—but nonetheless he excelled academically: he gained admission to the Coopers’ Company School and was selected by the school as an outstanding student for formal “indentureship” as a cooper, after which he was granted the freedom of the City of London.

He was awarded a place at the University of Leeds School of Medicine, and qualified with honours. He worked as house officer at Leeds General Infirmary to Professor Sir Ronald Tunbridge, then moved to be medical registrar at St Margaret’s Hospital, Epping, from 1957 to 1959, achieving his membership of the Royal College of Physicians in 1958. By this stage he had developed an interest in gastroenterology and liver disease, which was a relatively new specialty in those days. With great foresight he then went to work as an “assistant externe” at a specialist liver unit at the Hopital St Antoine, Paris, in 1960 with Jacques Caroli. He was awarded his MD by the University of Leeds in 1961 for of his clinical …
Correlation between tissue PD-L1, TMB, and blood PD-L1, MSI biomarkers in patients with advanced-stage non-small cell lung cancer (NSCLC).
Authors: Sujitha Nandimandalam, Nitika Sharma
Journal: Journal of Clinical Oncology (2020)

e21564 Background: Tissue biomarkers like programmed cell death ligand-1 (PD-L1), microsatellite instability (MSI) and high tumor mutational burden (TMB) are surrogates in identifying patients with non-small cell lung cancer (NSCLC) for treatment with immune checkpoint blockade (ICB) therapy. Although tissue biopsy is widely used for identifying the tumor biology, the invasive nature as well as insufficiency of tissue biopsy specimens limits its application. Liquid biopsy is a minimally invasive procedure and has gained interest in recent times for profiling cancer. We sought to study the correlation in the molecular tumor profile specifically PD-L1, MSI and TMB markers between the tissue and liquid biopsies. Methods: We conducted a retrospective review of patients with Stage 3, 4 and recurrent NSCLC that underwent tissue next generation sequencing (NGS) using Caris life sciences and liquid biopsy using Circulogene molecular diagnostics from January 2018 to December 2019 at East Carolina University. A total of 524 patients were reviewed out of which 199 patients had both liquid and tissue NGS performed at the time of initial diagnosis. TMB high was defined as greater than 10 mut/Mb whereas TMB low as less than or equal to 10 mut/Mb. PD-L1 was divided into negative (0%), 1-49% and ≥50%. The blood MSI was classified as positive or negative. We used frequency table, logistic regression and Pearson bivariate correlation for statistical analysis using SPSS platform. Results: The study cohort had 60% (n = 119) male and 40% (n = 80) female patients of which 53% (n = 105) were Caucasians and 45% (n = 89) were African Americans. A total of 87 patients (44%) had negative tissue PD-L1, 59 patients (30%) had tissue PD-L1 ≥ 50%. A linear correlation was seen between negative tissue PD-L1 and negative blood PD-L1 in 92% of patients (n = 80). However, only 15.3% (n = 9) had correlating tissue PD-L1 and blood PD-L1 ≥ 50%, p = 0.024. The negative blood MSI correlated to low tissue TMB in 83% ( n = 60) whereas positive blood MSI correlated to high tissue TMB in 25% (n = 19), p = 0.023. Conclusions: Our results indicate a linear correlation between tissue PD-L1 and blood PD-L1. Similarly, a linear correlation was seen between blood MSI and tissue TMB. Further studies are needed to elucidate the efficacy of ICB therapy using blood MSI and blood PD-L1 as biomarkers for response to therapy.